ISIS PHARMACEUTICALS INC
SC 13D/A, 1999-09-02
PHARMACEUTICAL PREPARATIONS
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                       SECURITIES AND EXCHANGE COMMISSION
                             Washington, D.C. 20549

                                  SCHEDULE 13D
                                 (Rule 13d-101)

             INFORMATION TO BE INCLUDED IN STATEMENTS FILED PURSUANT
            TO RULE 13d-1(a) AND AMENDMENTS THERETO FILED PURSUANT TO
                                  RULE 13d-2(a)

                                (AMENDMENT NO. 2)


                           ISIS PHARMACEUTICALS, INC.
       ------------------------------------------------------------------
                                (Name of Issuer)


              COMMON STOCK, PAR VALUE $0.001 PER SHARE
       ------------------------------------------------------------------
                         (Title of Class of Securities)

                                   464330 10 9
       ------------------------------------------------------------------
                                 (CUSIP Number)


                               HANS-PETER MUELLER
                     BOEHRINGER INGELHEIM INTERNATIONAL GmbH
                               BINGER STRASSE 173
                       D-55216 INGELHEIM AM RHEIN, GERMANY
                              011-49-61-32-77-2414
                                       AND
                              KLAUS H. JANDER, ESQ.
                               ROGERS & WELLS LLP
                                 200 PARK AVENUE
                               NEW YORK, NY 10166
                                 (212) 878-8000
       ------------------------------------------------------------------
                  (Name, Address and Telephone Number of Person
                Authorized to Receive Notices and Communications)

                                 AUGUST 31, 1999
       ------------------------------------------------------------------
             (Date of Event Which Requires Filing of This Statement)

                  If the  filing  person has  previously  filed a  statement  on
         Schedule  13G to report  the  acquisition  that is the  subject of this
         Schedule  13D, and is filing this  schedule  because of Rule  13d-1(e),
         13d-1(f) or 13d-1(g), check the following box |_|

           Note.  Schedules  filed  in  paper  format  should  include  a signed
           original and five copies of the schedule, including all exhibits. See
           Rule 13d-7(b) for the other parties to whom copies are to be sent.

                         (Continued on following pages)

                               (Page 1 of 8 Pages)
                           (Exhibit begins at Page 6)


<PAGE>

<TABLE>
<CAPTION>
CUSIP No. 464330 10 9                        13D                         Page 2 of 8 Pages
<S>        <C>         <C>   <C>

  1.       NAMES OF REPORTING PERSONS
           S.S. OR I.R.S. IDENTIFICATION NOS. OF ABOVE PERSONS (ENTITIES ONLY)

           Boehringer Ingelheim International GmbH

  2.       CHECK THE APPROPRIATE BOX IF A MEMBER OF A GROUP
                                                                                           (a)|_|
                                                                                           (b)|_|

  3.       SEC USE ONLY



  4.       SOURCES OF FUNDS

           OO

  5.       CHECK BOX IF DISCLOSURE OF LEGAL PROCEEDINGS IS REQUIRED PURSUANT TO ITEM 2(d) OR 2(e)
                                                                                              |_|

  6.       CITIZENSHIP OR PLACE OF ORGANIZATION

           Federal Republic of Germany

                       7.    SOLE VOTING POWER
  NUMBER OF
    UNITS                    2,412,607
 BENEFICIALLY
   OWNED BY
    EACH
  REPORTING
 PERSON WITH

                       8.    SHARED VOTING POWER

                             0

                       9.    SOLE DISPOSITIVE POWER

                             2,412,607

                       10.   SHARED DISPOSITIVE POWER

                             0

  11.      AGGREGATE AMOUNT BENEFICIALLY OWNED BY EACH REPORTING PERSON

           2,412,607

  12.      CHECK BOX IF THE AGGREGATE AMOUNT IN ROW (11) EXCLUDES CERTAIN SHARES
                                                                                              |_|

  13.      PERCENT OF CLASS REPRESENTED BY AMOUNT IN ROW (11)

           8.8%

  14.      TYPE OF REPORTING PERSON

           CO

</TABLE>

                                       2
<PAGE>


                                  SCHEDULE 13D
                          FILED PURSUANT TO RULE 13d-1
                   OF THE GENERAL RULES AND REGULATIONS UNDER
                 THE SECURITIES EXCHANGE ACT OF 1934, AS AMENDED


         This Amendment No. 2, which relates to shares of the common stock,  par
value $0.001 per share (the "Common Stock") of Isis  Pharmaceuticals,  Inc. (the
"Issuer")  and is  being  filed  by  Boehringer  Ingelheim  International  GmbH,
supplements and amends the statement on Schedule 13D,  originally filed with the
Commission  on July 28,  1995,  as  amended by  Amendment  No. 1, filed with the
Commission on December 23, 1996.

ITEM 4.  PURPOSE OF THE TRANSACTION.

The first paragraph of Item 4 is amended to read in its entirety as follows:

The Initial Shares and the Additional  Shares were acquired in connection with a
collaboration  between  the Issuer and  Boehringer  Ingelheim  in the  research,
development and commercialization of potential products in the field of cellular
adhesion for the treatment of immune and non-immune based inflammatory diseases.
By purchasing the shares,  Boehringer  Ingelheim  originally  desired in part to
assist  the  Issuer in  financing  its share of the costs of such  collaborative
research, development and commercialization. Boehringer Ingelheim and the Issuer
have mutually  agreed,  effective as of August 31, 1999, that a portion of their
research  collaboration will continue to be funded by Boehringer  Ingelheim only
through  December 31,  1999.  Other than  royalty  payments  that the Issuer and
Boehringer  Ingelheim will be obligated to pay one another and Isis's  repayment
of loans made by Boehringer  Ingelheim,  the development  and  commercialization
aspects of the collaboration have ended.

Item 4 is further amended by the addition of the following:

On August 31, 1999  Boehringer  and  Ingelheim  entered into an Amendment to the
Stock Purchase Agreement (the "Amendment"), a copy of which is filed herewith as
Exhibit B.

Pursuant to the  Amendment,  the provisions  under the Stock Purchase  Agreement
obligating the Issuer to sell, and Boehringer Ingelheim to purchase,  Additional
Shares have been deleted.  Under the Amendment,  Boehringer Ingelheim's right to
designate a director to the Issuer's  board of directors will terminate upon the
earliest to occur of May 1, 2000, the  effectiveness of a  change-of-control  of
the Issuer, or Boehringer  Ingelheim's ceasing to hold at least 2,000,000 shares
of Common Stock.

The  above  summary  of the  terms of the  Amendment  does not  purport  to be a
complete  summary of the Amendment and is qualified in its entirety by reference
to Exhibit B.

In addition, Dr. Burkhard Blank, Boehringer Ingelheim's designee on the Issuer's
board of directors,  has informed Boehringer Ingelheim and the Issuer that he is
resigning  from the board.  Boehringer  Ingelheim has decided to relinquish  its
right to nominate a member of the Issuer's board.

ITEM 6.  CONTRACTS, ARRANGEMENTS,  UNDERSTANDINGS OR  RELATIONSHIPS WITH RESPECT
TO SECURITIES OF THE ISSUER.

Item 6 is amended by the addition of the following:


                                       3

<PAGE>

As stated above,  on August 31, 1999  Boehringer and Ingelheim  entered into the
Amendment, which is described in Item 4.

ITEM 7.  MATERIAL TO BE FILED AS EXHIBITS.

         Exhibit A. Stock Purchase Agreement, dated  July 18, 1995, between  the
Issuer and Boehringer Ingelheim.*

         Exhibit B. Amendment to the Stock Purchase Agreement,  dated August 31,
1999, between the Issuer and Boehringer Ingelheim.

*Filed as an  exhibit  to the  Issuer's  Current  Report on Form 8-K on July 27,
1995, and incorporated herein by reference.


                                       4
<PAGE>


                                   SIGNATURES


         After reasonable  inquiry and to the best of my knowledge and belief, I
certify that the information  set forth in this statement is true,  complete and
correct.

Dated: August 31, 1999

                                 BOEHRINGER INGELHEIM INTERNATIONAL GmbH

                                            By:    /s/ Burkhard Blank
                                                 -----------------------
                                            Name:  Burkhard Blank
                                            Title: Authorized Signatory


                                            By:   /s/ Hans-Peter Mueller
                                                 -----------------------
                                            Name:  Hans-Peter Mueller
                                            Title: Authorized Signatory


                                       5
<PAGE>

                                    EXHIBIT B

                    AMENDMENT TO THE STOCK PURCHASE AGREEMENT

         This AMENDMENT TO THE STOCK PURCHASE  AGREEMENT  (this  "Amendment"),
made this 31st day of August, 1999, by and between Isis Pharmaceuticals, Inc., a
Delaware corporation  ("Isis"),  and Boehringer Ingelheim  International GmbH, a
German corporation ("Boehringer"),


                              W I T N E S S E T H :

     WHEREAS,  Isis and BI entered into that certain stock  purchase  agreement,
dated as of July 18, 1995 (the "Stock Purchase Agreement");

     WHEREAS,  Paragraph 11.5 of the Stock Purchase  Agreement provides that any
term thereof may be amended in a writing agreed to by Isis and Boehringer; and

     WHEREAS,  Isis and  Boehringer  have  agreed to amend  the  Stock  Purchase
Agreement as provided herein,

     NOW, THEREFORE, in consideration of the mutual agreements and covenants set
forth herein, and for other good and valuable consideration,  the parties hereby
agree that the Stock Purchase  Agreement  shall be amended as of the date hereof
as follows:

     Section 1.  Sub-paragraphs  (b), (c) and (d) of Paragraph 3.1 and the final
paragraph of Paragraph 3.1 of the Stock  Purchase  Agreement  (Agreement to Sell
and Purchase the Additional Shares) shall be deleted in their entirety.

     Section 2.  Paragraph  3.2 of the Stock  Purchase  Agreement  (Delivery  of
Additional Shares at a Subsequent  Closing;  Purchase price) shall be deleted in
its entirety.

     Section  3. The  first  sentence  of  Paragraph  10 of the  Stock  Purchase
Agreement (Termination) shall be amended to read in its entirety as follows:

               This Agreement  shall terminate upon (i) any Change in Control of
               Isis, (ii) the Bankruptcy of Isis or (iii) the termination of the
               New Agreement pursuant to Article 10 thereof.

     Section 4.  Sub-paragraph  (e) of Paragraph 8.1 (Board  Representation)  is
amended in its entirety to read as follows:

               (e)  Paragraph 8.1 shall terminate upon the earliest to occur of:
                       (i)  May 1, 2000;
                       (ii)  The effectiveness of any Change in Control; or
                       (iii)  Boehringer  ceases  to  hold  at  least  2,000,000
                   shares  of Common  Stock  (appropriately  adjusted  for stock
                   splits,  stock dividends,  recapitalization and the like).
                   If  Paragraph 8.1 terminates,  the BI Designate  shall resign
                   from the Board.

     Section 5. In Exhibit A, the  definition  of  "Additional  Shares  shall be
amended to read in its entirety as follows:


<PAGE>

                   "ADDITIONAL  SHARES"  shall  mean   the  shares  issued
                   to Boehringer  Ingelheim  under  Paragraph  3.1  of the
                   Agreement prior to the effective date of the Amendment.

     Section  6.  Exhibit A shall be amended by the  addition  of the  following
definitions:

                   "AMENDMENT"  shall mean that  certain  Amendment to the
                   Stock Purchase  Agreement,  dated August 31,  1999,  by
                   and between Isis and Boehringer.

                   "NEW AGREEMENT"  shall  mean  that  certain  Agreement,
                   dated  as of August 31, 1999, by and between Boehringer
                   and Isis.

     Section 7. This Amendment  shall be governed by and construed in accordance
with the laws of the State of Delaware and the federal law of the United  States
of America.


                                       7
<PAGE>

     IN WITNESS  WHEREOF,  the parties  hereto have caused this  Amendment to be
executed by their duly authorized  representatives  as of the day and year first
above written.



                                    ISIS PHARMACEUTICALS, INC.


                                    By: __________________________________
                                    Name:
                                    Title:




                                    BOEHRINGER INGELHEIM INTERNATIONAL GmBH


                                    By: __________________________________
                                    Name:
                                    Title:


                                    By: __________________________________
                                    Name:
                                    Title:



                                       8


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