EXHIBIT 10.7
SPONSORED RESEARCH AGREEMENT
THIS AGREEMENT is made by and between CytoGenix, Inc. whose
address is 9881 South Wilcrest, Houston, Texas 77099 (hereinafter
"SPONSOR") and Baylor College of Medicine, whose address is One Baylor
Plaza, Houston, Texas 77030 (hereinafter "BCM").
WHEREAS, SPONSOR desires that BCM perform certain technological
research work using SPONSOR's proprietary technology hereinafter
defined, and
WHEREAS, SPONSOR is willing to advance funds to sponsor such
Research, and
WHEREAS, SPONSOR desires to establish ownership of rights to
intellectual property and technology which may be developed during the
course of such work, and
WHEREAS, BCM is willing to perform such Research.
NOW, THEREFORE, in consideration of the mutual covenants and
promises herein contained, BCM and SPONSOR agree as follows.
I. EFFECTIVE DATE
This Agreement shall be effective as of March 1, 2000.
II RESEARCH PROGRAM
2.1 BCM will use its best efforts to conduct the Research Program
described in the attached Schedule A, "Statement of Work," utilizing
SPONSOR's proprietary technology as described in Schedule C and in
accordance with the "Budget" set forth in Schedule B, and will furnish the
facilities necessary to carry out such Research Program. The Research
Program will be under the direction of Bert W. O'Malley, M.D., (O'MALLEY)
Professor and Chairman, Department of Molecular and Cellular Biology,
acting as Principal Investigator.
2.2 The Research Program shall be performed during the period from
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March 1, 2000 to March 31, 2002. SPONSOR shall have the option of extending
the Research Program under mutually agreeable support terms.
2.3 SPONSOR understands that O'MALLEY's primary mission is Professor
and Chairman, consequently, the Research Program will be performed in a
manner consistent with that mission. Specifically, the manner of
performance of the Research Program shall be determined by mutual agreement
between O'MALLEY, as the representative of BCM, and SPONSOR. Neither
O'MALLEY nor BCM can guarantee specific results.
2.4 BCM and O'MALLEY will keep accurate financial and scientific
records relating to the Research Program and will make such records
available to SPONSOR or its authorized representative during normal
business hours upon reasonable notice.
2.5 BCM does not guarantee that any intellectual property will
result from the Research Program, that the scope of any intellectual
property obtained will cover SPONSOR's commercial interests, or that any
such intellectual property will be free of dominance by other intellectual
property, including those based upon inventions made by other inventors.
III.CONSULTATION AND REPORTS
3.1 During the period of this Agreement, SPONSOR's representative may
consult informally with O'MALLEY, as BCM's representative, regarding the
project both personally and by telephone. Access to work carried on in BCM
laboratories in the course of these investigations shall be entirely under
the control of BCM personnel and available on a reasonable basis to
SPONSOR.
3.2 O'MALLEY will provide to SPONSOR a written report every three (3)
months and shall also submit a comprehensive final report within 120 days
of termination of this Agreement.
IV. PUBLICATION
4.1 In the exercise of the rights of academic freedom of an
educational institution and its faculty, BCM, O'MALLEY, and the Project
Team shall have the right to publish in scientific or other journals, or to
present at professional conferences or other meetings. BCM, O'MALLEY, and
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the Project Team shall not have the right to disclose or publish CYGX's
proprietary information disclosed to BCM, O'MALLEY, and the Project Team to
facilitate the Research Program.
4.2 In order to permit the SPONSOR the opportunity to properly protect
patent and proprietary rights relating to the Research Program, a copy of
each proposed publication shall be provided to the SPONSOR thirty (30) days
in advance of submission for publication to permit the SPONSOR time in
which to prepare application(s) for letters of patent regarding the subject
matter of such publication. Any final proposed publication provided to the
SPONSOR shall be considered as acceptable for submission for publication
unless the SPONSOR notifies BCM and O'MALLEY within thirty (30) days of
receipt of the proposed publication that it requires additional time to
secure patents on such Research Program, in which case the SPONSOR shall
have an additional sixty (60) days to undertake such action before
publication. The SPONSOR shall also receive final drafts of any proposed
publication and the SPONSOR shall be named in the publication as the
SPONSOR of the Research Program or, as the case may be, the licensee of
such technology. The right to review publications as set forth herein shall
extend only to the work product of O'MALLEY and the Project Team pursuant
to the Research Program and not to the work product of other research
conducted in the laboratories of O'MALLEY, or member of the Project Team,
or in the laboratories of other researchers at BCM.
V. CONFIDENTIALITY OF INFORMATION
5.1 SPONSOR and BCM may wish, from time to time, in connection with
work contemplated under this Agreement, to disclose confidential
information to each other. SPONSOR and BCM will use reasonable efforts to
prevent the disclosure to third parties of any confidential information
belonging to the other, and use such information only for the purposes
expressed in this Agreement, during the term of the Agreement and for a
period of three (3) years thereafter, provided that the receiving party's
obligation hereunder shall not apply to information that:
(1) is already in the receiving party's possession at the time of
disclosure thereof;
(2) becomes part of the public domain through no fault or
unapproved action of the receiving party;
(3) is received from a third party having no obligations of
confidentiality to the disclosing party;
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(4) is independently developed by the receiving party;
(5) is required to be disclosed under the laws of the United
States of America pursuant to a court order. However, BCM
shall do so only after promptly providing SPONSOR with notice
of the actual or proposed court order or motion or cause of
action seeking such an order and thereafter, as soon as
available, a copy of the, court order or proposed order, and
giving SPONSOR the opportunity to intervene or otherwise
contest or appeal such motion, cause of action or order. In
any such event, until such time as SPONSOR is acknowledged by
the court or duly appointed officer as being the only party
having standing to object to such action, BCM will promptly
advise the judge or duly appointed officer of this Agreement
and of all restrictions upon the disclosure of confidential or
proprietary information or data and shall employ and use best
efforts to cause testimony or physical copies relating thereto
to be made a sealed record of the court or other forum.
5.2 SPONSOR may, at its own expense, provide such additional
security measures to preserve and protect developed confidential and
proprietary information as will not interfere with the ongoing
investigation and Research process.
5.3 The parties agree that sensitive, confidential and proprietary
information will not be communicated using unsecured media including but
not limited to cellular telephones or electronic mail.
VI. INTELLECTUAL PROPERTY
6.1 BCM shall have sole and exclusive ownership rights to any
invention of a product, device, process, or method, whether patentable or
unpatentable (an "Invention") arising out of the Research Program that is
patentably distinct from and not dominated by CYGX's proprietary
intellectual property disclosed and/or made available to BCM, O'MALLEY, and
Project Team to enable and/or facilitate the Research Project, subject to
the right of the sponsor to take an exclusive, or non-exclusive,
royalty-bearing license to the invention, as set forth in Section 6.2
below.
6.2 BCM grants to SPONSOR the right of first review with respect to
an Invention, discovered from the performance of the Research Program,
under the following terms:
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(1) SPONSOR shall comply with the terms of nondisclosure, as set
forth in Section V. of this Agreement.
(2) BCM shall notify SPONSOR, in writing, of any Invention within
thirty (30) days of actual or constructive conception or
reduction to practice of the Invention, and provide SPONSOR
with sufficient detail to evaluate the Invention.
(3) SPONSOR shall have forty-five (45) days after such
notification to evaluate the Invention and notify BCM, in
writing, that SPONSOR desires to license the Invention.
(4) Upon notification by SPONSOR of its desire to acquire rights
to the Invention, SPONSOR and BCM shall negotiate, in good
faith, for a period not to exceed sixty (60) days, unless
extended by mutual written agreement of SPONSOR and BCM, in an
effort to arrive at terms and conditions satisfactory to
SPONSOR and BCM for the license by SPONSOR of the Invention.
(5) If SPONSOR and BCM do not reach such agreement within said
sixty-day (60-day) period, or if the SPONSOR fails to notify
BCM within said forty-five-day (45-day) period, or if SPONSOR
decides not to acquire the rights to the Invention, BCM shall
be free to deal with the Invention as BCM in its discretion
may decide, and BCM shall have no further obligations to the
SPONSOR with respect to the Invention.
(6) The right of first review, as presented herein, shall
terminate at the earlier of the (a) second anniversary of the
Effective Date or (b) the termination of this Agreement.
6.3 With respect to inventions which SPONSOR has elected to take an
exclusive, or non-exclusive, royalty-bearing license, as provided in
Sections 6.1 and 6.2.
(1) SPONSOR shall select patent counsel and shall be responsible
for the preparation, filing, and prosecution of United States
and foreign Patent applications covering any Invention arising
out of the Research Program, as well as all costs and fees
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associated therewith from and after the Effective Date of such
license. BCM and its employees shall reasonably assist the
SPONSOR in the preparation, filing, and prosecution of such
patent application(s);
(2) SPONSOR shall also have the responsibility for filing all
applications which may be required by health or regulatory
authorities relating to the products arising from the Research
Program including without limitation, filing a New Drug
Application with the FDA. All costs and expenses associated
with such filings shall be borne by SPONSOR. SPONSOR shall own
all right, title, and interest in any FDA or other regulatory
approvals which are obtained by or on behalf of SPONSOR;
(3) BCM and its employees shall reasonably assist SPONSOR with
respect to any filings which may be required by appropriate
health or regulatory authorities.
VII. GRANT OF RIGHTS
BCM shall retain the right to use, for research purposes, the
technology developed as a result of this Agreement. SPONSOR shall retain
the right of first review with respect to any Invention as set forth in
Section VI of this Agreement.
VIII. INDEPENDENT CONTRACTOR
For the purpose of this Agreement and all services to be provided
hereunder, the parties shall be, and shall be deemed to be, independent
contractors and not agents or employees of the other party. Neither party
shall have authority to make any statements, representations or commitment
of any kind, or to take any action which shall be binding on the other
party, except as may be explicitly provided for herein or authorized in
writing.
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IX. TERM AND TERMINATION
9.1 This Agreement shall commence with the Effective Date hereof and
extend until the end of the Research Program as described hereinabove,
unless sooner terminated in accordance with the provisions of this
Section.
9.2 Either Party may earlier terminate this Agreement: as of the
first or subsequent anniversary dates hereof by giving the other party
ninety (90) days prior written notice. Such termination by either party
shall not effect license, assignment, ownership or royalty rights granted
herein.
9.3 In the event that either party shall be in default of any of its
obligations under this Agreement and shall fail to remedy such default
within sixty (60) days after receipt of written notice thereof, the party
not in default shall have the option of canceling this Agreement by giving
notice thereof.
9.4 Termination or cancellation of this Agreement shall not affect
the rights and obligations of the parties accrued prior to termination.
SPONSOR shall pay BCM for all reasonable expenses incurred or committed to
be expended as of the effective date. In the event of cancellation of this
Agreement, BCM shall return all materials, supplies, equipment, and work
in progress to SPONSOR.
9.5 Any provisions of this Agreement which by their nature extend
beyond termination hereof shall survive such termination.
X. ATTACHMENTS
The attached Schedules A, B, and C are made a part hereof for all
purposes.
XI. GENERAL
11.1 This Agreement may not be assigned by either party without the
prior written consent of the other party; provided, however, that SPONSOR
may assign this Agreement to any purchaser or transferee of all or
substantially all of SPONSOR'S business upon prior written notice to BCM.
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11.2 This Agreement constitutes the entire and only agreement between
the parties relating to the Research Program.
11.3 This section and all other headings contained in this Agreement
are for reference purposes only and shall not in any way affect the meaning
and interpretation of this Agreement.
11.4 SPONSOR shall have the right to publish press releases related to
this Agreement with written approval by BCM.
11.5 BCM shall publish the first press release related to this
Agreement upon execution of this Agreement.
11.6 Any notice under this Agreement must be in writing, may be
telecopied, sent by express 24-hour guaranteed courier, or hand-delivered,
or may be served by depositing the same in the United States mail,
addressed to the party to be notified, postage-prepaid and registered or
certified with a return receipt requested. The addresses of the parties for
the receipt of notice shall be as follows:
If to SPONSOR: 9881 S. Wilcrest
Houston, Texas 77099
If to BCM: Office of Research
Room S103
One Baylor Plaza
Houston, Texas 77030
Each notice given by registered or certified mail shall be deemed delivered
and effective on the date of delivery as shown on the return receipt, and
each notice delivered in any other manner shall be deemed to be effective as
of the time of actual delivery thereof. Each party may change its address
for notice by giving notice thereof in any of the manners provided above.
11.5 Any provision of this Agreement which imposes an obligation after
termination or expiration of this Agreement shall survive the termination or
expiration of this Agreement and be binding on SPONSOR and BCM.
11.6 This Agreement shall become effective as of the date set forth on
page 1 when signed by both SPONSOR and BCM.
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IN WITNESS WHEREOF, the parties hereto have caused this Agreement to be
executed as of the date first set forth above.
SPONSOR BCM
____________________________ ______________________________
Malcolm H. Skolnick
President & CEO
____________________________ ______________________________
Date Date
O'MALLEY
______________________________
Bert W. O'Malley, M.D.
Professor and Chairman
______________________________
Date
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SCHEDULE A TO
SPONSORED RESEARCH AGREEMENT
TITLE: An "Orally Regulable" Antisense Therapy for Breast Cancer: Proposal
to CytoGenix, Inc.
INTRODUCTION/BACKGROUND/RATIONALE:
INTRODUCTION
Based on our prior knowledge of steroid hormone receptors, we have
constructed a chimeric regulatory system for genetic therapy containing three
important modules that together constitute a regulable transcription factor: (I)
a domain able to bind a specific DNA-sequence, (II) a domain that regulates the
ability of the receptor to bind DNA upon administration of an exogenous chemical
(ligand) and (III) a domain with the potential to activate or repress
transcription. In order to regulate a specific target gene IN vivo, a desirable
chimeric regulator should contain the following features. The DNA-binding domain
should not bind to endogenous DNA elements in the nucleus and alter gene
expression. The ligand binding domain (LBD) must be stimulated by an easily
administerable, nontoxic drug which retains biological activity at low
concentrations without the interference of endogenous compounds. The regulation
mediated by the LBD should only occur in the presence of the ligand to guarantee
a finely controlled regulation without 'leaky" expression of the target gene in
absence of the drug. The activation (or repressor) domain must be sufficiently
potent to generate high expression (or tight repression) of the coupled target
genes. Our recent results indicate that our target "Gene Switch" regulatory
system approaches the ideal for "regulated gene therapy".
Our current advanced version of the Gene Switch is composed of: (I) an
"activation domain" peptide from the p65 protein (NFkB subunit) which imparts
strong capacity for target gene activation; (II) a Gal4 DNA binding domain
peptide; (III) a mutated ligand binding domain of the human progesterone
receptor, which does not bind progesterone or other endogenous steroids, but
which can bind and be "activated" by antiprogestins such as mifepristone
(RU486). Mifepristone (or other antiprogestins) is relatively nontoxic even at
very high doses in humans (100+ mg/day). Moreover, it has no known IN vivo
effects in humans at the doses required for activation of the Gene Switch
(10-9M); or ~ 250 (mu)g/kg), including any effects on reproduction and neonatal
viability.
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We have had extensive expertise with this Gene Switch in our laboratory
over the past six years. It is a very effective activator of accompanying target
genes under conditions of transfection in tissue culture cells, in transgenic
mice, and more recently, in viral infection of mice carrying the
mifepristone-dependent regulator and a target gene. We long have considered that
the ideal mode of gene therapy would involve such viral vectors in which
PERSISTENCE of the virus would occur, but where no detectable expression of the
therapeutic gene would occur until the Gene Switch is activated by mifepristone.
WE RECENTLY HAVE ACCOMPLISHED THIS GOAL; and now feel that short-term
application to human gene therapy can occur.
In order to facilitate initial delivery of the inducible system IN vivo,
adenoviral vector-mediated gene delivery was our choice of therapeutic approach.
Previously, such a means of delivery had inherent problems: (I) expression of
viral proteins in infected cells is believed to trigger a cellular immune
response that precludes long-term expression of the transferred gene; and (II)
the insert capacity of adenoviral vectors has been previously limited to 8 kb of
transgenic sequence. Recently an adenoviral vector (the "gutless" adenovector)
has been constructed which contains no viral coding sequences and possesses a
very large insert capacity (28 kb). Using this adenoviral vector in combination
with our inducible regulatory system should provide a "persistent" regulable
gene delivery system IN VIVO for use in human gene therapy.
This "gutless" adenoviral (GAd) expression has displayed impressive
characteristics to date. The modified adenovirus vector can easily accommodate
both the Gene Switch coding sequence and a large target vector. It is produced
in tissue culture cells with the aid of a helper virus, which can be eliminated
later by purification (99.98%). The virus can be administered I.V. and takes up
residence in a number of tissues (e.g., liver, lung, muscle, etc.) and most
importantly, remains capable of activation for 2 years IN VIVO. In this way,
genes contained in the GAd may be turned "on" and "off" repeatedly over two
years, or perhaps a considerably greater time period. Additional benefits are a
distinct lack of immunotoxicity (NO viral proteins are produced from the GAd
vector) and a low-to-nonexistent basal expression in the absence of the
mifepristone inducer compound. Upon IM, IP, S.C. or oral administration of
mifepristone (or other antiprogestins) to mice, the target gene (in our proof of
principle experiments we use the growth hormone gene for ease of detection), is
activated to a tremendous level that results in serum levels in excess of 50
(mu)g/ml (50,000 x normal levels) - a level much greater than that achievable
with transgenic animals producing regulatable constitutive levels of growth
hormone. Withdrawal of mifepristone leads to a relatively rapid decrease in GH,
consistent with the drug's half-life (~20 hours) in animals.
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In an analogous manner, we will insert the reverse transcriptase (RT)
gene, the encoding sequences for desired ODNs for antisense and/or other
therapeutic nucleic acids, and the sequence encoding for the RT primer binding
site (PBS) into our gutless adenoviral vector, behind the mifepristone regulable
GeneSwitch. Plasmid(s) containing the RT gene, MCS for insertion of encoding
sequences, and the PBS will be provided by CytoGenix. Viral preparations will be
according to our established procedures. Virus will be tested for efficacy,
first in tissue culture cells, prior to administration to animals.
In summary, we have developed a near-term genetic therapy, which can be
regulated by an orally effective, non-toxic, specific, activator ligand
(antiprogestin) which has minimal-to-no deleterious effects in the host species.
We feel this is an ideal way to administer gene therapy in a fully regulable
fashion. This gene therapy system is applicable to a wide variety of
anti-oncogenic therapeutic genes - and to a wide variety of tumors. As a primary
aim of the project, we will deplete normal breast cancer cells of SRA, a new
general coactivator for steroid hormone (i.e., ER, PR) receptor action.
SRA-ACTIONS AND RELEVANCE TO TUMORS
The cloning and characterization of several transcriptional coregulators
has provided new insights into nuclear receptor-mediated gene regulation, and
their role in tumorigenesis needs to be evaluated. We recently reported the
isolation and functional characterization of SRA, a novel transcriptional
coactivator with remarkable features. Unlike other known coactivators, SRA
functions as an RNA transcript and is selective for steroid hormone receptors.
Recently, we found that SRA is overexpressed in steroid-dependent tumor tissues,
suggesting that SRA may play an important role in tumorigenesis. We therefore
planned to validate the role of SRA as biological marker for steroid-dependent
cancers. We are currently analyzing a large variety of human tissues and
correlating SRA expression with stage and type of the tumors. In addition, since
SRA coactivation does not require the ligand-binding domain of the receptors,
and since SRA coactivates Tamoxifen antagonized estrogen receptor in culture
cells, we believe that SRA may play an important role in tamoxifen-resistant
breast cancers. Thus, we will put SRA in perspective with regards to hormonal
status of primary human breast tumor tissues. To answer the important question
as to whether SRA alone is sufficient to cause tumorigenesis, our studies will
be complemented by the analysis of transgenic mice that overexpress SRA
specifically in the mammary glands. This model, when completed, will be tested
for antisense inhibition of SRA using the vectors described above.
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ANIMAL TEST SYSTEMS
A. Transgenic SRA-Overexpression Breast Model
SRA has been introduced into animals transgenetically via an MMTV-breast
specific promoter. Our current analyses show a breast phenotype in the germline
SRA-overexpression animals; we predict an oncologically important model that
could be ideal for testing the antisense/catalytic therapeutic capabilities of
CytoGenix's proprietary ODN expression system.
B. An alternate "back-up" breast cancer exenograft model will be utilized in
addition to the SRA-overexpression model will be used to test the SRA-ODN
system. It is currently operative in the laboratory and the generation and
testing in this model are routine.
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SCHEDULE B TO
SPONSORED RESEARCH AGREEMENT
BUDGET
YEAR 01 YEAR 02
------- -------
SALARY AND FRINGE (34%)
Research Associate (50%) 33,000
Technical Help 42,500
Supplies 28,000
Viral Preparation 9,000
Animals/Care 12,500
Other/Misc. 5,000
--------
Total Direct Costs = 130,000
BCM's Indirect Costs @ 26% Direct = 34,000
--------
BCM Total Costs $164,000
Project Total 164,000 164,000
Two-Year Total 328,000
Time Line Year 01-Q2/Year 01-Q4/Year 02-Q2 /Year 02-Q4
Vector Constr. /Modif. +
Vector Testing/Cells + +
Vector/Animals +
SRA Model Completion +
SRA/Breast Ca Model Expts. Completed + +
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SCHEDULE C TO
SPONSORED RESEARCH AGREEMENT
The plasmid pssXD is approximately 6.26 Kb and was developed as a fusion
between two independent plasmids. When a desired sequence encoding for a given
ssDNA sequence is inserted into pssXD, and pssXD is subsequently transferred
into mammalian cells, pssXD produces detectable ssDNA (of any desired sequence)
which can be potentially used in antisense, sense, triplex, and/or catalytic
nucleic acid experiments. The plasmid encodes for one protein (reverse
transcripitase) which, in turn, directs the continued synthesis of a desired
ssDNA within the cell. The plasmid pssXD encodes for the neomycin (Neo)
resistance gene for positive selection in eukaryotic cells. It also contains
ColE origin of replication and the prokaryotic bla promoter driving Kanamycin
resistance for propagation in E. coli. The plasmid is provided with two Not I
cut sites with a small stuffer region between these two cut sites and a Pac I /
Bam HI MCS for the insertion of the desired sequence to be expressed as ssDNA.
Users simply synthesize both sense and antisense oligonucleotides of desired
length and sequence (complimentary to each other) with Not 1 sites or Pac I /
Bam HI sites at both ends. The synthesized fragment is then cloned into the
plasmid with subsequent selection of proper orientation of sense and antisense
producing vectors ready for transfection experiments. Instruction, and sequence
maps are provided.
SPONSOR's proprietary technology and improvements thereon are further
described in SPONSOR's patents and patent applications as listed below.
1. U.S. Patent Application -- Serial No. 08/236,504 (filed April 29, 1994) --
entitled "Stem-Loop Cloning Vector and Method"
2. U.S. Patent Application -- Serial No. 08/877,251 (filed June 17, 1997 --
Continuation of 08/236,504, 04/29/94) -- entitled "Stem-Loop Cloning Vector
and Method" Notice of Allowability 12/28/98
3. U.S. Patent Application -- Serial No. 09/169,793 (filed October 9, 1998 --
CIP of application 08/877,251) -- entitled "Production of ssDNA In Vivo"
4. U.S. Patent Application -- Serial No. 09/397,782 (filed September 16, 1999
-- CIP of 09/169,793 10/09/98) -- entitled "In Vivo Production of ssDNA
Using Reverse Transcriptase with Predefined Reaction Termination via
Step-Loop Formation"
5. U.S. Patent Application -- Serial No. 09/397,783 (filed September 16, 1999
-- CIP 09/169,793) -- entitled "Enzymatic Synthesis of ssDNA"
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6. U.S. Patent Application -- Serial No. 09/411,568 (filed October 4, 1999 --
CIP of 09/397,782 and 09/169,793) -- entitled "In Vivo Production of ssDNA
Containing DNA Enzyme Sequence with Rnase Activity"
7. International Application -- No. PCT/US99/23936 (filed October 12, 1999 --
entitled "Production of ssDNA In Vivo"
8. International Application -- No. PCT/US99/23933 (filed October 12, 1999) --
entitled "Enzymatic Synthesis of ssDNA"
9. U.S. Patent Application (filed February 28, 2000 -- CIP of 09/411,568 and
09/397/782 and 09/169,793 and 08/877,251 and 08/236,504) -- entitled
"Altering Gene Expression with ssDNA Produced In Vivo"
10. U.S. Patent Application (filed March 6, 2000 -- CIP of 09/397,783 and
09/169,793 and 08/877,251 and 08/236,504) -- entitled "Enzymatic Synthesis
of ssDNA In Vivo"
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