<PAGE> 1
U.S. SECURITIES AND EXCHANGE COMMISSION
WASHINGTON, D.C. 20549
FORM 10-QSB
[X] Quarterly Report Under Section 13 or 15(d) of the Securities
Exchange Act of 1934
For the quarterly period ended September 30, 1996
OR
[ ] Transition Report Under Section 13 or 15(d) of the Securities
Exchange Act of 1934
For the transition period from _________ to __________
Commission file number 1-12968
LXR BIOTECHNOLOGY INC.
(Exact name of small business issuer as specified in its charter)
Delaware 68-0282856
(State or other jurisdiction of ( I.R.S. Employer
incorporation or organization) Identification No.)
1401 Marina Way South, Richmond, California 94804
(Address of principal executive offices)
(510) 412-9100
(Issuer's telephone number)
Check whether the issuer (1) filed all reports required to be filed by Section
13 or 15(d) of the Securities Exchange Act during the past 12 months (or for
such shorter period that the registrant was required to file such reports) and
(2) has been subject to such filing requirements for the past 90 days:
Yes X No
--- ---
At October 30, 1996 the number of outstanding shares of the Registrant's Common
Stock, par value $0.0001, was 16,006,740.
Transitional Small Business Disclosure Format (check one): Yes No X .
--- ---
1
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LXR BIOTECHNOLOGY INC.
(A DEVELOPMENT STAGE ENTERPRISE)
QUARTERLY REPORT ON FORM 10-QSB
FOR THE NINE MONTHS ENDED SEPTEMBER 30, 1996
TABLE OF CONTENTS
<TABLE>
<CAPTION>
PART I. FINANCIAL INFORMATION Page No.
--------
<S> <C> <C>
Item 1. Financial Statements
Condensed Consolidated Balance Sheets as of
September 30, 1996 and December 31, 1995 3
Condensed Consolidated Statements of Operations for
the three and nine months ended September 30, 1996 and
1995 and for the period from April 20, 1992 (date of
incorporation) to September 30, 1996 4
Condensed Consolidated Statements of Cash Flows for the nine
months ended September 30, 1996 and 1995 and for the period
from April 20, 1992 (date of incorporation) to
September 30, 1996 5
Notes to Condensed Consolidated Financial Statements 6
Item 2. Plan of Operations 11
PART II. OTHER INFORMATION
Item 1. Legal Proceedings 14
Item 6. Exhibits and Reports on Form 8-K 14
SIGNATURES 15
</TABLE>
2
<PAGE> 3
PART I. FINANCIAL INFORMATION
ITEM I. FINANCIAL STATEMENTS
LXR BIOTECHNOLOGY INC.
(A DEVELOPMENT STAGE ENTERPRISE)
CONDENSED CONSOLIDATED BALANCE SHEETS
<TABLE>
<CAPTION>
SEPTEMBER 30, DECEMBER 31,
1996 1995
(UNAUDITED)
<S> <C> <C>
ASSETS
Current assets:
Cash and cash equivalents $ 2,747,066 $ 68,245
Prepaid expenses 194,545 183,691
Other receivables 199,641 33,355
------------ ------------
Total current assets 3,141,252 285,291
Equipment and leasehold improvements, net 674,781 890,468
Deposits 219,635 217,138
Organization costs, net 8,250 15,000
------------ ------------
Total assets $ 4,043,918 $ 1,407,897
============ ============
LIABILITIES AND STOCKHOLDERS' EQUITY (DEFICIT)
Current liabilities:
Accounts payable $ 183,927 $ 422,255
Accrued expenses 291,114 403,157
Deferred rent obligation 159,202 160,076
Short-term borrowings from related parties -- 600,000
Short-term portion of obligations under capital leases 203,374 223,420
------------ ------------
Total current liabilities 837,617 1,808,908
Obligations under capital leases, excluding short-term
portion 22,331 183,540
------------ ------------
Total liabilities 859,948 1,992,448
------------ ------------
Stockholders' equity (deficit):
Preferred stock, $0.01 par value; 5,000,000 shares
authorized; none issued or outstanding -- --
Common stock, $0.0001 par value; 45,000,000
shares authorized; 16,188,752 and 7,725,403
shares issued and outstanding at September 30,
1996 and December 31, 1995, respectively 1,589 773
Additional paid-in capital 24,623,873 15,396,249
Common stock subscribed 19 --
Notes receivable from stockholders (75,188) (79,000)
Deficit accumulated during the development stage (21,351,148) (15,892,720)
Treasury stock, at cost; 182,012 and 128,978 shares at
September 30, 1996 and December 31, 1995,
respectively (15,175) (9,853)
------------ ------------
Total stockholders' equity (deficit) 3,183,970 (584,551)
------------ ------------
Commitments and contingencies (notes 4, 6, 7, 8 and 9)
Total liabilities and stockholders' equity (deficit) $ 4,043,918 $ 1,407,897
============ ============
</TABLE>
See accompanying notes to condensed consolidated financial statements
3
<PAGE> 4
LXR BIOTECHNOLOGY INC.
( A DEVELOPMENT STAGE ENTERPRISE)
CONDENSED CONSOLIDATED STATEMENTS OF OPERATIONS
(UNAUDITED)
<TABLE>
<CAPTION>
APRIL 20, 1992
THREE MONTHS NINE MONTHS (DATE OF
ENDED ENDED INCORPORATION)
-------------------------------- -------------------------------- TO
SEPTEMBER 30, SEPTEMBER 30, SEPTEMBER 30, SEPTEMBER 30, SEPTEMBER 30,
1996 1995 1996 1995 1996
------------- ------------- ------------- ------------- -------------
<S> <C> <C> <C> <C> <C>
Revenues:
Grant revenue $ 29,754 $ -- $ 100,000 $ -- $ 100,000
License fee revenue 300,000 -- 300,000 -- 300,000
------------ ----------- ------------ ----------- ------------
Total revenues 329,754 -- 400,000 -- 400,000
------------ ----------- ------------ ----------- ------------
Expenses incurred in the
development stage:
Research and development 1,903,136 1,106,690 4,236,001 3,251,655 15,625,391
General and administrative 601,396 500,152 1,763,818 1,609,194 6,328,872
------------ ----------- ------------ ----------- ------------
Total expenses incurred
in the development
stage 2,504,532 1,606,842 5,999,819 4,860,849 21,954,263
------------ ----------- ------------ ----------- ------------
Loss from operations (2,174,778) (1,606,842) (5,599,819) (4,860,849) (21,554,263)
Interest income (expense), net:
Interest income 46,579 18,262 197,447 76,271 558,429
Interest expense (13,917) (18,767) (47,056) (61,607) 343,109
------------ ----------- ------------ ----------- ------------
Total interest income
(expense), net 32,662 (505) 150,391 14,664 215,320
------------ ----------- ------------ ----------- ------------
Loss before income taxes (2,142,116) (1,607,347) (5,449,428) (4,846,185) (21,338,943)
Income taxes 400 200 9,000 600 12,200
------------ ----------- ------------ ----------- ------------
Net loss $ (2,142,516) $(1,607,547) $ (5,458,428) $(4,846,785) $(21,351,143)
============ =========== ============ =========== ============
Net loss per share $ (0.13) $ (0.21) $ (0.35) $ (0.65)
============ =========== ============ ===========
Weighted average shares used to
compute net loss per share 15,971,556 7,494,950 15,406,964 7,494,950
============ =========== ============ ===========
</TABLE>
See accompanying notes to condensed consolidated financial statements
4
<PAGE> 5
LXR BIOTECHNOLOGY INC.
(A DEVELOPMENT STAGE ENTERPRISE)
CONDENSED CONSOLIDATED STATEMENTS OF CASH FLOWS
(UNAUDITED)
<TABLE>
<CAPTION>
APRIL 20, 1992
(DATE OF
INCORPORATION)
NINE MONTHS ENDED THROUGH
SEPTEMBER 30, SEPTEMBER 30, SEPTEMBER 30,
1996 1995 1996
----------- ----------- ------------
<S> <C> <C> <C>
Cash flows from operating activities $(5,033,090) $(4,244,284) $(19,192,070)
----------- ----------- ------------
Cash flows from investing activities:
Purchase of investments -- -- (3,910,150)
Purchase of equipment and leasehold improvements (157,220) (39,252) (1,425,460)
Proceeds from maturity of investments -- 2,000,000 3,000,000
Proceeds from sale of investments -- 1,000,000 1,000,000
----------- ----------- ------------
Net cash provided by (used in) investing
activities (157,220) 2,960,748 (1,335,610)
----------- ----------- ------------
Cash flows from financing activities:
Net proceeds from sale of common stock 8,630,967 -- 20,315,555
Proceeds from notes payable to related parties -- -- 4,694,500
Proceeds from line of credit -- -- 375,000
Repayment of notes payable and line of credit (600,000) -- (1,581,111)
Principal payments for obligations under
capital lease (181,255) (139,233) (550,808)
Payments received for notes receivable from
stockholders -- 1,257 2,147
Repurchase of common stock (1,510) -- (1,510)
Net proceeds from exercise of warrants 19,505 -- 19,505
Net proceeds from exercise of stock options 1,424 -- 1,468
----------- ----------- ------------
Net cash provided by (used in) financing
activities 7,869,131 (137,976) 23,274,746
----------- ----------- ------------
Net increase (decrease) in cash and cash equivalents 2,678,821 (1,421,512) 2,747,066
Cash and cash equivalents at beginning of period 68,245 2,071,664 --
----------- ----------- ------------
Cash and cash equivalents at end of period $ 2,747,066 $ 650,152 $ 2,747,066
=========== =========== ============
Supplemental cash flow information:
Cash paid for income taxes $ 5,500 $ 800 $ 8,100
=========== =========== ============
Cash paid for interest $ 57,382 $ 61,607 $ 343,631
=========== =========== ============
Noncash financing activities:
Common stock issued in exchange for notes
receivable from stockholders $ -- $ -- $ 107,385
=========== =========== ============
Equipment purchased under capital
lease obligation $ -- $ -- $ 855,022
=========== =========== ============
Stock dividend $ -- $ -- $ 5
=========== =========== ============
Common stock issued in exchange for note
payable to David Blech and others $ -- $ -- $ 3,594,500
=========== =========== ============
Repurchase of common stock in exchange for notes
receivable from stockholders $ 3,812 $ -- $ 13,665
=========== =========== ============
</TABLE>
See accompanying notes to condensed consolidated financial statements
5
<PAGE> 6
LXR BIOTECHNOLOGY INC.
(A DEVELOPMENT STAGE ENTERPRISE)
NOTES TO CONDENSED CONSOLIDATED FINANCIAL STATEMENTS
SEPTEMBER 30, 1996
(1) BASIS OF PRESENTATION
In the opinion of management, the accompanying unaudited condensed
consolidated financial statements contain all adjustments (consisting of normal
recurring adjustments) necessary to present fairly the Company's financial
position as of September 30, 1996 and December 31, 1995, and results of
operations for the three and nine months ended September 30, 1996 and 1995 and
for the period from April 20, 1992 (date of incorporation) to September 30,
1996, and changes in cash flows for the nine months ended September 30, 1996 and
1995, and for the period from April 20, 1992 (date of incorporation) to
September 30, 1996.
These condensed consolidated statements should be read in conjunction
with the Company's audited consolidated financial statements for the years ended
December 31, 1995 and 1994, which are included as part of the Company's Annual
Report on Form 10-KSB for the year ended December 31, 1995.
The Company's condensed consolidated financial statements include the
accounts and results of operations of the Company and its wholly owned
subsidiary, Optical Analytic, Inc. (OAI). All significant intercompany balances
and transactions have been eliminated in consolidation.
Certain items have been reclassified to conform with current financial
statement presentation.
(2) LICENSE AND COLLABORATIVE RESEARCH AGREEMENTS
Perkin Elmer License Agreement
In August 1996, the Company and OAI entered into an agreement with
Perkin Elmer (the Perkin Elmer Agreement) whereby Perkin Elmer was granted an
exclusive worldwide license to the patents OAI had licensed from Ohio State
University related to the Scanning Laser Digital Imaging microscope, for life
science and clinical diagnostic applications, for the life of any of the patent
claims. The Company also licensed certain related software, technical
information and rights to ongoing technological developments. In connection
therewith, Perkin Elmer agreed to (i) make up to $1.4 million of cash milestone
payments to the Company over a three-year period, (ii) contribute up to $400,000
of equipment to the Company in the future, (iii) make certain royalty payments
(which do not include minimums) to the Company on any sales of licensed products
and (iv) to commit certain funds to the development of products covered by the
licensed patents. Upon signing of the agreement, Perkin Elmer paid the Company
$300,000 of the cash milestone payments, which was included in the Company's
revenues as of September 30, 1996. The agreement may be terminated by Perkin
Elmer, in its discretion, subject to payment of certain amounts to the Company
in certain circumstances.
Ohio State University
As of July and August 1996, respectively, the Company and Ohio State
University amended the terms of their license agreement related to the Company's
scanning laser digital imaging (SLDI) microscope to delete the requirement that
an application with the FDA for regulatory approval of a licensed product or
service be filed by August 1996, and to delete from the scope of the license a
patent relating to optical multiplexers that was unrelated to the SLDI product.
6
<PAGE> 7
LXR BIOTECHNOLOGY INC.
(A DEVELOPMENT STAGE ENTERPRISE)
NOTES TO CONDENSED CONSOLIDATED FINANCIAL STATEMENTS (CONTINUED)
SEPTEMBER 30, 1996
(3) GRANT REVENUE
In September 1996, the Company received notice from the National
Institute of Health of a grant award in the amount of approximately $70,000 for
its research on the evaluation of Maspin as a widespread tumor suppressor.
Proceeds from the grant award have not been received as of September 30, 1996.
(4) ACQUISITION OF TECHNOLOGY
In August 1996, the Company acquired certain patent and other rights
related to Cardiosol, a preservation solution for use during heart
transplantation (the Cardiosol Acquisition). In connection with such
acquisition, the Company paid $98,000 in cash and committed to issue 225,000
shares of its common stock to the sellers, of which 37,500 shares have been
issued and are outstanding as of September 30, 1996. The remaining shares are
included in common stock subscribed, and an additional 75,000 shares may be
issued upon the attainment of certain milestones. The Company has granted
certain registration rights applicable to such shares. The total cost of the
acquisition, including cash and shares, amounted to approximately $675,000 and
is included in research and development expenses for the three months ending
September 30, 1996.
(5) STOCK OPTION PLANS
1993 Stock Option Plan
During 1996, the Company had the following activity under the 1993 Stock Option
Plan:
<TABLE>
<CAPTION>
Stock Options Outstanding
-----------------------------
Number of Price per
shares share
--------- ---------------
<S> <C> <C>
Balance as of December 31, 1995 479,385 $ 0.03 - 5.250
Options granted 378,505 1.875 - 6.188
Options canceled or expired (50,267) 0.03 - 2.125
Options exercised (9,969) 0.03 - 1.375
-------
Balance as of September 30, 1996 797,654
=======
</TABLE>
7
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LXR BIOTECHNOLOGY INC.
(A DEVELOPMENT STAGE ENTERPRISE)
NOTES TO CONDENSED CONSOLIDATED FINANCIAL STATEMENTS (CONTINUED)
SEPTEMBER 30, 1996
(5) STOCK OPTION PLANS (CONTINUED)
Directors Stock Option Plan
During 1996, the Company had the following activity under the Directors Stock
Option Plan:
<TABLE>
<CAPTION>
Stock Options Outstanding
-------------------------
Number of Price per
shares share
--------- ---------
<S> <C> <C>
Balance as of December 31, 1995 35,000 $1.00 - 1.875
Options granted 5,000 5.438
Options canceled or expired (8,834) 1.00 - 5.438
------
Balance as of September 30, 1996 31,166
======
</TABLE>
(6) CAPITAL STOCK
During 1996, the Company exercised its option to repurchase 53,034 shares
of unvested common stock for a repurchase price of $5,322.
In May 1996, the Company issued 305,694 shares of common stock upon
exercise of a warrant issued in the Company's Private Placement Offering in
January 1996 ("the Private Placement"). The warrant holder elected a cashless
exercise of this 404,789 share warrant resulting in a reduction of the shares
issuable under the warrant by 99,095. In July 1996, another warrant holder from
the Company's Private Placement exercised his option to purchase 14,186 shares
of the Company's common stock at a purchase price of $19,505. As of September
30, 1996, the Company had warrants to purchase 665,872 shares of common stock
remaining outstanding.
In June 1996, the Company's shareholders approved the proposal to amend
the Company's Restated Certificate of Incorporation to increase the number of
shares of common stock authorized for issuance from 30,000,000 shares to
45,000,000 shares.
In August 1996, in connection with the Cardiosol Acquisition (Note 4),
the Company committed to issue 225,000 shares of the Company's common stock
valued at approximately $577,000. In addition, the Company committed to issue an
additional 75,000 shares of common stock contingent upon the attainment of
certain milestones.
8
<PAGE> 9
LXR BIOTECHNOLOGY INC.
(A DEVELOPMENT STAGE ENTERPRISE)
NOTES TO CONDENSED CONSOLIDATED FINANCIAL STATEMENTS (CONTINUED)
SEPTEMBER 30, 1996
(7) OPERATING LEASE
In August 1996, the Company amended the terms of the lease for its
principal offices to extend the term for ten years, until June 2010, and to add
approximately 4,100 square feet of space.
Future minimum lease payments for this lease are as follows:
<TABLE>
<CAPTION>
Year ending
December 31,
------------
<S> <C>
1997 $ 311,638
1998 314,918
1999 314,918
2000 314,918
2001 314,918
Thereafter 3,306,643
-----------
Total minimum lease payments $ 4,877,953
===========
</TABLE>
(8) LITIGATION
The Company and/or certain of its past and present directors and officers
are named as defendants in three lawsuits, Katz vs. Blech, 95 Civ. 7215
(S.D.N.Y.) ("Katz"), In re Blech Securities Litigation, 94 Civ. 7696 (S.D.N.Y.)
("Blech"), and Degulis vs. LXR Biotechnology Inc., et al., 95 Civ. 4204
(S.D.N.Y) ("Degulis"), all pending in the Southern District of New York. All
three cases are brought on behalf of classes of persons purchasing common shares
of the Company prior to September 21, 1994, and assert claims arising out of the
Company's IPO and subsequent trading of those shares.
The suits allege violations of Sections 11 and 12 of the Securities Act
of 1933 and Sections 10(b) and 20 of the Securities Exchange Act of 1934,
including misrepresentations and omissions in connection with the IPO and
manipulation of share prices. The suits also allege common law claims for fraud
and deceit and seek punitive damages. The complaints allege that defendants,
including the Company and the defendant directors and officers, failed to
disclose in securities filings connected with the IPO the leveraged financial
condition of the Company's underwriter, D. Blech & Co., and its principal, David
Blech. The suits further allege that defendants failed to disclose that D. Blech
& Co. would act as principal market maker for the Company's shares following the
IPO, and that D. Blech & Co.'s extended financial commitments would affect its
ability to maintain a market for the Company's shares. The suits also allege
that defendants assisted or acquiesced in a post-offering scheme to manipulate
the market for the Company's shares and artificially inflate share prices.
Under the Company's bylaws, individual agreements, and state law, the
Company's current and former directors and officers may have certain rights to
indemnification and defense costs in the event they are named in litigation.
Four individual defendants in Katz and/or Degulis have submitted claims for
indemnity and advancement of defense costs, and the Company has agreed to
advance defense costs and indemnify those individuals to the extent permitted by
law. A demand by Mark Germain, the former chairman of the Company and a Managing
Director of D. Blech & Co., remains under consideration by the Company. A demand
by the independent underwriter for contractual indemnity has been denied; such
denial is subject to contest by the underwriter. The Company and the underwriter
entered into a tolling agreement whereby the Company agreed that the running of
any statute of limitations applicable to claims of the underwriter against the
Company would be tolled until the earlier of June 30, 1997 and the termination
of the tolling agreement.
9
<PAGE> 10
LXR BIOTECHNOLOGY INC.
(A DEVELOPMENT STAGE ENTERPRISE)
NOTES TO CONDENSED CONSOLIDATED FINANCIAL STATEMENTS (CONTINUED)
SEPTEMBER 30, 1996
(8) LITIGATION (CONTINUED)
The Company's primary level directors and officers liability insurance
carrier has tentatively agreed to provide coverage for reasonable attorneys fees
in the defense of the four current and former directors and/or officers
referenced above, but the carrier has refused to provide indemnity or defense
costs for the Company or for Mark Germain. The Company and the carrier have
entered into an allocation agreement whereby 83% of the defense costs related to
the Katz and Degulis actions will be borne by the carrier, with the remaining
17% to be borne by the Company. The carrier is not obligated to make any
payments until a $250,000 deductible (applicable to all covered claims, in the
aggregate) under the policy is exhausted. The extent to which costs of defending
the litigation will ultimately be covered by insurance is not yet known. The
extent to which insurance would cover any settlement or judgment has not been
determined and may not be determined until the litigation is completed.
On June 6, 1996, the court decided motions to dismiss previously filed by
the Company and other parties in all three cases. The motions to dismiss Degulis
and Katz were denied. The motion to dismiss In re Blech was granted as to the
Company. On July 26, 1996, plaintiffs filed an amended complaint in In re Blech
which does not name the Company as a defendant; of the remaining defendants in
In re Blech only Mark Germain has made a demand for indemnity against the
Company.
The Company denies any wrongdoing and is defending the above cases
vigorously. While it is possible that the litigation may have a material adverse
effect on the Company, the early stage of the litigation, uncertainty as to
whether any material judgment or settlement will result, and the possibility
that some portion of any settlement or judgment may be covered by insurance,
make it impossible to predict at this time whether the litigation will have a
material adverse financial impact on the Company. An adverse judgment or
settlement could have a material adverse effect on the Company.
(9) SUBSEQUENT EVENT
In October 1996, the Company entered into an employment agreement with a
new President and Chief Operating Officer (COO). The COO will receive an initial
salary of $225,000 per year, a $15,000 one-time recruitment bonus, and options
to purchase 310,000 shares of the Company's common stock, subject to provisions
of the Company's 1993 Stock Option Plan. The Company has agreed to cover the
COO's relocation costs and miscellaneous expenses during a six-month transition
period. The COO has agreed to reimburse the Company for all or a portion of the
relocation expenses and the recruitment bonus if he voluntarily terminates his
employment with the Company within two years. The Company has also agreed to
provide the COO a $175,000 home loan, which will be forgiven at the rate of
$25,000 per year beginning December 1997. The balance of the loan will become
due and payable if the COO resigns or is terminated for cause. If the Company
terminates the COO without cause, he will be entitled to receive severance equal
to one year's salary.
10
<PAGE> 11
ITEM 2.
PLAN OF OPERATIONS
The following Plan of Operations contains forward looking statements
regarding, among other things, product development and effectiveness, corporate
partnering, capital and other expenditures, timing of FDA filings, FDA approval
thereof and clinical trial progress, sufficiency of cash resources and the
ability of the Company to raise additional funding. These forward looking
statements concern matters that involve risks and uncertainties that could cause
actual results to differ materially from those projected in the forward looking
statements. Words such as "believe", "expects", "likely", "may" and "plans" are
intended to identify forward looking statements, although not all forward
looking statements contain these words. For a discussion of certain of these
risks and uncertainties, please see "Factors Affecting Future Results" below,
the Company's Annual Report on Form 10-KSB for the year ended December 31, 1995
and the "Risk Factors" section in the Registration Statement on Form S-3 filed
by the Company with the Securities and Exchange Commission on March 1, 1996.
In January 1996, the Company raised approximately $8.6 million (net of
offering expenses) through a private placement offering and sale of 7,360,000
shares of the Company's common stock at a price of $1.25 per share (the "Private
Placement"). The Company also issued 736,000 shares of common stock to the
placement agent as a selling commission for the Private Placement and a warrant
to purchase an additional 736,000 shares of the Company's common stock at an
exercise price of $1.375 per share. A portion of the proceeds from the Private
Placement were used to repay $600,000 in short-term borrowings and accrued
interest from related parties, to pay approximately $660,000 in accounts payable
and other accrued liabilities, and to fund the Company's operations through the
third quarter of 1996. As of September 30, 1996, the remaining proceeds from the
Private Placement were invested in short-term interest bearing investments and
amounted to approximately $ 2.7 million.
The Company filed an IND with the FDA in March 1996 to commence human
clinical trials of Lexirin for the suppression of severe diarrhea associated
with the pathogenesis of AIDS, as well as with the use of chemotherapeutic
agents and radiation in the treatment of cancer. The Company received approval
of its IND in April and Phase I clinical trials commenced in August 1996 at the
East Bay AIDS Clinic of Alta Bates Medical Center in Berkeley. The Company
currently has ten patients enrolled in the clinical trial. The Company is
investigating the possibility of conducting the trials in one or more additional
locations, and/or modifying the requirements for eligibility to participate in
the trial, in order to accelerate enrollment in the trial. There can be no
assurance that additional locations will be used, or that the enrollment
criteria will be modified, or that if implemented, such changes will result in
increased enrollment in the trial.
In June 1996, the Company sold its Scanning Laser Digital Imaging
prototype to Perkin Elmer for $150,000. The cost of constructing the prototype
was included in research and development costs of previous periods, therefore
the selling price of the prototype was recorded as a reduction of research and
development costs for the nine months ending September 30, 1996.
In August 1996, the Company and its wholly owned subsidiary, Optical
Analytic, Inc. (OAI) entered into an agreement with Perkin Elmer (the Perkin
Elmer Agreement) whereby Perkin Elmer was granted an exclusive worldwide license
to the patents OAI had licensed from Ohio State University related to the
Scanning Laser Digital Imaging microscope, for life science and clinical
diagnostic applications, for the life of any of the patent claims. The Company
also licensed certain related software, technical information and rights to
ongoing technological developments. In connection therewith, Perkin Elmer agreed
to (i) make up to $1.4 million of cash milestone payments to the Company over a
three-year period, (ii) contribute up to $400,000 of equipment to the Company in
the future, (iii) make certain royalty payments (which do not include minimums)
to the Company on any sales of licensed products and (iv) to commit certain
funds to the development of products covered by the licensed patents. Upon
signing of the agreement, Perkin Elmer paid the Company $300,000 of the cash
milestone payments, which was included in the Company's revenues as of September
30, 1996. The agreement may be terminated by Perkin Elmer, in its discretion,
subject to payment of certain amounts to the Company in certain circumstances.
11
<PAGE> 12
PLAN OF OPERATIONS
(CONTINUED)
In August 1996, the Company purchased the rights to a patented
preservation solution for use during heart transplantation, called the Cardiosol
solution (the Cardiosol Acquisition). In connection with such acquisition, the
Company paid $98,000 in cash and committed to issue 225,000 shares of its common
stock to the sellers, of which 37,500 shares have been issued and are
outstanding as of September 30, 1996. The remaining shares are included in
common stock subscribed, and an additional 75,000 shares may be issued upon the
attainment of certain milestones. The Company has granted certain registration
rights applicable to such shares. The total cost of the acquisition amounted to
approximately $675,000 and is included in research and development expenses for
the three and nine months ending September 30, 1996. As part of the agreement,
one of the solution's co-inventors joined the Company's Scientific Advisory
Board and the other co-inventor joined the Company to coordinate the project.
In August 1996, the Company also submitted to the FDA a 510(k) for use
of Cardiosol as a heart preservation solution. In November 1996, the Company
received notice from the FDA that the 510K application for Cardiosol was denied
due to the fact that the Company's formulation was considered materially
different from the formulation used in the original clinical trials of the
solution conducted prior to the Cardiosol Acquisition. The Company intends to
submit a revised application for an IDE to initiate clinical studies with the
revised formulation by the end of the first quarter of 1997. The Company is also
currently preparing an IND to conduct clinical studies of Cardiosol for use as a
cardioplegia solution.
In August 1996, the Company amended the terms of the lease for its
principal offices to extend the term for ten years and to add approximately
4,100 square feet of space. The Company plans to use the additional space for
manufacturing and clinical trial related activities.
In October 1996, Donald H. Picker, Ph.D. was appointed the Company's
President and Chief Operating Officer. Dr. Picker reports to L. David Tomei,
Ph.D., the Company's Chief Executive Officer and former President. Dr. Picker
will also become a member of the Company's Board of Directors. Dr. Picker was
Chief Operating Officer of Corvas International, Inc., a biotechnology company,
from March 1996 to June 1996. Prior to that Dr. Picker served as Senior Vice
President, Research & Development, at Genta, Inc., an antisense technology
company, from November 1991 to February 1996. Dr. Picker also held a senior
management position at Johnson Matthey, Inc., a biopharmaceutical company, from
1983 to 1991. Dr. Picker received a B.S. in chemistry from Brooklyn Polytechnic
Institute and a Ph.D. in organic chemistry from the State University of New York
at Albany.
In October 1996, Shelli J. Geer was appointed the Company's Vice
President, Finance and Administration. Ms. Geer had been the Company's
Controller since September 1994. Prior to joining the Company, Ms. Geer was an
accountant with KPMG Peat Marwick LLP since July 1988, most recently as Audit
Manager. Ms. Geer received a B.S. in Business Administration from California
State University at Chico and is a Certified Public Accountant in the State of
California.
The Company's capital expenditures through the third quarter of 1996
were approximately $157,000.
As of September 30, 1996, there was $225,705 outstanding under the
Company's equipment lease line. The lease line bears interest at the rate of
15.3% per annum and is secured by a deposit of $194,128. There are no further
borrowings available under the equipment lease line.
As of September 30, 1996, the Company had approximately $2.7 million of
cash and cash equivalents. The Company does not have any committed sources of
equity or debt funding, and the Company's only source of income is from the
Perkin Elmer license agreement, grant revenue, and interest earned on the
remaining proceeds from the Company's Private Placement. Accordingly, the
Company will need to raise substantial additional capital in the near future to
fund its operations, including the development of its lead compounds. The
Company believes its current resources will be adequate to fund the Company's
operations through 1996. The Company is currently expending significant efforts
to obtain the additional funding necessary to fund the Company's operations
beyond 1996. There can be no assurance that additional funding will be available
on favorable terms, if at all. Failure to raise additional funds in the near
future will have a material adverse effect on the Company.
12
<PAGE> 13
PLAN OF OPERATIONS
(CONTINUED)
Contingent upon obtaining additional funding, the Company expects to
significantly increase its expenditures over the next twelve months. The Company
expects these expenditures to be directed to increasing the Company's research
and development efforts, including continuation of its clinical trials for
Lexirin and the possible commencement of clinical trials for Cardiosol, the
construction of a pilot manufacturing facility (currently estimated to be
$650,000), the purchase of additional equipment (estimated to be approximately
$500,000 over the next twelve months) and general working capital. The Company
intends to focus its research and development efforts on LXR015 (Elirex and
Lexirin), Cardiosol, Maspin, Bak and Fas(DELTA)TM.
The Company has determined that Cardiosol has the potential of
receiving FDA marketing clearance as a heart preservation solution earlier than
had been anticipated for Elirex. Therefore, the Company has selected Cardiosol
as its primary near-term product for heart preservation. Elirex continues to be
one of the Company's lead drug candidates for suppressing apoptosis for
application in liver transplantation and suppression of acute myocardial
infarction following heart attack.
The Company plans to continue to seek corporate partners for its
research and development activities. There can be no assurance that the Company
will be able to secure any corporate partner relationships. The Company is
negotiating with a potential corporate partner to conduct a joint assessment of
the Maspin technology licensed by the Company from the Dana-Farber Cancer
Institute. These negotiations are at a very preliminary stage and there is
substantial uncertainty as to whether an agreement will be reached. If the
Company does not enter into a corporate collaboration regarding Maspin in the
near future, it will likely postpone the filing of an IND related to Maspin for
the time being and will not pursue at this time its contemplated CRADA with the
NIH.
Subject to the availability of funding, the Company expects to fund
future research at the Dana Farber Cancer Institute and the University of
Kentucky at Louisville relating to Maspin and Elirex, respectively, during the
next twelve months, and may enter into research relationships with other
universities and research institutions. The Company also regularly evaluates the
possibility of licensing or otherwise acquiring technologies from third parties.
As of September 30, 1996, the Company employed 47 full-time employees.
During the next twelve months, the Company expects to increase its number of
employees to approximately 55 in order to support the Company's increased
research and development activities. Further increases in employees may occur as
the Company increases its spending in efforts to undertake clinical studies.
FACTORS AFFECTING FUTURE RESULTS
The Company's plan of operations depends on numerous factors, including
the availability of funding, the progress of its research and development
programs, the progress of preclinical and clinical testing, the time and costs
involved in obtaining regulatory approvals, the cost of filing, prosecuting,
defending and enforcing any patent claims and other intellectual property
rights, the cost of obtaining certain technological rights, competing
technological and market developments, changes in the Company's existing
research relationships, the ability of the Company to establish collaborative
arrangements, the development of commercialization activities and arrangements,
the purchase of additional capital equipment, and legal expenses incurred in
connection with defending the securities lawsuits brought against the Company.
Accordingly, the Company's plans are subject to change.
There can be no assurance that the Company will be able to successfully
conduct clinical trials of Lexirin, or any other drug candidate, or that the
trial results will be favorable; that the FDA will approve the Company's IDE or
IND for the Cardiosol solution; that the pre-clinical trial results of Elirex,
Maspin, or any other drug candidate will support the filing of an IND, or that
the FDA will approve any such IND; that the Company will have sufficient funding
to conduct clinical trials; or that the Company will be able to submit to the
FDA an application to market any product, or that any such application will be
approved by the FDA.
13
<PAGE> 14
PART II. OTHER INFORMATION
ITEM 1. LEGAL PROCEEDINGS
The information called for by Part II, Item 1 is incorporated by
reference to Note 8 of the Condensed Consolidated Financial Statements included
in Part I of this document.
ITEM 6. EXHIBITS AND REPORTS ON FORM 8-K.
(a) Exhibits. The following exhibits are attached hereto:
Exhibit
Number Title
10.29 First Amendment to sublease for Building C of Marina Bay
Business Park, 1401 Marina Way South, Richmond, California
94804 dated August 5, 1996 between the Company and Marina
Westshore Partners.
10.30 Patent and Technology Transfer and Stock Purchase Agreement
entered into between the Company and Geoffrey M. Collins and
Winston N. Wicomb.
10.31 Amendment effective as of July 10, 1996 to the License
Agreement between Optical Analytic, Inc., The Ohio State
Research Foundation and the Ohio State University.
10.32 Amendment as of August 27, 1996 to the License Agreement
between Optical Analytic, Inc., The Ohio State Research
Foundation and the Ohio State University.
**10.33 License Agreement between the Company on behalf of itself and
Optical Analytic, Inc., its wholly owned subsidiary, and The
Perkin-Elmer Corporation, dated as of August 29, 1996.
*10.34 President and Chief Operating Officer Letter Agreement, dated
September 24, 1996.
27.01 Financial Data Schedule.
- -----------------------
* Represents a management contract or compensatory plan or arrangement.
** Confidential treatment has been requested with respect to certain portions
of this document.
(b) Reports on Form 8-K.
No reports on Form 8-K were filed by the Company during the period for
which this report is filed.
14
<PAGE> 15
SIGNATURES
In accordance with the requirements of the Exchange Act, the registrant
has duly caused this report to be signed on its behalf by the undersigned
thereunto duly authorized.
LXR BIOTECHNOLOGY INC.
Date: November 14, 1996 By: /s/ Mark J. Tomei
----------------- -----------------------------------
Mark J. Tomei
Chief Financial Officer and Secretary
15
<PAGE> 16
EXHIBIT INDEX
Exhibit
Number Title
10.29 First Amendment to sublease for Building C of Marina Bay
Business Park, 1401 Marina Way South, Richmond, California
94804 dated August 5, 1996 between the Company and Marina
Westshore Partners.
10.30 Patent and Technology Transfer and Stock Purchase Agreement
entered into between the Company and Geoffrey M. Collins and
Winston N. Wicomb.
10.31 Amendment effective as of July 10, 1996 to the License
Agreement between Optical Analytic, Inc., The Ohio State
Research Foundation and the Ohio State University.
10.32 Amendment as of August 27, 1996 to the License Agreement
between Optical Analytic, Inc., The Ohio State Research
Foundation and the Ohio State University.
**10.33 License Agreement between the Company on behalf of itself and
Optical Analytic, Inc., its wholly owned subsidiary, and The
Perkin-Elmer Corporation, dated as of August 29, 1996.
*10.34 President and Chief Operating Officer Letter Agreement, dated
September 24, 1996.
27.01 Financial Data Schedule.
- -----------------------
* Represents a management contract or compensatory plan or arrangement.
** Confidential treatment has been requested with respect to certain portions
of this document.
16
<PAGE> 1
Exhibit 10.29
FIRST AMENDMENT TO LEASE (SUBLEASE)
This First Amendment to Lease (Sublease) is entered into as of August
5, 1996 between MARINA WESTSHORE PARTNERS, a California limited partnership
("LANDLORD") and LXR BIOTECHNOLOGY, INC., a Delaware corporation ("TENANT").
RECITALS
A. Quick Response Services, Inc., a California corporation ("QRS")
and Tenant entered into that certain Sublease dated August 19, 1993 pertaining
to premises located in a portion of Building C of the property located at 1400
Marina Way South, Richmond, California. All capitalized terms not defined herein
shall have the meanings set forth in the August 19, 1993 Sublease between QRS
and Tenant.
B. Subsequent thereto, QRS, Landlord and Tenant entered into that
certain Assignment and Agreement dated as of October 8, 1993, pursuant to which
Landlord succeeded to the rights of QRS under the August 19, 1993 Sublease.
Concurrent with that transaction, Landlord also acquired the fee interest in the
Marina Bay Business Park project, including all of Building C. The August 19,
1993 Sublease as affected by the August 8, 1993 Assignment and Agreement is
referred to herein as the "LEASE".
C. Landlord and Tenant desire to amend the Lease to extend the term
thereof and to add approximately 4,098 square feet of Rentable Area to the
Subleased Premises.
NOW THEREFORE, Landlord and Tenant amend the Lease as follows:
AMENDMENT
1. Additional Space. The Subleased Premises are expanded to include
an adjacent approximately 4,098 square feet of Rentable Area shown on the
drawing attached as Exhibit A hereto (the "ADDITIONAL SPACE"). Within ten days
after the date of this First Amendment, Landlord shall deliver possession of the
Additional Space to Tenant. Tenant shall at its sole cost and expense make
improvements to the Additional Space, which improvements shall include
connecting the Additional Space to Tenant's existing premises and constructing a
demising wall to separate the Additional Space from the area occupied by
Landlord. Such improvements shall be done pursuant to plans prepared by Tenant
and submitted to Landlord for its approval, which shall not be unreasonably
withheld.
2. Term. The Term of the Lease is hereby extended to terminate on
June 30, 2010. Tenant's option to extend the term as set forth in Section 23 of
the Lease is hereby deleted.
<PAGE> 2
3. Monthly fixed rent.
(a) Tenant shall commence paying rent for the Additional Space
on November 1, 1996. Effective November 1, 1996, the monthly Fixed Rent for the
entire 32,804 square feet of the Subleased Premises shall be $24,603. Such
monthly Fixed Rent shall be increased, effective March 1, 1997 through June 30,
2002, to $26,243.20 per month.
(b) Commencing July 1, 2002, monthly Fixed Rent shall be
increased to $32,804; provided however, that if Tenant believes that the Fair
Market Rent is less than $1.00 per square foot of Rentable Area, Tenant may
request that the Fair Market Rent be determined in accordance with Section 25.4
of the Master Lease, and upon completion of the determination of Fair Market
Rent as provided therein, the rent shall be established in accordance with such
appraisal, provided however that in no event shall the monthly Fixed Rent be
less than $.76 per square foot of Rentable Area and in no event shall the
monthly Fixed Rent exceed $1.00 per square foot of Rentable Area.
(c) Commencing July 1, 2004 and each two years thereafter (the
"ADJUSTMENT DATE"), the monthly Fixed Rent, as established above, shall be
adjusted to reflect the percentage change in the Consumer Price Index (the
"INDEX") that has occurred during each preceding two-year period in the Consumer
Price Index (the "INDEX") that has occurred during each preceding two-year
period. For purposes hereof, the Index shall be the United States Department of
Labor, Bureau of Labor Statistics Consumer Price Index for All Urban Consumers
San Francisco- Oakland-San Jose Metropolitan Area Average, Subgroup "All Items"
(1982-84 = 100). The monthly Fixed Rent shall be adjusted on the Adjustment Date
to an amount determined by multiplying the Fixed Rent for the month immediately
preceding the Adjustment Date by a fraction, the denominator of which shall be
the most recent monthly Index figure published prior to the previous Adjustment
Date (or July 1, 2002 in the case of the first adjustment) and the numerator of
which shall be the most recent monthly Index figure published prior to the date
of such adjustment. If at any Adjustment Date the Index no longer exists in the
form described herein, Landlord may substitute any substantially equivalent
official index published by the Bureau of Labor Statistics or its successor. The
substitute index shall then become the Index hereunder. Notwithstanding the
foregoing, in no event shall the monthly Fixed Rent be reduced on any Adjustment
Date, nor shall it be increased on any Adjustment Date by more than eight
percent of the monthly Fixed Rent most recently in effect.
(d) The monthly Fixed Rent shall be payable by Tenant to
Landlord in addition to Tenant's obligation to pay its prorata share of
Operating Expenses.
4. Operating Expenses. Tenant's current prorata share of Operating
Expenses is 26.54% of the Operating Expenses owed under the Master Lease for the
Premises, which is 22.40% of total Operating Expenses for the 128,160 square
foot project (the "PROJECT") of which the Premises are a part. Effective
November 1, 1996, Tenant's prorata share of the Project's Operating Expenses
shall increase from 22.40% to 25.60%. The limitation on Tenant's obligation to
pay Operating Expenses set forth at Section 7(b) of the Lease shall be
determined on a per square foot basis.
<PAGE> 3
Except as expressly provided herein, the Lease shall remain in
full force and effect; provided however that any provisions of the Lease that
are not expressly amended herein but become inconsistent with the express terms
of this First Amendment shall be interpreted in such manner as is necessary to
make such terms consistent with the provisions of this First Amendment.
IN WITNESS WHEREOF, Landlord and Tenant have executed this First
Amendment as of the date and year first above written.
LANDLORD
MARINA WESTSHORE PARTNERS,
a California limited partnership
By: Pinnacle Enterprises, Inc.,
an Oklahoma corporation dba
Pinnacle Maritime Corporation,
its general partner
By: /s/ Richard Poe
-----------------------------------
Richard R. Poe, Its Authorized Officer
TENANT:
LXR BIOTECHNOLOGY, INC.,
a Delaware corporation
By: /s/ L. David Tomei
------------------------------------
Name/Title CEO
<PAGE> 1
Exhibit 10.30
PATENT AND TECHNOLOGY TRANSFER AND STOCK PURCHASE AGREEMENT
This Patent and Technology Transfer and Stock Purchase Agreement (this
"Agreement") is made and entered into as of August 8, 1996 (the "Effective
Date") by and among LXR Biotechnology Inc., a Delaware corporation (the
"Company"), Geoffrey M. Collins ("Collins") and Winston N. Wicomb ("Wicomb").
Collins and Wicomb are hereinafter sometimes referred to individually as
"Purchaser" and together as "Purchasers".
1. PURCHASE OF SHARES. Subject to the terms and conditions of this
Agreement, Purchasers hereby purchase from the Company, and Company hereby sells
to Purchasers, a total of up to 300,000 shares of the Company's common stock,
$0.0001 par value per share (the "Shares"). As used in this Agreement, the term
"Shares" refers to the Shares purchased under this Agreement and (a) includes
all securities received in replacement of the Shares, whether as a result of a
recapitalization, merger, reorganization or otherwise, and (b) shall be adjusted
to reflect stock dividends, stock splits or reverse stock splits in respect of
the Shares.
2. PAYMENT OF PURCHASE PRICE.
(A) DELIVERIES BY PURCHASER. Purchasers hereby deliver to the Company
the full purchase price of the Shares by Purchasers' assignment to the Company
of certain technology and related rights co-owned by Purchasers (the
"Technology"), evidenced by delivery to the Company of an Assignment Agreement
in the form of Exhibit 1 attached hereto (the "Assignment Agreement") and a
Joint Assignment in the form of Exhibit A to the Assignment Agreement, each duly
executed by Purchasers. If a Purchaser is married, such Purchaser also hereby
delivers to the Company a Consent of Spouse in the form of Exhibit 2 attached
hereto, duly executed by such Purchaser's spouse.
(B) DELIVERIES BY THE COMPANY. Upon its receipt of the documents to be
executed and delivered by Purchasers to the Company under Section 2(a), the
Company will issue one or more duly executed stock certificates evidencing a
total of 37,500 Shares, registered in the name of each Purchaser as set forth on
Exhibit 3 attached hereto, as completed by such Purchaser. The allocation of
such Shares between Purchasers will be as set forth on Exhibit 4 attached hereto
(the "Allocation Schedule").
(D) FUTURE DELIVERIES BY THE COMPANY. As further consideration for
Purchasers' assignment of the Technology to the Company, the Company agrees to
issue up to an additional 262,500 Shares to Purchasers as follows:
(i) 37,500 Shares on January 1, 1997;
(ii) 75,000 Shares on January 1, 1998;
(iii) 75,000 Shares on January 1, 1999; and
<PAGE> 2
Patent and Technology Transfer
and Stock Purchase Agreement
(iv) 75,000 Shares upon first commercial sale and shipment of
a preservation solution based on the Technology to a customer in the United
States that is unaffiliated with Purchasers (or other customer agreed upon by
the parties), after receipt of all necessary FDA approvals and commencement of
general marketing activities by the Company for such product.
The Company will issue the Shares to Purchasers as set forth above and
in the Allocation Schedule; provided, however, that at the time of each such
future issuance, each Purchaser receiving Shares shall represent to the Company
that (a) the representations and warranties of such Purchaser in Section 4,
paragraphs (a) through (i), are true and correct on the date of such issuance,
as if they were made on such date, and (b) the warranties of such Purchaser in
Section 4, paragraph (j) were true and correct as of the Effective Date.
(d) ACKNOWLEDGMENT OF PAYMENT OF CASH CONSIDERATION.
Purchasers acknowledge that they previously received a total of $110,000 in cash
from the Company in connection with the Company's acquisition of the Technology
(i.e., a $30,000 diligence fee, a $68,000 document execution fee and a $12,000
prepayment of consulting fees in connection with Collins' service as a member of
the Company's Science Advisory Board), and that such cash payments were
allocated between Purchasers as agreed by Purchasers.
(e) OTHER AGREEMENTS. As of the Effective Date, the Company and the
Purchasers have entered into the following other agreements in connection with
Purchasers' assignment of the Technology to the Company:
(i) Wicomb Employment Agreement. The Company and Wicomb have
entered into an employment agreement in substantially the form attached hereto
as Exhibit 5.
(ii) Collins Science Advisory Board Consulting Agreement. The
Company and Collins have entered into a Science Advisory Board Consulting
Agreement in substantially the form attached hereto as Exhibit 6.
Notwithstanding the fact that the parties are also entering into the Wicomb
Employment Agreement and Collins Science Advisory Board Consulting Agreement
(together, the "Other Agreements"), the Company's obligation to issue Shares
shall not be affected by the Other Agreements, and accordingly a breach or
alleged breach by Wicomb or Collins under the Other Agreements shall not entitle
the Company to withhold delivery of the Shares. Additionally, the transfer of
Technology by the Purchasers to the Company shall not be affected by the Other
Agreements, and accordingly a breach or alleged breach by the Company under the
Other Agreements shall not entitle the Purchasers to revoke or otherwise affect
the transfer of Technology to the Company.
3. REPRESENTATIONS AND WARRANTIES OF THE COMPANY. The Company hereby
represents and warrants to each Purchaser that the statements in the following
paragraphs of this Section 3 are all true and correct as of the Effective Date:
- 2 -
18438-201/JTH/437684.6/070396
<PAGE> 3
Patent and Technology Transfer
and Stock Purchase Agreement
(a) ORGANIZATION, GOOD STANDING AND QUALIFICATION. The Company is a
corporation duly organized, validly existing and in good standing under the laws
of the State of Delaware.
(b) CAPITALIZATION. The capitalization of the Company will consist of
the following:
(i) Preferred Stock. A total of 5,000,000 authorized shares of
preferred stock, $0.01 par value per share (the "Preferred Stock"), none of
which will be issued or outstanding.
(ii) Common Stock. A total of 45,000,000 authorized shares of
common stock, $0.0001 par value per share (the "Common Stock"), of which
approximately 16,000,000 shares will be issued and outstanding.
(iii) Options, Warrants, Reserved Shares. Except for: (1) the
1,049,850 shares of Common Stock reserved for issuance under the Company's 1993
Stock Option Plan, as amended, under which options to purchase approximately
600,000 shares are outstanding; (2) the 200,000 shares of Common Stock reserved
for issuance under the Company's 1993 Directors Stock Option Plan, as amended,
under which options to purchase approximately 40,000 shares are outstanding; (3)
warrants to purchase approximately 685,000 shares of Common Stock; and (4) the
Company's agreement to issue Shares to Purchasers pursuant to this Agreement;
there are not outstanding any options, warrants, rights (including conversion or
preemptive rights) or agreements for the purchase or acquisition from the
Company of any shares of its capital stock or any securities convertible into or
ultimately exchangeable or exercisable for any shares of the Company's capital
stock.
(c) DUE AUTHORIZATION. All corporate action on the part of the Company
and its officers, directors and stockholders necessary for the authorization,
execution and delivery of, and the performance of all obligations of the Company
under, this Agreement, and the authorization, issuance, reservation for issuance
and delivery of all of the Shares being sold under this Agreement has been taken
or will be taken prior to the Effective Date, and this Agreement constitutes the
valid and legally binding obligation of the Company, enforceable in accordance
with its terms, except as may be limited by (i) applicable bankruptcy,
insolvency, reorganization or others laws of general application relating to or
affecting the enforcement of creditors' rights generally and (ii) the effect of
rules of law governing the availability of equitable remedies.
(d) VALID ISSUANCE OF STOCK.
(i) The Shares, when issued, sold and delivered in accordance
with the terms of this Agreement for the consideration provided for herein, will
be duly and validly issued, fully paid and nonassessable.
(ii) Based in part on the representations made by Purchasers in
Section 4 hereof, the Shares to be issued on the Effective Date and (assuming no
change in applicable law and no unlawful distribution of Shares by Purchasers or
other parties) the Shares
- 3 -
18438-201/JTH/437684.6/070396
<PAGE> 4
Patent and Technology Transfer
and Stock Purchase Agreement
to be issued pursuant to Section 2(d) hereof, will be issued in full compliance
with the registration and prospectus delivery requirements of the U.S.
Securities Act of 1933, as amended (the "1933 Act") and the registration and
qualification requirements of the securities laws of the State of California.
4. REPRESENTATIONS AND WARRANTIES OF PURCHASER. Each Purchaser
represents and warrants to the Company, with respect to the Shares received by
such Purchaser, that:
(a) PURCHASE FOR OWN ACCOUNT FOR INVESTMENT. Purchaser is
purchasing the Shares for Purchaser's own account for investment purposes only
and not with a view to, or for sale in connection with, a distribution of the
Shares within the meaning of the Securities Act of 1933, as amended (the "1933
Act"). Purchaser has no present intention of selling or otherwise disposing of
all or any portion of the Shares and no one other than Purchaser has any
beneficial ownership of any of the Shares.
(b) ACCESS TO INFORMATION. Purchaser has had access to all
information regarding the Company and its present and prospective business,
assets, liabilities and financial condition that Purchaser reasonably considers
important in making the decision to purchase the Shares, and Purchaser has had
ample opportunity to ask questions of the Company's representatives concerning
such matters and this investment. Without limiting the foregoing, Purchaser
acknowledges receipt of the Company's 1995 Annual Report on Form 10-KSB, report
on Form 10-QSB for the period ending March 31, 1996 and Proxy Statement for the
1996 Annual Meeting of Company Stockholders.
(c) UNDERSTANDING OF RISKS. Purchaser is fully aware of: (i)
the highly speculative nature of the investment in the Shares; (ii) the
financial hazards involved; (iii) the lack of liquidity of the Shares and the
restrictions on transferability of the Shares (e.g., that Purchaser may not be
able to sell or dispose of the Shares or use them as collateral for loans); (iv)
the qualifications and backgrounds of the management of the Company; and (v) the
tax consequences of investment in the Shares.
(d) PURCHASER'S QUALIFICATIONS. Purchaser has consulted with
independent tax, legal and all other advisors he deems necessary before entering
into this Agreement. By reason of Purchaser's business or financial experience,
Purchaser is capable of evaluating the merits and risks of this investment and
has the ability to protect Purchaser's own interests in this transaction.
Purchaser is financially capable of bearing a total loss of this investment.
(e) NO GENERAL SOLICITATION. At no time was Purchaser
presented with or solicited by any publicly issued or circulated newspaper,
mail, radio, television or other form of general advertising or solicitation in
connection with the offer, sale and purchase of the Shares.
(f) COMPLIANCE WITH SECURITIES LAWS. Purchaser understands and
acknowledges that, in reliance upon the representations and warranties made by
Purchaser herein, the Shares are not being registered with the Securities and
Exchange Commission ("SEC") under the 1933 Act but instead are being issued
under an exemption or exemptions from
- 4 -
18438-201/JTH/437684.6/070396
<PAGE> 5
Patent and Technology Transfer
and Stock Purchase Agreement
the registration requirements of the 1933 Act which impose certain restrictions
on Purchaser's ability to transfer the Shares.
(g) RESTRICTIONS ON TRANSFER. Purchaser understands that
Purchaser may not transfer any Shares unless such Shares are registered under
the 1933 Act or unless, in the opinion of counsel to the Company, exemptions
from such registration requirements are available. Purchaser understands that
only the Company may file a registration statement with the SEC and that the
Company is under no obligation to do so with respect to the Shares other than as
set forth in Section 4, below. Purchaser has also been advised that exemptions
from registration may not be available or may not permit Purchaser to transfer
all or any of the Shares in the amounts or at the times proposed by Purchaser.
(h) RULE 144. In addition, Purchaser has been advised that SEC
Rule 144 promulgated under the 1933 Act, which permits certain limited sales of
unregistered securities, is not presently available with respect to the Shares
and, in any event, requires that the Shares be held for a minimum of two years,
and in certain cases three years, after they have been purchased and paid for
(within the meaning of Rule 144), before they may be resold under Rule 144.
(i) LICENSE AGREEMENT TERMINATED. The Assignors hereby agree
and acknowledge that that certain Agreement effective as of November 15, 1988 by
and among Waters Instruments, Inc., Collins and Wicomb, as amended by that
certain Amendment to Agreement dated December 15, 1989, is hereby terminated and
of no further force and effect, and represent that no other license or other
agreements are outstanding relating to the Technology.
(j) "ASSIGNOR WARRANTIES." The Assignor Warranties set forth
in Section 4 of the Assignment Agreement are hereby incorporated by reference.
5. REGISTRATION RIGHTS. The Company agrees to provide Purchasers
with reasonable "piggyback" registration rights with respect to the Shares, to
permit Purchasers to sell the Shares in connection with future public offerings
of the Company's common stock, to the extent feasible.
6. RESTRICTIVE LEGENDS AND STOP-TRANSFER ORDERS.
(a) LEGENDS. Each Purchaser understands and agrees that the
Company will place the legends set forth below or similar legends on any stock
certificate(s) evidencing the Shares received by such Purchaser, together with
any other legends that may be required by state or federal securities laws, the
Company's Restated Certificate of Incorporation or Bylaws, any other agreement
between such Purchaser and the Company or any agreement between such Purchaser
and any third party:
THE SECURITIES REPRESENTED HEREBY HAVE
NOT BEEN REGISTERED UNDER THE SECURITIES
ACT OF 1933, AS AMENDED (THE "ACT"), OR
UNDER THE SECURITIES LAWS OF CERTAIN
STATES. THESE SECURITIES ARE SUBJECT TO
- 5 -
18438-201/JTH/437684.6/070396
<PAGE> 6
Patent and Technology Transfer
and Stock Purchase Agreement
RESTRICTIONS ON TRANSFERABILITY AND RESALE AND MAY NOT
BE TRANSFERRED OR RESOLD EXCEPT AS PERMITTED UNDER THE
ACT AND APPLICABLE STATE SECURITIES LAWS, PURSUANT TO
REGISTRATION OR EXEMPTION THEREFROM. INVESTORS SHOULD BE
AWARE THAT THEY MAY BE REQUIRED TO BEAR THE FINANCIAL
RISKS OF THIS INVESTMENT FOR AN INDEFINITE PERIOD OF
TIME. THE ISSUER OF THESE SECURITIES MAY REQUIRE AN
OPINION OF COUNSEL IN FORM AND SUBSTANCE SATISFACTORY TO
THE ISSUER TO THE EFFECT THAT ANY PROPOSED TRANSFER OR
RESALE IS IN COMPLIANCE WITH THE ACT AND ANY APPLICABLE
STATE SECURITIES LAWS.
(b) STOP-TRANSFER INSTRUCTIONS. Each Purchaser agrees that,
in order to ensure compliance with the restrictions imposed by this Agreement,
the Company may issue appropriate "stop-transfer" instructions to its transfer
agent, if any, and if the Company transfers its own securities, it may make
appropriate notations to the same effect in its own records.
(c) REFUSAL TO TRANSFER. The Company will not be required
(i) to transfer on its books any Shares that have been sold or otherwise
transferred in violation of any of the provisions of this Agreement or (ii) to
treat as owner of such Shares, or to accord the right to vote or pay dividends,
to any purchaser or other transferee to whom such Shares have been so
transferred.
7. COMPLIANCE WITH LAWS AND REGULATIONS. The issuance and
transfer of the Shares will be subject to and conditioned upon compliance by the
Company and Purchaser with all applicable state and federal laws and regulations
and with all applicable requirements of any stock exchange or automated
quotation system on which the Company's common stock may be listed or quoted at
the time of such issuance or transfer.
8. SUCCESSORS AND ASSIGNS. The Company may assign any of its
rights under this Agreement. This Agreement will be binding upon and inure to
the benefit of the successors and assigns of the Company. Subject to the
restrictions on transfer herein set forth, this Agreement will be binding upon
each Purchaser and such Purchaser's heirs, executors, administrators, successors
and assigns. If the Company assigns all or substantially all of its rights under
this Agreement, then all remaining Shares not previously issued to the
Purchasers shall automatically vest and be issued to the Purchasers by the
Company.
9. GOVERNING LAW; SEVERABILITY. This Agreement will be governed
by and construed in accordance with the internal laws of the State of
California, excluding that body of laws pertaining to conflict of laws. If any
provision of this Agreement is determined by a court of law to be illegal or
unenforceable, then such provision will be enforced to the maximum extent
possible and the other provisions will remain fully effective and enforceable.
- 6 -
18438-201/JTH/437684.6/070396
<PAGE> 7
10. NOTICES. Any notice required or permitted hereunder will be given
in writing and will be deemed effectively given upon personal delivery, three
(3) days after deposit in the United States mail by certified or registered mail
(return receipt requested), one (1) business day after its deposit with any
recognized express courier (prepaid), or one (1) business day after transmission
by telecopier, addressed to the other party at its address (or facsimile number,
in the case of transmission by telecopier) as shown below its signature to this
Agreement, or to such other address as such party may designate in writing from
time to time to the other party.
11. FURTHER INSTRUMENTS. The parties agree to execute such further
instruments and to take such further action as may be reasonably necessary to
carry out the purposes and intent of this Agreement.
12. HEADINGS. The captions and headings of this Agreement are
included for ease of reference only and will be disregarded in interpreting or
construing this Agreement. All references herein to Sections will refer to
Sections of this Agreement.
13. ENTIRE AGREEMENT. This Agreement, together with all its Exhibits,
constitutes the entire agreement and understanding of the parties with respect
to the subject matter of this Agreement, and supersedes all prior understandings
and agreements, whether oral or written, between the parties hereto with respect
to the specific subject matter hereof, specifically including the letter
agreements among the parties dated February 14, 1996 and May 21, 1996.
14. COUNTERPARTS. This Agreement may be executed in counterparts,
each of which shall be deemed an original, but all of which together shall
constitute one and the same instrument.
15. TITLE TO SHARES. The exact spelling of the name(s) under and
manner in which a Purchaser will take title to such Purchaser's Shares is set
forth on Exhibit 3.
16. ARBITRATION. Any controversy or claim arising out of this Agreement
shall be settled by arbitration in accordance with the Commercial Arbitration
Rules of the American Arbitration Association in San Francisco, California, and
judgment upon the award rendered by the arbitrator(s) may be entered in any
court having jurisdiction thereof. There shall be reasonable right to discovery
under the California Code of Civil Procedure. The prevailing party shall be
entitled to costs and reasonable attorneys' fees.
REST OF PAGE INTENTIONALLY LEFT BLANK
- 7 -
18438-201/JTH/437684.6/070396
<PAGE> 8
Patent and Technology Transfer
and Stock Purchase Agreement
IN WITNESS WHEREOF, the Company has caused this Agreement to be
executed in triplicate by its duly authorized representative and each Purchaser
has executed this Agreement in triplicate, as of the Effective Date.
COMPANY PURCHASERS
LXR BIOTECHNOLOGY INC.
By: /s/ L. David Tomei /s/ Geoffrey M. Collins
------------------------------- ----------------------------------
L. David Tomei, Ph.D., President & Geoffrey M. Collins
Chief Executive Officer
Address: 1401 Marina Parkway Address: 14 Leeward Road
Richmond, CA 94804-3746 Belvedere, CA 94920
Fax: (510) 412-9109 Fax:(____)
/s/ Winston N. Wicomb
----------------------------------
Winston N. Wicomb
Address: 138 Yolo Street
Corte Madera, CA 94925
Fax:(415) 885-8607
SIGNATURE PAGE TO
TECHNOLOGY TRANSFER AND STOCK PURCHASE AGREEMENT
- 8 -
18438-201/JTH/437684.6/070396
<PAGE> 9
Patent and Technology Transfer
and Stock Purchase Agreement
LIST OF EXHIBITS
----------------
Exhibit 1: Assignment Agreement
Exhibit 2: Consent of Spouse
Exhibit 3: Title to Shares
Exhibit 4: Allocation Schedule: Allocation of Shares Between Purchasers
Exhibit 5: Wicomb Employment Agreement
Exhibit 6: Collins Science Advisory Board Consulting Agreement
- 9 -
18438-201/JTH/437684.6/070396
<PAGE> 10
EXHIBIT 1
ASSIGNMENT AGREEMENT
This Assignment Agreement (this "Agreement") is made and entered into effective
as of August 8, 1996 by and among LXR Biotechnology Inc., a Delaware corporation
(the "Company"), Geoffrey M. Collins ("Collins") and Winston N. Wicomb
("Wicomb"). Collins and Wicomb are hereinafter sometimes referred to
individually as "Assignor" and together as "Assignors."
R E C I T A L S
A. Assignors are the co-inventors and co-owners of the Technology
(as defined below).
B. Assignors desire to assign and transfer to the Company all of
Assignors' right, title and interest in and to the Technology and other related
rights in exchange for the Company's issuance to Assignors of a total of up to
300,000 shares of the Company's common stock, $0.0001 par value per share
("Common Stock"), and certain other consideration, as described in the Patent
and Technology Transfer and Stock Purchase Agreement among the parties dated of
even date herewith (the "Stock Purchase Agreement").
NOW THEREFORE, the parties hereby agree as follows:
1. CERTAIN DEFINITIONS. As used herein, the following terms will
have the meanings set forth below:
1.1 Technology. The term "Technology" means that invention
disclosed in United States Patent No. 4,938,961, titled "Organ Preservation
Solution containing Pokyethylene (sic) Glycol and Method of Performing
Cardioplegia," and all technology, trade secrets and know-how related thereto.
1.2 Derivative. The term "Derivative" means: (a) any
derivative work of the Technology (as defined in Section 101 of the U.S.
Copyright Act); (b) all improvements, modifications, alterations, adaptations,
enhancements and new versions of the Technology ("Technology Derivatives"); and
(c) all technology, inventions, products or other items that, directly or
indirectly, incorporate, or are derived from, any part of the Technology or any
Technology Derivative.
1.3 Intellectual Property Rights. The term "Intellectual
Property Rights" means, collectively, all worldwide patents (including but not
limited to United States Patent No. 4,938,961), patent rights, copyrights,
copyright registrations, moral rights, trade names, trademarks, service marks
and registrations and applications therefor, trade secrets, know-how, mask work
rights, rights in trade dress and packaging, goodwill and all other intellectual
property rights and proprietary rights relating in any way to the Technology,
any Derivative or any Embodiment, whether arising under the laws of the United
States of America or the laws of any other state, country or jurisdiction.
<PAGE> 11
Collins/Wicomb
Assignment Agreement
1.4 Embodiment. The term "Embodiment" means all
documentation, drafts, papers, designs, schematics, diagrams, models,
prototypes, source and object code (in any form or format and for all hardware
platforms), computer-stored data, diskettes, manuscripts and other items
describing all or any part of the Technology, any Derivative, any Intellectual
Property Rights or any information related thereto or in which all of any part
of the Technology, any Derivative, any Intellectual Property Right or such
information is set forth, embodied, recorded or stored.
1.5 Assigned Assets. The term "Assigned Assets" refers to
the Technology, all Derivatives, all Intellectual Property Rights and all
Embodiments, collectively.
2. ASSIGNMENT. Assignors acknowledge that as of the date hereof,
upon the Effective Date (as defined in the Stock Purchase Agreement), Assignors
have received from the Company a total of 37,500 shares of Common Stock and
$98,000 in cash. In consideration of the foregoing and the Company's agreement
to issue to Assignors up to an additional 262,500 shares of Common Stock, as set
forth in the Stock Purchase Agreement, Assignors hereby forever sell, assign,
transfer, release and convey to the Company, and its successors and assigns,
Assignors' entire right, title and interest in and to each and all of the
Assigned Assets. In furtherance thereof, Assignors hereby deliver to the Company
a Joint Assignment in the form of Exhibit A attached hereto, duly executed by
Assignors.
3. DELIVERY. The Assignors agree to deliver all Embodiments of
all Assigned Assets to the Company at a location designated by the Company no
later than August __, 1996.
4. ASSIGNOR WARRANTIES. Each Assignor represents and warrants to
the Company that, except only for the interest of the other Assignor, such
Assignor is the sole owner, inventor and/or author of, and that such Assignor
owns, and can grant exclusive right, title and interest in and to, each of the
Assigned Assets without the consent of any other party, and that none of the
Assigned Assets is currently subject to any dispute, claim, prior license or
other agreement, assignment, lien or rights of any third party, or any other
rights that might interfere with the Company's use, or exercise of ownership of,
any Assigned Assets. Each Assignor further represents and warrants to the
Company that the Assigned Assets are free of any claim of any prior employer of
such Assignor or any school, university or other institution such Assignor
attended, and that such Assignor is not aware of any claims by any third party
to any rights of any kind in or to any of the Assigned Assets other than the
claims of the other Assignor.
5. FURTHER ASSURANCES. Each Assignor further agrees, promptly upon
request of the Company, or any of its successors or assigns, to execute and
deliver, without further compensation of any kind, any power of attorney,
assignment, application for copyright, patent or other intellectual property
right protection, or any other papers which may be necessary or desirable to
fully secure to the Company, its successors and assigns, all right, title and
interest in and to each of the Assigned Assets, and to cooperate and assist in
the prosecution of any opposition proceedings involving said rights and any
adjudication of the same. Further, each Assignor agrees never to assert any
claims, rights or moral rights in or to any of the Assigned Assets. The
Assignors' obligations under this Section 5 shall be suspended during any period
of time that the Company is in material breach of the Stock Purchase Agreement.
2
18438-201/JTH/437688.7/073196
(ver 8/080796)
<PAGE> 12
Collins/Wicomb
Assignment Agreement
6. INDEMNITY.
6.1 Indemnity by Assignors. Assignors agree, severally, to indemnify
and hold the Company harmless from and against one-half of any loss, damages or
expense (including without limitation reasonable attorneys' fees) incurred by
the Company in connection with any claim, suit or other proceeding in which a
third party asserts (i) any claim to any right, title, license or other interest
in or to any Assigned Asset, or (ii) any claim that, if true, would be
inconsistent with any representation made by Assignors in Section 4 above;
provided, however, that each Assignor's liability under this Agreement shall be
limited to $500,000 unless such loss, damages or expense arises from matters of
which an Assignor was aware on or prior to the date of this Agreement and has
not disclosed to the Company as of the date hereof.
6.2 Indemnity by the Company. The Company agrees to indemnity the
Assignors for any third party claims by reason of claims or lawsuits filed
claiming injury or damages arising from the use, sale or distribution of any
product based on the Technology (except claims based on intellectual property
issues). In the event of the notice of any such third party claims, the
Assignors shall advise the Company of such claims or action. If the Company
fails to defend such action on their behalf, the Assignors may retain their own
counsel at the Company's expense. The Company shall maintain reasonable
liability insurance and add the Assignors as additional insureds. The Company,
on request, will furnish the Assignors with evidence of such insurance.
7. COUNTERPARTS; GOVERNING LAW. This Agreement may be executed in any
number of counterparts, each of which will constitute an original, and all of
which will together constitute this one Agreement. This Agreement will be
governed exclusively by the internal laws of the State of California.
8. ENTIRE AGREEMENT. This Agreement and the Stock Purchase Agreement
constitute the entire understanding and agreement between Assignors and the
Company regarding the subject matter of such agreements, and supersede any and
all other agreements or understandings of the parties regarding such subject
matter.
IN WITNESS WHEREOF, the undersigned have executed this Agreement
effective as of the date and year first above written.
COMPANY ASSIGNORS
LXR BIOTECHNOLOGY INC.
By: /s/ L. David Tomei /s/ Geoffrey M. Collins
-------------------------------- -----------------------------
L. David Tomei, Ph.D., President Geoffrey M. Collins
and Chief Executive Officer
/s/ Winston N. Wicomb
-----------------------------
Winston N. Wicomb
Exhibit A: Joint Assignment
3
18438-201/JTH/437688.7/073196
(ver 8/080796)
<PAGE> 13
EXHIBIT A
ASSIGNMENT
JOINT
THIS ASSIGNMENT, by Geoffrey M. Collins and Winston N. Wicomb
(hereinafter referred to as the assignors), residing at 14 Leeward Road,
Belvedere, California 94920 and 138 Yolo Street, Corte Madera, California 94925,
respectively, witnesseth:
WHEREAS, said assignors have invented certain new and useful
improvements in organ preservation solutions, in the form of the inventions
disclosed in United States Patent No. 4,938,961, titled "Organ Preservation
Solution containing Pokyethylene (sic) Glycol and Method of Performing
Cardioplegia" (the "961 Patent"); and
WHEREAS, LXR Biotechnology Inc., a corporation duly organized under and
pursuant to the laws of Delaware and having its principal place of business at
1401 Marina Way South, Richmond, California 94804 (hereinafter referred to as
the assignee), is desirous of acquiring the entire right, title and interest in
and to said inventions and the 961 Patent, and in and to any application for
Letters Patent to be submitted in connection therewith and any Letters Patent,
United States or foreign, to be obtained therefor and thereon:
NOW, THEREFORE, in consideration of One Dollar ($1.00) and other good
and sufficient consideration set forth in that certain Patent and Technology
Transfer and Stock Purchase Agreement among the assignors and the assignee, the
receipt of which is hereby acknowledged, said assignors have sold, assigned,
transferred and set over, and by these presents do sell, assign, transfer and
set over, unto said assignee, its successors, legal representatives and assigns,
as co-owners in undivided one-half interest, respectively, the entire right,
title and interest in and to the above-mentioned inventions, the 961 Patent, any
and all applications for Letters Patent to be submitted in connection therewith
and any Letters Patent, in the United States of America and all foreign
countries, which may be granted therefor and thereon, and in and to any and all
divisions, continuations and continuations-in part of said applications, or
reissues or extensions of said 961 Patent or Letters Patent, and all rights
under the International Convention for the Protection of Industrial Property,
the same to be held and enjoyed by said assignee, for its own use and the use of
its successors, legal representatives and assigns, to the full end of the term
or terms for which said 961 Patent or Letters Patent are or may be granted, as
fully and entirely as the same would have been held and enjoyed by the
assignors, had this sale and assignment not been made.
AND for the same consideration, said assignors hereby covenant and
agree to and with said assignee, its successors, legal representatives and
assigns, that, at the time of execution and delivery of these presents, said
assignors are the sole and lawful owners of the entire right, title, interest in
and to said inventions and the 961 Patent above-mentioned, and that the same are
unencumbered and that said assignors have good and full right and lawful
authority to sell and convey the same in the manner herein set forth.
<PAGE> 14
AND for the same consideration, said assignors hereby covenant and
agree to and with said assignee, its successors, legal representatives and
assigns, that said assignors will, whenever counsel of said assignee, or the
counsel of its successors, legal representative and assigns, shall advise that
any proceeding in connection with said inventions or 961 Patent, or any
proceeding in connection with any application for Letters Patent or any Letters
Patent for said inventions in any country, including interference proceedings,
is lawful and desirable, or that any division, continuation or
continuation-in-part of any application for Letters Patent or any reissue or
extension of the 961 Patent or any Letters Patent, to be obtained thereon, is
lawful and desirable, sign all papers and documents, take all lawful oaths, and
do all acts necessary or required to be done for the procurement, maintenance,
enforcement and defense of the 961 Patent or any Letters Patent for said
inventions, without charge to said assignee, its successors, legal
representatives and assigns, but at the cost and expense of said assignee, its
successors, legal representatives and assigns;
This Assignment may be executed in counterparts, each of which will be
deemed an original, but all of which together will constitute one and the same
instrument.
8/8/96 /s/ Geoffrey M. Collins
- ---------------- --------------------------------------
Date Geoffrey M. Collins
8/8/96 /s/ Winston N. Wicomb
- ---------------- --------------------------------------
Date Winston N. Wicomb
State of California
-------------------------------
County of San Francisco
-----------------------------
On ___August 8,_____, 1996, before me, __Edward Joseph
Tinsley________, personally appeared ______Winston N. Wicomb and Geoffrey M.
Collins_________, personally known to me or proved to me on the basis of
satisfactory evidence to be the person whose name is subscribed to the within
instrument and acknowledged to me that he/she executed the same in his/her
authorized capacity, and that by his/her signature on the instrument the person,
or the entity upon behalf of which the person acted, executed the instrument.
Witness my hand and official seal.
/s/ Edward Joseph Tinsley
-------------------------------
Notary Public
Notary's Seal
- 2 -
18438-00201/JTH/437692.5/070396
<PAGE> 15
EXHIBIT 2
CONSENT OF SPOUSE
I, the undersigned, am the spouse of ______________________________
("Purchaser"). I have read and hereby consent to and approve all the terms and
conditions of the Patent and Technology Transfer and Stock Purchase Agreement
(the "Agreement") dated July ______, 1996 among LXR Biotechnology Inc., a
Delaware corporation (the "Company"), Purchaser and another party, pursuant to
which Purchaser has purchased shares of the Company's common stock
(collectively, the "Shares") and received certain other consideration (the
"Other Consideration"), and that certain Assignment Agreement ("Assignment
Agreement") executed by Purchaser in connection with the Agreement.
In consideration of the Company granting my spouse the right to
purchase the Shares and receive the Other Consideration under the Agreement, I
hereby agree to be irrevocably bound by all the terms and conditions of the
Agreement and further agree that any community property interest I may have in
the Shares, the Other Consideration and all property assigned by Purchaser to
the Company under the Assignment Agreement will be similarly bound by the
Agreement.
I hereby appoint Purchaser as my attorney-in-fact, to act in my name,
place and stead with respect to any amendment of the Agreement and the
Assignment Agreement.
Dated: July ______, 1996
_______________________________
Signature of Spouse [Sign Here]
_______________________________
Name of Spouse [Please Print]
<PAGE> 16
EXHIBIT 3
TITLE TO SHARES
I, the undersigned ("Purchaser"), desire to take title to the Shares as follows:
[ ] Individually, as separate property
[ ] Husband and wife, as community property
[ ] Joint Tenants
[ ] Alone or with spouse as trustee(s) of the
following trust (including date):_____________________________
______________________________________________________________
______________________________________________________________
[ ] Other; please specify:________________________________________
______________________________________________________________
The exact spelling of the name(s) under which Purchaser will take title to the
Shares is:
______________________________________________________________
______________________________________________________________
Purchaser's social security number is:__________________________________________
PURCHASER
_________________________________
(signature)
_________________________________
(print name)
<PAGE> 17
EXHIBIT 4
ALLOCATION SCHEDULE
ALLOCATION OF SHARES BETWEEN PURCHASERS
<TABLE>
<CAPTION>
Total No. of Shares Shares Issuable Shares Issuable
------------------- --------------- ---------------
Milestone to be Issued to Collins to Wicomb
--------- ------------ ---------- ---------
<S> <C> <C> <C>
January 1, 1997 37,500 18,750 18,750
January 1, 1998 75,000 37,500 37,500
January 1, 1999 75,000 37,500 37,500
First Commercial 75,000 37,500 37,500
Sale and Shipment to
Customer in U.S.
TOTAL 262,500 131,250 131,250
======= ------- -------
</TABLE>
<PAGE> 18
EXHIBIT 5
EMPLOYMENT AND PROPRIETARY INFORMATION AGREEMENT
1. PARTIES
1.1 Company. LXR Biotechnology Inc., a Delaware corporation
("Company"), is engaged in the business of research, development, marketing and
sales of human pharmaceuticals based upon biotechnology.
1.2 Employee. Winston N. Wicomb ("Employee") desires to be employed
by Company.
2. EFFECTIVE DATE OF EMPLOYMENT
Company and Employee agree to each and every term of this Employment
and Proprietary Information Agreement (this "Agreement"). The first day of
employment (the "Effective Date") is July 1, 1996.
3. DUTIES AND PERFORMANCE
3.1 Employee's employment position with the Company will be Director
of Pre- Clinical Affairs at the outset of employment. Employee will have such
duties and responsibilities as are appropriate for such position. It is
contemplated that Employee will work at the Company on approximately a 50%
basis, and that for the remaining 50% of Employee's work time he will work at
the California Pacific Medical Center ("CPMC") on a project funded and approved
by the Company. Employee shall keep Company apprised on a regular basis of the
nature and progress of his work at CPMC.
3.2 Employee must devote reasonable time and efforts during the
Company's normal business hours to the performance of the duties as indicated in
paragraph 3.1. Employee will report to the President or Chief Financial Officer
of the Company and must conform to the rules and regulations of Company, as of
the date of this document, or as amended by mutual agreement, including those
referred or described in an employee handbook or practices and procedures manual
or similar document. Neither an employee handbook nor any other manual
constitutes a part of this Agreement, but are meant only as guidelines for
management and may be altered at any time without notice.
3.3 Employee will work for the Company and not provide services of any
type for any other person or entity, except as provided in 3.1 and this
paragraph. If Employee wishes, however, to provide substantial services, of any
type, to any other third party for compensation of any type, Employee must
submit a written request to Company stating (i) the total time commitment
involved; (ii) when that time commitment will be fulfilled; (iii) the identity
of the third party; (iv) an explanation of the scope and nature of the services;
and (v) such other information or details as Company may request. Company will
approve the request if Company determines that such services (i) will not
detract from the ability of Employee to perform under this Agreement; (ii) will
not benefit, directly or indirectly, a competitor or potential competitor of
Company; and (iii) do not in any way involve any products or services which
compete, directly
<PAGE> 19
or indirectly, with the products and services that Company contemplates offering
in the future. Any approval will be limited in scope and apply only to
Employee's written request. All services rendered by Employee, other than those
authorized in writing by Company under the terms of this paragraph, shall be
performed solely on behalf of Company or related business entities, and all
proceeds resulting therefrom shall be the sole property of Company or such
related business entities.
4. TERM AND TERMINATION
4.1 INITIAL TERM. The initial term of this Agreement shall commence as
of the Effective Date of this Agreement set forth above and shall continue for a
period of one (1) year of the Effective Date.
4.2 RIGHT TO EXTEND. At the end of the initial one (1) year term,
provided the Agreement has not previously been terminated, the Agreement is
automatically renewed on a month to month basis.
4.3 TERMINATION WITHOUT CAUSE. Either party may terminate this
Agreement, without cause, by giving the other party notice at least thirty (30)
days in advance of the date of termination. In the event the Company terminates
this Agreement without cause then Employee shall be entitled to severance
compensation set forth below: (a) SEVERANCE COMPENSATION. Subject to provisions
of paragraph 4.3(b) below, Employee shall be entitled to severance compensation
in an amount equal to three (3) months at the Employee's monthly base salary on
the date of notice of termination. (b) OFFSET FROM OTHER BENEFITS. Any payments
made to the Employee in the event of an involuntary termination of employment
under the provisions of paragraph 4.3(a) will be decreased by the amount of any
payments received under entitlements from any other Company (LXR) severance or
layoff plan, program or arrangement, currently in place or hereafter adopted, in
which Employee is entitled to share or participate as an employee of the
Company.
4.4 TERMINATION FOR CAUSE. The Company may terminate this Agreement
for cause at any time effective immediately upon delivery of written notice,
Cause shall consist of any of the following:
(a) material breach of any of the
provisions of this Agreement;
(b) willful failure to reasonably perform normally assigned
duties;
(c) willful misconduct which has a material and adverse effect on
the Company's reputation or profitability;
(d) conviction of a felony.
In order for the Company to terminate for cause, the Company must first give
Employee written notice of the basis of cause and, if curable, thirty (30) days
to cure such cause. If such cause has
2
<PAGE> 20
not been fully remedied within the thirty-day period, then the termination shall
be effective automatically on the thirtieth day following delivery of the
notice. If the cause is not curable, then no notice need be given, and
termination shall be effective as of the date of written notice of termination.
If the Company terminates this Agreement for cause, it shall thereafter not be
responsible for any additional payments of salary or provisions of benefits
under this Agreement except the salary and benefits otherwise due as of the date
of termination.
4.5 TERMINATION ON DEATH. This Agreement shall terminate immediately
upon Employee's death, if not terminated earlier. The Company shall not be
responsible for additional payments of salary or provision of benefits under
this Agreement after Employee dies except as are owed (to employee estate) with
respect to employment prior to death and continued issuance of the common stock
per the terms of the Patent and Technology Transfer and Stock Purchase Agreement
dated July __, 1996 (the "Transfer Agreement").
4.6 TERMINATION OF DISABILITY. If Employee is unable to perform the
services required by this Agreement for a period of ninety (90) days within any
calendar year as a result of incapacity due to physical or mental illness or
injury, the Company may terminate this Agreement and shall pay Employee
severance compensation in accordance with paragraph 4.3(a).
5. COMPENSATION EXPENSES AND FRINGE BENEFITS
5.1 For all employment services rendered by Employee during the term
of this Agreement, Company shall pay Employee a salary of $4166.67 per month
plus normal employee benefits including medical coverage for employee and his
dependents. Additionally, the Company will provide funding to CPMC to provide
Employee with an additional $4166.67 of salary per month from CPMC.
5.2 In addition to the compensation provided above, and subject to
review of management, Company will pay the reasonable expenses incurred and
promptly reported to Company by Employee in furtherance of and in connection
with Company's business under Company's established policies.
6. ASSIGNABILITY
Neither party shall have the right to assign this Agreement or any of
its rights or obligations without the consent of the other party; provided,
however, that upon the sale of all or substantially all of the assets, business
and goodwill of Company or upon the merger or consolidation of Company with
another corporation or corporations, then, this Agreement may be assigned to the
purchaser of such assets, business and goodwill, or to the surviving entity of
any such aforementioned merger or consolidation, as the case may be, in the same
manner and to the same extent as though such purchaser or surviving entity were
Company, with effective date for initial term becoming that of the date of such
acquisition or transition.
7. CONFIDENTIALITY
3
<PAGE> 21
7.1 Employee shall keep confidential, and shall not at any time during
or after Employee's employment, disclose to anyone outside of Company any trade
secrets, confidential or proprietary information, confidential or proprietary
knowledge, or confidential or proprietary data of Company relating to products,
processes, know-how, designs, formulae, test data, customer lists, business
plans, marketing plans and strategies, or pricing strategies, or any
documentation relating thereto, or any other subject matter pertaining to any
business of Company or any of its clients, customers, consultants, licensees,
distributors, partners or affiliates ("Confidential Material"), which Employee
may produce, obtain, learn about, or otherwise acquire during Employee's
employment, except as herein provided. Employee shall not deliver, reproduce or
in any way allow any such Confidential Material to be delivered to or used by
any third parties without specific written consent of a duly authorized
representative of Company.
7.2 Company's agreements with other persons or with the U.S.
government, or its agencies, may include agreements that impose obligations or
restrictions regarding inventions that occur in connection with work relating to
such an agreement, or regarding the confidential nature of work pursuant to such
an agreement. Employee agrees to be bound by all such lawful obligations and
restrictions, and exert reasonable business efforts to satisfy the obligations
of Company.
7.3 If this Agreement is terminated for any reason, Employee shall
promptly surrender and deliver to Company all Confidential Materials. Employee
will not retain any description or other document that contains or relates to
any Confidential Material that Employee may produce, obtain or otherwise learn
about during employment with Company. Employee agrees to sign, date and return
the Termination Certificate in the form attached as Exhibit A on Employee's last
day of employment with Company.
8. ASSIGNMENT OF INVENTIONS
Employee assigns and transfer to Company Employee's entire right, title and
interest in and to all inventions including, but not limited to, ideas,
improvements, designs and discoveries (Inventions"), whether or not patentable
and whether or not reduced to practice, made or conceived by Employee (whether
made solely by Employee or jointly with others) during the term of Employee's
employment with Company which relate in any manner to the actual or demonstrably
anticipated business, work or research and development of Company or its
subsidiaries, or result from or are suggested by any task assigned to Employee
or any work performed by Employee for or on behalf of Company or its
subsidiaries or that involve the use of any Company equipment, facilities, trade
secrets or information. It is acknowledged that the Company is to own such
Inventions, regardless of whether such Invention is made at the Company, CPMC or
otherwise, and Employee hereby represents to the Company that Employee has not
entered into any agreement with CPMC or any other person providing them with any
rights to Employee's Inventions, that the Employee will not do so without the
written approval of the Company, and that neither CPMC nor any other person has
or will have any rights in or to such Inventions. All inventions are the sole
property of Company; provided, however, that this Agreement does not require
assignment or an invention which qualified fully for protection under Section
2870 of the California Labor Code ("Section 2870"), which provides as follows:
4
<PAGE> 22
(a) Any provision in an employment agreement which provides
that an employee shall assign any of his or her rights in an invention to his or
her employer shall not apply to an invention that the employee developed
entirely on his or her own time and without using the employer's equipment,
supplies, facilities or trade secrets information except for those inventions
that either;
(1) Relate at the time of conception or reduction to
practice of the invention to the employer's business, or actual or demonstrably
anticipated research or development of the employer.
(2) Result from any work performed by the employee for the
employer.
(b) To the extent a provision in an employment agreement purports
to require an employee to assign an invention otherwise excluded from being
required to be assigned under subdivision (a), the provision is against the
public policy of this state and is unenforceable.
9. DISCLOSURE OF INVENTIONS; PATENTS, COPYRIGHTS, AND MASK WORK RIGHTS.
Employee agrees that in connection with any Invention:
(a) to keep and maintain adequate and current written
records of all inventions made by Employee (in the form of notes, sketches,
drawings and other form of specified by Company) while employed by Company.
These records shall be available to Company and shall be and remain the sole
property of Company at all times. Employee will disclose such Inventions
promptly in writing to Employee's immediate supervisor at Company, with a copy
to Company President, whether or not Employee believes the inventions is
protected by Section 2870. Such disclosure shall be received in confidence by
Company. Within 30 days after receipt of such disclosure, Company shall respond
to Employee specifying that Company either (i) claims that the Invention is an
assignable invention (as defined below in paragraph 9(b)), (ii) relinquishes any
claim to the Invention or (iii) requires further or more detailed disclosure to
assess its rights to the Invention under this Agreement. In the case of clause
(iii) above, Company shall permit Employee time during normal business hours
reasonably necessary to prepare a more detailed disclosure; and Company shall
provide an additional response as described in this paragraph 9(a) within 30
days after receipt by Company of such further or more detailed disclosure;
(b) upon request, to promptly execute a written assignment of
title to Company for any Invention required to be assigned by Section 8
("assignable invention") and Employee will preserve any such assignable
invention as Confidential Material;
(c) upon request, to assist Company or its nominee (at its
expense) during and at any time subsequent to Employee's employment in every
reasonable way to obtain for Company's or its nominee's benefit, patents,
copyrights, mask work rights and other statutory rights ("Statutory Rights") for
such assignable inventions in any and all countries, which inventions shall be
and remain the sole and exclusive property of Company or its nominee
5
<PAGE> 23
whether or not patented, copyrighted or the subject of a mask work right.
Employee shall execute such papers and perform such lawful acts as Company deems
necessary to exercise all rights, title and interest in such Statutory Rights;
and
(d) to execute and deliver to Company or its nominee upon request
and at its expense all documents, including applications for and assignments of
Statutory Rights to be issued therefore, as Company determines are necessary or
desirable to apply for and obtain Statutory Rights on such assignable inventions
in any and all countries and/or to protect the interest of Company or its
nominee in Statutory Rights and to vest title thereto in Company or its nominee.
10. EMPLOYEE'S INVENTIONS PRIOR TO THIS AGREEMENT
All inventions, if any, patented or unpatented, which Employee made prior to
employment by Company, are excluded from the scope of this Agreement other than
those transferred pursuant to the Transfer Agreement. To preclude any possible
uncertainty, Employee has set forth on Exhibit B attached hereto a complete list
of all of Employee's prior inventions, including numbers of all patents and
patent applications, and a brief description of all unpatented inventions which
are not the property of a previous employer. Employee represents and covenants
that the list is complete and that, if no items are on the list, Employee has no
such prior inventions. Employee shall notify Company in writing before Employee
makes any disclosure or performs any work on behalf of Company which appears to
threaten or conflict with proprietary rights Employee claims in any invention or
idea. In the event of the failure to give such notice, Employee shall make no
claim against Company with respect to any such inventions or ideas.
11. TRADE SECRETS ACQUIRED PRIOR TO THIS AGREEMENT
Employee represents that Employee's performance of this Agreement and as an
employee of Company does not and will not breach any agreement to keep in
confidence proprietary information, knowledge or data acquired by Employee in
confidence or in trust prior to employment with Company, and Employee will not
disclose to Company, or induce Company to use, any confidential or proprietary
information or material belonging to any previous employer or others. Employee
agrees not to enter into any agreement either written or oral in conflict
herewith.
12. GENERAL
12.1 Governing Law. The validity, performance and all other matters
pertaining to this Agreement shall be governed by California law as it would
apply to agreements between California corporation and an employee in California
for services to be rendered within California.
12.2 Non waiver. The waiver or failure of any party to enforce at any time
in any of the provisions hereof shall not be construed to be a waiver of the
right of such party thereafter to enforce any such provision.
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<PAGE> 24
12.3 Severability. If any covenant, agreement, term or provision of this
Agreement of the application thereof to any situation or circumstance shall be
invalid or unenforceable, the remainder of this Agreement or the application of
such covenant, agreement, term or provision to situations or circumstances other
than those as to which it is invalid or unenforceable shall not be affected; and
each covenant, agreement, term or provision of this Agreement shall be valid and
enforceable to the fullest extent permitted by applicable law. In such event,
the parties shall negotiate in good faith to substitute for any such invalid or
unenforceable provision a valid and enforceable provision which most nearly
effects the parties' original intent in entering into this Agreement.
12.4 Notices. Notices under this Agreement shall be sufficient only if
mailed by certified or registered United States mail, return receipt requested,
or personally delivered, to the parties at their addresses set forth below or as
amended by notice pursuant to this subsection. Notice by mail shall be deemed
received two (2) days after deposit.
12.5 Entire Agreement. This Agreement contains the entire agreement of the
parties with regard to employment capacity, and supersedes all proposals, oral
or written, all negotiations, conversations or discussions between or among the
parties relating to this Agreement and all past course of dealing or industry
custom, with the exception of those documents listed below. Employee has not
entered into this Agreement or employment relationship in reliance on any
representations other than those contained herein. This Agreement may be
modified only by a writing signed by Employee and the President or Chief
Financial Officer of Company.
Other pertinent documents:
The Transfer Agreement
IN WITNESS WHEREOF, the parties hereto have executed this Agreement as
of the date and year first above written.
COMPANY: EMPLOYEE:
LXR Biotechnology Inc. Winston N. Wicomb
By: /s/ L. David Tomei Address: 138 Yolo Street
---------------------------- ----------------------------
Print Name: L. David Tomei Corte Madera, CA 94925
------------------- -------------------------------------
Title: President Print Name: /s/ Winson N. Wicomb
------------------------- -------------------------
7
<PAGE> 25
EXHIBIT A
TERMINATION CERTIFICATION
This is to certify that: (a) I do not have in my possession, nor have I
failed to return, any devices, records, data, notes, reports, proposals, lists,
correspondence, specifications, drawings, blueprints, sketches, materials,
equipment, other documents or property, or reproductions of any of these items
belonging to Company; (b) I have complied with all terms of Company's Employment
and Proprietary Information Agreement signed by me; and (c) I will preserve as
confidential all trade secrets, confidential knowledge, data or other
proprietary information relating to products, processes, know-how, designs,
formulas, developmental or experimental work, computer programs, data bases,
other original works of authorship, customer lists, business plans, financial
information or other subject matter pertaining to any business of Company or any
of its clients, consultants or licenses.
Date:
------------------------------
- -----------------------------------
(Signature)
- -----------------------------------
(Type/Print Name)
<PAGE> 26
EXHIBIT B
LIST OF PRIOR INVENTIONS AND OTHER DEVELOPMENT
Title Date Identifying Number or
Brief Description
Memoirs 1994-present Autobiography
Fizz Bottle 1995-present Device that maintains
carbonation in soda.
Portable Langendorff 1994-1996 Portable device to test hearts
at 37(degree) C.
Air-lift Pump 1981-1982 Perfusion device used to
preserve hearts at 0(degree)-
4(degree) C.
Microperfusion device 1989-1992 Low-flow heart preservation
machine
Wine bottle cartridge 1996-present Device to protect against
oxidation of alcohol.
Portable infusion device 1996-present Patient infusion without
confinement to bed.
<PAGE> 27
EXHIBIT 6
LXR BIOTECHNOLOGY INC.
SCIENCE ADVISORY BOARD CONSULTING AGREEMENT
This SCIENCE ADVISORY BOARD CONSULTING AGREEMENT (the
"Agreement") is made as of April 1, 1996 (the "Effective Date") by and between
LXR Biotechnology Inc., a Delaware corporation (the "Company"), and Geoffrey M.
Collins ("Consultant").
R E C I T A L S
The Company desires to retain Consultant as a member of the
Science Advisory Board of the Company and in a consulting capacity as described
in this Agreement, and Consultant is willing to so act.
NOW, THEREFORE, Consultant and the Company agree as follows:
1. DESCRIPTION OF SERVICES. The Company hereby retains
Consultant as a member of the Science Advisory Board of and consultant to the
Company, and Consultant hereby agrees to act in such capacities and to perform
such services as are reasonably requested by the Company (the "Services"). The
Services are expected to focus on the area of research and development of
preservation solutions for use in organ transplantation and cardioplegia. The
Company anticipates that Consultant will perform Services for one year ending
March 31, 1997.
2. TERM AND EXPIRATION.
(a) Term. This Agreement will become effective as of
the Effective Date and remain in effect for one (1) year thereafter.
(b) Breach. Either party may terminate the Agreement
in the event of a material breach of the Agreement by the other party if such
material breach has not been cured (if such is capable of cure) within ten (10)
days after written notice.
3. COMPENSATION. For all Services provided hereunder, the
Company will pay Consultant at the rate of $12,000 per annum (to cover the
period from April 1, 1996 through March 31, 1997). Consultant acknowledges
receipt of a check from the Company for $80,000 on June 14, 1996, $12,000 of
which represented payment in advance for one year of Services to be performed
during the term of this Agreement.
4. EXPENSES. The Company will reimburse Consultant for any
reasonable expenses incurred by Consultant in the course of rendering the
Services. Requests for reimbursement will be in a form acceptable to the
Company. Consultant will notify the Company in advance before incurring any
expenses over $200 or $500 in the aggregate.
<PAGE> 28
5. PROPERTY OF COMPANY.
(a) Definition. For the purposes of this Agreement,
the term "Inventions" will mean all discoveries, inventions, improvements,
developments, products, processes, procedures, techniques, formulae, computer
programs, drawings, designs, notes, documents, information and materials made,
conceived, developed or reduced to practice by Consultant, alone or with others,
which result from or relate to the Services, or which are funded in whole or in
part by the Company or which result from the use of any premises or resources
owned, leased or contracted for by the Company.
(b) Assignment of Ownership.
(i) Assignment. Consultant hereby
irrevocably transfers and assigns to the Company any and all of his right,
title, and interest in and to Inventions, including but not limited to all
copyrights, patent rights, trade secrets and trademarks. Inventions will be the
sole property of the Company. The Company will have the sole right to determine
the treatment of any Inventions, including the right to keep them as trade
secrets, to file and execute patent applications on them, to use and disclose
them without prior patent application, to file registrations for copyrights or
trademarks on them in its own name, or to follow any other procedure that the
Company deems appropriate.
(ii) Disclosure, Assistance and
Confidentiality. Consultant agrees: (a) to disclose all Inventions to the
Company promptly, in writing; (b) to cooperate with and assist the Company to
apply for and to prosecute, and to execute any applications and/or assignments
and/or other documents reasonably necessary to obtain or maintain, any patent,
copyright, trademark or other statutory protection for Inventions in the
Company's name as the Company deems appropriate; (c) to deliver to the Company
evidence for interference purposes or other legal proceedings and to testify in
any interference or other legal proceedings and to otherwise assist the Company
related thereto, whenever requested to do so by the Company; and (d) to
otherwise treat all Inventions as "Confidential Information," as defined below.
Consultant hereby grants the Company a limited power of attorney to execute any
documents necessary or appropriate to effectuate the Company's rights hereunder.
If Consultant has any question as to whether a given invention, discovery or the
like qualifies as an "Invention" hereunder, Consultant will inform the Company
of the nature of such invention or discovery for determination as to whether
such is an Invention.
(iii) Reimbursement of Expenses. The Company
will reimburse Consultant for all reasonable expenses incurred by Consultant at
the Company's request in assisting the Company to protect its rights in any
Invention.
6. CONFIDENTIAL INFORMATION.
(a) Acknowledgment and Definition. Consultant
acknowledges that Consultant will acquire information and materials from the
Company and knowledge about the Company's business, products, techniques,
experimental work, customers, clients and suppliers. Consultant further
acknowledges that all such knowledge, information and materials acquired, the
existence, terms and conditions of this Agreement, and the Inventions are and
will be the trade secrets and confidential and proprietary information of
Company (collectively, the "Confidential Information"). Confidential Information
will not include, however, any information which is or becomes part of the
public domain through no fault of Consultant or that the Company regularly gives
to third parties without restriction on use or disclosure.
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<PAGE> 29
(b) Maintaining Confidentiality. To ensure the
continued confidentiality of the Confidential Information, Consultant agrees as
follows:
(i) to hold all Confidential Information in
strict confidence; not to disclose it to others or use it in any way,
commercially or otherwise, except in performing the Services; and not to allow
any unauthorized person access to it.
(ii) to take all action reasonably necessary
to protect the confidentiality of the Confidential Information including,
without limitation, implementing and enforcing operating procedures to minimize
the possibility of unauthorized use or copying of the Confidential Information.
(iii) that Confidential Information
furnished to Consultant by the Company or produced by Consultant or others in
connection with the Services will be and remain the sole property of the
Company. Consultant agrees to return all Confidential Information and any
materials or other property provided by the Company promptly, at the Company's
request, upon expiration of this Agreement, or upon termination of Consultant's
Services by Consultant or by the Company for any reason, whichever occurs first.
Consultant agrees not to retain any Confidential Information or reproductions
thereof, or other such property or materials, after such request, expiration or
termination.
7. COVENANT NOT TO COMPETE.
(a) During the term of this Agreement, Consultant
will not directly or indirectly assist any person, business or enterprise which
is engaged in research or development related to preservation solutions for
organ transplantation and cardioplegia without the express prior written consent
of the Company. For purposes of this Section 7, to "assist" is defined as
follows: (a) to be an officer, director, employee, partner, shareholder (other
than a holder of less than 1% of the voting power of a public company, where
Consultant has no other relationship to such public company), principal, agent,
representative or consultant for such person or entity, or to carry on any
similar activities for such person or entity, in whatever capacity; (b) to
promote or endorse or allow his or her name to be used in any Annual Report,
Quarterly Report, Private Placement Memorandum or advertisement of such entity;
or (c) to solicit or attempt to solicit business or other opportunities on
behalf of such entity.
(b) Nothing in this Section 7 will prohibit
Consultant from serving as an expert in malpractice cases or on Boards of
charitable organizations, provided that such activities do not require or result
in the disclosure of any Confidential Information.
8. SURVIVAL OF OBLIGATIONS. The obligations of Sections 5 and
6 hereof will survive any expiration or termination of this Agreement.
9. REMEDIES. Consultant acknowledges that the Company will
have no adequate remedy at law if Consultant violates the terms of Sections 5,
6, or 7 hereof. In such event, the Company will have the right, in addition to
any other rights it may have, to obtain in any court of competent jurisdiction
injunctive relief to restrain any breach or threatened breach of this Agreement.
3
<PAGE> 30
10. NOTICES. Any notice required or permitted hereunder will
be given in writing and will be deemed effectively given as follows: (a) upon
personal delivery; (b) three (3) days after deposit in the United States mail by
certified or registered mail (return receipt requested); (c) one (1) business
day after its deposit with any recognized express courier (prepaid); or (d) one
(1) business day after transmission by rapifax or telecopier, addressed to the
other party at its address (or facsimile number, in the case of transmission by
telecopier) as shown below its signature to this Agreement, or to such other
address as such party may designate in writing from time to time to the other
party. Any notice to the Company shall be addressed to the President.
11. GOVERNING LAW; SEVERABILITY. This Agreement will be
construed and enforced in accordance with the internal laws of the State of
California, excluding that body of laws pertaining to conflict of laws. If any
provision of this Agreement is determined by a court of law to be illegal or
unenforceable, then such provision will be enforced to the maximum extent
possible and the other provisions will remain in full force and effect.
IN WITNESS WHEREOF, the parties hereto have executed this
Agreement as of the day and year first written above.
COMPANY CONSULTANT
LXR BIOTECHNOLOGY INC.
By: /s/ L. David Tomei /s/ Geoffrey M. Collins
------------------------------------- ------------------------------
L. David Tomei, Ph.D., President Geoffrey M. Collins
and Chief Executive Officer
Address: 1401 Marina Way South Address: 14 Leeward Road
----------------------
Richmond, CA 94804-3746 Belvedere, CA 94920
------------------------------
------------------------------
Fax: (510) 412-9109 Fax:
--------------------------
SIGNATURE PAGE TO COLLINS SCIENCE ADVISORY BOARD
CONSULTING AGREEMENT
4
<PAGE> 1
Exhibit 10.31
AMENDMENT TO SLDI LICENSE AGREEMENT
The License Agreement among Optical Analytic, Inc., The Ohio State Research
Foundation and The Ohio State University dated August 26, 1991, as amended to
date (the "License"), is hereby further amended to delete paragraphs 3.2 and
3.3 of the License, effective as of July 10, 1996.
OPTICAL ANALYTIC, INC.
By: /s/ L. David Tomei
-----------------------------
L. David Tomei, President
THE OHIO STATE UNIVERSITY
By: /s/ Paul G. Lafayatis
-----------------------------
Its: Director, Technology Transfer
-----------------------------
THE OHIO STATE UNIVERSITY RESEARCH FOUNDATION
By: /s/ Paul G. Lafayatis
-----------------------------
Its: Director, Technology Transfer
-----------------------------
<PAGE> 1
Exhibit 10.32
AMENDMENT TO SLDI LICENSE AGREEMENT
The License Agreement among Optical Analytic, Inc. ("OAI"), The Ohio
State Research Foundation ("OSRF") and The Ohio State University ("OSU") dated
August 26, 1991, as amended to date ( the "License"), is hereby further amended
to delete U.S. Patent No. 4,601,537, titled "APPARATUS AND METHOD FOR FORMING
IMAGES AND FOR OPTICAL DEMULTIPLEXING" (the "'537 Patent"), from Schedule A to
the License, and thereby from the definition of "Licensed Patent" in Section 1.1
of the License, so that the '537 Patent is no longer licensed to OAI under the
License.
All other provisions of the License shall remain in full force and
effect.
IN WITNESS WHEREOF, the parties hereto have entered into this Amendment
as of August 27, 1996.
OPTICAL ANALYTIC, INC.
By: /s/ L. David Tomei
-----------------------------------
L. David Tomei, President
THE OHIO STATE UNIVERSITY
By: /s/ Janet G. Pichette
-----------------------------------
Its: Vice President for Business & Admin.
THE OHIO STATE UNIVERSITY RESEARCH FOUNDATION
By: /s/ Paul G. Lafayatis
-----------------------------------
Its: Director, Technology Transfer
<PAGE> 1
CONFIDENTIAL TREATMENT REQUESTED
by LXR Biotechnology Inc.
Located at 1401 Marina Way South
Richmond, CA 94804
Exhibit 10.33
LICENSE AGREEMENT
LICENSE AGREEMENT dated as of August 29, 1996, between, LXR
BIOTECHNOLOGY INC., a Delaware corporation, on behalf of itself and OPTICAL
ANALYTIC, INC., its wholly-owned subsidiary ("Licensor"), and THE PERKIN-ELMER
CORPORATION, a New York corporation ("Licensee").
W I T N E S S E T H :
WHEREAS, Licensor has developed and patented or filed patent
applications or otherwise obtained the rights to certain technology related to
laser scanning digital imaging; and
WHEREAS, Licensor has developed or otherwise obtained the rights to
certain software related to laser scanning digital imaging; and
WHEREAS, Licensor has skill and knowledge ("know-how") in the practice
of such technology; and WHEREAS, Licensee desires to obtain a license from
Licensor to use such patented technology, software and know-how, and Licensor is
willing to grant such a license, subject to the terms and conditions of this
Agreement.
NOW, THEREFORE, in consideration of the foregoing and of the mutual
covenants hereinafter set forth, the parties hereto agree as follows:
ARTICLE I
DEFINITIONS
Unless the context otherwise requires, the following terms, for all
purposes of this Agreement, shall have the meanings specified in this Section
1.1.
1.1 "Affiliate" shall mean a Person who, directly or indirectly,
controls, is controlled by, or is under common control with the specified
entity.
1.2 "Agreement" shall mean this Agreement, all Schedules annexed
hereto, and all properly executed amendments hereto.
1
<PAGE> 2
1.3 "Confidential Information" shall include verbal information and
documentation in writing concerning the practice and use of or embodying the
Intellectual Property and Improvements thereto. Such documentation shall
include, without limitation any technical drawings, designs, computer programs,
algorithms, formulas, diagrams, flow charts, application information,
specifications, notebooks, tracings, photographs, reports, findings,
recommendations, manuals or other materials concerning the design, development,
manufacture and/or use of the Licensed Patents, Licensed Patent Applications,
Proprietary Information and Licensed software in any medium.
1.4 "Effective Date" shall mean August 29, 1996.
1.5 "Field of Use" shall mean any area of business activity in which
the Intellectual Property can be or is being developed and/or commercialized
related to hybridization based assays for life science research and any other
life science or clinical diagnostic application. Field of Use is subject to
Section 9.6 herein.
1.6 "Final Adjudication" shall mean an adjudication, by a trial court
or court of appeal of competent jurisdiction, which adjudication shall be final,
binding and unappealable, whether by its terms or the passage of time.
1.7 "Improvement(s)" shall mean any modifications, improvements, or
developments, whether or not patentable, copyrightable or protectable under any
trade secret law or any other domestic or foreign statutory or legal principle
now or hereafter defining, creating or protecting any interest in intellectual
property, solely within the Field of Use, which (i) improve the performance of
any of the inventions described in the Licensed Patents; (ii) modify a component
(or material) useful in the inventions described in the Licensed Patents; (iii)
add functions to the Licensed Patents; or (iv) improve, update, or enhance the
software and that are developed by Licensor and made generally available by
Licensor without a separate charge to licensees of the Licensed Products.
2
<PAGE> 3
1.8 "Infringing" and "Infringement" shall mean any infringement of any
patent, any copyright, any misappropriation of any trade secrets or know-how, or
any other violation of any intellectual property right of any Person.
1.9 "Infringer" shall mean a Person who Infringes.
1.10 "Intellectual Property" shall mean the Licensed Patents, Licensed
Patent Applications, Licensed Software and the Proprietary Information,
collectively.
1.11 "Liabilities" shall mean all liabilities, damages, losses, costs
and expenses (including court costs and reasonable attorneys' fees and experts'
fees.)
1.12 "Licensed Patents" shall mean the Patents set forth in Schedule
1.12 hereto, individually or collectively, and all divisions, reissues,
continuations, continuations-in-part and extensions thereof and corresponding
foreign patents and patent applications. Copies of the Licensed Patents are
included in Exhibit C hereto.
1.13 "Licensed Patent Applications" shall mean the United States patent
applications set forth in Schedule 1.13 hereto, individually or collectively,
and all divisions, reissues, continuations, continuations-in-part and extensions
thereof and corresponding foreign patents and patent applications. Any patents
which issue from the patent applications set forth in Schedule 1.13 shall be
deemed to be Licensed Patents as of the date of such issue. Copies of the
Licensed Patent Applications are included in Exhibit C hereto.
1.14 "Licensed Products" shall mean any and all products containing a
light generating component, a light collecting component, a light directing
component or a light detecting component the functional combination of which is
covered by one or more Subsisting Claims, together with the underlying
electronics and firmware necessary for the coordination and control of the
foregoing components and/or Licensed Software (object code form).
1.15 "Licensed Software" shall mean the copyrighted software programs
as set forth in Schedule 1.15 for use with Licensed Products in object code form
within the Field of Use. Except for purposes of Article II hereof, the term
`Licensed Software' shall also mean the Source Code for such object code (the
"Licensed Source Code").
3
<PAGE> 4
1.16 "Net Sales" shall mean (i) the gross proceeds received by Licensee
and sublicensees thereof from the sale or lease of the Licensed Products minus
(A) all returns of Licensed Products, (B) customary discounts made available by
Licensee to customers for the Licensed Products, and (C) all charges incurred by
Licensee for the shipping and handling of the Licensed Products. Gross proceeds
shall not be diminished by any present or future taxes and levies, imposts,
fees, assessments, deductions, or charges and withholdings whatsoever imposed,
assessed, levied or collected by any political subdivision or taxing authority.
1.17 "Ohio State License Agreement" shall mean the License Agreement
dated August 15, between, Optical Analytic, Inc., The Ohio State University and
The Ohio State University Research Foundation as amended May 21, 1993, September
7, 1993 November 29, 1993, July 10, 1996 and August __, 1996 (not executed)
[copies attached hereto as Exhibit B] or at any other time, relating to the
license of the Licensed Patents.
1.18 "Person" shall mean any natural person, corporation, partnership,
trust, joint venture or other entity.
1.19 "Proprietary Information" shall mean the Licensor's trade secrets
and know-how relating to the Licensed Patents, Licensed Patent Applications and
Licensed Software. Proprietary Information includes without limitation the
listing of categories involving transfer of technology and trade secrets as set
forth in Schedule 1.19.
1.20 "Source Code" shall mean a series of instructions or statements in
a computer programming language which is normally readily read by humans trained
in that language, and which is normally transformed by an interpreter or
compiler into object code for actual use on a computer.
1.21 "Subsisting Claim" shall mean any claim under a Licensed Patent
required to practice the invention covered thereby, which claim has not expired
or lapsed, or been abandoned, canceled, disclaimed, awarded to another party in
an interference proceeding, or declared invalid by a court of competent
jurisdiction in a Final Adjudication.
1.22 "Term" shall mean the term of this Agreement pursuant to Section
9.1 hereof.
4
<PAGE> 5
ARTICLE II
LICENSE RIGHTS
2.1 License Grant. Subject to the terms and conditions of this
Agreement, Licensor hereby grants to Licensee for the Term and, within the Field
of Use, an exclusive, worldwide license under the Licensed Patents and Licensed
Patent Applications to make, have made, use, sell or lease the Licensed
Products. Licensor further grants to Licensee for the Term and, within the Field
of Use, an exclusive worldwide license for the use of the Licensed Software in
object code form and Proprietary Information to make, have made, use, sell or
lease the Licensed Products. Licensor does not grant to Licensee an independent
license to sell or distribute the Licensed Software apart from the executable
form incorporated in or otherwise as a unit within the Licensed Products.
2.2 Sublicensing. Licensee may sublicense to any Person all or a
portion of its rights hereunder subject to review by Licensor with respect to
sublicenses for manufacturing of the Licensed Products. Licensor shall not
unreasonably withhold the right to sublicense. Sublicense of the Licensed
Software is limited to executable form accompanying the sale of the Licensed
Products and Sublicensee agrees not to distribute the Licensed Product
containing an object code version of the Licensed Software other than pursuant
to a valid license agreement containing substantially the term that, "End User
will not adapt, translate, reverse engineer, decompile, disassemble or create
derivative works based on the Licensed Software or any part thereof".
2.3 Source Code License Grant.
(a) Subject to the terms and conditions of this Agreement,
Licensor hereby grants to Licensee for the term and within the Field of Use, a
non-exclusive, worldwide license to modify the Licensed Source Code for internal
purposes and only to the extent reasonably necessary for Licensee to exercise
fully the object code license granted in Section 2.1 hereof, including without
limitation the making of Improvements. Licensee shall have the right to make and
retain copies of such Licensed Source Code only to the extent necessary for the
exercise of
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the license granted herein, and shall destroy all copies that become
unnecessary. Licensor does not grant to Licensee any license to use or modify
the Licensed Source Code outside of the scope of the object code license, or to
sell or distribute the Licensed Source Code, or to sublicense to any third party
the license granted to Licensee in this Section 2.3. Licensor does not grant to
Licensee an independent license to sell or distribute the Licensed Source Code
apart from the executable form incorporated in or otherwise as a unit within the
Licensed Products.
(b) Notwithstanding any other provision of this Agreement,
including without limitation the provisions of Article V regarding Improvements,
all modifications to or other derivative works of the Licensed Source Code made
by Licensee pursuant to the foregoing Section 2.3(a) shall be owned by Licensee.
Subject to the terms and conditions of this Agreement, Licensee hereby grants to
Licensor a non-exclusive, royalty-free worldwide license to such modifications
and derivative works solely for the internal use of Licensor within the Field of
Use. Licensee further grants to Licensor a non-exclusive, worldwide license to
sublicense such modifications and derivative works to third parties for use
outside the Field of Use, upon terms agreed upon in an amendment hereto, which
shall include provisions for a reasonable royalty to Licensee as will be set
forth on a schedule attached hereto. Licensee does not otherwise grant any
rights to Licensor to use or sublicense for use such modifications and
derivative works outside the Field of Use. Upon the development of any such
modification or derivative work, Licensee shall provide to Licensor in both
Source Code and compiled object code formats, a copy of the revised Licensed
Software, together with adequate documentation and information to enable a
person of reasonable skill in the relevant programming language(s) to understand
and maintain the Licensed Software as modified by Licensee.
2.4 Licensee agrees to reproduce and apply any copyright, patent,
trademark or other proprietary rights notices to all copies of the Licensed
Product as requested by Licensor.
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** Confidential Treatment Requested
ARTICLE III
PAYMENTS
3.1 License Fee.
(a) Licensee agrees to pay to Licensor a license fee,
allocated according to the following ratio [**] divided between Licensed
Patents, Licensed Patent Applications, and Licensed Software respectively, in
accordance with the following schedule:
(1) Three Hundred Thousand Dollars ($300,000)
simultaneously with the execution of this Agreement.
(2) [**] on the first anniversary of the Effective
Date. Licensee agrees to deliver to Licensor by the first anniversary of the
Effective Date Four Hundred Thousand Dollars ($400,000) worth of Licensee's
products selected by Licensor, the value of which shall be determined using
prices which are generally offered to commercial purchasers of such products in
similar quantities.
(3) [**] on the second anniversary of the Effective
Date.
(4) [**] on the third anniversary of the Effective
Date.
(b) The obligation of Licensee to pay said license fees shall
immediately terminate upon the termination of Licensor's right to license the
Licensed Patents subject to Section 10.2(d).
(c) Payment of the license fee shall be made by wire transfer
to the account of the Licensor specified in Section 3.2(c) hereof or to such
other account as may be specified in a notice to Licensee not later than two
business days prior to the due date of such payment.
3.2 Royalty Payment.
(a) Commencing on the Effective Date, Licensee shall pay to
licensor a royalty on the Licensed Products of [**] of Net Sales of all
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** Confidential Treatment Requested
Licensed Products covered by a Subsisting Claim and containing Licensed
Software; provided, however, that in the event that Licensee is required to pay
a royalty to any third party for an element of the Licensed Product covered by
one or more Subsisting Claims and in order to make, use or sell a Licensed
Product, Licensor shall reduce the total fees payable to Licensor or Licensor's
Affiliate hereunder or pursuant to any other arrangement relating to the sale of
the Licensed Products (collectively, the "Total Payments") by one half of the
amount of the royalty paid to such third party. In the event a Licensed Product
is not covered by a Subsisting Claim, the royalty shall be [**] of Net Sales of
all such Licensed Products. In the event a Licensed Product does not contain
Licensed Software, the royalty shall be [**] of Net Sales of all such Licensed
Products. The royalty payments shall be subject to the same ratio applied in
Section 3.1 herein, where the portion of the payment pertaining to Licensed
Patents shall persist as long as there is a Subsisting Claim.
(b) Licensee shall pay to Licensor within thirty (30) calendar
days after the last day of each calendar quarter during the Term (each a
"Royalty Period") the respective royalty payable to Licensor pursuant to this
Section 3.2. Each royalty payment shall be made by wire transfer to the account
of Licensor at West America or to such other account specified in a notice to
Licensee prior to the last day of the applicable Royalty Period. Simultaneously
with each royalty payment, Licensee shall furnish to Licensor a report showing
(i) the Net Sales of the Licensed Products during the Royalty Period then ended
and (ii) the calculation of the royalties payable for such Royalty Period.
3.3 Books and Records. Licensee agrees to maintain accurate and
complete books and records concerning the sale of Licensed Products and the
calculation of Net Sales. Licensee shall permit Licensor or its authorized
agents to inspect such books and records at Licensee's facilities upon
reasonable notice during regular business hours during the Term. Licensee agrees
to maintain accurate and complete books and records concerning all copies made
of the Licensed Source Code and all persons who see or access the Licensed
Source Code or any copy thereof. Such books and records shall include a record
of each copy made and destroyed, a description of
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each change made to the Licensed Source Code, and all parties involved in making
such change, and the relevant dates for all of the foregoing.
3.4 Calculation Dispute. The parties shall endeavor to resolve promptly
any dispute regarding the calculation of the amounts payable or expended under
Sections 3.2, 9.2 and 10.2(c). If the parties are unable to resolve any such
dispute within ninety (90) calendar days of the day that such disputed payment
would be payable hereunder, then the Licensor and Licensee shall submit the
items in dispute for resolution to Ernst & Young, and each party shall advise
such firm in writing of its position regarding such dispute. Ernst & Young shall
be instructed to determine such disputed items in accordance with the terms of
this Agreement and issue its determination in writing to both parties together
with the reasons therefor within thirty (30) calendar days after submission.
Such determination shall be final and binding on both parties and the parties
agree to promptly make appropriate payments in accordance with such
determination. All royalties or license fees due within this time period shall
be held in escrow and shall accrue reasonable interest. If the determination
results in a finding that Licensee underpaid more than or equal to ten percent
(10%) of the established amount, Licensee shall pay the fees and disbursements
of Ernst & Young. If the determination results in a finding that Licensee
underpaid less than ten percent (10%), the fees and disbursements of Ernst &
Young shall be allocated equally between the Licensor and the Licensee. The
choice of Ernst & Young as the accounting firm is subject to its lack of
representation of either party at the time of the Calculation Dispute. Should
Ernst & Young represent either party at that time, the parties shall mutually
appoint a "big six" independent certified public accounting firm.
3.5 Exclusions from Royalty. No royalty shall be payable on any
Licensed Products used by Licensee, its Affiliates or sublicensees for testing,
research and development in connection with exercising the licenses granted
herein, or solely for other internal, non-commercial purposes, including,
without limitation, training, demonstration and marketing.
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ARTICLE IV
DOCUMENTATION
4.1 Documentation. As promptly as practicable after the execution of
this Agreement, Licensor shall deliver to Licensee, as reasonably required to
exercise the rights granted hereunder, documentation in writing concerning the
practice and use of the Intellectual Property and Improvements thereto. Such
documentation shall include the Licensed Source Code and any technical drawings,
manuals or other materials concerning the design, development, manufacture
and/or use of the Licensed Patents, Licensed Patent Applications, Proprietary
Information and Licensed Software. Licensor represents and warrants that the
documentation furnished to Licensee under this Section 4.1 shall be complete,
accurate and sufficient to permit a person reasonably skilled in the relevant
art to practice the Intellectual Property in the Field of Use as contemplated by
this Agreement. Such documentation shall be considered Confidential Information
and shall be kept confidential in accordance with Section 9.4 herein.
ARTICLE V
IMPROVEMENTS
5.1 Improvements by Licensor. In the event that Licensor shall make any
Improvements during the Term, Licensor shall promptly disclose in writing the
same to Licensee subject to the confidentiality provisions of this Agreement and
such Improvement shall be deemed to be included within the Intellectual Property
licensed hereunder; provided, however, that in the event that Licensor shall
secure the grant of Letters Patent on any such Improvements, it shall so notify
Licensee and, if Licensee elects to be licensed under such patent, Licensor
shall include such patent within the Licensed Patents upon the terms agreed upon
herein, which shall include provisions for a reasonable royalty to Licensor and
will be set forth on a schedule attached hereto. Any patents which may issue
from the Licensed Patent Applications shall not be subject to this Section 5.1.
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5.2 In the event that Licensee shall make any Improvements during the
Term other than modifications to or derivative works of the Licensed Source Code
which shall be controlled by the provisions of Section 2.3, Licensee shall
promptly disclose the same to Licensor subject to the confidentiality provisions
of this Agreement. Licensee grants and hereby does grant to Licensor a license
for such Improvement on a non-exclusive, royalty-free worldwide basis for uses
outside the Field of Use, upon the terms agreed upon herein, excluding royalty
payments.
5.3 Notification of each Improvement shall be made promptly, but in any
event, no later than the quarterly reporting period after the reduction to
practice or the acquisition of such an Improvement which is already reduced to
practice, and shall include a disclosure, in written or other tangible form
reasonably acceptable to the party receiving such disclosure and sufficient to
allow such party to practice the Improvement.
ARTICLE VI
INFRINGEMENT
6.1 Infringement Notice. During the Term, if either party becomes aware
that a Person is Infringing any Intellectual Property in the Field of Use, such
party shall promptly notify the other party thereof. Such notice shall set
forth, to the extent known, the identity of the alleged Infringer, the nature of
the Infringement, the date and location of the same, and any other information
such party may have regarding the Infringement.
6.2 Commencement of Action.
(a) Licensor represents and warrants that to the best of
Licensor's knowledge no Person is Infringing any of the Intellectual Property as
of the date of this Agreement.
(b) Not more than one hundred and twenty (120) calendar days
after it becomes aware of any Infringement of the Intellectual Property in the
Field of Use, whether by notice from Licensee or otherwise, Licensor shall
commence and diligently prosecute an action for infringement and/or
misappropriation against the alleged Infringer; provided, however, that Licensor
may, in its sole discretion, extend said one hundred and twenty (120) day period
for up
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to sixty (60) additional calendar days for the purpose of making good faith
efforts to resolve the situation with the alleged Infringer. Licensor shall be
entitled to use its reasonable discretion in determining whether to pursue an
action for infringement, and such reasonable discretion may include reliance on
opinions by counsel.
(c) At Licensor's reasonable discretion, Licensor shall
furnish to Licensee information and materials disclosing material developments
in any action so commenced by Licensor (or in any declaratory judgment action
commenced by the alleged Infringer).
(d) If Licensor decides not to commence an action as specified
in Section 6.2(b) hereof, Licensee may, upon approval of Licensor not to be
unreasonably withheld or delayed, commence such action in its own name and at
its own expense, and may join Licensor as a party plaintiff or as a co-plaintiff
or, in any declaratory judgment action the Infringer may commence, as a
co-defendant. The right of Licensor to withhold approval of commencement of such
action by Licensee is subject to advice by counsel that such suit would not be
advisable. If any such action is commenced properly by Licensee pursuant to this
Section 6.2(d) then the following shall govern:
i) Licensee shall have the right to settle any such
claim, suit or proceeding upon written consent of Licensor, such consent not to
be unreasonably withheld or delayed;
ii) If damages or settlement amounts are received,
Licensee's costs will be reimbursed and if Licensor was joined and incurred
costs associated with the litigation, said costs will also be reimbursed; and
iii) If, after reimbursing Licensee and Licensor, if
necessary, there are remaining damages or settlement amounts, these will be
allocated evenly (50:50) between Licensor and Licensee.
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6.3 Indemnity by Licensor for Intellectual Property Infringement.
(a) Licensor represents and warrants to Licensee that (i) it
holds all proprietary right, title and interest in and to the Licensed Software,
(ii) it has the right to license to Licensee the Licensed Patents in the manner
set forth herein and, (iii) as of the Effective Date, Licensor has not been put
on notice that the use of the Intellectual Property by Licensee as contemplated
by this Agreement constitutes an Infringement. At its expense, Licensor shall
defend or settle any claim, suit or proceeding brought against Licensee by a
Person claiming Infringement based on the licensed use of the Intellectual
Property otherwise in accordance with this Agreement. In addition, Licensor
shall indemnify and hold harmless Licensee from any Liabilities resulting from
an adjudication of any such claim, suit or proceeding in which it is determined
that Licensee's practice of the Intellectual Property hereunder in compliance
with the terms and conditions of the Agreement constitutes Infringement. At the
option of Licensor, Licensee may participate, at the expense of the Licensee, in
the defense of any such claim, suit or proceeding. Licensor shall retain control
of the proceeding and shall, at its reasonable discretion, furnish to Licensee
copies of all material papers filed in the proceeding.
(b) As a condition precedent to Licensor's obligations under
this Section 6.3, Licensee shall (i) give Licensor notice of the written threat
of any such claim, suit or proceeding or the written assertion by any Person
that Licensee's use of the Intellectual Property constitutes an Infringement of
such Person's intellectual property rights, and (ii) reasonably cooperate with
Licensor in respect to any defense of such claim, suit or proceeding. Licensor
shall control the defense of any such legal action and may rely on opinions of
counsel. Licensor shall have the right to settle any such claim, suit or
proceeding without the consent of Licensee, provided, however, that in the event
any such settlement would cause Licensee to incur substantial liability or
obligation, financial or otherwise, or to be restricted from the practice of the
Intellectual Property as contemplated by this Agreement, such settlement shall
require the prior written consent of Licensee, which consent shall not be
unreasonably withheld.
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(c) The foregoing indemnity shall not extend to any claim of
infringement resulting from any modification of the Intellectual Property not
furnished by Licensor, including without limitation any modification of or
derivative work of the Licensed Source Code or the combination of the
Intellectual Property with any other technology or intellectual property not
provided by Licensor hereunder. In addition, at its expense, Licensee shall
indemnify and hold harmless Licensor from any Liabilities arising from an
adjudication or settlement of any claim, suit or proceeding in which it is
alleged or determined that any modifications of the Licensed Source Code
constitute Infringement.
ARTICLE VII
LIMITATION OF REMEDIES
7.1 Except for the termination penalties set forth in Section 10.2
hereof and any Liabilities covered by Section 6.3, neither party to this
Agreement shall be liable for any incidental, consequential or special damages
of any kind, whether arising in tort, contract or otherwise, and regardless of
whether a party had been advised of the possibility of such damages.
ARTICLE VIII
REPRESENTATIONS AND WARRANTIES
8.1 Representations and Warranties of Licensor. Licensor represents and
warrants to Licensee that (i) it is a corporation organized and existing under
the laws of the State of Delaware, (ii) it has full right, power and authority
to execute and perform this Agreement, (iii) the execution and performance of
this Agreement do not and will not violate any law, rule, regulation, order,
writ, injunction or decree of any court or government, domestic or foreign, or
any commission, bureau or administrative agency, or any agreement or instrument
by which Licensor is bound, and (iv) upon its execution, this Agreement will
constitute the binding obligation of Licensor enforceable against it in
accordance with its terms, except as the same may be limited by bankruptcy,
insolvency, reorganization or other laws relating to or affecting
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the enforcement of creditors' rights generally or by limitations on the
availability of equitable remedies.
8.2 The warranties set forth herein are exclusive and in lieu of all
other warranties express or implied, including, without limitation, the implied
warranties of merchantability and fitness for a particular purpose. Licensor
neither assumes, nor authorizes any person to assume for it, any other liability
in connection with the Licensed Product, including, without limitation,
liability arising out of the delivery or use of the Licensed Product.
8.3 Representations and Warranties of Licensee. Licensee represents and
warrants to Licensor that (i) it is a corporation organized and existing under
the laws of the State of New York, (ii) it has full right, power and authority
to execute and perform this Agreement, (iii) the execution and performance of
this Agreement do not and will not violate any law, rule, regulation, order,
writ, injunction or decree of any court or government, domestic or foreign, or
any commission, bureau or administrative agency, or any agreement or instrument
by which Licensee is bound, and (iv) upon its execution, this Agreement will
constitute the binding obligation of Licensee enforceable against it in
accordance with its terms, except as the same may be limited by bankruptcy,
insolvency, reorganization or other laws relating to or affecting the
enforcement of creditors' rights generally or by limitations on the availability
of equitable remedies.
ARTICLE IX
ADDITIONAL OBLIGATIONS OF THE PARTIES
9.1 Performance under the Ohio State License Agreement. During the
Term, Licensor shall use its best efforts to maintain in full force and effect
the Ohio State License Agreement and shall perform all of its obligations
thereunder. In furtherance of the foregoing and not by way of limitation,
Licensor shall, among other things, timely pay all license fees and royalty
payments under such agreement. Licensor shall promptly provide Licensee with
copies of any and all notices or other communications to or from Licensor
relating to the Ohio State
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** Confidential Treatment Requested
License Agreement and shall not amend, modify or terminate the Ohio State
License Agreement without the prior written consent of Licensee which consent
shall not be unreasonably withheld. Licensor shall provide Licensee with written
notice within sixty (60) days prior to the obligation to meet a payment under
the Ohio State License if Licensor does not intend to meet the obligation. At
its discretion upon receipt of such notice, Licensee may meet the obligation,
and any such expenditures shall be offset against any future royalties or
license fees due to Licensor under this Agreement. Upon loss by Licensor of the
right to license the Licensed Patents, Licensee may then pursue an agreement
with OSU in accordance with the terms of Exhibit A attached hereto.
9.2 Research and Development. Licensee agrees to commit at least [**]
per year, for at least two years following the Effective Date, for research and
development related to the commercial exploitation of fluorescence imaging
systems for use in the Field of Use.
9.3 Announcement of Agreement. The parties agree that any public
announcement of this Agreement may make reference to the terms of Section 9.2
and to the fact that royalty provisions are included in the Agreement without
stating the details of such provisions. The parties further agree that each
shall make copies of the public announcements available to the other in
sufficient time to allow review by counsel. Release of the announcements by one
party shall be subject to the approval of the other party, such approval not to
be unreasonably withheld.
9.4 Confidentiality. Licensee acknowledges that the Confidential
Information and Proprietary Information disclosed by Licensor pursuant to this
Agreement is the confidential information of Licensor. Licensee agrees that it
shall not use the Confidential Information or Proprietary Information except as
is necessary for the exercise of the license granted in this Agreement, nor
shall Licensee disclose the Confidential Information or Proprietary Information
to any third party (other than subcontractors approved by Licensor who agree not
to disclose or use the Confidential Information or Proprietary Information
except as necessary in the exercise of a sublicense permitted by this Agreement
and excluding Licensed Source Code) without the
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prior written consent of Licensor. The parties acknowledge and agree that the
foregoing restrictions shall not apply to any information which:
(a) was in the public domain at the time of Licensor's
disclosure to Licensee;
(b) entered the public domain through no fault of Licensee
subsequent to the time of Licensor's disclosure to Licensee;
(c) was in Licensee's possession free of any obligation of
confidence at the time of Licensor's disclosure to Licensee; or
(d) was developed by Licensee independently of and without
reference to the Proprietary Information.
9.5 Licensed Source Code Confidentiality. Without limiting the
foregoing, and without limiting the restrictions on Licensee included in the
provisions of Section 2.2 hereof, Licensee acknowledges that the Licensed Source
Code constitutes a valuable trade secret of Licensor; and shall protect the
confidentiality of the Licensed Source Code in a manner at least as protective
as that used by Licensee to protect its own similar trade secrets and source
code.
9.6 Reversion of Rights
(a) For purposes of this Section 9.6, the phrase "Reversionary
Field of Use" shall mean all uses of the Intellectual Property within the Field
of Use, where "hybridization" shall include any binding event such as nucleic
acid hybridization and protein/protein hybridization in conjunction with
fluorescence emission and absorbance determinations. Hybridization based assays
include, without limitation, slide-based cytometry, analysis of arrays of
biomolecules on slides, and analysis of hybridization occurring on spots or on
wells in slides or plates. The Reversionary Field of Use shall include
non-hybridization-based assays including, without limitation, clinical
diagnostics, gel scanning, thin layer chromatography scanning and
electrophoresis-based nucleic acid sequencing.
(b) Licensee and Licensor hereby agree that if Licensee
decides not to exploit or to cease exploiting the Intellectual Property in all
or part of the Reversionary Field of Use, Licensee shall so inform Licensor in
the quarterly royalty report issued immediately following
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the making of such decision. Upon the receipt of such written notification,
Licensor shall have 30 (thirty) days to inform Licensee in writing if Licensor
has decided to exploit the Intellectual Property for such use or uses. If
Licensor does not provide timely written notice, then all rights in this
Intellectual Property for such use(s) shall remain with Licensee, to the extent
they are granted to Licensee in this Agreement. If Licensor provides timely
written notice, Licensee's right to exploit the Intellectual Property for such
use(s) shall terminate, and such use(s) shall be excluded from the Field of Use
for the remaining term of this Agreement. All such terminated rights shall
revert to Licensor, and Licensor shall have unrestricted rights (as against
Licensee) in and to the Intellectual Property in such part of the Reversionary
Field of Use.
ARTICLE X
TERM AND TERMINATION
10.1 Term. Unless otherwise renewed or terminated as provided in
Section 10.2 below, this Agreement shall commence on the Effective Date and
shall continue for so long as there exists a Subsisting Claim in any of the
Licensed Patents or the Licensed Software is included in a Licensed Product.
10.2 Termination. This Agreement may be terminated by the parties as
follows:
(a) The parties may terminate this Agreement at any time by
mutual written consent.
(b) Either party may terminate this Agreement upon thirty (30)
calendar days prior notice if the other party shall commit a material breach of
this Agreement and such breach shall not be cured by such other party within
thirty (30) calendar days of receipt of such notice.
(c) Subject to the following termination penalty, Licensee may
terminate this Agreement at any time upon thirty (30) calendar days prior notice
upon payment of the termination penalty. If Licensee elects to terminate at any
time within the first nine (9) months following the Effective Date, Licensee
shall pay no penalty provided that the anticipated research and development fees
under Section 9.2 have been spent. At the nine month date, the anticipated
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** Confidential Treatment Requested
expenditures are 9/12 of [**] or [**] or a pro rata share of such amount as of
an earlier termination within this nine (9) month period (e.g., [**] at six (6)
months). Should Licensee fail to spend at least [**] within this time period or,
such pro rata amount, Licensee will pay Licensor fifty percent (50%) of the cash
amount set forth in Section 3.1(a)(2). If Licensee terminates the agreement
after the ninth (9th) but before the end of the twelfth (12th) month following
the Effective Date, Licensee shall pay seventy-five percent (75%) of the cash
amount set forth in Section 3.1(a)(2). The termination penalty after this period
shall be on a pro rata basis calculated as the equation (1-(X/[**]))Y where X is
the amount of actual expenditures under section 9.2 and Y is the amount set
forth in Section 3.1(a)(3).
(d) Upon payment in full of all outstanding license fees and
royalty payments due and payable, Licensee may terminate this Agreement at any
time upon the termination of Licensor's right to license the Licensed Patents.
10.3 Consequences of Termination; Expiration. Upon the termination of
this Agreement:
(a) Any amounts due and payable to either party hereunder as
of the date of termination shall continue to be payable in accordance with the
terms hereof.
(b) Licensee shall cease the manufacturing and sale of the
Licensed Products, except for a limited period as necessary to sell off its
work-in-process and finished inventory of Licensed Products (the "Sell-Off
Period"), as of the date of the notification, such Sell-Off Period not to exceed
six months. There shall be no Sell-Off-Period if Licensor's right to license the
Licensed Patents expires or is otherwise terminated or if Licensor no longer has
no right to license the Intellectual Property.
(c) The licenses granted to Licensee hereunder shall terminate
except that a license to sell shall continue for the duration of the Sell-Off
Period.
(d) Licensee shall return to Licensor or certify in writing
the destruction of all original materials and copies thereof that embody the
Proprietary Information including without limitation all copies of the original
Licensed Source Code and all documentation relating thereto.
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10.4 Survival. Licensee's obligation to maintain the confidentiality of
the Proprietary Information shall survive any termination of this Agreement. The
indemnity obligations of Licensor pursuant to Article VI and the obligations of
the parties pursuant to this Article X shall also survive any termination or
expiration of this Agreement.
10.5 Suspension of Performance. If Licensor shall commit a material
breach and not cure such breach within thirty (30) days of Notice, in accordance
with Section 10.2(b), Licensee shall have the option of (i) exercising its right
to terminate this Agreement pursuant to Section 10.2(b) or (ii) notifying
Licensor of such breach and suspending performance of all its duties hereunder
(excluding payment of licensee fees and royalties as otherwise required by
Sections 3.1 and 3.2 hereof) until such breach is cured. In the event of a
dispute, other than a dispute under Section 3.4, in which Licensee in good faith
asserts that Licensor's alleged breach warrants a suspension of royalty payments
and license fees to Licensor under Section 3.2, Licensee shall have the right to
pay all amounts payable to Licensor under Section 3.2 into a third-party escrow
account during the pendency of such dispute, provided that all escrowed funds
remain in such escrow account until resolution of the dispute by an arbitrator
pursuant to Section 11.3 (the "Escrow Period"). Licensee shall continue to be
obligated by all other terms and conditions of this Agreement except as
otherwise set forth in this Section 10.5 during any such Escrow Period.
Licensee's suspension of the performance of its obligations pursuant to this
Section 10.5 shall not constitute a breach of this Agreement. Nothing in this
Section 10.5 shall limit the right of Licensee to seek such other remedies as
may be available to it under this Agreement or otherwise by reason of any such
breach of Licensor.
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ARTICLE XI
MISCELLANEOUS
11.1 Notices. Any notice or other communication provided for in this
Agreement shall be in writing and shall be delivered personally, or sent by
facsimile transmission or nationally recognized overnight courier service, and
shall be deemed given when so delivered personally or by facsimile transmission,
with receipt confirmed, or one (1) business day after the date of deposit with
such courier service. All notices and other communications shall be addressed to
the parties at their respective addresses as set forth below. Each party hereto
may change its address upon written notice to the other party in the manner
provided in this Section 11.1.
If to Licensor:
LXR Biotechnology Inc.
1401 Marina Way South
Richmond, CA 94804
Facsimile No.: (510) 412 9109
If to Licensee:
The Perkin-Elmer Corporation
761 Main Avenue
Norwalk, CT 06859-0001
Attention: Secretary
Facsimile No.: (203) 761-5000
11.2 Governing Law. This Agreement shall be governed by, and construed
and enforced in accordance with, the laws of the State of New York without
giving effect to its rules governing choice of law.
11.3 Arbitration; Injunctions. Subject to Section 3.4 hereof, all
disputes, controversies or differences between the parties which may arise out
of, in relation to, or in connection with this Agreement shall, unless settled
by mutual consultation in good faith, be settled by arbitration in New York in
accordance with the Commercial Arbitration Rules then in effect of the American
Arbitration Association, and judgment upon the award rendered by the arbitrators
may
21
<PAGE> 22
be entered in any court having jurisdiction thereof. Prior to filing for
Arbitration, the parties will set aside a "cool-off" period of thirty (30) days
during which senior management of the parties will meet and attempt to resolve
any disputes amicably. Notwithstanding anything to the contrary contained in
this Section 11.3, each party reserves the right to pursue injunctive relief or
other equitable remedies in a court of competent jurisdiction in connection with
any breach of the terms of this Agreement.
11.4 Attorneys' Fees. If any action at law or in equity, including
action for arbitration or injunctive relief, is brought relating to this
Agreement or the breach thereof, the prevailing party in any final judgment or
arbitration award, or the non-dismissing party in the event of a dismissal
without prejudice, shall be entitled to the full amount of all reasonable
expenses, including all court costs, arbitration fees and actual attorneys' fees
paid or incurred in good faith.
11.5 Assignment. Subject to Section 2.2 hereof, this Agreement may not
be assigned by either party, except that either party may assign all of its
rights and delegate all of its obligations hereunder to an Affiliate or to any
third party that is a successor to all or substantially all of the assets and
business operations of such party and either party may assign all of its rights
and delegate all of its obligations hereunder to a Person acquiring all of the
assigning party's rights to the Intellectual Property within all or a portion of
the Field of Use upon prior written notice and subject to approval by the other
party which approval will not be unreasonably withheld. This Agreement shall be
binding upon and inure to the benefit of the parties and their respective
successors and permitted assigns.
11.6 Force Majeure. Neither party to this Agreement will be liable for
failure to perform any of its obligations hereunder during any period in which
such performance is delayed by acts beyond its reasonable control, including,
without limitation, fire, flood, war, riot, embargo, organized labor stoppage,
earthquake, and acts of civil and military authorities, provided that the party
suffering such delay immediately notifies the other party of the delay, and,
further, that either party shall have the right to terminate this Agreement upon
ninety (90)
22
<PAGE> 23
days prior written notice if the delay of the other party due to any of the
above-mentioned causes continues for a period of four (4) months.
11.7 Severability. In the event that a provision, or part thereof, of
this Agreement shall be held to be invalid, illegal or unenforceable, the
validity, legality and enforceability of the remaining provisions, or parts
thereof, shall not in any way be affected or impaired thereby.
11.8 Waiver. No waiver of any breach of this Agreement shall be
effective unless made in writing, and no waiver shall constitute a waiver of any
subsequent breach.
11.9 Relationship between Parties. No license is granted hereunder to
any party other than as specifically set forth herein. The relationship
established by this Agreement is solely that of a licensor and licensee and
nothing contained herein shall create a partnership, joint venture or any other
business relationship between Licensor and Licensee. Except as expressly set
forth herein, neither party shall have authority to obligate or bind the other
party with respect to any matter, to make any contract, sale, agreement,
warranty or representation, express or implied, on behalf of the other party, or
to accept any legal process for or on behalf of the other party.
11.10 Headings; References. The Article and Section headings contained
herein are for reference purposes only and shall not in any way affect the
meaning or interpretation of this Agreement.
11.11 Entire Agreement. This Agreement constitutes the entire agreement
and understanding between the parties hereto with respect to the subject matter
hereof and supersedes all prior discussions, agreements, and understandings of
any and every nature, whether written or oral, with respect to the same matter.
11.12 Amendments. No amendments, modifications or supplements to this
Agreement shall be enforceable or binding upon the parties hereto unless made in
a writing expressly referring to this Agreement and executed by a duly
authorized representative or officer of each of the parties hereto.
23
<PAGE> 24
11.13 Counterparts. This Agreement may be executed in one or more
counterparts, each of which when executed shall be deemed to be an original, but
all of which taken together shall constitute one and the same instrument. This
Agreement may be executed via facsimile signature.
IN WITNESS WHEREOF, the parties hereto have caused this Agreement to be
executed as of the day and year first written above.
LXR BIOTECHNOLOGY INC.
By: /s/L. David Tomei
-----------------------------------
Name: L. David Tomei
Title: LXR Biotechnology Inc.
President
THE PERKIN-ELMER CORPORATION
By: /s/Mark C. Rogers
-----------------------------------
Name: Mark C. Rogers
Title: Senior Vice President Corporate
Development and
Chief Technology Officer
24
<PAGE> 25
SCHEDULE 1.12
Licensed Patents
U.S. Patent No. 5,037,207 to Tomei et al.
U.S. Patent No. 4,877,966 to Tomei et al.
U.S. Patent No. 4,758,727 to Tomei et al.
25
<PAGE> 26
** Confidential Treatment Requested
SCHEDULE 1.13
Licensed Patent Applications
1. U.S. Serial No. 08/451,325 "Multi-Channel Acquisition Using Integrating
Sphere," filed May 26, 1995.
2. WO/US96/06808 PCT of 08/451,325, filed May 13, 1996.
3. U.S. Serial No. 08/452,035, "Wide Angle Scattering Detector," filed May
26, 1995.
4. WO/US96/07374 PCT of 08/452,035, filed May 21, 1996.
5. [**]
26
<PAGE> 27
** Confidential Treatment Requested
SCHEDULE 1.15
A. Licensed Software
[**]
B. Licensed Source Code
[**]
27
<PAGE> 28
** Confidential Treatment Requested
SCHEDULE 1.19
DESIGNS OF ALL MECHANIC COMPONENTS, CONSISTING OF:
[**]
DRAWINGS OF ELECTRONIC AND ELECTRICAL WIRING, CONSISTING OF: (16)
[**]
INFORMATION ON ALL OTHER (COMMERCIAL) PARTS AND PARTS VENDORS
PERFORMANCE ANALYSIS ON SYSTEM (VIBRATION) ISOLATION
PERFORMANCE ANALYSIS ON OPTICAL FOCUSING SYSTEM
INSTRUMENTATION CONCERNING HARDWARE AND FIRMWARE, CONSISTING OF:
[**]
INSTRUMENTATION CONCERNING SOFTWARE, CONSISTING OF:
[**]
28
<PAGE> 29
** Confidential Treatment Requested
[**]
COMPLETE DOCUMENTATION INCLUDING:
[**]
TECHNOLOGY (OR PRODUCT) CURRENTLY UNDER DEVELOPMENT:
[**]
29
<PAGE> 30
CONFIDENTIAL TREATMENT REQUESTED
LXR BIOTECHNOLOGY INC.
LOCATED AT 1401 MARINA WAY SOUTH
RICHMOND, CALIFORNIA 94804
MORRISON & FOERSTER LLP
SAN FRANCISCO ATTORNEYS AT LAW NEW YORK
LOS ANGELES WASHINGTON, D.C.
SACRAMENTO 755 PAGE MILL ROAD LONDON
ORANGE COUNTY PALO ALTO, CALIFORNIA 94304-1018 BRUSSELS
WALNUT CREEK TELEPHONE (415) 813-5600 HONG KONG
SEATTLE TELEFACSIMILE (415) 494-0792 TOKYO
DENVER
EXHIBITS
TO
LICENSE AGREEMENT
LICENSE AGREEMENT dated as of August 29, 1996, between, LXR BIOTECHNOLOGY INC.,
a Delaware corporation, on behalf of itself and OPTICAL ANALYTIC, INC., its
wholly-owned subsidiary ("Licensor"), and THE PERKIN-ELMER CORPORATION, a New
York corporation ("Licensee").
CONFIDENTIAL
<PAGE> 31
** CONFIDENTIAL TREATMENT REQUESTED
TABLE OF CONTENTS
CONFIDENTIAL
A. Letter of August 27, 1996 from Ohio State University to Perkin-Elmer .......
B. Ohio State University/LXR License and Modifications ........................
1. Letter of August 15, 1991 from Ohio State to Optical Analytic, Inc.
regarding Cooperative Agreement, with Agreement attached. .........
2. Letter of November 23, 1993 from Optical Analytic, Inc. to LXR
regarding extension of Milestones. ................................
3. Letter of November 29, 1993 from Ohio State University to
Optical Analytic, Inc. regarding extension of Milestones. .........
4. Amendment to Agreement of July 10, 1996, deleting
Milestone paragraphs ..............................................
5. Unexecuted Amendment to Agreement, deleting patent No. 4,601,537 ..
C. Patents and Applications. ..................................................
1. U.S. Patent No. 5,037,207 to Tomei et al. .........................
2. U.S. Patent No. 4,877,966 to Tomei et al. .........................
3. U.S. Patent No. 4,758,727 to Tomei et al. .........................
4. U.S. Serial No. 08/451,325 ........................................
"Multi-Channel Acquisition Using Integration Sphere," filed
May 26, 1995 (WO/US96/06808 PCT of 08/451,325, Filed May 13,
1996)
5. U.S. Serial No. 08/452,035 ........................................
"Wide Angle Scattering Detector," filed May 26, 1995
(WO/US96/07374 PCT of 08/452,035, Filed May 21, 1996)
6. **[" "]....
<PAGE> 32
Exhibit A to Perkin-Elmer License Agreement
<PAGE> 33
- ------------------------
T . H . E Office of Technology Transfer 1960 Kenny Road
OHIO Columbus, OH 43210-1063
STATE
UNIVERSITY Phone 614-292-2550
- ------------------------
August 27, 1996
Richard J. Bartlett
Perkin-Elmer Corporation
761 Main Avenue
Norwalk, CT 06859-0199
Subject: License Agreement for Scanning Laser Imaging Technology.
Dear Mr. Bartlett:
I understand that Perkin-Elmer (PE) is negotiating a license with LXR
Biotechnology Inc. through its wholly owned subsidiary Optical Analytic, Inc.
(OA) a license for the subject technology in the field of Research and Clinical
Applications. The technology was exclusively licensed to OA by The Ohio State
University and The Ohio State University Research Foundation (collectively OSU)
in an agreement dated August 15, 1991, which has been amended and now covers the
intellectual property in U.S. Patents # 4,758,727; 4,877,966 and 5,037,207.
This letter is to assure PE that OSU will negotiate a similar exclusive license
containing the same conditions of diligence, minimum royalties, liability etc.
as contained in the OA agreement should the agreement with OA (LXR) be
terminated.
Please let me know if you have any further questions.
Regards,
/s/ Paul G. Lafayatis
- ---------------------
Paul G. Lafayatis, Director Technology Transfer
cc: J.J. Biancamano, OSU
L.D. Tomei, LXR
<PAGE> 34
Exhibit B1 to Perkin-Elmer License Agreement
<PAGE> 35
- ------------------------
T . H . E Office of Technology Transfer 1960 Kenny Road
OHIO Columbus, OH 43210-1063
STATE
UNIVERSITY Phone 614-292-2550
- ------------------------
August 15, 1991
F. David Resch
Optical Analytic, Inc.
6400 Riverside Drive
Dublin, OH 43017
Subject: SLI license
Dear Mr. Resch:
I enclose three counterparts of the final license agreement for the SLI
technology that you approved in draft. These have been executed by the
University and the Research Foundation. Please have them executed by OAI and
return two to me.
Pursuant to our phone conversation earlier this week, if OAI and Fettig, Inc. go
forward with a joint venture (or a merger or any other cooperative arrangement)
for the commercial development of the SLI technology, we would expect that our
rights and interests under each of your primary co-exclusive license agreements
would be fully protected and that all of the obligations of the licensee under
each of those primary license agreements would be cumulatively fulfilled, with
any exceptions to be only with our express written consent. For example, we
would expect that the total royalties payable to us under both primary license
agreements for any period would never be less than the sum of the minimum
royalties specified in those two agreements for that period, i.e. that no
royalty amount accrued in respect of any transaction would be credited against
the minimum royalties specified in both primary license agreements and that no
minimum royalty paid or payable under one primary license agreement would be
credited against royalties paid or payable under the other.
On the other hand, we would not expect that duplicate royalties would be paid or
payable under both primary licenses in respect of any particular unit of
Licensed Product or Service merely because the royalty-generating transaction
involving such unit might technically be made under the authority of both
primary licenses rather than only under the authority of one of them.
Furthermore, to cover all of the hypothetical possibilities, in case there
should be a joint or cooperative transaction not solely attributable to either
primary licensee, and in respect of which the two primary license agreements
called for different royalty payments to us, we would expect
<PAGE> 36
that an undivided half of such transaction would be deemed to have been subject
to each of the primary license agreements.
Finally, we construe the provisions of 8.2 of the OAI license agreement as
creating both obligations of OAI and rights of OSURF respecting activities
undertaken by joint ventures in which OAI has an interest, or by other joint
venture "partners" for the benefit of such a joint venture.
It would probably be best to formalize these understandings among all interested
parties when actual arrangements for any joint venture or other cooperation have
been worked out.
Sincerely,
/s/ James B. Wilkens
--------------------
James B. Wilkens
Patent and Copyright Administrator
Encl. - 3 partially executed counterparts of "oaisli.lc4"
<PAGE> 37
oaisli.lc4
LICENSE AGREEMENT
This License Agreement is entered into between Optical Analytic, Inc., ("OAI"),
a corporation of Ohio having a principal place of business at 6400 Riverside
Dr., Dublin, Ohio 43017, and The Ohio State University Research Foundation
("OSURF"), a non-profit corporation of Ohio having a principal place of business
at 1960 Kenny Road, Columbus, Ohio 43210-1063 and acting on behalf of itself and
The Ohio State University ("University"), an instrumentality of the State of
Ohio, on the terms and conditions set forth hereinbelow, to cover commercial
development by OAI of Scanning Laser Imaging ("SLI") technology developed by Dr.
L. David Tomei and co-workers at the University.
Definitions.
1.0. The following definitions shall apply throughout this document and any
correspondence between the parties relating to the subject matter thereof,
except insofar as the context clearly indicates a different meaning.
1.1. "Licensed Patent" means a patent or patent application identified in
Schedule A, and any other patent or patent application, including any division,
continuation, continuation-in-part, reissue or foreign counterpart, insofar as
it derives therefrom or covers an SLI invention developed by Dr. Tomei and
coworkers at the University prior to the effective date of this License
Agreement.
1.2. "Licensed Product" means (i) an SLI instrument or device the manufacture,
import, sale or use of which is covered by a Licensed Patent or (ii) a component
intended for use as part of or in connection with such instrument or device
insofar as the manufacture, import, sale or use of such component is covered by
a Licensed Patent.
1.3. "Licensed Service" means the use of Licensed Product and/or of a method
covered by a Licensed Patent.
License Scope.
2.0. OSURF hereby grants to OAI, and OAI hereby accepts, a worldwide license
under all Licensed Patents to manufacture, import, export, use, sell and lease
Licensed Products and Licensed Services, and to sublicense others to do so,
subject to the reservation of the right of the University to operate under
Licensed Patents for research and/or educational purposes, and to the other
provisions of this License Agreement.
2.1. This License is co-exclusive, by which is meant that OSURF may grant only
one additional license under Licensed Patents for Licensed Products or Licensed
Services for any
<PAGE> 38
combination of field use, geographical area and period of time for which this
License is in effect. A single additional license has been granted for all
fields, all geographical areas and the life of the licensed patents. If such
additional license shall terminate, then OAI shall be notified in writing and
shall have the option, for sixty (60) days following such notice, of converting
its co-exclusive License to exclusive, provided that this License (to OAI)
remains in effect, that OAI is not in default or breach of this Agreement and
that OAI agrees in writing to thereafter pay minimum royalties equal to twice
those specified in Section 4.4 hereof.
2.2. This License shall take effect with respect to any Licensed Patent upon the
later of (i) the effective date of this License Agreement and (ii) the filing of
a patent application which falls within the definition of Licensed Patent. This
License shall terminate with respect to any Licensed Patent upon the earlier of
(iii) the termination of this License Agreement and (iv) the expiration,
cancellation or final unappealable determination of invalidity of such Licensed
Patent or the abandonment of a patent application which falls within the
definition of Licensed Patent.
Licensee Performance.
3.0. OAI will diligently exert its reasonable best efforts to develop and
market, either directly or through sub-licensees, Licensed Products and/or
Licensed Services for a broad range of applications. In particular, OAI
undertakes to achieve, directly or through sub-licensees, the milestones of
sections 3.1-3.4. OAI will notify OSURF of its achievement, partial achievement
or lack of achievement of these milestones in a timely manner, and in the
absence of such notice, it will be presumed that the milestones have not been
achieved. These milestones are established to manifest and exemplify the
understanding of the parties and the commitment of OAI that continuous progress
will be made toward accomplishing this objective. It is recognized that specific
times or periods set forth in sections 3.1-3.4 may become unachievable due to
unanticipated and/or uncontrollable circumstances, and in such cases consent to
reasonable adjustment thereof, not to exceed doubling of any stated or implied
period, shall not be unreasonably withheld by OSURF. However, it is also
understood that such times or periods have been specified with reasonable
allowance for problems and delays that are typical of such projects, and in
particular only where funds substantially in excess of those reasonably
anticipatable prove to be required for the achievement of any milestone will be
the period for achieving such milestone be adjusted on the basis of shortage of
funds.
3.1. Not later than twelve (12) months after the effective date of this
Agreement, OAI will have assembled a prototype SLI device for demonstration
purposes.
3.2. Not later than thirty-six (36) months after the effective date of this
Agreement, OAI will have accumulated data suitable for submission to the FDA for
regulatory approval of a Licensed Product or Service.
3.3. Not later than thirty-six (36) months after the effective date of this
Agreement, OAI will submit to the FDA an application for regulatory approval of
a Licensed Product or Service.
<PAGE> 39
3.4. Not later than twenty-four (24) months after the effective date of this
Agreement OAI will have a Licensed Product on the market, it being the
contemplation of the parties that this milestone will be met by a Licensed
Product not requiring FDA approval.
3.5. Thereafter introduction of Licensed Products and/or Services for sale or
lease will, as rapidly as practicable, be actively promoted by OAI and/or
sub-licensees for a broad range of applications.
3.6. OAI and its sub-licensees will mark all Licensed Products subject to this
License Agreement with the numbers of all applicable U.S. Licensed Patents.
Royalties and Other Payments.
4.0. [Reserved]
4.1. OAI will pay royalties to OSURF based upon the net sales and leases by OAI
and sub-licensees of Licensed Products and Licensed Services. For such
transactions not at arms-length, the royalties will be based upon similar
transactions that are at arms-length. No royalties will be due OSURF upon resale
of a Licensed Product for which royalties have accrued in favor of OSURF on the
initial sale pursuant to 4.1-4.3 and 4.5 hereof. No royalties will be due OSURF
in respect of Licensed Services provided through the use of a Licensed Product
upon which royalties have been paid to OSURF, unless royalties are payable to or
at the direction of OAI or a sub-licensee in respect of such Licensed Service
(herein referred to as "Section 4.1 Service Royalties").
4.2. Subject to section 4.1 above, royalties due OSURF hereunder will be five
percent (5.0%) of cumulative net sales and leases of Licensed Products and
Licensed Services under authority of this License Agreement, except that
royalties will be payable to OSURF in the amount of twenty percent (20%) of
Section 4.1 Service Royalties accrued on or before the second anniversary of the
effective date of this Agreement and thirty-three and one-third percent
(33-1/3%) of Section 4.1 Service Royalties accrued thereafter.
4.3. Royalties accrued in favor of OSURF hereunder during each calendar quarter
will be paid to OSURF by OAI within forty-five (45) days after the end of such
quarter, accompanied by a concise statement of the basis upon which the amount
due was determined.
4.4. For complete calendar quarters following the third anniversary of the
effective date of this License Agreement, royalties of not less than the
following amounts will be deemed to have accrued hereunder in favor of OSURF:
<TABLE>
<S> <C> <C>
Year 4 $ 5,000.00 per quarter
Year 5 7,500.00 per quarter
Year 6 10,000.00 per quarter
Year 7 15,000.00 per quarter
Year 8 20,000.00 per quarter
Thereafter 25,000.00 per quarter
</TABLE>
<PAGE> 40
4.5. The fair value of any payment, thing, right or forbearance transferred to
or at the direction of OAI or a sub-licensee in exchange for the sale or lease
of Licensed Product or Licensed Service hereunder shall be included in the net
sale or lease amount upon which any royalties due OSURF hereunder are
calculated.
Records.
5.0. OAI and sub-licensees shall maintain records adequate to determine the
amount of royalties due to OSURF hereunder, and shall preserve such records and
make them available to OSURF for reasonable audit for three years following the
end of the period to which they pertain, or for such longer time as may be
necessary to finally resolve any questions that may be raised by OSURF. If any
audit reveals that payment of royalties due OSURF hereunder is delinquent by
$10,000.00 or more, OAI shall reimburse OSURF for its expenses in determining
and collecting the delinquent amount.
Term and Termination.
6.0. This License Agreement shall become effective upon execution by the last of
the parties to execute it.
6.1. Upon termination of this License Agreement all accrued royalties will
become due and payable within forty-five (45) days thereafter, and such
obligation, together with any other specific obligations of payment or otherwise
that have then matured, shall survive until discharged.
6.2. OAI may terminate this License Agreement at will upon written notice to
OSURF.
6.3. OSURF may terminate this License Agreement for breach of any material
provision thereof by OAI, including any of the undertakings set forth in
sections 3.0-3.6, particularly including the milestones set forth in sections
3.1-3.4, and in sections 4.1-4.5 and 8.2. OSURF shall notify OAI in writing of
any alleged breach of a material provision of this Agreement. OAI shall have
thirty (30) days after said notice to cure the alleged breach, after which
OSURF, subject to the terms of this Agreement, may terminate this License
Agreement.
6.4. Either party may terminate this License Agreement upon the insolvency or
bankruptcy of, or the seeking of protection from creditors by, the other.
6.5. Waiver of any breach shall not be deemed to impair the right of a party to
seek and obtain any remedy for any other breach.
Limitation of Liability.
7.0. OSURF makes no representations or warranties as to the accuracy or
reliability of any results or information provided in connection with this
License Agreement, or as to the validity or enforceability of any patent or
other rights conveyed hereunder, or as to the freedom of any Licensed Product or
Licensed Service hereunder from claim of infringement by others. IN
<PAGE> 41
PARTICULAR, OSURF MAKES NO WARRANTIES OF MERCHANTABILITY OR OF FITNESS FOR ANY
PARTICULAR PURPOSE IN RESPECT OF ANY GOODS, SERVICES OR INFORMATION.
Furthermore, OSURF will not be liable for any consequential or punitive damages
in connection with the subject matter of this License Agreement, nor in any
event will its liability exceed the amounts it has received pursuant to this
License Agreement.
Miscellaneous.
8.0. This License Agreement shall be construed in accordance with the laws of
the State of Ohio, except for provisions relating to conflict of law.
8.1. Neither party shall use the name of the other, or of any affiliate or
sub-licensee of the other, in connection with any commercial promotion, except
with prior express written consent.
8.2. OAI acknowledges the position of OSURF and The Ohio State University that
the existing SLI prototype at the University will not be available for
commercial demonstrations and that, except with the express and fully informed
approval of the University's Associate Vice President for Research and its
Director of the Comprehensive Cancer Center, or their authorized delegates, (i)
no research, development and/or testing activities relating to SLI technology
and supported or arranged for by or on behalf of OAI or any other licensee or
sublicensee of the SLI technology will be undertaken by or under the auspices of
OSURF or the University, and any approved exceptions should not discriminate to
the unfair disadvantage of any other licensee, (ii) Dr. Tomei will not
participate in research or development activities conducted by or under the
auspices of OSURF or the University to develop the SLI technology, and (iii) Dr.
Tomei will neither directly nor beneficially own, control or have an option or
other claim to more than a five percent (5%) interest in either the equity or
the debt of OAI or its successors, assigns or sublicensees and whatever direct
or beneficial interest he has will be held in a voting trust over which he has
no direct or indirect control. OAI will not take, or authorize or encourage
others to take, any action to subvert such positions, will not accept or retain
the fruits of any subversion of them, and will promptly report to said Associate
Vice President for Research any evidence of which it becomes aware that others
may be attempting to subvert them. However, it shall not be deemed a breach of
the provisions of this section 8.2 for OAI to solicit informed approval of
exceptions to these positions.
8.3. This License Agreement incorporates by reference the Confidentiality
Agreement between the parties dated December 17, 1990, and with that
incorporation sets forth the entire understanding between the parties relating
to its subject matter, integrating all prior representations and negotiations.
SCHEDULE A
U.S. Patent No. (or Issue (or
Appl'n. No.) Filing Date) Name Inventor(s) Title
<PAGE> 42
<TABLE>
<C> <C> <C> <C>
4,601,537 7/22/86 Sean M. Saccocia APPARATUS AND METHOD FOR FORMING IMAGES
AND FOR OPTICAL DEMULTI-PLEXING
4,758,727 7/19/88 L. David Tomei METHOD AND APPARATUS FOR THE
Cornhill, F. MEASUREMENT OF LOW-LEVEL LASER-INDUCED
Jagadeesh, J. FLUORESCENCE
Boninger, M.
4,877,966 10/31/89 L. David Tomei METHOD AND APPARATUS FOR THE
Cornhill, F. MEASUREMENT OF LOW-LEVEL LASER-INDUCED
Jagadeesh, J. FLUORESCENCE
Boninger, M.
5,037,207 08/06/91 L. David Tomei IMPROVED LASER IMAGING SYSTEM
Jagadeesh, J.
Cornhill, F.
Chen, Inching
(SN650,455) (02/04/91) L. David Tomei IMPROVED LASER IMAGING SYSTEM
Jagadeesh, J.
Cornhill, F.
Chen, Inching
</TABLE>
AGREED TO AND ACCEPTED:
Optical Analytic, Inc.
By:_______________________________________________________Date__________________
Print name/title________________________________________________________________
The Ohio State University Research Foundation
By: /s/ Thomas L. Sweeney Date 8/16/91
--------------------------------
Print name/title Executive Director, Thomas L. Sweeney
The Ohio State University
By: /s/ E.F. Hayes Date August 16, 1991
--------------------------------
Print name/title Edward F. Hayes, Vice President for Research
<PAGE> 43
Exhibit B2 to Perkin-Elmer License Agreement
<PAGE> 44
OPTICAL
ANALYTIC, INC.
------------------------------------------------------------------------
River Ridge Office Park
6400 Riverside Drive
Dublin, Ohio 43017
(614) 798-5300
November 23, 1993
VIA FACSIMILE
(510) 262-9932
Mr. Scott Minick
President and Chief
Executive Officer
LXR Biotechnology, Inc.
3065 Richmond Parkway
Richmond, California 94806-1900
Dear Scott:
Please find with this fax a copy of our signed License Agreement from Ohio State
and letter dated May 18, 1993, which extended the milestones to November 30,
1995, and removed the ownership caps on David's interest in the company.
It is my understanding that Ohio State will issue another extension letter
tomorrow. We will forward that letter along with the revised contracts at that
time.
Sincerely,
/s/ F. David Resch/bb
---------------------------
F. David Resch
FDR:bb
Enclosure
<PAGE> 45
oaisli.lc4
LICENSE AGREEMENT
This License Agreement is entered into between Optical Analytic, Inc., ("OAI"),
a corporation of Ohio having a principal place of business at 6400 Riverside
Dr., Dublin, Ohio 43017, and The Ohio State University Research Foundation
("OSURF"), a non-profit corporation of Ohio having a principal place of business
at 1960 Kenny Road, Columbus, Ohio 43210-1063 and acting on behalf of itself and
The Ohio State University ("University"), an instrumentality of the State of
Ohio, on the terms and conditions set forth hereinbelow, to cover commercial
development by OAI of Scanning Laser Imaging ("SLI") technology developed by Dr.
L. David Tomei and co-workers at the University.
Definitions.
1.0. The following definitions shall apply throughout this document and any
correspondence between the parties relating to the subject matter thereof,
except insofar as the context clearly indicates a different meaning.
1.1. "Licensed Patent" means a patent or patent application identified in
Schedule A, and any other patent or patent application, including any division,
continuation, continuation-in-part, reissue or foreign counterpart, insofar as
it derives therefrom or covers an SLI invention developed by Dr. Tomei and
coworkers at the University prior to the effective date of this License
Agreement.
1.2. "Licensed Product" means (i) an SLI instrument or device the manufacture,
import, sale or use of which is covered by a Licensed Patent or (ii) a component
intended for use as part of or in connection with such instrument or device
insofar as the manufacture, import, sale or use of such component is covered by
a Licensed Patent.
1.3. "Licensed Service" means the use of Licensed Product and/or of a method
covered by a Licensed Patent.
License Scope.
2.0. OSURF hereby grants to OAI, and OAI hereby accepts, a worldwide license
under all Licensed Patents to manufacture, import, export, use, sell and lease
Licensed Products and Licensed Services, and to sublicense others to do so,
subject to the reservation of the right of the University to operate under
Licensed Patents for research and/or educational purposes, and to the other
provisions of this License Agreement.
2.1. This License is co-exclusive, by which is meant that OSURF may grant only
one additional license under Licensed Patents for Licensed Products or Licensed
Services for any
<PAGE> 46
combination of field use, geographical area and period of time for which this
License is in effect. A single additional license has been granted for all
fields, all geographical areas and the life of the licensed patents. If such
additional license shall terminate, then OAI shall be notified in writing and
shall have the option, for sixty (60) days following such notice, of converting
its co-exclusive License to exclusive, provided that this License (to OAI)
remains in effect, that OAI is not in default or breach of this Agreement and
that OAI agrees in writing to thereafter pay minimum royalties equal to twice
those specified in Section 4.4 hereof.
2.2. This License shall take effect with respect to any Licensed Patent upon the
later of (i) the effective date of this License Agreement and (ii) the filing of
a patent application which falls within the definition of Licensed Patent. This
License shall terminate with respect to any Licensed Patent upon the earlier of
(iii) the termination of this License Agreement and (iv) the expiration,
cancellation or final unappealable determination of invalidity of such Licensed
Patent or the abandonment of a patent application which falls within the
definition of Licensed Patent.
Licensee Performance.
3.0. OAI will diligently exert its reasonable best efforts to develop and
market, either directly or through sub-licensees, Licensed Products and/or
Licensed Services for a broad range of applications. In particular, OAI
undertakes to achieve, directly or through sub-licensees, the milestones of
sections 3.1-3.4. OAI will notify OSURF of its achievement, partial achievement
or lack of achievement of these milestones in a timely manner, and in the
absence of such notice, it will be presumed that the milestones have not been
achieved. These milestones are established to manifest and exemplify the
understanding of the parties and the commitment of OAI that continuous progress
will be made toward accomplishing this objective. It is recognized that specific
times or periods set forth in sections 3.1-3.4 may become unachievable due to
unanticipated and/or uncontrollable circumstances, and in such cases consent to
reasonable adjustment thereof, not to exceed doubling of any stated or implied
period, shall not be unreasonably withheld by OSURF. However, it is also
understood that such times or periods have been specified with reasonable
allowance for problems and delays that are typical of such projects, and in
particular only where funds substantially in excess of those reasonably
anticipatable prove to be required for the achievement of any milestone will be
the period for achieving such milestone be adjusted on the basis of shortage of
funds.
3.1. Not later than twelve (12) months after the effective date of this
Agreement, OAI will have assembled a prototype SLI device for demonstration
purposes.
3.2. Not later than thirty-six (36) months after the effective date of this
Agreement, OAI will have accumulated data suitable for submission to the FDA for
regulatory approval of a Licensed Product or Service.
3.3. Not later than thirty-six (36) months after the effective date of this
Agreement, OAI will submit to the FDA an application for regulatory approval of
a Licensed Product or Service.
<PAGE> 47
3.4. Not later than twenty-four (24) months after the effective date of this
Agreement OAI will have a Licensed Product on the market, it being the
contemplation of the parties that this milestone will be met by a Licensed
Product not requiring FDA approval.
3.5. Thereafter introduction of Licensed Products and/or Services for sale or
lease will, as rapidly as practicable, be actively promoted by OAI and/or
sub-licensees for a broad range of applications.
3.6. OAI and its sub-licensees will mark all Licensed Products subject to this
License Agreement with the numbers of all applicable U.S. Licensed Patents.
Royalties and Other Payments.
4.0. [Reserved]
4.1. OAI will pay royalties to OSURF based upon the net sales and leases by OAI
and sub-licensees of Licensed Products and Licensed Services. For such
transactions not at arms-length, the royalties will be based upon similar
transactions that are at arms-length. No royalties will be due OSURF upon resale
of a Licensed Product for which royalties have accrued in favor of OSURF on the
initial sale pursuant to 4.1-4.3 and 4.5 hereof. No royalties will be due OSURF
in respect of Licensed Services provided through the use of a Licensed Product
upon which royalties have been paid to OSURF, unless royalties are payable to or
at the direction of OAI or a sub-licensee in respect of such Licensed Service
(herein referred to as "Section 4.1 Service Royalties").
4.2. Subject to section 4.1 above, royalties due OSURF hereunder will be five
percent (5.0%) of cumulative net sales and leases of Licensed Products and
Licensed Services under authority of this License Agreement, except that
royalties will be payable to OSURF in the amount of twenty percent (20%) of
Section 4.1 Service Royalties accrued on or before the second anniversary of the
effective date of this Agreement and thirty-three and one-third percent
(33-1/3%) of Section 4.1 Service Royalties accrued thereafter.
4.3. Royalties accrued in favor of OSURF hereunder during each calendar quarter
will be paid to OSURF by OAI within forty-five (45) days after the end of such
quarter, accompanied by a concise statement of the basis upon which the amount
due was determined.
4.4. For complete calendar quarters following the third anniversary of the
effective date of this License Agreement, royalties of not less than the
following amounts will be deemed to have accrued hereunder in favor of OSURF:
<TABLE>
<S> <C> <C>
Year 4 $ 5,000.00 per quarter
Year 5 7,500.00 per quarter
Year 6 10,000.00 per quarter
Year 7 15,000.00 per quarter
Year 8 20,000.00 per quarter
Thereafter 25,000.00 per quarter
</TABLE>
<PAGE> 48
4.5. The fair value of any payment, thing, right or forbearance transferred to
or at the direction of OAI or a sub-licensee in exchange for the sale or lease
of Licensed Product or Licensed Service hereunder shall be included in the net
sale or lease amount upon which any royalties due OSURF hereunder are
calculated.
Records.
5.0. OAI and sub-licensees shall maintain records adequate to determine the
amount of royalties due to OSURF hereunder, and shall preserve such records and
make them available to OSURF for reasonable audit for three years following the
end of the period to which they pertain, or for such longer time as may be
necessary to finally resolve any questions that may be raised by OSURF. If any
audit reveals that payment of royalties due OSURF hereunder is delinquent by
$10,000.00 or more, OAI shall reimburse OSURF for its expenses in determining
and collecting the delinquent amount.
Term and Termination.
6.0. This License Agreement shall become effective upon execution by the last of
the parties to execute it.
6.1. Upon termination of this License Agreement all accrued royalties will
become due and payable within forty-five (45) days thereafter, and such
obligation, together with any other specific obligations of payment or otherwise
that have then matured, shall survive until discharged.
6.2. OAI may terminate this License Agreement at will upon written notice to
OSURF.
6.3. OSURF may terminate this License Agreement for breach of any material
provision thereof by OAI, including any of the undertakings set forth in
sections 3.0-3.6, particularly including the milestones set forth in sections
3.1-3.4, and in sections 4.1-4.5 and 8.2. OSURF shall notify OAI in writing of
any alleged breach of a material provision of this Agreement. OAI shall have
thirty (30) days after said notice to cure the alleged breach, after which
OSURF, subject to the terms of this Agreement, may terminate this License
Agreement.
6.4. Either party may terminate this License Agreement upon the insolvency or
bankruptcy of, or the seeking of protection from creditors by, the other.
6.5. Waiver of any breach shall not be deemed to impair the right of a party to
seek and obtain any remedy for any other breach.
Limitation of Liability.
7.0. OSURF makes no representations or warranties as to the accuracy or
reliability of any results or information provided in connection with this
License Agreement, or as to the validity or enforceability of any patent or
other rights conveyed hereunder, or as to the freedom of any Licensed Product or
Licensed Service hereunder from claim of infringement by others. IN
<PAGE> 49
PARTICULAR, OSURF MAKES NO WARRANTIES OF MERCHANTABILITY OR OF FITNESS FOR ANY
PARTICULAR PURPOSE IN RESPECT OF ANY GOODS, SERVICES OR INFORMATION.
Furthermore, OSURF will not be liable for any consequential or punitive damages
in connection with the subject matter of this License Agreement, nor in any
event will its liability exceed the amounts it has received pursuant to this
License Agreement.
Miscellaneous.
8.0. This License Agreement shall be construed in accordance with the laws of
the State of Ohio, except for provisions relating to conflict of law.
8.1. Neither party shall use the name of the other, or of any affiliate or
sub-licensee of the other, in connection with any commercial promotion, except
with prior express written consent.
8.2. OAI acknowledges the position of OSURF and The Ohio State University that
the existing SLI prototype at the University will not be available for
commercial demonstrations and that, except with the express and fully informed
approval of the University's Associate Vice President for Research and its
Director of the Comprehensive Cancer Center, or their authorized delegates, (i)
no research, development and/or testing activities relating to SLI technology
and supported or arranged for by or on behalf of OAI or any other licensee or
sublicensee of the SLI technology will be undertaken by or under the auspices of
OSURF or the University, and any approved exceptions should not discriminate to
the unfair disadvantage of any other licensee, (ii) Dr. Tomei will not
participate in research or development activities conducted by or under the
auspices of OSURF or the University to develop the SLI technology, and (iii) Dr.
Tomei will neither directly nor beneficially own, control or have an option or
other claim to more than a five percent (5%) interest in either the equity or
the debt of OAI or its successors, assigns or sublicensees and whatever direct
or beneficial interest he has will be held in a voting trust over which he has
no direct or indirect control. OAI will not take, or authorize or encourage
others to take, any action to subvert such positions, will not accept or retain
the fruits of any subversion of them, and will promptly report to said Associate
Vice President for Research any evidence of which it becomes aware that others
may be attempting to subvert them. However, it shall not be deemed a breach of
the provisions of this section 8.2 for OAI to solicit informed approval of
exceptions to these positions.
8.3. This License Agreement incorporates by reference the Confidentiality
Agreement between the parties dated December 17, 1990, and with that
incorporation sets forth the entire understanding between the parties relating
to its subject matter, integrating all prior representations and negotiations.
SCHEDULE A
U.S. Patent No. (or Issue (or
Appl'n. No.) Filing Date) Name Inventor(s) Title
<PAGE> 50
<TABLE>
<C> <C> <C> <C>
4,601,537 7/22/86 Sean M. Saccocia APPARATUS AND METHOD FOR FORMING IMAGES
AND FOR OPTICAL DEMULTI-PLEXING
4,758,727 7/19/88 L. David Tomei METHOD AND APPARATUS FOR THE
Cornhill, F. MEASUREMENT OF LOW-LEVEL LASER-INDUCED
Jagadeesh, J. FLUORESCENCE
Boninger, M.
4,877,966 10/31/89 L. David Tomei METHOD AND APPARATUS FOR THE
Cornhill, F. MEASUREMENT OF LOW-LEVEL LASER-INDUCED
Jagadeesh, J. FLUORESCENCE
Boninger, M.
5,037,207 08/06/91 L. David Tomei IMPROVED LASER IMAGING SYSTEM
Jagadeesh, J.
Cornhill, F.
Chen, Inching
(SN650,455) (02/04/91) L. David Tomei IMPROVED LASER IMAGING SYSTEM
Jagadeesh, J.
Cornhill, F.
Chen, Inching
</TABLE>
<PAGE> 51
AGREED TO AND ACCEPTED:
Optical Analytic, Inc.
By: /s/ James McCormick Date 8/15/91
--------------------------------
Print name/title James McCormick, President
The Ohio State University Research Foundation
By: /s/ Thomas L. Sweeney Date 8/16/91
--------------------------------
Print name/title Thomas L. Sweeney/Executive Director
The Ohio State University
By: /s/ Edward F. Hayes Date August 16, 1991
--------------------------------
Print name/title Edward F. Hayes, Vice President for Research
<PAGE> 52
- ----------------------
T . H . E Office of Technology Transfer 1960 Kenny Road
OHIO Columbus, OH 43210-1063
STATE
UNIVERSITY May 18, 1993 Phone 614-292-2550
FAX 614-292-1727
- ----------------------
James M. McCormick
Optical Analytic, Inc.
6400 Riverside Drive
Dublin, OH 43017
Re: Amendment of License Agreement of August 26, 1991 for SLI
Technology (Original Document and Identified by Running Header
"oaisli.1c4")
Dear Mr. McCormick:
In response to your requests, and in view of Optical Analytical's efforts to
date to press forward after the termination of your joint venture with
colicensee Fettig, Inc. and of OAI's plans for the future, we are willing to--
(i) consent to adjusting the milestone deadlines specified in
sections 3.1 through 3.4,
(ii) waive non-compliance by OAI with the milestone deadline
specified in section 3.1 (as extended by letter dated August 12, 1992), and
(iii) release OAI from the restrictions on Dr. Tomei's
interest in OAI and related entities specified in section 8.2 (iii) --
by amending the above-identified License Agreement as follows:
A. In each of the sections 3.1. through 3.4., inclusive, the period for
meeting their respective milestone is extended by fifteen (15) months
beyond that specified in the original Agreement, and any default by OAI
prior to the effective date of this amendment in meeting the original
deadline for the milestone in any of these sections is waived;
provided, however, that the SLI devices referred to, directly or by
implication, in these sections are based on second-generation
multiparametric SLI technology.
B. In section 8.2., the test reading --
and (iii) Dr. Tomei will neither directly nor beneficially
own, control or have an option or other claim to more than a
five percent (5%) interest in either the equity or the debt of
OAI or its successors, assigns or sublicensees and whatever
direct or beneficial interest he has will be held in a voting
trust over which he has no direct or indirect control--
is deleted.
<PAGE> 53
C. These amendments will be effective as of the date when this document
has been executed below by all parties.
If these amendments are acceptable, please have all three copies signed below
where indicated and return two copies to me.
Sincerely,
/s/ James B. Wilkens
---------------------------
James B. Wildens
AGREED AND ACCEPTED--
The Ohio State University Research Foundation
By: /s/ T.L. Sweeney Date: 5/19/93
--------------------------------
Print name/title: Thomas L. Sweeney, Executive Director
The Ohio State University
By: /s/ Janet G. Pitchette Date: 18 May 93
--------------------------------
Print name/title: Janet G. Pichette, Vice President
By: /s/ James M. McCormick Date: 5/21/93
--------------------------------
Print name/title: James M. McCormick -President
<PAGE> 54
- ----------------------
T . H . E Office of Technology Transfer 1960 Kenny Road
OHIO Columbus, OH 43210-1063
STATE
UNIVERSITY August 31, 1993 Phone 614-292-2550
FAX 614-292-1727
- ----------------------
James M. McCormick
Optical Analytic, Inc.
6400 Riverside Drive
Dublin, Ohio 43017
Subject: Option Under License Agreement of August 26, 1991 for SLI Technology
(Original Document Identified by Running Header "oaisli.lc4"), as
Amended by a Document Dated May 18, and Effective May 21, 1993.
Dear Mr. McCormick:
Pursuant to Section 2.1 of the above-identified license agreement, we hereby
inform you that we have given notice to the additional (co-exclusive) licensee
terminating that additional (co-exclusive) license for cause, effective (as
permitted by the terms of that license) upon receipt of our notice, which the
carrier's proof of delivery return shows was no later than July 30, 1993. We
have had no response to that notice (or to an earlier notice dated July 7, 1993
for which the carrier has been unable to produce proof of delivery). In any
case, we regard that additional (co-exclusive) license as terminated, and that
option provisions of Section 2.1 as in effect as of September 1, 1993.
If you wish to exercise that option, as I understand from Bill Root you do, you
may do so according to the EXERCISE OF OPTION language below by signing where
indicated on all three original counterparts of this letter and returning them
to me within sixty days of this notice for affixation of our signatures,
whereupon one will be returned to you. Please let me know if you have any
questions.
Sincerely,
/s/ James B. Wilkens
-----------------------
James B. Wilkens
EXERCISE OF OPTION
Optical Analytic, Inc., having received the foregoing notice of termination of
the additional (co-exclusive) license referred to in Section 2.1 of the
above-identified license agreement, hereby
<PAGE> 55
exercises its option under such Section 2.1 to convert its license to an
exclusive license and, in accordance with the provisions of such Section 2.1,
will hereafter pay minimum royalties equal to twice those specified in Section
4.4 of such above-identified license agreement.
Optical Analytic, Inc.
By /s/ James M. McCormick Date September 7, 1993
----------------------------
Print name/title James M. McCormick, President
The Ohio State University Research Foundation and The Ohio State University
accept the above EXERCISE OF OPTION and recognize the above-identified license
agreement as amended in accordance therewith as of the date written adjacent the
signature above.
The Ohio State University Research Foundation
By: /s/ T.L. Sweeney Date 9/23/93
- ----------------------------
The Ohio State University
By /s/ Janet G. Pichette Date 17 Sep 93
- ----------------------------
Janet G. Pichette, V.P. Business & Admin.
<PAGE> 56
Exhibit B3 to Perkin-Elmer License Agreement
<PAGE> 57
- ----------------------
T . H . E Office of Technology Transfer 1960 Kenny Road
OHIO Columbus, OH 43210-1063
STATE
UNIVERSITY August 31, 1993 Phone 614-292-2550
FAX 614-292-1727
- ----------------------
James M. McCormick
Optical Analytic, Inc.
6400 Riverside Drive
Dublin Ohio
Subject: Amendment of License Agreement of August 26, 1991 for Scanning Laser
Imaging Technology and Amendment to said License in Wilkens to
McCormick letter dated May 28,1993.
Dear Mr. McCormick:
In response to your requests and in view of your further efforts to
commercialize the Scanning Laser Imaging Technology (SLI) developed at
UNIVERSITY (referring hereinafter collectively to The Ohio State University and
The Ohio State University Research Foundation), and with the realization that
Optical Analytic, Inc. (OAI) will have the exclusive license to develop and
commercialize this technology, the University is willing to:
a. extend the milestone deadlines specified in sections 3.1 through 3.4
beyond the maximum contemplated in Section 3.0, and extend the period
till the minimum royalties are required.
b. provide restricted permission for the use of UNIVERSITY's name in
documents describing the relationship between UNIVERSITY and OAI with
respect to the SLI,
in return for OAI's agreement to reimburse certain patenting expenses.
To achieve these ends the subject License Agreement is amended as follows:
1. In each of the sections 3.1. through 3.4. inclusive, the period for
meeting the respective milestone is extended by twenty-four (24) months
beyond that specified in the original agreement and any default by OAI
prior to the effective date of this amendment in meeting the original
deadline for the milestone in any of these sections is waived; provided
however, that the SLI devices referred to directly or by implication,
in these sections are based on second-generation multiparametric SLI.
2. Amend section 4.4. to state that minimum royalties begin after the
fourth anniversary of the original agreement and that those minimums
are $5,000., $7,500., $10,000., $15,000., $20,000. and $25,000. per
quarter for Year 5, Year 6, Year 7, Year 8, Year 9, and Thereafter,
respectively.
<PAGE> 58
3. Insert section 4.0.:
OAI shall reimburse UNIVERSITY for patenting expenses, for the patents
which are the subject of this license agreement, billed after the date
of this letter. Reimbursement shall be within sixty (60) days of
receipt by OAI of an invoice from UNIVERSITY.
Section 8.1 restricts the use by either party of the name of the other party for
use in any commercial promotion. Permission is hereby given for use of the name
in a legal Prospectus only to refer to UNIVERSITY for the limited purpose of
giving the information that the SLI was invented at UNIVERSITY and that OAI has
an exclusive license from UNIVERSITY to commercialize the SLI. No other use is
permitted without prior written permission from UNIVERSITY.
These amendments will be effective as of the date when this document is executed
below by all parties.
Regards,
Paul G. Lafayatis
Director, Technology Transfer
AGREED AND ACCEPTED:
The Ohio State University Research Foundation
By: /s/ T.L. Sweeney Date: 11/29/93
----------------------
Title: Executive Director
The Ohio State University
By: /s/ T.L. Sweeney Date: 11/29/93
----------------------
Title: Assoc VP - Research
Optical Analytic, Inc.
By: /s/ James M. McCormick Date: 11/29/93
----------------------
Title: President
<PAGE> 59
Exhibit B4 to Perkin-Elmer License Agreement
<PAGE> 60
AMENDMENT TO SLDI LICENSE AGREEMENT
The License Agreement among Optical Analytic, Inc., The Ohio State Research
Foundation and The Ohio State University dated August 26, 1991, as amended to
date ( the "License"), is hereby further amended to delete paragraphs 3.2 and
3.3 of the License, effective as of July 10, 1996.
OPTICAL ANALYTIC, INC.
By: /s/ L. David Tomei
----------------------------
L. David Tomei, President
THE OHIO STATE UNIVERSITY
By: /s/ Paul G. Lafayatis
----------------------------
Its: Director, Technology Transfer
THE OHIO STATE UNIVERSITY RESEARCH FOUNDATION
By: /s/ Paul G. Lafayatis
----------------------------
Its: Director, Technology Transfer
<PAGE> 61
Exhibit B5 to Perkin-Elmer License Agreement
<PAGE> 62
AMENDMENT TO SLDI LICENSE AGREEMENT
The License Agreement among Optical Analytic, Inc. ("OAI"), The Ohio
State Research Foundation ("OSRF") and The Ohio State University ("OSU") dated
August 26, 1991, as amended to date ( the "License"), is hereby further amended
to delete U.S. Patent No. 4,601,537, titled "APPARATUS AND METHOD FOR FORMING
IMAGES AND FOR OPTICAL DEMULTIPLEXING" (the "'537 Patent"), from Schedule A to
the License, and thereby from the definition of "Licensed Patent" in Section 1.1
of the License, so that the '537 Patent is no longer licensed to OAI under the
License.
All other provisions of the License shall remain in full force and
effect.
IN WITNESS WHEREOF, the parties hereto have entered into this Amendment
as of August 27, 1996.
OPTICAL ANALYTIC, INC.
By:
----------------------------
L. David Tomei, President
THE OHIO STATE UNIVERSITY
By:
----------------------------
Its: Vice President for Business & Admin.
THE OHIO STATE UNIVERSITY RESEARCH FOUNDATION
By:
----------------------------
Its: Director, Technology Transfer
<PAGE> 63
Exhibit C1 to Perkin-Elmer License Agreement
<PAGE> 64
US PATENT 5,037,207
<=2> GET 1st DRAWING SHEET OF 74
Aug. 6, 1991
Laser imaging system
INVENTOR: Tomei, L. David, Columbus, Ohio
Jagadeesh, Jogikal, Columbus, Ohio
Cornhill, Fred, Worthington, Ohio
Chen, Inching, Columbus, Ohio
ASSIGNEE-AT-ISSUE: Ohio State University Research Foundation, Columbus, Ohio
(02)
APPL-N0: 174,977
FILED: Mar. 28, 1988
REL-US-DATA:
Continuation-in-part of Ser. No. 828,651, Feb. 12, 1986 now abandoned
INT-CL: [5] G01J 3#10
US-CL: 356#444; 250#458.1; 356#344; 356#417
CL: 356;250
SEARCH-FLD: 356#344, 444, 317, 318, 417; 250#458.1, 459.1, 461.1, 461.2
REF-CITED:
U.S. PATENT DOCUMENTS
3,450,455 6/1969 * Landre 356#444
3,516,746 6/1970 * Shibata et al. 356#319
3,981,590 9/1976 * Perkins 356#419
4,107,534 8/1978 * Piltingsrud 250#368
4,523,799 6/1985 * Delhaye 350#6.3
4,586,781 5/1986 * Gunther et al. 350#3.7
4,758,727 7/1988 * Tomei et al. 250#461.2
FOREIGN PATENT DOCUMENTS
<PAGE> 65
0123942 11/1984 * European Patent Organization
0155813 9/1985 * European Patent Organization
OTHER PUBLICATIONS
Nicoll, F., "Mural Television Display Using Fiber Optics", RCA Technical Notes
(RCA TN No. 188, 1958).
Dyer et al., "Vidicon Microscope for Counting Fluorescent Particles", Review of
Scientific Instruments, vol. 24, No. 4 (1971), p. 508.
Slomba et al., "A Laser Flying Spot Scanner for Use in Automated Fluorescence
Antibody Instrumentation", Journal of the Association for the Advancement of
<PAGE> 66
PAGE 2
Pat. No. 5037207, *
Medical Instrumentation, vol. 6, No. 3, May-Jun. 1972.
Bussini et al., "A Silicon Rubber Scintillation Compound for Complex Geometry
Radiation Detectors", Nuclear Instruments and Methods, No. 2, (1973), pp.
333-335.
"The New FACS 400 Series, FACS 440, FACS 420, FACS 400, Fluorescence Activated
Cell Sorting", Becton Dickenson FACS Systems, 1981.
"The FACS Analyzer Fluorescence and Volume Cell Analysis" Brochure, Becton
Dickenson FACS Systems, 1982.
Young et al., IEEE Transactions on Biomed. Engineering, BME-29;2, 1983.
Shoemaker et al., IEEE Transactions on Biomed. Engineering, BME-33, 1984.
"Photodigitizing with PDS Microdensitometer Systems" Brochure, Perkin-Elmer, not
dated.
"Microdensitometer 3 CS" Brochure, Joyce-Loebl, not dated.
"Microdensitometer 6" Brochure, Joyce-Loebl, not dated.
"EIKONIX Registered TM Applied Research Software and Product Development
Feasibility and Impact Studies Automated Instruments" Brochure, EIKONIX
Registered TM Corporation, not dated.
"ACAS 470 Workstation" Brochure, Meridian Instruments, Inc., not dated.
"Cytoscan-Cytogenetic Scanning Analyser System" Brochure, Image Recognition
Systems, Ltd., not dated.
PRIM-EXMR: Rosenberger, Richard A.
LEGAL-REP: Emch, Schaffer, Schaub & Porcello Co.
ABST:
A laser imaging system is disclosed which provides the versatility of wide
field digital imaging with enhanced spatial resolution and light gathering
efficiency. The system will scan targets of any size, dependent only upon the
data retrieval and storage limitation of the computer support system, for
forward light loss densitometry images as well as fluorescent and forward
scatter images. The system is easily adaptable for rare event detection and
tracking. The laser system will provide image capture of an entire target within
10 to 60 seconds and controls the scan of the laser beam in three-dimensional
pattern and speed. The beam may be repositioned to any one of 16 million
locations on a target within an accuracy of + / - 0.5 um. Finally, the imaging
system of the present invention utilizes a novel optical fiber based detector
assembly having NA values of 0.58-0.95 and filters having less than 15% loss at
emission wavelengths. Thus, the imaging system of the present invention can
capture from 14% to 32% of total fluorescence emission.
<PAGE> 67
NO-OF-CLAIMS: 11
EXMPL-CLAIM: <=10> 1
NO-OF-FIGURES: 77
NO-DRWNG-PP: 74
PARCASE:
This is a continuation-in-part of copending application Ser. No. 828,651
filed on Feb. 12, 1986, now abandoned.
<PAGE> 68
PAGE 3
Pat. No. 5037207, *
SUM:
BACKGROUND OF THE INVENTION
The laser imaging system of the present invention is designed to provide a
means for rapid quantitative image capture and digitization where requirements
for field size, speed, spatial resolution, dynamic range, and low light
sensitivity are not adequately provided for by conventional optical imaging
devices.
Specifically, optical devices that incorporate lenses to form a real or
virtual image at any point in the system are limited with respect to the target
field size, given a particular effective numerical aperture (NA) and spatial
resolution. For instance, a microscope provides a means of imaging using lenses
of high light gathering power, i.e., high numerical aperture (NA). Typically the
value of the NA for an objective lens with 20X is 0.50 (range 0.40-0.75).
However, this type of lens is capable of imaging a field of only 3 square
millimeters. See for example FIG. 1. If a field of 20 mm x 40 mm is to be imaged
(approximately the area of a standard microscope slide), then the maximum
effective NA for conventional optical lenses would be approximately 0.04-0.10.
For this reason highly sensitive fluorescence measuring devices have
incorporated microscopes with high NA lenses equipped with mechanical stages to
move the target and effect the wide field scan.
Gross mechanical translation of targets such as microscope slides is
generally slow and subject to maintenance problems related to wear and failure.
The ability of mechanical stages to physically move the target is limited by the
need for high positioning accuracy which is typically within 0.5 um. Thus, a
high precision autostage will have a maximal translation rate of only about 20
mm/second. Other additional complicating factors involved in image capture
require that the mechanical stage stop at each field location long enough for
the capture device to electronically transfer the image data to some storage
form. Thus, these conventional optical devices, when used for high resolution,
low light level scans (e.g., immunofluorescence), can require several hours to
capture target fields the size of a standard microscope slide.
If a field of 20 mm x 40 mm is to be imaged, then compromises are necessary
when using optical lenses. Wide field imaging with effective numerical apertures
of 0.9 or higher has led to complex designs and instruments that require hours
for image capture. A significant improvement upon these conventional optical
devices is the flying spot scanner. However, the flying spot scanners available
<PAGE> 69
today including the most recent laser-induced devices, have a significant
problem, which is the simple fact that the focal point of the light beam is
fixed. Therefore, for a two dimensional scan, the beam spot is found on a curved
surface. Correction for this curvature in the present day flying spot scanner
requires the incorporation of cumbersome multisided spinning mirrors of complex
design. These mirrors afford little control over the location of the laser beam.
Conventional flying spot scanners also move the laser in a preprogrammed
ballistic direction. The direction and velocity parameters are preprogrammed and
the scan cannot be controlled outside of the programming.
Another problem associated with the design of a flying spot scanner for use
in fluorescence detection or forward scatter detection is the relatively low
efficiency light gathering available using conventional design which use lenses
for detection. For instance, a design described by Slomba, et al., (J. Assoc.
<PAGE> 70
PAGE 4
Pat. No. 5037207, *
Adv. Medical Instr., 6:230, 1972) for a flying spot fluorescence detection is
capable of capturing less than 1% of the total target emission. This is
equivalent to an unacceptable NA of 0.10.
Imaging systems can be designed for a large variety of applications.
Generally, however, the requirements of target field size, NA, and spatial
resolution dictate specific structures for specific applications. There is
little crossover in design for the varying applications. The imaging system of
the present invention overcomes the design limitations of current imaging
devices and is easily adaptable to perform a large number of imaging operations.
SUMMARY OF THE INVENTION
The laser imaging system of the present invention eliminates the need for
mechanical translation stages for targets. The system is capable of scanning
targets of any size without gross stage movement subject only to the limitations
of available data processing and storage capabilities. The imaging provided by
the present invention is based not only upon optical density and forward light
loss (FLL) densitometry, but light scatter and fluorescence emission as well.
The scanning system can also be programmed to scan for rare event detection and
tracking, (i.e., the following of a neutron path in a target). The system will
provide image capture of an entire target within 10 to 60 seconds and controls
the scan of the laser beam in both pattern and speed. The beam spot may be
repositioned to any one of 16 million locations on a target within an accuracy
of + / - 0.5 um. Finally, the imaging system of the present invention utilizes a
novel optical fiber based detector assembly having NA values of 0.58-0.95 and
filters having less than 15% loss at emission wavelengths. Thus, the imaging
system of the present invention can capture from 14% to 32% of total
fluorescence emission.
The imaging system is easily adaptable to undertake a large variety of
imaging applications. The system will perform Clonogenic Assays and cDNA and
genomic DNA imaging. The system will perform multiwell plate assays such as a
fluorescence assay from any immobilized immunofluorescence assay system. Another
application is the imaging of submicron particles based on scatter
characteristics. Other applications include the discrimination of plane
polarized fluorescence emissions and qualitative and quantitative imaging of
those emissions. The imaging system of the present invention will perform
neuroautoradiographs yielding quantitative digital images in neutral density or
digital color. Yet another application is the migration inhibition assay using
multiwell plates for bone marrow transplantation testing. The imaging system of
the present invention will perform 3D Interferometry Surface Profiling for
<PAGE> 71
non-contact micro-surface quantitative analysis. Another application for the
imaging system is the measurement of scatter or density for a cytochemistry
analysis of large sample screening.
The imaging system of the present invention performs opaque gel scanning as
well as transparent or semitransparent (i.e., translucent) gel scanning.
Scanning densitometry is used to quantitate typical translucent gels such as
agarose gels following chemical staining of the DNA, RNA, or protein bound to
the gel. However, the high degree of biochemical resolution required for gene
sequence analyses has resulted in the development of analytical techniques which
involve the electrophoretic transfer of material from translucent separation
gels to opaque membranes typically constructed of glass fibers or nylon matrix.
The material on these membranes is visualized by introducing a chemical stain to
colorimetrically mark the position and amount of the material. The material
<PAGE> 72
PAGE 5
Pat. No. 5037207, *
can also be labeled with a radioactive marker for subsequent analysis using
autoradiographic techniques and additional photosensitive elements such as x-ray
film. The membrane matrix prevents the use of conventional optical scanning
densitometry techniques because of the high light diffusion and attenuation
produced by the matrix. This is comparable to a high resolution image located on
a single side of heavy photographic paper. The optical fiber detector assembly
of the laser imaging system of the present invention collects all light, from
the entire scanned area, emitted at angles up to 90o from the optical axis
simultaneously at each and every position of the laser spot and assigns the
value of the light intensity to that individual position or pixel. Within
seconds, this process is performed several million times and a quantitative
digital reproduction is obtained of the image on the surface of the stained
membrane, photographic paper, or similar target scanned. Since this differs from
simple axial light loss or optical density, it is referred to as Forward Light
Loss (FLL) scanning.
Finally, the imaging system will perform the scanning of fluorescence
shadowing and forward scatter fluorescence shadowing through the use of a
fluorescent sensor, thus eliminating the problems of measuring the laser spot
size and focusing the spot.
These applications of the present invention are currently known, however,
this list is not intended to be limiting upon the range of potential uses for
this system.
DRWDESC:
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a graph showing the relationship of the numerical aperture (NA) and
target field image size for conventional lenses.
FIG. 2 is a schematic illustration of the laser imaging system of the present
invention.
FIG. 3 is an illustrative representation of a typical microscope slide and a
pattern of laser scanning the slide.
FIG. 4 is an illustrative representation of the light detection properties of
a blunt-cut optical fiber faceplate and a bias-cut optical fiber faceplate.
FIG. 5 is a schematic illustration of a typical detector assembly as used
<PAGE> 73
with the present invention.
FIG. 6 is a schematic illustration of a detector assembly for use with the
present invention in detecting fluorescence and forward light scatter.
FIG. 7 is a conceptical illustration of the detector assembly of FIG. 6.
FIG. 8 is a graph showing optical fiber polarimetry for square
cross-sectional optical fibers.
FIG. 9 is an illustrative schematic of the plane polarization by a square
cross-sectional optical fiber of fluorescence emissions.
<PAGE> 74
PAGE 6
Pat. No. 5037207, *
FIG. 10A is a schematic block diagram of the image memory controller and
image memory array for the imaging system of the present invention.
FIG. 10B is a schematic block diagram of the CRT controller and graphics
memory array for the imaging system of the present invention.
FIG. 11 is a schematic illustration of the light acceptance cone of a
bias-cut optical fiber faceplate.
FIGS. 12A, B, C and D are schematics for the Image Memory Controller of the
present invention showing the circuitry for the Memory Request Arbiters and the
Input/Out Access circuitry.
FIGS. 13A, B, C and D are schematics for the Image Memory Controller of the
present invention showing the circuitry for the Memory and the Input/Output
Address Decoder.
FIGS. 14A, B, C and D are schematics for the Image Memory Controller of the
present invention showing the circuitry for the Memory Refresh Function and the
Interrupt Request Function and Data Transfer Acknowledgement Generation.
FIGS. 15A, B, C and D are schematics showing the Address Multiplexer
circuitry for the Image Memory Controller of the present invention.
FIGS. 16A and B are schematics showing the Memory Buffers circuitry for the
Image Memory Controller of the present invention.
FIGS. 17A and B are schematics showing the Input/Output registers circuitry
for the Image Memory Controller of the present invention.
FIGS. 18A, B, C and D through 20A, B, C and D are schematics showing the
Memory Chip Array circuitry for the Image Memory Array of the present invention.
FIGS. 21A, B, C and D are schematics showing the Memory Arrays, Address
liners, and Control Bus circuitry for the Image Memory Array of the present
invention.
FIGS. 22A, B, C and D are schematics showing the Image Data Shift Register
circuitry for the Image Memory Array of the present invention.
FIG. 23 is a schematic showing the Memory Array circuitry for the Image
<PAGE> 75
Memory Array of the present invention.
FIGS. 24A, B, C and D are schematics showing the Video Display Generator
Interface circuitry for the CRT controller of the present invention.
FIGS. 25A, B, C and D are schematics showing the Address Decoder, Graphics
Memory Interface and Interrupt Request and Acknowledge circuitry of the CRT
Controller of the present invention.
FIGS. 26A, B, C and D are schematics showing the Zoom Control and Look-up
Table Circuitry for the CRT Controller of the present invention.
FIGS. 27A, B, C and D are schematics showing the Memory Chip Array circuitry
for the Graphics Memory Array of the present invention.
<PAGE> 76
PAGE 7
Pat. No. 5037207, *
FIGS. 28A, B, C and D are schematics showing the Graphics Display and Shift
Register circuitry for the Graphics Memory Array of the present invention.
FIGS. 29A, B, C and D are schematics showing the D/A Converter circuitry for
the Graphics Memory Array of the present invention.
DETDESC:
DESCRIPTION OF THE PREFERRED EMBODIMENT
The laser imaging system of the present invention provides wide field digital
imaging with enhanced spatial resolution and light gathering efficiency.
Referring now to FIG. 2, the optical design used with the imaging system is
shown. The primary laser 10, a 25 mW He-Cd, Omnichrome 450X, provides a beam 12
to a beam expander 14 composed of an objective lens and a 50 um spatial filter.
The beam 12 exits the beam expander 14 as an input collimated beam 16, 10 mm in
diameter. A three dimensional beam position controller 18, manufactured by
General Scanning Corp., receives the collimated beam 16.
The beam expander 14 ensures the utilization of the greatest possible surface
area of the mirrors of the beam controller 18. The beam 12 from the laser 10 is
too small and the beam expander 14 provides an adjustable spot size from 1 mm to
10 mm according to the needs of the controller 18. The beam expander 14 can be
modified optically to take advantage of Bessel Function beam characteristics if
desired. Such beam characteristics are evidenced by diminishing diffraction
rings which circle around the center spot. The optics of the beam expander 14
can be modified by replacement of the spatial filter with a circular disc to
block the high energy diffraction rings. Such a modification focuses the imaging
beam to a carefully selected spot size without any unwanted spillover.
The beam controller 18 includes an imaging lens (not shown) which produces a
2-10 um diameter spot depending on the diameter of the collimated beam 16.
Galvanometrically driven mirrors (not shown) incorporated within the beam
controller 18 provide for control over the 2-10 um diameter spot in the X, Y and
Z axes as the spot is focused on the target plane 20. The beam controller 18
allows for maximum scanning rates up to 100 Hz or an approximate spot vector
rate of 800 cm/sec. Each of the three axes of the beam controller 18 are under
individual software control which permits any desired scanning or tracking
pattern to be performed. Placement of the laser spot is accurate within + / -
0.5 um, thus the laser spot can be fixed on any specified cell in the target 20
<PAGE> 77
area after scanning. Such placement accuracy permits further imaging at a higher
resolution and the recording of cell location for further direct examination if
desired.
The 3-D beam controller 18 manufactured by General Scanning, Inc.,
incorporates independent temperature control on all three main galvanometer
drives which maintains the temperature at 40 ( + / - 0.5) degrees C. The upper
scanner and lower laser chambers incorporate sensors (not shown) for continuous
monitoring of ambient temperature during operation. The He-Cd or Argon-ION laser
in the lower chamber is provided with ducted positive ventilation using room air
in order to minimize environmental contamination and control the operating
temperatures of the optical components.
<PAGE> 78
PAGE 8
Pat. No. 5037207, *
As shown in FIG. 4, the imaging system can scan the entire sample area of a
microscope slide of prepared cells which will include 5 million to 20 million
cells. The system is driven at rates up to 100 Hz, which means that a single
line can be scanned in 0.005 seconds. The system can be programmed to perform
either vector scans or raster scans equally efficiently. The X and Y steps are
variable from 0.6 um to 40 mm in 0.6 um units. To illustrate the effectiveness
of this approach to scanning blood smears, the system is capable of detecting a
single positive fluorescent cell on a slide area of 400 sq. mm. (which can
include as many as 20 million cells), measure the fluorescence emission level
(up to 12 bit resolution), and specify the location of the cell within an
accuracy of + / - 0.5 um.
The basic detector assembly 22 is comprised of three basic elements: a high
numerical aperture optical fiber faceplate 24; a diffusion assembly 26 and a
photomultiplier tube (PMT) 32. The basic diffusion assembly 26 includes flashed
opal diffusion filters 30 and an internally reflective cylindrical coupling 28.
Two basic configurations of the optical fiber faceplate 24 are utilized
dependent on whether the imaging is to be based upon light transmission or
fluorescence emission within the target.
Referring to FIG. 4, laser imaging based upon detection of differences in
optical density [i.e., wide angle forward light loss (FLL)] utilizes a blunt-cut
high numerical aperture optical fiber faceplate 24 to collect and transmit light
to the PMT 28. However, for imaging fluorescence emissions the primary beam is
initially blocked on axis by introducing a bias end cut on the optical fibers.
Referring to FIG. 11, the acceptance cone of the component fibers is "tipped" by
angle B which is related to the bias end cut angle A as follows:
B = sin< - 1> [(N2/N1) sin A] - A
where N1 and N2 are the indices of refraction of air and the fiber core
respectively. The numerical aperture is not significantly changed when A is
approximately 30 degrees and, therefore, the light gathering power of the fibers
is not diminished when the incidence angle of the excitation beam remains close
to 90o however, the energy at the PMT is reduced more than 99%.
The PMT 32 is a high gain, low noise unit (Hamamatsu) having a 300-650 nm
response (max. 400 nm) typically operated at 600 to 1250 volts. It is critical
that transmitted light be diffused uniformly across the 2 inch diameter PMT 32
window to minimize variations in output related to spot position on target
plane. This is effectively accomplished by the combination of inherent annular
<PAGE> 79
ray rotation at fiber output the optical and the diffusion assembly 26 which
includes the cylindrical internally reflective coupling 28.
Referring now to FIG. 5, the basic detector assembly 22 for standard
densitometric imaging of translucent objects by a laser beam is shown. The
detector assembly includes a blunt-cut optical fiber faceplate 24 and a
diffusion assembly 26 composed of a internal reflectance tube 28 and a pair of
flashed opal diffusion filters 30 and a photomultiplier tube 32.
Referring to FIG. 6, the basic detector assembly 22 is modified by the
introduction of a dielectric interference filter 34 designed to transmit forward
scatter. The critical angle of the interference filter 34 is matched to the
emission cone of the optical fibers, thus eliminating primary light and
accepting forward scatter. The interference filter 34 can also be replaced by
<PAGE> 80
PAGE 9
Pat. No. 5037207, *
a Bragg Diffraction filter which allows for 100% transmission of light with the
exception of a narrow band. The Bragg Diffraction Filter has a 10< - 16 >
blocking ability.
When it is desirable to image both fluorescence and forward light scatter the
standard blunt-cut fiber faceplate is replaced by a bias-end cut optical fiber
faceplate 36 and the interference or dielectric filter 34 as shown in FIG. 6.
When it might be desirable to capture images based on optical density and
forward light scatter, the interference filter 34 can be placed between the
standard blunt-cut fiber faceplate 24 of FIG. 5 and the internal reflecting tube
28. The addition of the interference filter 34 permits the imaging of forward
light scatter with both types of optical fiber faceplates.
Referring to FIG. 7, the concept of using the interference filter 34 to
detect forward light scatter is shown. The interference filter 34 can be
optically tuned to detect forward scatter of a variety of discrete images having
discrete ranges of forward scatter angles. In the special instance where the
"exclusion" cone determined by the critical angle of the interference filter 34
exceeds the maximum emission angle of the optical fibers, no light of the
primary wavelength passes through to the photomultiplier tube 32. If the
interference filter 34 is designed to block only the wavelength of the laser
beam and pass other wavelengths, the imaging of laser-excited fluorescence from
the scanned target is possible. With the bias-end cut fibers the only light that
is propagated to the PMT is scattered laser light from the target and
fluorescence emission. Selection of scatter versus fluorescence signals is then
determined by the variable diffraction filter characteristics. The forward light
scatter angle window is variable and determined by the combination of fiber NA
and the characteristics of the filter incorporated in the assembly.
For the special instances of fluorescence shadowing and forward scatter
fluorescence shadowing, the detector assembly 22 is further modified by placing
a fluorescence sensor between the interference filter 34 and the diffusion
assembly 26. For the process of fluorescence shadowing the interference filter
34 is tuned to pass densitometric images to the fluorescence sensor consisting
of a material such as dyed glass which fluorescence at wavelengths accepted by
the photomultiplier tube 32. Images are formed by placing the densitometric
target over the detector assembly 22 and scanning the target. When it is
desirable to perform the process of forward scatter fluorescence shadowing, the
interference filter 34 is tuned to pass forward scatter images onto the
fluorescent sensor which emits fluorescent signals to the PMT 32. The process of
forward scatter fluorescence shadowing has achieved detection resolution of
<PAGE> 81
submicron particles in the target in the 0.2-1.0 um range.
It may be desirable to insert an F-theta collimating lens (not shown) between
the beam controller 18 and the target plane 20. Such use of an F-theta lens will
eliminate the changing angle of incidence of the beam of light 16 and direct the
beam in a perpendicular orientation to the target plane 20 to ensure the
accurate propagation of forward light scatter. The Z axis of the beam controller
18 can be preprogrammed to automatically correct for the predictable lack of
flatness in the lens field and the resulting non-perfect image.
An alternative design of the optical fiber faceplate for use in the detection
of fluorescence incorporates square optical fibers instead of round optical
fibers. Square optical fibers can be used to propagate plane-polarized light by
the phenomenon of fluorescence anisotropy.
<PAGE> 82
PAGE 10
Pat. No. 5037207, *
The phenomenon of fluorescence anisotropy is the degree to which the
fluorescence emission from a target is polarized relative to polarization of the
excitation light. Measurement can be accomplished by simply determining the
relative intensities of fluorescence emission with electric field vectors
parallel and perpendicular to the electric field vector of the incident
excitation light. A typical design of an instrument for such a purpose is
presented in a paper by S. Kinoshita, T. Fukami, Y. Ido, and T. Kushida,
published in Cytometry, Vol. 8, pp. 35-41, 1987. These authors define
anisotropy, r, as
r = (I = - I + )/(I = + 2I + )
where I = and I + are the fluorescence intensities with electric field
vectors parallel and perpendicular to the electric vector of the incident
excitation light.
The improved method makes use of the fact that square optical fibers having
light absorbing cladding (i.e., extramural light absorbing material or E.M.A.)
possess an unusual property when used to propagate plane-polarized light. As the
plane of polarization of input light rotates about the axis parallel to the
direction of propagation, the plane of polarization of light exiting the fibers
also rotates as expected. However, unlike circular cross section optical fibers,
an additional rotation is observed between plus and minus 20-25 degrees. This
same phenomenon is observed using fibers without E.M.A., however, the range of
differential rotation imparted on the emerging light is reduced to approximately
+ / - 9 degrees.
In effect, the use of square optical fibers with E.M.A. provides a novel
means of amplifying a rotation in fluorescence emission polarization, or the
degradation of polarization relative to excitation light. This is a consequence
of the fact that the square optical fibers tend to rotate the plane of
polarization in the direction of a plane parallel with either diagonal inscribed
within the square core geometry in a manner illustrated in FIG. 8. Therefore, if
incident fluorescent light is rotated (e.g., + 7 degrees relative to the
excitation beam), the emergent light from the fiber optics will be rotated
approximately + 17 degrees as illustrated in FIG. 9. This additional rotation is
imparted as a result of the square cross section geometry and is enhanced by the
presence of E.M.A.
Referring now to FIGS. 10A and 10B, a schematic block diagram of the computer
support system is shown. The processor board is based on the Motorola 68020 32
<PAGE> 83
bit microprocessor and the 68881 floating point co-processor. It provides data
collection at a burst rate of one and a quarter million 12 bit words per second
with 256K bytes on board memory accessible with no wait states. A dual-ported
memory card, designed to support the image updating via a random port while the
display RAM features one megabyte dual-ported memory utilizing 32 64K x 4 video
RAM chips, two bit error detection and one bit error correction circuitry is
provided. The sequential (video) port features a row-access to the video memory
providing four 1024 pixels/line data in the internal buffer. With a newly
designed VMEbus display controller board, several display options are provided
for in the system: any continuous 8 bit display out of 16 bit video information
available per pixel is under software control; two display formats are provided,
512 x 480 and 1024 x 960; B/W and color (true and pseudo) displays are provided;
pixel resolution is user selectable 8 to 24 bits; zoom and scroll.
<PAGE> 84
PAGE 11
Pat. No. 5037207, *
Referring to FIGS. 12-17, the image memory controller board is VME bus
compatible. VME bus is a trademark of Motorola, Inc., and is also known as the
IEC821 bus or the IEEE Pio14/DI.O. The VME bus defines an interfacing system
used to connect data processing, data storage, and peripheral control devices in
a closely coupled hardware configuration. The image memory controller board
enables 8, 16 and 32 bit data bus structures. The controller board offers the
following functions. A power-up SCRUB function is provided to fill the memory
array with Hex value FF. This function is not performed when the board is used
as a display memory. The SCRUB is used when the board is used as a conventional
memory. An address range-select function is provided and is based on 1M byte
blocks located on 1M boundaries. For the 32 bit address configuration the upper
8 bits are fixed in a user programmable PAL. This allows for 16 switch
selectable 1M byte ranges using the next lowest four bits. The 1M byte memory is
located on a daughter card and is divided into four banks of 256K bytes each.
Four fully decoded input/output ports are provided. The input/output ports are
located in short address range only (the lower 16 bits), the upper 8 or 16 bits
are fixed. The input/output ports provide the following various support
functions: they enable and disable the EDC circuitry; they report erroneous
addresses; and, they enable and disable the interrupt, overflow, single bit
error, multibit error, register clear, bus error, system failure, and diagnosis
functions. The memory can interrupt any processer card on the bus if there is a
single bit error, multibit error or overflow, provided that the corresponding
enabling bit has been activated. This is a vector interrupt (i.e., a vector will
be supplied to the host processer during the interrupt acknowledge cycle). The
interleaved memory access is supported. Such support makes it possible for 2
memory cards to supply 16 bits two bytes per pixel. All even bytes of the pixel
are stored in one memory card and all odd bytes are stored in the other memory
card.
Referring to FIGS. 18-33, the image memory array board connects to the image
memory controller board by way of two 60 pin interboard connecters. The image
memory array board contains 1M byte of memory divided into four banks. Each bank
consists of 8 dual ported video DRAM (Dynamic Random Access Memory) chips (uPD
41264-15). The random access port of the memory is intended for use by the VME
bus (processer or DMA). The sequential port is dedicated to the video display
circuit. This is an 8 bit per pixel display system although 32 bits are read at
a time from the video memory through the sequential port. A shift register
stores the 32 bits that are read and then supplies them in groups of eight.
Referring to FIGS. 24-26, the CRT controller board is also VME bus compatible
and has a 16 bit data bus structure accessible through a set of input/output
address locations. A 512K byte graphic memory is provided. This memory is
<PAGE> 85
organized as a 1K x 1K, 4 bit pixel memory. This organization allows for a color
graphics plane where each pixel may have one of eight colors. This design
supports two dimensional scrolling, zooming and graphic drawing. The CRT
controller board functions as follows. At power up the controller is configured
for no scrolling or zooming and the graphics plane is disabled. The input/output
address is selectable from several ranges. The bit-0 of each graphics nibble is
used to enable or disable an individual pixel. The remaining 3 bits are used to
turn on or off the 3 primary colors of the color monitor system. This provides
for 8 color combinations per pixel. Each color channel is driven by a
digital/analog converter with an internal look-up table (256 x 8 bits). This
table can be used for pseudo color displays of the image stored in memory or for
certain primitive image processing algorithms. The designed display system board
provides 8 bits per channel. Up to three 8 bit image plane boards may provide
the input to the display system board. Therefore, 1-3 image plane boards may
<PAGE> 86
PAGE 12
Pat. No. 5037207, *
be used with a single display system board. The three cases are treated as
follows: in an 8 bit black and white system using one image plane board the same
8 bits are used as input to the look-up tables of the red, green and blue D/A
converters. If two image plane boards are used, the 16 bits per pixel and
special programming hardware is provided to allow the user to chose any
contiguous 8 bits for display. In the case of the three image plane boards, the
overall system becomes a true color system with each image plane board providing
its 8 bits to an individual color channel.
Vertical scrolling may be achieved on an every other line basis. The system
is designed for interlace display and horizontal scrolling is provided for every
4 pixels due to the imaging memory organization. Image zooming is accomplished
by duplication of pixels. The zooming factor is from 2 to 16. Graphics drawing
is supported directly by a Hitachi video display controller (HD63484-8). Various
drawings such as line, circle, ellipsis, etc., are command driven.
Referring to FIGS. 27-29, the graphics memory array board is connected to the
CRT controller board by way of two 60 pin interboard connectors. The graphics
memory array board consists of 512K bytes of DRAM memory for the graphics
display. This board accepts three 8 bit video data channels, displaying the
information on a CRT by using three AM8151 video D/A converters. A circuit is
provided to handle any of the three special cases regarding the number of video
channels. A combination circuit is provided which mixes the video (image) and
graphics display information together for display. Both the video (image) and
graphics can be enabled/disabled without interfering with each other.
The above description of the preferred embodiment is intended for
illustrative purposes and is not intended to be limiting upon the scope and
content of the following claims.
CLAIMS: We claim:
[*1] 1. An improved laser imaging apparatus comprising, in combination:
means for generating a coherent beam of light;
means for securing a target in a fixed position;
a beam controller for receiving and directing such coherent beam of light
into the target in a desired position to position pattern and at a desired rate
of travel;
<PAGE> 87
control means for determining the pattern and rate of travel of such beam;
an optical fiber faceplate having a selected emission cone for collecting
light emission transmitted from such target;
a dielectric interference filter having a critical angle matched relative to
such emission cone of said optical fiber faceplate for receiving and blocking
such beam of light and accepting all forward scatter from said faceplate;
means for receiving and filtering such forward scatter from said dielectric
filter;
<PAGE> 88
PAGE 13
Pat. No. 5037207, *1
means for receiving such filtered forward scatter and generating signals as a
function of the intensity and location of the forward scatter received; and
means for receiving such signals and generating a visual display as a
function of the intensity and location of such light emission.
[*2] 2. The imaging apparatus of claim 1, wherein said dielectric
interference filter is a Bragg Diffraction filter.
[*3] 3. The imaging apparatus of claim 1, wherein said beam controller has X,
Y coordinate scanning capability with a simultaneous Z coordinate correction to
cause such beam to have a topographical field of focus in the plane of the
target.
[*4] 4. An improved laser imaging apparatus comprising, in combination:
means for generating a coherent beam of light;
means for securing a target in a fixed position;
a beam controller for receiving and directing such coherent beam of light
into the target in a desired position to position pattern and at a desired rate
of travel;
control means for determining such pattern and rate of travel of such beam;
a blunt-cut optical fiber faceplate having a selected emission cone and
having a selected acceptance angle of a high numerical aperture to capture
differences in the optical density of such light emission being transmitted from
the target;
a dielectric interference filter having a critical angle matched relative to
such emission cone of said optical fiber faceplate for accepting and
transmitting light emission based on optical density and forward scatter;
means for receiving and filtering such light transmitted from said dielectric
interference filter;
means for receiving such filtered light and generating signals as a function
of the intensity and location of the light received; and,
<PAGE> 89
means for receiving such signals and generating a visual display as a
function of the intensity and location of such light emission.
[*5] 5. The imaging apparatus of claim 4 further including a fluorescent
sensor located between said dielectric interference filter and said filter
means, said fluorescent sensor receiving light emission from said dielectric
interference filter and creating fluorescent shadow images from said light
emission.
[*6] 6. The imaging apparatus of claim 4, wherein said beam controller has X,
Y coordinate scanning capability with a simultaneous Z coordinate correction to
cause such beam to have a topographical field of focus in the plane of the
target.
<PAGE> 90
PAGE 14
Pat. No. 5037207, *6
[*7] 7. An improved laser imaging apparatus comprising, in combination:
means for generating a coherent beam of light;
means for securing a target in a fixed position;
a beam controller for receiving and directing such coherent beam of light
into the target in a desired position to position pattern and at a desired rate
of travel;
control means for determining such pattern and rate of travel of such beam;
an optical fiber faceplate having a selected emission cone for collecting
light emission transmitted from the target, said optical fibers of said
faceplate being of a square cross section to propagate plane polarized light
through fluorescence anisotropy;
filter means for receiving and filtering such light collected by said
faceplate;
means for receiving such filtered light and generating signals as a function
of intensity and location of the light received; and,
means for receiving such signals and generating a visual display as a result
of the intensity and location of such light emission.
[*8] 8. The imaging apparatus of claim 7, wherein said cross sectional
optical fibers include extramural light absorbing material, said material
enhancing the ability of said square optical fibers to propagate plane polarized
light.
[*9] 9. The imaging apparatus of claim 7, wherein said beam controller has X,
Y coordinate scanning capability with a simultaneous Z coordinate correction to
cause such beam to have a topographical field of focus in the plane of the
target.
[*10] 10. An improved laser imaging apparatus comprising, in combination:
means for generating a coherent beam of light;
means for securing a target in a fixed position;
<PAGE> 91
a three-dimensional beam controller for receiving and directing such coherent
beam of light into the target in a desired position to position pattern and at a
desired rate of travel, said beam controller having X, Y coordinate scanning
capability with a simultaneous Z coordinate correction to cause such beam to
have a topographical field of focus in the plane of the target;
control means for determining the three-dimensional pattern and rate of
travel of such beam;
a bias-cut optical fiber faceplace having a selected acceptance angle to
block any light being transmitted from the target which is outside of such
acceptance angle and capture any other light emission from the target which is
within such specified acceptance angle;
<PAGE> 92
PAGE 15
Pat. No. 5037207, *10
a dielectric interference filter having a critical angle matched relative to
said selected acceptance angle of said bias-cut optical fiber faceplate to
accept and transmit submicron light emission based on fluorescence and forward
light scatter while blocking such beam of light;
means for receiving and filtering such submicron emission from said
dielectric interference filter;
means for receiving such filtered submicron emission and generating signals
as a function of the intensity and location of the fluorescence and forward
light scatter comprising such submicron emission; and
means for receiving such signals and generating a visual display as a
function of the intensity and location of such images.
[*11] 11. The imaging apparatus of claim 10 further including a fluorescent
sensor for receiving such fluorescence and forward scatter submicron emission
from said dielectric interference filter and creating fluorescent shadow images
in the 0.2-1.0 um range.
<PAGE> 93
FIGURES TO PATENT NO. 5,037,207
<PAGE> 94
[FIG. 1 is a graph showing the relationship of the numerical aperture (NA) and
target field image size for conventional lenses.]
<PAGE> 95
[FIG. 2 is a schematic illustration of the laser imaging system of the present
invention.]
<PAGE> 96
[FIG. 3 is an illustrative representation of a typical microscope slide and a
pattern of laser scanning the slide.]
<PAGE> 97
[FIG. 4 is an illustrative representation of the light detection properties of a
blunt-cut optical fiber faceplate and bias-cut optical fiber faceplate.]
<PAGE> 98
[FIG 5. is a schematic illustration of a typical detector assembly as used with
the present invention.]
<PAGE> 99
[FIG. 6 is a schematic illustration of a detector assembly for use with the
present invention in detecting fluorescence and forward light scatter.]
<PAGE> 100
[FIG. 7 is a conceptical illustration of the detector assembly of FIG. 6.]
<PAGE> 101
[FIG. 8 is a graph showing optical fiber polarimetry for square cross-sectional
optical fibers.]
<PAGE> 102
[FIG. 9 is an illustrative schematic of the plane polarization by a square
cross-sectional optical fiber of fluorescence emissions.]
<PAGE> 103
[FIG. 10A is a schematic block diagram of the image memory controller and image
memory array for the imaging system of the present invention.]
<PAGE> 104
[FIG. 10B is a schematic block diagram of the CRT controller and graphics memory
array for the imaging system of the present invention.]
<PAGE> 105
[FIG. 11 is a schematic illustration of the light acceptance cone of a bias-cut
optical fiber faceplate.]
<PAGE> 106
[FIGS. 12A, B, C and D are schematics for the Image Memory Controller of the
present invention showing the circuitry for the Memory Request Arbiters and the
Input/Out Access circuitry.]
<PAGE> 107
[FIGS. 13A, B, C and D are schematics for the Image Memory Controller of the
present invention showing the circuitry for the Memory and the Input/Output
Address Decoder.]
<PAGE> 108
[FIGS. 14A, B, C and D are schematics for the Image Memory Controller of the
present invention showing the circuitry for the Memory Refresh Function and the
Interrupt Request Function and Data Transfer Acknowledgment Generation.]
<PAGE> 109
[FIGS. 15A, B, C and D are schematics showing the Address Multiplexer circuitry
for the Image Memory Controller of the present invention.]
<PAGE> 110
[FIGS. 16A and B are schematics showing the Memory Buffers circuitry for the
Image Memory Controller of the present invention.]
<PAGE> 111
[FIGS. 17A and B are schematics showing the Input/Output registers circuitry for
the Image Memory Controller of the present invention.]
<PAGE> 112
[FIGS. 18A, B, C and D through 20A, B, C and D are schematics showing the Memory
Chip Array circuitry for the Image Memory Array of the present invention.]
<PAGE> 113
[FIGS. 21A, B, C and D are schematics showing the Memory Arrays, Address liners,
and Control Bus circuitry for the Image Memory Array of the present invention.]
<PAGE> 114
[FIGS. 22A, B, C and D are schematics showing the Image Data Shift Register
circuitry for the Image Memory Array of the present invention.]
<PAGE> 115
[FIG. 23 is a schematic showing the Memory Array circuitry for the Image Memory
Array of the present invention.]
<PAGE> 116
[FIGS. 24A, B, C and D are schematics showing the Video Display Generator
Interface circuitry for the CRT controller of the present invention.]
<PAGE> 117
[FIGS. 25A, B, C and D are schematics showing the Address Decoder, Graphics
Memory Interface and Interrupt Request and Acknowledge circuitry of the CRT
Controller of the present invention.]
<PAGE> 118
[FIGS. 26A, B, C and D are schematics showing the Zoom Control and Look-up Table
Circuitry for the CRT Controller of the present invention.]
<PAGE> 119
[FIGS. 27A, B, C and D are schematics showing the Memory Chip Array circuitry
for the Graphics Memory Array of the present invention.]
<PAGE> 120
[FIGS. 28A, B, C and D are schematics showing the Graphics Display and Shift
Register circuitry for the Graphics Memory Array of the present invention.]
<PAGE> 121
[FIGS. 29A, B, C and D are schematics showing the D/A Converter circuitry for
the Graphics Memory Array of the present invention.]
<PAGE> 122
Exhibit C2 to Perkin-Elmer License Agreement
<PAGE> 123
US PATENT 4,877,966
<=2> GET 1st DRAWING SHEET OF 14
Oct. 31, 1989
Method and apparatus for the measurement of low-level
laser-induced fluorescence
INVENTOR: Tomei, L. David, Dublin, Ohio
Cornhill, Fred, Worthington, Ohio
Jagadeesh, Jogikal, Columbus, Ohio
Boninger, Michael, Columbus, Ohio
DISCLAIMER: Jul. 19, 2005
ASSIGNEE-AT-ISSUE: Ohio State University Research Foundation, Columbus, Ohio
(02)
APPL-N0: 150,293
FILED: Jan. 29, 1988
REL-US-DATA:
Division of Ser. No. 828,694, Feb. 12, 1986
INT-CL: [4] G01J 3#10
US-CL: 250#458.1; 250#461.2
CL: 250
SEARCH-FLD: 250#458.1, 459.1, 461.2, 461.1; 350#96.27, 527
REF-CITED:
U.S. PATENT DOCUMENTS
3,450,455 6/1969 * Landre
3,516,746 6/1970 * Shibata et al.
3,981,590 9/1976 * Perkins
4,107,534 8/1978 * Piltingsrud 25#368
4,523,799 6/1985 * Delhaye 250#527
4,758,727 7/1988 * Tomei et al. 250#458.1
<PAGE> 124
FOREIGN PATENT DOCUMENTS
0123942 7/1984 * European Patent Organization 250#327.2
0155813 9/1985 * European Patent Organization 250#368
OTHER PUBLICATIONS
Bussini, et al., "A Silicon Rubber Scintillation Compound for Complex Geometry
Radiation Detectors", Nuclear Instruments and Methods, No. 2, (1973) pp.
333-335.
Dyer, et al., "Vidicon Microscope for Counting Fluorescent Particles", Review
<PAGE> 125
PAGE 17
Pat. No. 4877966,*
of Scientific Instruments, vol. 42, No. 4 (1971) p. 508.
Nicoll, F., "Mural Television Display Using Fiber Optics", RCA Technical Notes
(RCA TN No. 188 (1958).
"The FACS Analyzer Fluorescence and Volume Cell Analysis" Brochure, Becton
Dickenson FACS System, 1982.
"The New FACS Series, FACS 440, FACS 420, FACS 400, Fluorescence Activated Cell
Sorting", Becton Dickenson FACS Systems, 1981.
"Photodigitizing with PDS Microdensitometer Systems" Brochure, Perkin-Elmer,
not dated.
"Microdensitometer 3CS" Brochure, Joyce-Loebl, not dated.
"Microdensitometer 6" Brochure, Joyce-Loebl, not dated.
"EIKONIX Registered TM Applied Research Software and Product Development
Feasibility and Impact Studies Automated Instruments" Brochure, EIKONIX
Registered TM Corporation, not dated.
"ACAS 470 Workstation" Brochure, Meridian Instruments, Inc., not dated.
PRIM-EXMR: Howell, Janice A.
ASST-EXMR: Hanig, Richard
LEGAL-REP: Emch, Schaffer, Schaub & Porcello Co.
ABST:
A method and apparatus for measuring low-level laser-induced fluorescence are
disclosed. A laser is used to produce a coherent beam of light which is
sequentially passed through a beam expander, iris diaphragm, focusing lens and
three-dimensional scanner before being focused onto a rigidly mounted target. A
computer is used to predeterminately control the pattern and the rate at which
the scanner passes the beam of light over the target. The light transmitted onto
the target induces fluorescent light in the target. The fluorescent light is
sequentially gathered by a biased cut optical fiber member and directed into a
photomultiplier tube where the intensity of the fluorescent light is measured.
The intensity data is then digitized and recorded by the computer as a function
of the coordinates of each preprogrammed point location of the beam impinging
upon the target. This data is used to produce an image of all or a portion of
the target on a visual monitor. In addition, the data can be recalled and used
for further analysis of the target.
NO-OF-CLAIMS: 26
EXMPL-CLAIM: <=9> 1
<PAGE> 126
NO-OF-FIGURES: 18
NO-DRWNG-PP: 14
PARCASE:
This is a divisional of copending U.S. application Ser. No. 828,694 filed on
2/12/86.
SUM:
<PAGE> 127
PAGE 18
Pat. No. 4877966, *
BACKGROUND OF THE INVENTION
The present invention relates a method and apparatus for the measurement of
low-level laser-induced fluorescence in the field of cytofluorometry.
Cytofluorometry has been greatly enhanced with the development of fluorescence
dyes that are specific for deoxyribonucleic acid (DNA). These dyes permit the
determination of the ratios of total DNA present in a cell population and, since
the total amount of DNA doubles as a cell progresses through its proliferation
cycle, the distribution of cell cycle positions that existed in a cell
population is easily determined statistically. This is based upon the fact that,
within necessary tolerances, the amount of dye bound to a cell is directly
proportional to the amount of DNA present.
Fluorescence is the emission of light whose wavelength is different from that
used to induce or excite the molecule of dye. Therefore, common fluorescence
techniques require that the dye bind specifically to some component which is to
be measured such as DNA. Such specificity is obtained by structurally modifying
the dye molecule or coupling a dye molecule to another molecule that has the
required specificity of binding. Another technique which utilizes fluorescence
emission is based upon other properties of some dye molecules. When these
molecules are in an aqueous environment, their fluorescence characteristics are
distinctly different from that obtained in a hydrophobic environment. Since all
biological membranes have hydrophobic regions, the amount and kind of
fluorescence obtained following staining is related to the structural state of
that membrane.
Several analytical techniques have been developed which exploit these various
properties of fluorescent dyes. These techniques include photobleaching,
fluorescence quenching, and shifts in fluorescence emission spectra. Problems
are continuously encountered with these various techniques in that total
fluorescence per cell, following any general technique with any particular dye,
varies markedly and the variation is not quantitated for the expressed purpose
of defining the degree or nature of cell cooperativity in a coordinating,
interacting, cell mass.
Another fluorescence technique, stereological computer assisted
cytofluorometry (SCAC) provides for the measurement of laser-induced cellular
fluorescence in a cell or tissue mass (e.g. monolayer cell cultures or tissue
sections). Dependent upon the nature of the fluorescent dye employed, the
cellular response-density distribution profile will provide data of profound
theoretical as well as practical significance. SCAC provides a technique for the
<PAGE> 128
quantitation of cell behavior and responses to drugs within the context of the
cell mass or tissue. This has led to the development of new pharmacological
parameters and is expected to lead to more refined and sophisticated parameters
with which to study drug actions in the fields of cancer diagnosis,
chemoprevention and chemotherapy, environmental and forensic toxicology, as well
as basic biological sciences.
Currently there are two basic apparatuses for performing cytofluorometric
studies. A fluorescence microscope such as the FACS TM series analyzer
manufactured by Becton Dickinson provides observation of cells contained in a
culture dish. The fluorescence microscope is highly accurate when analyzing a
small area but cannot measure cell groupings larger than a culture dish without
destroying the spatial relationship of cells. The second apparatus, a Flow
Cytometer is designed to provide observation for a large number of cells, but
<PAGE> 129
PAGE 19
Pat. No. 4877966, *
the cells must be in suspension, thereby eliminating any possibility of
obtaining spatial data. The CYTOFLUOROGRAF system from the Ortho Instruments
Corporation is an example of a flow cytometer. The flow cytometer provides
highly accurate information on the frequency distribution of fluorescence
intensity in a randomly dispersed cell populations. However, no information is
provided regarding the spatial relationship that may exist between cells in the
tissue, tumor or culture prior to dispersal and staining.
Interpretation of frequency distributions of fluorescence intensity is
seriously hampered by the fact that the response of the original cell population
is rarely spatially homogenous. Heterogeneity of cell identity, morphology and
drug responsiveness is commonly observed but not considered in current
cytofluorometric analytic techniques. However, population heterogeneity is
regarded by biologists as being an inherent quality of coordinating cell
populations found in all animal tissues, tumors, primary cell cultures, and in
rudimentary form, laboratory cell lines. The present invention, method and
apparation, provides the ability to observe large areas of tissue, while
maintaining full spatial relationships without the need for any special
preparation.
SUMMARY OF THE INVENTION
The present invention relates a method and apparatus capable of rapid
wide-field scanning of low-level laser induced fluorescence of tissue sections,
cell cultures, and other biological materials, while maintaining high spatial
resolution. The method and apparatus of the present invention measures off-axis
fluorescence. The fluorescence measurements permits full digitalization of
images with 16 bit precision for 2-4 x 10<6> pixels. The target area scanned
are greater than 25 cm<2> with a resolution of 5-10 mu m and the scanning time
is between 1 and 6 seconds dependent upon computer processing and storage
limitations. The SCAC methodology, provides for the acquisition of information
from a large number of individual cells as does flow cytofluorometry. However,
in addition to individual cell responses, the present invention will provide
highly accurate information regarding the spatial distribution of those cells
within the total population. This is of particular importance in the areas of
tumor biology, pathology and early detection of abnormal cells in tissues and
organs. The SCAC design of the present invention provides for analysis of large
cell numbers in vitro with high spatial precision.
The apparatus of the present invention incorporates an optical fiber taper
for high efficiency light gathering and transmission to a highly sensitive
<PAGE> 130
detector. The properties of the fibers can be exploited to shift the detector
offaxis. This apparatus of the present invention makes use of two fiber
properties: tapered fiber transmission and biased cut deflection. Further,
extra-mural absorption material are added to provide further attenuation of
off-axis incident laser light. The method and apparatus of the present invention
will be further understood by the following description of the preferred
embodiment with reference to the following figures.
DRWDESC:
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a block diagram of a scanning device according to the present
invention.
<PAGE> 131
PAGE 20
Pat. No. 4877966, *
FIG. 2 is an exemplary view of a scanning pattern of a translucent object
with a scanning device according to the present invention.
FIG. 3 is a block diagram of the electronic interface used to control the
various components of a scanning device according to the present invention.
FIG. 4 is a block diagram showing an alternate embodiment of the fiber optic
bundle as used with a scanning device according to the present invention.
FIG. 5 is a flowchart representing the scanning program by which the present
invention operates.
FIG. 6a is an exemplary view of a biased cut optical fiber faceplate.
FIG. 6b is an exemplary view of a biased cut tapered optical fiber faceplate.
FIG. 7 is a schematic showing an analogue to digital convertor board as used
in the present invention.
FIG. 8 is a schematic showing the clock circuitry as used in the present
invention.
FIG. 9 is a schematic showing the low-order Address but Interface circuitry
as used in the present invention.
FIG. 10A, B is a schematic showing the DMA/Versabus Interface circuitry as
used in the present invention.
FIG. 11 is a schematic showing the DMA data path circuitry as used in the
present invention.
FIG. 12 is a schematic showing the timer interface circuitry as used in the
present invention.
FIG. 13a is a schematic showing the 1.5 volt local voltage source as used in
the present invention.
FIG. 13b is a schematic showing the Power-On Clear circuitry as used in the
present invention.
FIG. 14A, B is a schematic showing the board select logic as used in the
<PAGE> 132
present invention.
DETDESC:
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
The present invention relates to a method and apparatus for the off-axis
detection of laser-induced fluorescence. Referring to FIG. 1, there is shown a
block diagram of the components of a scanning device 10 according to the present
invention. The scanning device 10 uses coherent light to scan a object or target
12. In the preferred embodiment, the components of the device 10 include; a
tuneable laser 14, a beam expander 16, an iris diaphragm 18, a focusing lens 20,
a three-dimensional scanner 22, a target mount 24, a fiber optic faceplate
having a bias cut 26, a diffusion member 28, a photomultiplier tube 30, a
<PAGE> 133
PAGE 21
Pat. No. 4877966, *
programmable computer with memory 32 and a visual monitor 34. Together, these
components provide for rapid scanning of translucent targets to yield high
resolution, wide-field fluorescence analyses of a large number of cells in
vitro, with high spatial precision.
The means for generating the coherent beam of light is a laser 14. It is
desirable that the laser 14, shown in FIG. 1 emit a coherent polarized beam of
light 15 having a wavelength in the range of 350 to 540 nanometers. The light
beam 15 exiting the laser 14 is approximately 1 millimeter in width, which is
too small to be used effectively by the reflecting mirrors within the scanner
22. Therefore, the present invention provides a beam expander 16 which receives
the laser beam 15 and enlarges the size of the beam 15 to ensure utilization of
the greatest possible surface area of the reflecting mirrors within the scanner
22. The preferred beam expander 16, as shown in FIG. 1, is a Buschnell variable
beam expander having a magnification power range of 9 x to 30 x . In the
preferred embodiment, the beam expander 16 is adjustable to expand the beam size
through a range from 1 millimeter to 10 millimeters.
As an alternative to the use of a variable beam expander, a single power beam
expander may also be used with Applicants' invention. In such cases an iris
diaphragm 18 is included to receive the expanded beam 15 from the single power
beam expander. The iris diaphragm 18, also known as a field iris, is intended to
vary the diameter of the beam 15 input to the focusing lens 20 and the scanner
22, thus varying the spot size on the target 12. Consequently, the iris
diaphragm 18 is used to more finely tune the size of the beam of light 15.
Referring now to FIG. 1, the beam of light 15 is exiting the beam expander 16
or iris diaphragm 18 is passed through the focusing lens 20 which focuses the
beam of light 15 on the target 12. Together, the beam expander 16/iris diaphragm
18 and focusing lens 20 permit the beam of light to be focused to a spot of
predetermined dimension at the target plane of the translucent target 12.
In the preferred embodiment, the light received by the focusing lens 20 is a
gaussian columnated coherent beam of light. Using this assumption, the final
spot size upon the target 12 is diffraction limited and governed by the
following equation:
d = 4F lambda / pi D, TM (1)
,
<PAGE> 134
wherein
d = spot size
F = focal length of focusing lens
lambda = wavelength of the light
D = aperture of input beam to focusing lens
According to equation (1), the proper selection of the focal length (F) of
the focusing lens 20, the wavelength ( lambda ) of the coherent light beam 15,
and the aperture (D) of the input beam to the focusing lens 20, will allow for
the size of the beam spot (d) on the target 12 to be varied as desired. The
<PAGE> 135
PAGE 22
Pat. No. 4877966, *
smallest available spot size is approximately one micron. Thus, the present
invention is capable of scanning at a variety of intervals with the smallest
being a one micron interval.
The focused beam of light 15 exiting the focusing lens 20 is received by the
three-dimensional scanner 22 which operates to control the passing of the light
beam 15 over the target 12. The scanner 22 as shown in FIG. 1 is manufactured by
General Scanning, Inc. and uses computer controlled mirrors to pass the focused
beam of light 15 back and forth across the target 12. The scanner 22 is capable
of scanning an area of any size, up to 20 millimeters by 40 millimeters, while
operating at a raster rate of up to 20 Hz or a vector rate of up to 280 mm/sec.
Computer controlled drive motors cause the mirrors of the scanner 22 to move
such that the scanner 22 has accurate X and Y coordinate scanning capabilities
with a simultaneous Z coordinate correction to yield a beam of light 15 with a
flat field of focus. If desired, the Z coordinate of the scanner 22 can be
programmed to coordinate with an uneven topographical field of focus on the
target 12.
The scanner 22 passes the focused coherent beam of light to the target 12,
thereby inducing fluorescence in a predetermined pattern and at a predetermined
rate set by the computer 32 so that data is obtained as to the intensity of the
fluorescence at differing points on the target 12. At precise predetermined
points during the scanning process, the intensity of the light is measured by
the photomultiplier tube 30 and recorded by the computer 32 as a function of
location of the beam 15 on the target 12. By taking successive point
measurements of the intensity of the fluorescence and relating them back to the
location data in the computer 32, the data is used to analyze the target 12 or
recreate a visual image of the target 12 on a visual monitor 34.
The target 12 is scanned over a very large series of points using a back and
forth pattern as shown in FIG. 2. The X, Y coordinates and the rate of scanning
are predetermined and programmed through the computer 32. The scanning program
is individually drawn to the specifics of the application. The flowchart for the
scanning program is shown in FIG. 5. At each scanning point, the fluorescence
intensity is measured and recorded as a function of the X, Y coordinates of the
beam. For example, the scanner 22 would be programmed to scan the target 12, as
shown in FIG. 2, in a sequential pattern over the following (X,Y) coordinates:
(1,1), (1,2), (1,3), (1,4), (2,4), (2,3), (2,2), (2,1), (3,1), (3,2), (3,3),
(3,4), (4,4), (4,3), (4,2) and (4,1). The intensity of the fluorescence being
excited at each of the scanning points is measured by the photomultiplier tube
30 in terms of analogue data. The analogue data for each scanning point is then
<PAGE> 136
digitized by the computer 32 and recorded as a function of the X,Y coordinates
of that particular scanning point.
The present invention utilizes a three-dimensional scanner, such as that
manufactured by General Scanning, Inc. The use of such a scanner provides in
that the target mount 24 is stationary, thereby eliminating wobble and jitter
experienced with moving target mounts. Due to the minute size of the focused
beam spot on the target 12 and the large amount of point data being taken, it is
important that the target 12 be rigidly mounted in a fixed position on the
target mount 24 to maintain the proper focusing, depth of field, and spot size.
Positioned directly below the target mount 24 and thus below the target 12
itself is a fiber optic faceplate 26 which is used in conjunction with a
diffusion member 28 to increase the efficiency of the highly sensitive
<PAGE> 137
PAGE 23
Pat. No. 4877966, *
photomultiplier tube 30. The sensing surfaces of photomultiplier tubes are
characteristically nonuniform. The fluorescent light transmitted by the target
12 is minute in the form of a narrow columnated beam. If this beam were received
by the photomultiplier tube 30, variations in the recorded intensity of the beam
would occur as a result of variations in the location at which the narrow
columnated light beam strikes the sensing surface of the photomultiplier tube
30. Therefore, the present invention utilizes the fiber optic faceplate 26 to
gather as much light as possible and the diffusion member 28 spreads the light
beam broadly as possible to achieve full use of the photomultiplier tube 30.
One of two types of fiber optic faceplates 26 may be used with the present
invention, depending upon the size of the window of the photomultiplier tube 30.
When the window of the photomultiplier tube 30 is comparable in size to the
target 12, then a flat disk-type faceplate, as shown in FIGS. 1 and 2, is used.
When the scanning area of the target 12 is larger than the window of the
photomultiplier tube 30, a tapered or frustoconical shaped fiber optic faceplate
26A, such as shown in FIG. 4, is used. The use of such fiber optic faceplates
presents a marked improvement over prior art systems in which lenses are relied
upon to gather and direct the light beam. The light gathering or flux-carrying
capacity of the optical fibers within the taper 26A as used with the present
invention is 10 to 70 times higher than that of standard optical lenses. The
relative increase in light gathering capacity is numerically equal to the ratio
of the squares of the numerical apertures. The effective numerical aperture of a
typical lens capable of imaging a target area of at least several square
millimeters is 0.10 to 0.20 as compared with optical fibers which have nominal
numerical aperture values of greater than 0.60. Therefore, the use of optical
fibers in conjunction with highly sensitive photomultiplier tubes 30 produces a
marked advantage over instrument designs incorporating optical lens systems
and/or solid-state light detectors.
The fiber optic faceplate 26 is biased cut at a angle alpha , preferably 30o.
Referring to FIG. 6, the bias cut on the optical fiber faceplate 26 is shown as
angle alpha and the acceptance angle of the fiber optic faceplate 26 is
deflected by angle beta . This provides a total deflection by angle beta or
shift of the acceptance angle theta which comprises the acceptance cone of the
fiber optic bundle. If laser light is shown onto a fiber outside of the
acceptance cone, the amount of light transmitted along the length of the fiber
will be severely limited. Thus, the present invention provides a fiber optic
faceplate 26 having a bias cut such that light hitting perpendicular to the face
of the fibers will not be in the acceptance cone. In this manner, a light source
hitting perpendicular to the surface will be attenuated while excited
<PAGE> 138
fluorescence or scattered light may enter the acceptance cone. The bias cut
fiber optic system of the present invention is capable of gathering 30% of the
excited fluorescence from the target being scanned, as compared with current
technology in which only 2% of the excited fluorescent light is gathered.
The optical fibers in the faceplate 26 also function as the first stage for
light diffusion. Optical fibers will gather light from all angles within the
acceptance cone. Upon exit from the faceplate 26 this light is rotated about a
solid angle through which the intensity is uniformly distributed. This optic
fiber property thus enhances the light scattering efficiency of the diffusion
member 28.
Further attenuation of the light is accomplished by insertion of neutral
density filters 27 between the fiber optic faceplate 26 and the diffusion
<PAGE> 139
PAGE 24
Pat. No. 4877966, *
member 28. In the preferred embodiment, a 620 nanometer filter is incorporated
in order to eliminate the normal fluorescent room lighting, thus permitting
operation of the instrument without extensive light protection. Further, a
barrier filter (not shown) may be incorporated at this point to absorb light at
the excitation wavelength while transmitting light at the fluorescent
wavelength.
The diffusion member 28, shown in FIG. 1, is an open-ended hollow elongated
member with a reflective interior surface. Such a member can be constructed of
an open-end box using mirrored glass for the interior surface. Alternatively,
milk glass may be used as the diffusion member 28. The primary functions of the
diffusion member 28 are two-fold. First, the diffusion member 28 blocks out any
remaining ambient light which will affect the intensity readings of the
photomultiplier tube 30. Secondly, the diffusion member 28 allows the
transmitted light to diffuse within its confines to more fully utilize the
window of the photomultiplier tube 30 and thus yield more accurate results.
After the fluorescent light transmitted from the target 12 is directed to the
photomultiplier tube 30 by the fiber optic faceplate 26 and diffusion member 28,
the photomultiplier tube 30 detects and measures the fluorescence levels. The
photomultiplier tube 30 is in turn linked to the computer 32 so that data
obtained by the photomultiplier tube 30 regarding the intensity of the light is
fed into the computer 32.
Once the device 10 is activated and scanning of the target 12 begins, the
output of the photomultiplier tube 30 is sampled by the computer 32 as often as
desired. The electrical signals relating the intensity of the fluorescent light
are converted from analogue to digital values by the computer 32 for storage
purposes. Using the preprogrammed position data and the stored intensity values,
the computer 32 can provide a realtime pictorial reconstruction of the target 12
on a visual monitor 34. The capacity of the computer 32 to rapidly store the
highly detailed data being viewed makes it possible to depict the entire area of
the target 12 on the visual monitor as well as focus on particular points of
interest by providing enlarged viewing of select portions of the target 12.
Referring now to FIG. 3, an interface is provided to collect the analogue
intensity data output of the photomultiplier tube 30 and convert the data into
digital form for the versabus-based computer 32. The interface 33 communicates
with the computer 32 through direct memory access (DMA) with a minimum
instantaneous transfer rate of 100,000 picture elements (pixels) per second. The
interface 33 of the present invention is composed of five main subsystems
<PAGE> 140
including: an analogue-to-digital (A/D) converter 36 as shown in FIG. 7; a set
of buffers and latches 38; bus interface logic 40 as shown in FIGS. 9, 10; a DMA
controller 42 as shown in FIG. 11; and a system timing controller 44 as shown in
FIG. 12. The DMA controller 42 and system timing controller 44 are used to
properly operate the A/D converter 36, the set of buffers and latches 38 and the
bus interface logic 40.
Referring now to FIG. 7, the A/D converter 36 transforms the image data
signals which are received from the photomultiplier tube 30 into a digital form
which is understandable by the host computer 32. The buffers change the voltage
of the signals to a level which is compatible with the host computer 32 while
the latches store the transformed data until it is efficient for the computer 32
to accept them.
<PAGE> 141
PAGE 25
Pat. No. 4877966, *
Referring now to FIG. 11, the DMA controller 42 and the bus interface logic
40 of FIGS. 9 and 10 store and control information about the flow of the data to
the computer 32 so that the computer 32 receives the data only when it is able
to accept the information. The system timing controller 44 of FIG. 12 ensures
that the proper number of pixels are placed into the memory 46 of the computer
32. In addition, the system timing controller 44 generates all the needed
signals for the A/D converter 36.
Since the A/D converter 36 outputs emitter coupled logic (ECL) compatible
signals, level shifters are required to provide transistor-transistor logic
(TTL) signals. These signals are tied directly to a combination bus buffer/latch
chips. The conversion timing is derived from a 1 MHz crystal feeding an AM9513
timing controller. It should be noted that higher frequency crystals may be
used. The timing controller is started by means of an enable convert signal
which can be generated by the host computer 32 under user control, or by a
signal external to the board. The timing controller 44 generates the convert and
latch signal, and also terminates its count automatically. The controller is
completely software programmable.
The bus interface logic permits the use of both a positive true logic and
negative true logic CPU bus. The bus also allows for a choice of an 8 or 16 MHz
CPU clock speed. The board is memory-mapped, and may reside on any 256 byte
boundary in memory.
The DMA controller circuit is designed to provide for both cycle steal and
burst modes, under software programmability. This feature allows for increased
efficiency at high data rates. Regardless of the mode chosen, the eight most
significant bits are latched, and the next sample is latched in the same manner.
At this point, the DMA transfer will proceed in the specified mode. It is
important to note that by first latching 16 bits and then requesting the bus,
the bus bandwidth used in cycle steal mode is cut to one half of what it would
otherwise have been.
The remainder of the circuitry includes a 1.5 volt local power supply 48
(FIG. 13a), as required by the DMA control circuitry, and a dual speed
power-on-clear circuit 50 (FIG. 13b) which included to ensure the circuit powers
up in a predictable and stable manner.
With the circuitry in place, the device 10 is used to scan the object 12. The
excited fluorescent intensity is determined using the highly efficient optical
fiber faceplate 26 and the sensitive photomultiplier tube 30 without respect to
<PAGE> 142
the precise position of the laser beam on the target object. Such position is
alternatively determined by the computer 32 which controls the threedimensional
scanner 22. The computer 32 then combines the X, Y coordinate spatial
information with the intensity information to yield a high resolution wide-field
image of the object 12.
Having thus described the invention in detail, it should be understood that
various modifications and changes can be made in the apparatus without departing
from the scope and content of the following claims.
CLAIMS: What we claim:
[*1] 1. An improved method for measuring the excited fluorescence of an
object comprising:
<PAGE> 143
PAGE 26
Pat. No. 4877966, *1
binding a specific dye to such object;
securing such object in a fixed position;
generating a coherent beam of light;
scanning such fixed object with said coherent beam of light in a
preprogrammed three dimensional pattern and at a preselected rate to induce such
fluorescence;
gathering such fluorescent light with an optical fiber member, such optical
fiber member attenuating said coherent beam of light used to induce such
fluorescence;
measuring the intensity of said fluorescent light in a light intensity
measuring device; and
sequentially recording data regarding the intensity of said fluorescent light
as a function of the location of said scanning beam of light on said object.
[*2] 2. The method of claim 1 further including the step of filtering said
fluorescent light upon receipt from said optical fiber member and prior to
measuring the intensity of said light.
[*3] 3. The method of claim 2 further including the step of diffusing said
filtered light upon receipt from said filter and prior to measuring the
intensity of said light.
[*4] 4. The method of claim 1 which further includes the step of producing a
visual image of at least a portion of said object based upon said sequentially
recorded data of the intensity of said fluorescent light as a function of the
location of said scanning beam of light on said object.
[*5] 5. The method of claim 4, wherein said visual image is realtime produced
on a visual monitor.
[*6] 6. The method of claim 1, which further includes the step of focusing
said beam of light through a focusing lens after the step of generating a
coherent beam of light and before the step of directing said beam of light into
said three dimensional scanner.
<PAGE> 144
[*7] 7. The method of claim 6, which further includes the step of expanding
said beam of light between the steps of generating and focusing said beam of
light.
[*8] 8. The method of claim 1, which further includes the step of storing
said sequentially recorded data in a retrievable digital form.
[*9] 9. The method of claim 1, wherein a laser is used to generate said
coherent beam of light.
[*10] 10. The method of claim 1, wherein a programmable computer is used to
control the movement of said scanner and record said data regarding the
intensity of said fluorescent light.
<PAGE> 145
PAGE 27
Pat. No. 4877966, *10
[*11] 11. The method of claim 3, wherein an open-ended hollow elongated
member having a reflective interior surface is used to diffuse said fluorescent
light.
[*12] 12. The method of claim 1, wherein said light measuring device is a
photomultiplier tube.
[*13] 13. The method of claim 7, wherein a beam expander is used to expand
said beam of light.
[*14] 14. A method measuring the excited fluorescence of an object
comprising;
binding a specific dye to said object;
securing such object in a fixed position;
generating a coherent beam of light;
expanding said beam of light;
focusing said expanded beam of light;
scanning such fixed object with said focused beam of light in a preprogrammed
three dimensional pattern and at a preselected rate to induce such fluorescence;
collecting such induced fluorescent light from said object by means of a
biased cut optical fiber faceplate such bias cut of such optical fiber faceplate
acting to eliminate any light directed perpendicular to the surface of such
object;
filtering said fluorescent light;
diffusing said filtered light;
measuring the intensity of said diffused light in a light intensity measuring
device; and
sequentially recording data regarding the intensity of said fluorescent light
as a function of the location of said scanning beam of light on said object.
<PAGE> 146
[*15] 15. The method of claim 14 which further includes the step of storing
said sequentially recorded data in a retrievable digital form.
[*16] 16. The method of claim 14 which further includes the step of producing
a visual image of at least a portion of said object based upon said sequentially
recorded data of the intensity of said fluorescent light as a function of the
location of said scanning beam of light on said object.
[*17] 17. The method of claim 16, wherein said visual image is produced on
a visual monitor.
[*18] 18. The method of claim 14, wherein a laser is used to generate said
coherent beam of light.
<PAGE> 147
PAGE 28
Pat. No. 4877966, *18
[*19] 19. The method of claim 14, wherein a programmable computer is used to
control the movement of said scanner and record said data regarding the
intensity of said fluorescent light.
[*20] 20. The method of claim 14, wherein an open-ended hollow elongated
member having a reflective interior surface is used to diffuse said filtered
light.
[*21] 21. The method of claim 14, wherein said light measuring device is a
photomultiplier tube.
[*22] 22. The method of claim 14, wherein a beam expander is used to expand
said beam of light.
[*23] 23. A method for measuring the excited fluorescence of an object
comprising;
binding a specific dye to said object;
securing such object in a fixed position;
generating a coherent beam of light of specified wavelength within the range
of 350 to 540 nanometers;
expanding said beam of light;
focusing said expanded beam of light;
scanning such fixed object with said focused beam of light in a preprogrammed
three dimensional pattern and at a raster rate of 20 Hz while maintaining the
diameter of the light beam impinging upon said object at between 1 to 20
microns;
collecting the fluorescent light emitted from said object and attenuating all
other light by means of a biased cut optical fiber faceplate;
filtering said fluorescent light by means of a neutral density filter;
diffusing said filtered light in an open-ended hollow elongated member having
a reflective interior surface;
<PAGE> 148
measuring said diffused light in a photomultiplier tube;
sequentially recording data regarding the intensity of said fluorescent light
as a function of the location of said scanning beam of light on said object; and
producing a visual image of at least a portion of said object based upon said
sequentially recorded data of the intensity of said fluorescent light as a
function of the location of said scanning beam of light.
[*24] 24. The method of claim 23, wherein a laser is used to generate said
coherent beam of light.
[*25] 25. The method of claim 23, wherein a programmable computer is used
to control the movement of said scanner and record said data regarding the
<PAGE> 149
PAGE 29
Pat. No. 4877966, *25
intensity of said fluorescent light.
[*26] 26. The method of claim 23, wherein a beam expander is used to expand
said beam of light.
<PAGE> 150
FIGURES TO PATENT NO. 4,877,966
<PAGE> 151
[FIG. 1 is a block diagram of a scanning device according to the present
invention.]
<PAGE> 152
[FIG. 2 is an exemplary view of a scanning pattern of a translucent object with
a scanning device according to the present invention.]
<PAGE> 153
[FIG. 3 is a block diagram of the electronic interface used to control the
various components of scanning device according to the present invention.]
<PAGE> 154
[FIG. 4 is a block diagram showing an alternate embodiment of the fiber optic
bundle as used with a scanning device according to the present invention.]
<PAGE> 155
[FIG. 5 is a flowchart representing the scanning program by which the present
invention operates.]
<PAGE> 156
[FIG. 6a is an exemplary view of a biased cut optical fiber faceplate.]
<PAGE> 157
[FIG. 6b is an exemplary view of a biased cut tapered optical fiber faceplate.]
<PAGE> 158
[FIG. 7 is a schematic showing an analogue to digital convertor board as used in
the present invention.]
<PAGE> 159
[FIG. 8 is a schematic showing the clock circuitry as used in the present
invention.]
<PAGE> 160
[FIG. 9 is a schematic showing the low-order Address but Interface circuitry as
used in the present invention.]
<PAGE> 161
[FIG. 10A, B is a schematic showing the DMA/Versabus Interface circuitry as used
in the present invention.]
<PAGE> 162
[FIG. 11 is a schematic showing the DMA data path circuitry as used in the
present invention.]
<PAGE> 163
[FIG. 12 is a schematic showing the timer interface circuitry as used in the
present invention.]
<PAGE> 164
[FIG. 13a is a schematic showing the 1.5 volt local voltage source as used in
the present invention.]
<PAGE> 165
[FIG. 13b is a schematic showing the Power-On Clear circuitry as used in the
present invention.]
<PAGE> 166
[FIG. 14A, B is a schematic showing the board select logic as used in the
present invention.]
<PAGE> 167
Exhibit C3 to Perkin-Elmer License Agreement
<PAGE> 168
US PATENT 4,758,727
<=2> GET 1st DRAWING SHEET OF 14
Jul. 19, 1988
Method and apparatus for the measurement of low-level
laser-induced fluorescence
INVENTOR: Tomei, L. David, Dublin, Ohio
Cornhill, Fred, Worthington, Ohio
Jagadeesh, Jogikal, Columbus, Ohio
Boninger, Michael, Columbus, Ohio
ASSIGNEE-AT-ISSUE: Ohio State University Research Foundation, Columbus, Ohio
(02)
APPL-N0: 828,694
FILED: Feb. 12, 1986
INT-CL: [4] G01J 3#10
US-CL: 250#458.1; 250#461.2
CL: 250
SEARCH-FLD: 250#458.1, 459.1, 461.2, 461.1; 350#96.27, 527
REF-CITED:
U.S. PATENT DOCUMENTS
3,450,455 6/1969 Landre
3,516,746 6/1970 Shibata et al.
3,981,590 9/1976 Perkins
4,107,534 8/1978 Piltingsrud 250#368
4,523,799 6/1985 Delhaye et al. 350#527
FOREIGN PATENT DOCUMENTS
0123942 11/1984 European Patent Organization 250#327.2
0155813 9/1985 European Patent Organization 250#368
<PAGE> 169
OTHER PUBLICATIONS
Bussini et al, "A Silicon Rubber Scint. Comp. . . . for Rad. Det.", Nucl. Inst.
& Methods 107, #2, (1973) p. 333.
Nicoll, F., "Mural T.V. Display using Fiber Optics", RCA Technical Notes (RCA TN
No.:188); (1958).
Dyer et al, "Vidicon Microscope for Count. Fluorescent Particles", Rev. of
Scient. Instru., vol. 42, #4, (1971) p. 508.
"The FACS Analyzer Fluorescence and Volume Cell Analysis" brochure, Becton and
Dickenson FACS Systems, 1982.
"The New FACS 400 Series, FACS 440, FACS 420, FACS 400, Fluorescence Activated
Cell Sorting" brochure, Becton Dickenson FACS Systems, 1981.
<PAGE> 170
PAGE 31
Pat. No. 4758727, *
"Photodigitizing with PDS Microdensitometer Systems" brochure, Perkin-Elmer not
dated.
"Microdensitometer 3CS" brochure, Joyce-Loebl, not dated.
"Microdensitometer 6" brochure, Joyce-Loebl, not dated.
"EIKONIX Registered TM Applied Research Software and Product Development
Feasibility and Impact Studies Automated Instruments" brochure, EIKONIX
Registered TM Corp., not dated.
"ACAS 470 Workstation" Brochure, Meridian Instruments, Inc., not dated.
PRIM-EXMR: Howell, Janice A.
ASST-EXMR: Hanig, Richard
LEGAL-REP: Emch, Schaffer, Schaub & Porcello Co.
ABST:
A method and apparatus for measuring low-level laser-induced fluorescence are
disclosed. A laser is used to produce a coherent beam of light which is
sequentially passed through a beam expander, iris diaphragm, focusing lens and
three-dimensional scanner before being focused onto a rigidly mounted target. A
computer is used to predeterminately control the pattern and the rate at which
the scanner passes the beam of light over the target. The light transmitted onto
the target induces fluorescent light in the target. The fluorescent light is
sequentially gathered by a biased cut optical fiber member and directed into a
photomultiplier tube where the intensity of the fluorescent light is measured.
The intensity data is then digitized and recorded by the computer as a function
of the coordinates of each preprogrammed point location of the beam impinging
upon the target. This data is used to produce an image of all or a portion of
the target on a visual monitor. In addition, the data can be recalled and used
for further analysis of the target.
NO-OF-CLAIMS: 26
EXMPL-CLAIM: <=8> 1
NO-OF-FIGURES: 18
NO-DRWNG-PP: 14
<PAGE> 171
SUM:
BACKGROUND OF THE INVENTION
The present invention relates a method and apparatus for the measurement of
low-level laser-induced fluorescence in the field of cytofluorometry.
Cytofluorometry has been greatly enhanced with the development of fluorescence
dyes that are specific for deoxyribonucleic acid (DNA). These dyes permit the
determination of the ratios of total DNA present in a cell population and, since
the total amount of DNA doubles as a cell progresses through its proliferation
cycle, the distribution of cell cycle positions that existed in a cell
population is easily determined statistically. This is based upon the fact that,
within necessary tolerances, the amount of dye bound to a cell is directly
proportional to the amount of DNA present.
<PAGE> 172
PAGE 32
Pat. No. 4758727, *
Fluorescence is the emission of light whose wavelength is different from that
used to induce or excite the molecule of dye. Therefore, common fluorescence
techniques require that the dye bind specifically to some component which is to
be measured such as DNA. Such specificity is obtained by structurally modifying
the dye molecule or coupling a dye molecule to another molecule that has the
required specificity of binding. Another technique which utilizes fluorescence
emission is based upon other properties of some dye molecules. When these
molecules are in an aqueous environment, their fluorescence characteristics are
distinctly different from that obtained in a hydrophobic environment. Since all
biological membranes have hydrophobic regions, the amount and kind of
fluorescence obtained following staining is related to the structural state of
that membrane.
Several analytical techniques have been developed which exploit these various
properties of fluorescent dyes. These techniques include photo-bleaching,
fluorescence quenching, and shifts in fluorescence emission spectra. Problems
are continuously encountered with these various techniques in that total
fluorescence per cell, following any general technique with any particular dye,
varies markedly and the variation is not quantitated for the expressed purpose
of defining the degree or nature of cell cooperativity in a coordinating,
interacting, cell mass.
Another fluorescence technique, stereological computer assisted
cytofluorometry (SCAC) provides for the measurement of laser-induced cellular
fluorescence in a cell or tissue mass (e.g. monolayer cell cultures or tissue
sections). Dependent upon the nature of the fluorescent dye employed, the
cellular response-density distribution profile will provide data of profound
theoretical as well as practical significance. SCAC provides a technique for the
quantitation of cell behavior and responses to drugs within the context of the
cell mass or tissue. This has led to the development of new pharmacological
parameters and is expected to lead to more refined and sophisticated parameters
with which to study drug actions in the fields of cancer diagnosis,
chemoprevention and chemotherapy, environmental and forensic toxicology, as well
as basic biological sciences.
Currently there are two basic apparatuses for performing cytofluorometric
studies. A fluorescence microscope such as the FACS TM series analyzer
manufactured by Becton Dickinson provides observation of cells contained in a
culture dish. The fluorescence microscope is highly accurate when analyzing a
small area but cannot measure cell groupings larger than a culture dish without
destroying the spatial relationship of the cells. The second apparatus, a Flow
<PAGE> 173
Cytometer is designed to provide observation for a large number of cells, but
the cells must be in suspension, thereby eliminating any possibility of
obtaining spatial data. The CYTOFLUOROGRAF system from the Ortho Instruments
Corporation is an example of a flow cytometer. The flow cytometer provides
highly accurate information on the frequency distribution of fluorescence
intensity in a randomly dispersed cell populations. However, no information is
provided regarding the spatial relationship that may exist between cells in the
tissue, tumor or culture prior to dispersal and staining.
Interpretation of frequency distributions of fluorescence intensity is
seriously hampered by the fact that the response of the original cell population
is rarely spatially homogenous. Heterogeneity of cell identity, morphology and
drug responsiveness is commonly observed but not considered in current
cytofluorometric analytic techniques. However, population heterogeneity is
<PAGE> 174
PAGE 33
Pat. No. 4758727, *
regarded by biologists as being an inherent quality of coordinating cell
populations found in all animal tissues, tumors, primary cell cultures, and in
rudimentary form, laboratory cell lines. The present invention, method and
apparation, provides the ability to observe large areas of tissue, while
maintaining full spatial relationships without the need for any special
preparation.
SUMMARY OF THE INVENTION
The present invention relates a method and apparatus capable of rapid
wide-field scanning of low-level laser induced fluorescence of tissue sections,
cell cultures, and other biological materials, while maintaining high spatial
resolution. The method and apparatus of the present invention measures off-axis
fluorescence. The fluorescence measurements permits full digitalization of
images with 16 bit precision for 2-4 x 10<6> pixels. The target areas scanned
are greater than 25 cm<2> with a resolution of 5-10 mu m and the scanning time
is between 1 and 6 seconds dependent upon computer processing and storage
limitations. The SCAC methodology, provides for the acquisition of information
from a large number of individual cells as does flow cytofluorometry. However,
in addition to individual cell responses, the present invention will provide
highly accurate information regarding the spatial distribution of those cells
within the total population. This is of particular importance in the areas of
tumor biology, pathology and early detection of abnormal cells in tissues and
organs. The SCAC design of the present invention provides for analysis of large
cell numbers in vitro with high spatial precision.
The apparatus of the present invention incorporates an optical fiber taper
for high efficiency light gathering and transmission to a highly sensitive
detector. The properties of the fibers can be exploited to shift the detector
off-axis. This apparatus of the present invention makes use of two fiber
properties: tapered fiber transmission and biased cut deflection. Further,
extra-mural absorption material are added to provide further attenuation of
off-axis incident laser light. The method and apparatus of the present invention
will be further understood by the following description of the preferred
embodiment with reference to the following figures.
DRWDESC:
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a block diagram of a scanning device according to the present
invention.
<PAGE> 175
FIG. 2 is an exemplary view of a scanning pattern of a translucent object
with a scanning device according to the present invention.
FIG. 3 is a block diagram of the electronic interface used to control the
various components of a scanning device according to the present invention.
FIG. 4 is a block diagram showing an alternate embodiment of the fiber optic
bundle as used with a scanning device according to the present invention.
FIG. 5 is a flowchart representing the scanning program by which the present
invention operates.
FIG. 6a is an exemplary view of a biased cut optical fiber faceplate.
<PAGE> 176
PAGE 34
Pat. No. 4758727, *
FIG. 6b is an exemplary view of a biased cut tapered optical fiber faceplate.
FIG. 7 is a schematic showing an analogue to digital convertor board as used
in the present invention.
FIG. 8 is a schematic showing the clock circuitry as used in the present
invention.
FIG. 9 is a schematic showing the low-order Address bus Interface circuitry
as used in the present invention.
FIG. 10 is a schematic showing the DMA/Versabus Interface circuitry as used
in the present invention.
FIG. 11 is a schematic showing the DMA data path circuitry as used in the
present invention.
FIG. 12 is a schematic showing the timer interface circuitry as used in the
present invention.
FIG. 13a is a schematic showing the 1.5 Volt local voltage source as used in
the present invention.
FIG. 13b is a schematic showing the Power-On Clear circuitry as used in the
present invention.
FIG. 14 is a schematic showing the board select logic as used in the present
invention.
DETDESC:
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
The present invention relates to a method and apparatus for the off-axis
detection of laser-induced fluorescence. Referring to FIG. 1, there is shown a
block diagram of the components of a scanning device 10 according to the present
invention. The scanning device 10 uses coherent light to scan a object or target
12. In the preferred embodiment, the components of the device 10 include; a
tuneable laser 14, a beam expander 16, an iris diaphragm 18, a focusing lens 20,
a three-dimensional scanner 22, a target mount 24, a fiber optic faceplate
having a bias cut 26, a diffusion member 28, a photomultiplier tube 30, a
<PAGE> 177
programmable computer with memory 32 and a visual monitor 34. Together these
components provide for rapid scanning of translucent targets to yield high
resolution, wide-field fluorescence analyses of a large number of cells in
vitro, with high spatial precision.
The means for generating the coherent beam of light is a laser 14. It is
desirable that the laser 14, shown in FIG. 1 emit a coherent polarized beam of
light 15 having a wavelength in the range of 350 to 540 nanometers. The light
beam 15 exiting the laser 14 is approximately 1 millimeter in width, which is
too small to be used effectively by the reflecting mirrors within the scanner
22. Therefore, the present invention provides a beam expander 16 which receives
the laser beam 15 and enlarges the size of the beam 15 to ensure utilization of
the greatest possible surface area of the reflecting mirrors within the scanner
22. The preferred beam expander 16, as shown in FIG. 1, is a Buschnell
<PAGE> 178
PAGE 35
Pat. No. 4758727, *
variable beam expander having a magnification power range of 9 x to 30 x . In
the preferred embodiment, the beam expander 16 is adjustable to expand the beam
size through a range from 1 millimeter to 10 millimeters.
As an alternative to the use of a variable beam expander, a single power beam
expander may also be used with Applicant's invention. In such cases an iris
diaphragm 18 is included to receive the expanded beam 15 from the single power
beam expander. The iris diaphragm 18, also known as a field iris, is intended to
vary the diameter of the beam 15 input to the focusing lens 20 and the scanner
22, thus varying the spot size on the target 12. Consequently, the iris
diaphragm 18 is used to more finely tune the size of the beam of light 15.
Referring now to FIG. 1, the beam of light 15 exiting the beam expander 16 or
iris diaphragm 18 is passed through the focusing lens 20 which focuses the beam
of light 15 on the target 12. Together, the beam expander 16/iris diaphragm 18
and focusing lens 20 permit the beam of light to be focused to a spot of
predetermined dimension at the target plane of the translucent target 12.
In the preferred embodiment, the light received by the focusing lens 20 is a
gaussian columnated coherent beam of light. Using this assumption, the final
spot size upon the target 12 is diffraction limited and governed by the
following equation:
d = 4F lambda / pi D, (1)
wherein
d = spot size
F = focal length of focusing lens
lambda = wavelength of the light
D = aperture of input beam to focusing lens
According to equation (1), the proper selection of the focal length (F) of
the focusing lens 20, the wavelength ( lambda ) of the coherent light beam 15,
and the aperture (D) of the input beam to the focusing lens 20, will allow for
the size of the beam spot (d) on the target 12 to be varied as desired. The
smallest available spot size is approximately one micron. Thus, the present
invention is capable of scanning at a variety of intervals with the smallest
<PAGE> 179
being a one micron interval.
The focused beam of light 15 exiting the focusing lens 20 is received by the
three-dimensional scanner 22 which operates to control the passing of the light
beam 15 over the target 12. The scanner 22 as shown in FIG. 1 is manufactured by
General Scanning, Inc. and uses computer controlled mirrors to pass the focused
beam of light 15 back and forth across the target 12. The scanner 22 is capable
of scanning an area of any size, up to 20 millimeters by 40 millimeters, while
operating at a raster rate of up to 20 Hz or a vector rate of up to 280 mm/sec.
Computer controlled drive motors cause the mirrors of the scanner 22 to move
such that the scanner 22 has accurate X and Y coordinate scanning capabilities
with a simultaneous Z coordinate correction to yield a beam of light 15 with a
flat field of focus. If desired, the Z coordinate of the scanner 22 can be
programmed to coordinate with an uneven topographical field of focus on the
<PAGE> 180
PAGE 36
Pat. No. 4758727, *
target 12.
The scanner 22 passes the focused coherent beam of light to the target 12,
thereby inducing fluorescence in a predetermined pattern and at a predetermined
rate set by the computer 32 so that data is obtained as to the intensity of the
fluorescence at differing points on the target 12. At precise predetermined
points during the scanning process, the intensity of the light is measured by
the photomultiplier tube 30 and recorded by the computer 32 as a function of
location of the beam 15 on the target 12. By taking successive point
measurements of the intensity of the fluorescence and relating them back to the
location data in the computer 32, the data is used to analyze the target 12 or
recreate a visual image of the target 12 on a visual monitor 34.
The target 12 is scanned over a very large series of points using a back and
forth pattern as shown in FIG. 2. The X, Y coordinates and the rate of scanning
are predetermined and programmed through the computer 32. The scanning program
is individually drawn to the specifics of the application. The flowchart for the
scanning program is shown in FIG. 5. At each scanning point, the fluorescence
intensity is measured and recorded as a function of the X, Y coordinates of the
beam. For example, the scanner 22 would be programmed to scan the target 12, as
shown in FIG. 2, in a sequential pattern over the following (X,Y) coordinates:
(1,1), (1,2), (1,3), (1,4), (2,4), (2,3), (2,2), (2,1), (3,1), (3,2), (3,3),
(3,4), (4,4), (4,3), (4,2) and (4,1). The intensity of the fluorescence being
excited at each of the scanning points is measured by the photomultiplier tube
30 in terms of analogue data. The analogue data for each scanning point is then
digitized by the computer 32 and recorded as a function of the X, Y coordinates
of that particular scanning point.
The present invention utilizes a three-dimensional scanner, such as that
manufactured by General Scanning, Inc. The use of such a scanner provides in
that the target mount 24 is stationary, thereby eliminating the wobble and
jitter experienced with moving target mounts. Due to the minute size of the
focused beam spot on the target 12 and the large amount of point data being
taken, it is important that the target 12 be rigidly mounted in a fixed position
on the target mount 24 to maintain the proper focusing, depth of field, and spot
size.
Positioned directly below the target mount 24 and thus below the target 12
itself is a fiber optic faceplate 26 which is used in conjunction with a
diffusion member 28 to increase the efficiency of the highly sensitive
photomultiplier tube 30. The sensing surfaces of photomultiplier tubes are
<PAGE> 181
characteristically nonuniform. The fluorescent light transmitted by the target
12 is minute in the form of a narrow columnated beam. If this beam were received
by the photomultiplier tube 30, variations in the recorded intensity of the beam
would occur as a result of variations in the location at which the narrow
columnated light beam strikes the sensing surface of the photomultiplier tube
30. Therefore, the present invention utilizes the fiber optic faceplate 26 to
gather as much light as possible and the diffusion member 28 spreads the light
beam broadly as possible to achieve full use of the photomultiplier tube 30.
One of two types of fiber optic faceplates 26 may be used with the present
invention, depending upon the size of the window of the photomultiplier tube 30.
When the window of the photomultiplier tube 30 is comparable in size to the
target 12, then a flat disk-type faceplate, as shown in FIGS. 1 and 2, is used.
When the scanning area of the target 12 is larger than the window of the
<PAGE> 182
PAGE 37
Pat. No. 4758727, *
photomultiplier tube 30, a tapered or frustoconical shaped fiber optic faceplate
26A, such as shown in FIG. 4, is used. The use of such fiber optic faceplates
presents a marked improvement over prior art systems in which lenses are relied
upon to gather and direct the light beam. The light gathering or flux-carrying
capacity of the optical fibers within the taper 26A as used with the present
invention is 10 to 70 times higher than that of standard optical lenses. The
relative increase in light gathering capacity is numerically equal to the ratio
of the squares of the numerical apertures. The effective numerical aperture of a
typical lens capable of imaging a target area of at least several square
millimeters is 0.10 to 0.20 as compared with optical fibers which have nominal
numerical aperture values of greater than 0.60. Therefore, the use of optical
fibers in conjunction with highly sensitive photomultiplier tubes 30 produces a
marked advantage over instrument designs incorporating optical lens systems
and/or solid-state light detectors.
The fiber optic faceplate 26 is biased cut at a angle alpha , preferably 30o.
Referring to FIG. 6, the bias cut on the optical fiber faceplate 26 is shown as
angle alpha and the acceptance angle of the fiber optic faceplate 26 is
deflected by angle beta . This provides a total deflection by angle beta or
shift of the acceptance angle theta which comprises the acceptance cone of the
fiber optic bundle. If laser light is shown onto a fiber outside of the
acceptance cone, the amount of light transmitted along the length of the fiber
will be severely limited. Thus, the present invention provides a fiber optic
faceplate 26 having a bias cut such that light hitting perpendicular to the face
of the fibers will not be in the acceptance cone. In this manner, a light source
hitting perpendicular to the surface will be attenuated while excited
fluorescence or scattered light may enter the acceptance cone. The bias cut
fiber optic system of the present invention is capable of gathering 30% of the
excited fluorescence from the target being scanned, as compared with current
technology in which only 2% of the excited fluorescent light is gathered.
The optical fibers in the faceplate 26 also function as the first stage for
light diffusion. Optical fibers will gather light from all angles within the
acceptance cone. Upon exit from the faceplate 26 this light is rotated about a
solid angle through which the intensity is uniformly distributed. This optic
fiber property thus enhances the light scattering efficiency of the diffusion
member 28.
Further attenuation of the light is accomplished by insertion of neutral
density filters 27 between the fiber optic faceplate 26 and the diffusion member
28. In the preferred embodiment, a 620 nanometer filter is incorporated in order
<PAGE> 183
to eliminate the normal fluorescent room lighting, thus permitting operation of
the instrument without extensive light protection. Further, a barrier filter
(not shown) may be incorporated at this point to absorb light at the excitation
wavelength while transmitting light at the fluorescent wavelength.
The diffusion member 28, shown in FIG. 1, is an open-ended hollow elongated
member with a reflective interior surface. Such a member can be constructed of
an open-end box using mirrored glass for the interior surface. Alternatively,
milk glass may be used as the diffusion member 28. The primary functions of the
diffusion member 28 are two-fold. First, the diffusion member 28 blocks out any
remaining ambient light which will affect the intensity readings of the
photomultiplier tube 30. Secondly, the diffusion member 28 allows the
transmitted light to diffuse within its confines to more fully utilize the
window of the photomultiplier tube 30 and thus yield more accurate results.
<PAGE> 184
PAGE 38
Pat. No. 4758727, *
After the fluorescent light transmitted from the target 12 is directed to the
photomultiplier tube 30 by the fiber optic faceplate 26 and diffusion member 28,
the photomultiplier tube 30 detects and measures the fluorescence levels. The
photomultiplier tube 30 is in turn linked to the computer 32 so that data
obtained by the photomultiplier tube 30 regarding the intensity of the light is
fed into the computer 32.
Once the device 10 is activated and scanning of the target 12 begins, the
output of the photomultiplier tube 30 is sampled by the computer 32 as often as
desired. The electrical signals relating the intensity of the fluorescent light
are converted from analogue to digital values by the computer 32 for storage
purposes. Using the preprogrammed position data and the stored intensity values,
the computer 32 can provide a realtime pictorial reconstruction of the target 12
on a visual monitor 34. The capacity of the computer 32 to rapidly store the
highly detailed data being viewed makes it possible to depict the entire area of
the target 12 on the visual monitor as well as focus on particular points of
interest by providing enlarged viewing of select portions of the target 12.
Referring now to FIG. 3, an interface is provided to collect the analogue
intensity data output of the photomultiplier tube 30 and convert the data into
digital form for the versabus-based computer 32. The interface 33 communicates
with the computer 32 through direct memory access (DMA) with a minimum
instantaneous transfer rate of 100,000 picture elements (pixels) per second. The
interface 33 of the present invention is composed of five main subsystems
including: an analogue-to-digital (A/D) converter 36 as shown in FIG. 7; a set
of buffers and latches 38; bus interface logic 40 as shown in FIGS. 9, 10; a DMA
controller 42 as shown in FIG. 11; and a system timing controller 44 as shown in
FIG. 12. The DMA controller 42 and system timing controller 44 are used to
properly operate the A/D converter 36, the set of buffers and latches 38 and the
bus interface logic 40.
Referring now to FIG. 7, the A/D converter 36 transforms the image data
signals which are received from the photomultiplier tube 30 into a digital form
which is understandable by the host computer 32. The buffers change the voltage
of the signals to a level which is compatible with the host computer 32 while
the latches store the transformed data until it is efficient for the computer 32
to accept them.
Referring now to FIG. 11, the DMA controller 42 and the bus interface logic
40 of FIGS. 9 and 10 store and control information about the flow of the data to
the computer 32 so that the computer 32 receives the data only when it is able
<PAGE> 185
to accept the information. The system timing controller 44 of FIG. 12 ensures
that the proper number of pixels are placed into the memory 46 of the computer
32. In addition, the system timing controller 44 generates all the needed
signals for the A/D converter 36.
Since the A/D converter 36 outputs emitter coupled logic (ECL) compatible
signals, level shifters are required to provide transistor-transistor logic
(TTL) signals. These signals are tied directly to a combination bus buffer/latch
chip. The conversion timing is derived from a 1 MHz crystal feeding an AM9513
timing controller. It should be noted that higher frequency crystals may be
used. The timing controller is started by means of an enable convert signal
which can be generated by the host computer 32 under user control, or by a
signal external to the board. The timing controller 44 generates the convert and
latch signal, and also terminates its count automatically. The controller is
completely software
<PAGE> 186
PAGE 39
Pat. No. 4758727, *
programmable.
The bus interface logic permits the use of both a positive true logic and
negative true logic CPU bus. The bus also allows for a choice of an 8 or 16 MHz
CPU clock speed. The board is memory-mapped, and may reside on any 256 byte
boundary in memory.
The DMA controller circuit is designed to provide for both cycle steal and
burst modes, under software programmability. This feature allows for increased
efficiency at high data rates. Regardless of the mode chosen, the eight most
significant bits are latched, and the next sample is latched in the same manner.
At this point, the DMA transfer will proceed in the specified mode. It is
important to note that by first latching 16 bits and then requesting the bus,
the bus bandwidth used in cycle steal mode is cut to one half of what it would
otherwise have been.
The remainder of the circuitry includes a 1.5 volt local power supply 48
(FIG. 13a), as required by the DMA control circuitry, and a dual speed
power-on-clear circuit 50 (FIG. 13b) which included to ensure the circuit powers
up in a predictable and stable manner.
With the circuitry in place, the device 10 is used to scan the object 12. The
excited fluorescent intensity is determined using the highly efficient optical
fiber faceplate 26 and the sensitive photomultiplier tube 30 without respect to
the precise position of the laser beam on the target object. Such position is
alternatively determined by the computer 32 which controls the three-dimensional
scanner 22. The computer 32 then combines the X, Y coordinate spatial
information with the intensity information to yield a high resolution wide-field
image of the object 12.
Having thus described the invention in detail, it should be understood that
various modifications and changes can be made in the apparatus without departing
from the scope and content of the following claims.
CLAIMS: What we claim is:
[*1] 1. An apparatus for measuring the excited fluorescence of an object
comprising:
means for generating a coherent beam of light;
<PAGE> 187
a three dimensional scanner having means for securing such object in a fixed
position, said scanner receiving and passing said coherent beam of light onto
such fixed object in a desired pattern and at a desired rate, said scanner
having X, Y coordinate scanning capability with simultaneous Z coordinate
correction to cause said beam to have a topographical field of focus in the
place of said object;
means for controlling the pattern and rate at which said beam of light is
passed onto said object;
an optical fiber member for gathering and directing the fluorescent light
induced from said object by said beam of light and for attenuating any direct
light received by said object;
<PAGE> 188
PAGE 40
Pat. No. 4758727, *1
means for collecting and measuring the intensity of the fluorescent light
received from said object; and,
means for sequentially recording data regarding the intensity of the
fluorescent light received from said object as a function of the location of
said scanning beam of light on said object by said scanner.
[*2] 2. The apparatus of claim 1 further including a means for filtering
said fluorescent light emanating from said optical fiber member.
[*3] 3. The apparatus of claim 1 further including a means for diffusing
said fluorescent light emanating from said optical fiber member.
[*4] 4. The apparatus of claim 1, further including means for producing a
visual image of at least a portion of said object based upon said sequentially
recorded data of the intensity of said transmitted light as a function of the
location of said scanning beam of light on said object.
[*5] 5. The apparatus of claim 1, which further includes a focusing lens
interposed between said means for generating a coherent beam of light and said
three dimensional scanner.
[*6] 6. The apparatus of claim 5, which further includes a beam expander
interposed between said means for generating a coherent beam of light and said
focusing lens.
[*7] 7. The apparatus of claim 6, which further includes an iris diaphragm
interposed between said beam expander and said focusing lens.
[*8] 8. The apparatus of claim 1, wherein said means for diffusing said
transmitted light comprises an open-ended hollow elongated member having a
reflective interior surface.
[*9] 9. The apparatus of claim 1, wherein said means for collecting and
measuring the intensity of the light transmitted through said translucent object
comprises a photomultiplier tube.
[*10] 10. The apparatus of claim 1, wherein said means for predeterminately
controlling the pattern and rate at which said beam of light is passed over said
object is a programmable computer.
<PAGE> 189
[*11] 11. The apparatus of claim 1, wherein said means for sequentially
recording data is a programmable computer.
[*12] 12. An apparatus for measuring the excited fluorescence of an object
having a binding fluorescent dye application comprising:
means for generating a coherent beam of light;
means for expanding said coherent beam of light;
means for focusing said expanded beam of light;
a three dimensional scanner having means for securing such object in a fixed
position, said scanner receiving and passing said focused beam of light over
<PAGE> 190
PAGE 41
Pat. No. 4758727, *12
such fixed object in a selected pattern and at a selected rate, said scanner
having X, Y coordinate scanning capability with simultaneous Z coordinate
correction to cause said focused beam of light to have a topographical field of
focus in the plane of said object;
means for controlling the pattern and rate at which said beam of light is
passed through said translucent object;
a biased cut optical fiber faceplate for receiving and directing the
fluorescent light transmitted from said object;
means for filtering said fluorescent light emanating from said fiber
faceplate;
means for diffusing said filtered light;
means for collecting and measuring the intensity of the fluorescent light
transmitted through said object; and
means for sequentially recording data regarding the intensity of the
fluorescent light transmitted from said object as a function of the location of
said scanning beam of light on said object.
[*13] 13. The apparatus of claim 12, which further includes means for
producing a visual image of at least a portion of said object based upon said
sequentially recorded data as a function of the location of the fluorescent
light transmitted from said object.
[*14] 14. The apparatus of claim 12, which further includes an iris diaphragm
interposed between said means for expanding said beam of light and said means
for focusing said expanded beam of light.
[*15] 15. The apparatus of claim 12, wherein said means for generating a
coherent beam of light is a laser.
[*16] 16. The apparatus of claim 12, wherein said means for expanding said
beam of light is a variable beam expander.
[*17] 17. The apparatus of claim 12, wherein said means for controlling the
pattern and rate at which said beam of light is passed over said object is a
programmable computer.
<PAGE> 191
[*18] 18. The apparatus of claim 12, wherein said means for diffusing said
fluorescent light is an open-ended hollow elongated member having a reflective
interior surface.
[*19] 19. The apparatus of claim 12, wherein said means for collecting and
measuring the intensity of the fluorescent light transmitted from said
translucent object is a photomultiplier tube.
[*20] 20. The apparatus of claim 12, wherein the means for sequentially
recording data is a programmable computer.
[*21] 21. An apparatus for measuring the excited fluorescence of an object
having a finding fluorescent dye application comprising;
<PAGE> 192
PAGE 42
Pat. No. 4758727, *21
a laser for generating a coherent beam of light at a specified wavelength
with the range of 350 to 540 nanometers;
a variable beam expander for expanding said coherent beam of light;
a focusing lens to focus said expanded beam of light;
a three dimensional scanner having means for securing such object in a fixed
position, said scanner receiving and passing said focused beam of light over
such fixed object in a selected pattern and at a selected rate, said scanner
having X, Y coordinate scanning capability with simultaneous Z coordinate
correction to cause said focused beam of light to have a topographical field of
focus in the plane of said object;
means for controlling the pattern and rate at which said focused beam of
light is passed over said object;
a biased cut optical fiber faceplate for receiving and directing the
fluorescent light transmitted from said object;
filter means for receiving said fluorescent light from said fiber optic
bundle and removing unwanted light input;
diffusion means for diffusing said filtered light;
a photomultiplier for measuring the intensity of the fluorescent light
transmitted and received from said diffusion means; and,
means for sequentially recording data regarding the intensity of the
fluorescent light transmitted from said object as a function of the location of
said scanning beam of light on said object.
[*22] 22. The apparatus of claim 21, wherein said means for controlling the
pattern and the rate at which said focused beam of light is passed over said
object is a programmable computer.
[*23] 23. The apparatus of claim 21, wherein said means for sequentially
recording data is a programmable computer.
[*24] 24. The apparatus of claim 21, wherein said diffusion means is an
open-ended hollow elongated member having a reflective interior surface.
<PAGE> 193
[*25] 25. The apparatus of claim 21, which further includes an iris diaphragm
interposed between said beam expander and said focusing lens.
[*26] 26. The apparatus of claim 21, which further includes means for
producing a visual image of at least a portion of said object based upon said
sequentially recorded data as a function of the location of the fluorescent
light transmitted from said object.
<PAGE> 194
FIGURES TO PATENT NO. 4,758,727
<PAGE> 195
[FIG. 1 is a block diagram of a scanning device according to the present
invention.]
<PAGE> 196
[FIG. 2 is an exemplary view of a scanning pattern of a translucent object with
a scanning device according to the present invention.]
<PAGE> 197
[FIG. 3 is a block diagram of the electronic interface used to control the
various components of scanning device according to the present invention.]
<PAGE> 198
[FIG. 4 is a block diagram showing an alternate embodiment of the fiber optic
bundle as used with a scanning device according to the present invention.]
<PAGE> 199
[FIG. 5 is a flowchart representing the scanning program by which the present
invention operates.]
<PAGE> 200
[FIG. 6a is an exemplary view of a biased cut optical fiber faceplate.]
<PAGE> 201
[FIG. 6b is an exemplary view of a biased cut tapered optical fiber faceplate.]
<PAGE> 202
[FIG. 7 is a schematic showing an analogue to digital convertor board as used in
the present invention.]
<PAGE> 203
[FIG. 8 is a schematic showing the clock circuitry as used in the present
invention.]
<PAGE> 204
[FIG. 9 is a schematic showing the low-order Address but Interface circuitry as
used in the present invention.]
<PAGE> 205
[FIG. 10 is a schematic showing the DMA/Versabus Interface circuitry as used in
the present invention.]
<PAGE> 206
[FIG. 11 is a schematic showing the DMA data path circuitry as used in the
present invention.]
<PAGE> 207
[FIG. 12 is a schematic showing the timer interface circuitry as used in the
present invention.]
<PAGE> 208
[FIG. 13a is a schematic showing the 1.5 volt local voltage source as used in
the present invention.]
<PAGE> 209
[FIG. 13b is a schematic showing the Power-On Clear circuitry as used in the
present invention.]
<PAGE> 210
[FIG. 14 is a schematic showing the board select logic as used in the
present invention.]
<PAGE> 211
CONFIDENTIAL TREATMENT REQUESTED
LXR BIOTECHNOLOGY INC.
LOCATED AT 1401 MARINA WAY SOUTH
RICHMOND, CALIFORNIA 94804
Exhibit C4 to Perkin-Elmer License Agreement
<PAGE> 212
**CONFIDENTIAL TREATMENT REQUESTED
MULTI-CHANNEL ACQUISITION USING INTEGRATING SPHERE
** [ ]
<PAGE> 213
CONFIDENTIAL TREATMENT REQUESTED
LXR BIOTECHNOLOGY INC.
LOCATED AT 1401 MARINA WAY SOUTH
RICHMOND, CALIFORNIA 94804
Exhibit C5 to Perkin-Elmer License Agreement
<PAGE> 214
**CONFIDENTIAL TREATMENT REQUESTED
WIDE ANGLE SCATTERING DETECTOR
** [ ]
<PAGE> 215
CONFIDENTIAL TREATMENT REQUESTED
LXR BIOTECHNOLOGY INC.
LOCATED AT 1401 MARINA WAY SOUTH
RICHMOND, CALIFORNIA 94804
Exhibit C6 to Perkin-Elmer License Agreement
<PAGE> 216
** CONFIDENTIAL TREATMENT REQUESTED
[**]
<PAGE> 1
EXHIBIT 10.34
September 24, 1996
PRIVATE & CONFIDENTIAL
Dr. Donald H. Picker, Ph.D.
15828 Highland Court
Solana Beach, CA 92075
Dear Don:
On behalf of the Board of Directors, I am pleased to offer you the position of
President and Chief Operating Officer of LXR Biotechnology Inc. ("the Company").
In this capacity, you will report to L. David Tomei, Ph.D., Chief Executive
Officer. It is expected that you will commence employment on or before October
1, 1996. At the next scheduled meeting of the Board of Directors, you will be
invited to join the board. In the event that the position of Chief Executive
Officer becomes vacant in the future, the Board of Directors will consider your
qualifications as a candidate for this position along with any other qualified
candidates. This consideration, will remain in effect so long as you are a
full-time, active employee of LXR Biotechnology Inc.
Your starting salary will be $18,750 per month ($225,000.00 annually) paid
semi-monthly. A one time recruitment bonus of $15,000 will also be paid to you
subject to the terms noted below.
Subject to approval by our Board of Directors, you will participate in LXR
Biotechnology Inc.'s employee stock option program. Your initial stock option
grant will give you the right to purchase 310,000 shares of LXR Biotechnology
Inc. common stock at the last price quoted on the American Stock Exchange on the
business day prior to your first day of employment. Please note that the option
to purchase these shares exceeds the amount currently available under the
Company's stock option plan. Therefore, the right to purchase 150,000 of these
shares will be granted outside of the Company's option plan. Although issued
outside the plan, these options will be subject to all provisions, including
vesting, of the Company's option plan.
To assist you in your relocation to the San Francisco Bay Area, LXR
Biotechnology Inc. will reimburse your reasonable and actual costs for the
following items, subject to submission of receipts:
- House hunting trip for your and your spouse.
- The transportation of household goods to your new residence.
- Customary Seller's closing costs (including commissions) related to
the sale of your home in Solana Beach, California.
It is anticipated that you will also require temporary living arrangements
including lodging, meals, car rental and mileage during your transition to your
new position for a period of up to six months. Therefore, LXR Biotechnology Inc.
will reimburse you for reasonable costs associated with your temporary living
needs up to $2,000 per month.
<PAGE> 2
If you voluntarily terminate employment with LXR Biotechnology Inc. prior to 24
months after initially commencing employment, the recruitment bonus and all the
above described reimbursed relocation costs will become immediately due and
payable to LXR according to the following schedule:
1-180 days after commencing 100%
181-360 days after commencing 70%
361-720 after commencing 40%
712 days after commencing 0%
In addition, the Company will reimburse economy airfare costs for your travel
between Richmond and Solana Beach during the six month transition period.
A home loan of $175,000 will be provided to you at the time you purchase a new
home in the San Francisco metropolitan area. The loan will be forgiven over an
eight year period in the amount of $25,000 per year, commencing with the first
segment ($25,000) to be forgiven on December 31, 1997. The eighth segment will
forgive any accumulated interest expense remaining at that time. In the event
you resign or are terminated for cause from LXR Biotechnology Inc. before the
loan forgiveness is complete, the remainder (if any) of this loan will be due
and payable.
LXR Biotechnology Inc. has a benefits package for its employees that includes
medical, dental, life and long term disability insurance. We also have a 401K
Retirement Savings Plan and a Flexible Benefit Spending Plan available for
participation. As a regular, full-time employee, you will be eligible to
participate in these programs. The LXR Biotechnology Inc. vacation plan for your
position allows 20 days per year.
This letter, when signed by you, will constitute the agreement between LXR
Biotechnology Inc. and yourself concerning your employment by LXR Biotechnology
Inc. and supersedes any and all previous agreements and discussions. Either you
or LXR Biotechnology Inc. can terminate this employment relationship at any time
without prior notice for any reason. Neither you nor LXR Biotechnology Inc. has
to give "cause" for termination.
As a condition of your employment, you will be required to execute the enclosed
employee proprietary information agreement.
This offer of employment will remain in effect until September 26, 1996.
All of us at LXR Biotechnology Inc. look forward to you joining us. We are
confident that you will make a valuable contribution to the success of the
company.
Sincerely,
/s/ L. David Tomei
- -------------------------------
L. David Tomei, Ph.D.
Chief Executive Officer
<PAGE> 3
This is to verify my acceptance of the above stated offer.
Donald H. Picker, Ph.D.
- --------------------------
Name
/s/ Donald H. Picker
- --------------------------
Authorized Signature
10/7/96
- --------------------------
Date
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