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Research Collaboration and License Agreement [Amendment No. 1] - Tularik Inc. and Syntex (U.S.A.) Inc.

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       Amendment No. 1 to Research Collaboration and License Agreement
                 Between Tularik Inc. and Syntex (U.S.A.) Inc.

          This Amendment No. 1 (this "Amendment") to the Research Collaboration
 and License Agreement dated as of July 8, 1997 (the "Agreement") by and between
 Syntex (U.S.A.) Inc., a Delaware corporation, through its Roche Bioscience
 division, having offices at 3401 Hillview Avenue, Palo Alto, California 94304
 ("Roche Bioscience"), and Tularik Inc., a Delaware corporation having offices
 at Two Corporate Drive, South San Francisco, California 94080 ("Tularik"), is
 entered into as of December 19, 1997.

          Whereas, the parties previously entered into the Agreement, which
provided for a collaboration between Roche Bioscience and Tularik to discover
proprietary Targets to use to identify proprietary compounds for development
into Products;

          Whereas, the Parties wish to clarify certain Sections of the Agreement
relating to the disclosure of structural information on Validated Hits and the
transferring of compounds between the Parties;

          Whereas, the parties desire to modify Schedule B of the Agreement to
clarify the universe of Tularik Background Patent Rights and Existing Third
Party Agreements;

          Whereas, in order to accomplish the foregoing, the parties have agreed
to amend the Agreement in part;

          Now, Therefore, in consideration of the premises and the mutual
covenants and agreements expressed herein, and for other good and valuable
consideration, the receipt and sufficiency of which is hereby acknowledged, and
intending to be legally bound, Tularik and Roche Bioscience hereby agree as
follows:

     1.   Section 1 of the Agreement is hereby amended by adding the following
Sections:

               1.77  "Collaboration Medicinal Chemistry Program" means a program
     for the chemical synthesis of structural analogs of a Validated Hit in
     order to improve the biological properties of such Validated Hit towards a
     Target as part of the Research Collaboration

               1.78  "Primary Interest" means a small molecule that (i) is, at
     the time of identification of such molecule as a Validated Hit, [ * ].


[ * ] = Certain confidential information contained in this document, marked by
brackets, has been omitted and filed separately with the Securities and Exchange
Commission pursuant to Rule 406 of the Securities Act of 1933, as amended.

                                       1.

<PAGE>

               1.79  "Roche Medicinal Chemistry  Program" means a program
     conducted by or on behalf of Roche for the chemical synthesis of structural
     analogs of a compound in order to improve the biological properties of such
     compound, excluding [ * ].

               1.80  "Screening Party" has the meaning set forth in Section 5.7.

               1.81  "Transferring Party" has the meaning set forth in Section
     5.7.

     2.   Section 5.5 is hereby amended to read in its entirety as set forth
below:

               5.5  Roche Bioscience Screening Library.  The Roche Bioscience
     Screening Library is not part of the Research Compound Library, but may, in
     Roche Bioscience's sole discretion, be used in HTS against the Targets.
     Except for the Roche Bioscience Screening License, Tularik shall have no
     rights to compounds originating from the Roche Bioscience Screening Library
     unless a Library Compound becomes a Development Compound under Section 5.2.
     Roche Bioscience shall provide structural information on Validated Hits
     from the Roche Bioscience Screening Library; [ * ].  Structural information
     on compounds in the Roche Bioscience Screening Library that are not
     Validated Hits shall [ * ].  Derivatives made as part of a Collaboration
     Medicinal Chemistry Program from compounds originating from the Roche
     Bioscience Screening Library shall be considered part of the Roche Compound
     Library.  The Roche Bioscience Screening Library shall be treated as Roche
     Bioscience's Confidential Information.  .

     3.   The penultimate sentence of Section 5.6 of the Agreement is hereby
amended to read as follows:

     Derivatives made as part of a Collaboration Medicinal Chemistry Program
     from compounds originating from the Tularik Screening Library shall be
     considered part of the Research Compound Library.

     4.   Article 5 of the Agreement is hereby amended by adding a new Section
5.7:

          Section 5.7 Transfer of Compounds.  If either party (the "Transferring
     Party") transfers compounds to the other party (the "Screening Party")
     pursuant to the screening licenses set forth in Section 12.2 below, the
     Screening Party shall use such compounds solely in accordance with the
     terms of this Agreement.  Such use must be at the Screening Party's place
     of business and in accordance with the Research Plan. Any unused quantities
     of the compounds shall be returned to the Transferring Party no later than
     the end of the Research Term or, upon written request by Transferring
     Party, destroyed according to prescribed federal, state and local
     guidelines, including any written instructions received from the
     Transferring Party.  THE TRANSFERRING PARTY DOES NOT MAKE ANY WARRANTY AS
     TO THE IDENTITY, PURITY OR ACTIVITY OF THE COMPOUNDS.  The Screening Party
     shall bear all risk and liability for all harm arising from its use of the
     compounds.

     5.  Schedule B of the Agreement is hereby amended to read in its entirety
as set forth on Schedule B hereto.


[ * ] = Certain confidential information contained in this document, marked by
brackets, has been omitted and filed separately with the Securities and Exchange
Commission pursuant to Rule 406 of the Securities Act of 1933, as amended.

                                       2.

<PAGE>

     6.  Capitalized terms used herein but not otherwise defined herein shall
have the respective meanings assigned to such terms in the Agreement.

     7.  Except as expressly modified by this Amendment, all of the terms and
conditions of the Agreement shall remain in full force and effect.

     8.  This Amendment may be executed in two or more counterparts, each of
which shall be deemed an original but all of which shall be considered one and
the same instrument.

     In Witness Whereof, the parties have executed, or caused their duly
authorized officer or representative to execute, this Amendment as of October
__, 1997.

Tularik Inc.

By:  /s/  David V. Goeddel
     ----------------------------------------
Name:  David V. Goeddel, Ph.D.
Title:  President and Chief Executive Officer

Syntex (U.S.A.) Inc.,
through its Roche Bioscience division


By:  /s/  James N. Woody
     ----------------------------------------
Name:  James N. Woody, M.D., Ph.D.
Title:  President


[ * ] = Certain confidential information contained in this document, marked by
brackets, has been omitted and filed separately with the Securities and Exchange
Commission pursuant to Rule 406 of the Securities Act of 1933, as amended.

                                      3.

<PAGE>

                                   Schedule B

           TULARIK BACKGROUND PATENT RIGHTS AND EXISTING THIRD PARTY
                                   AGREEMENTS

[ * ]

[ * ]

[ * ]

[ * ]

[ * ]

[ * ]

[ * ]

[ * ]

[ * ]


[ * ]


[ * ] = Certain confidential information contained in this document, marked by
brackets, has been omitted and filed separately with the Securities and Exchange
Commission pursuant to Rule 406 of the Securities Act of 1933, as amended.

                                       4.