Document:

Exhibit 10.8

 

[ * ] = 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.

 

 

CONTRACT RESEARCH AND DEVELOPMENT AGREEMENT

 

ON

 

INTERFERON-OMEGA
(IFN-OMEGA)

 

 

TABLE OF CONTENTS

 

	
  1.

  	
  DEFINITIONS

  	
   

  
	
   

  	
   

  	
   

  
	
   

  	
  1.1

  	
  “Affiliate”

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  1.2

  	
  “BioMedicines”

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  1.3

  	
  “BI Pharma KG”

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  1.4

  	
  “BioMedicines Confidential Information”

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  1.5

  	
  “Cell Line(s)”

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  1.6

  	
  “Certificate of Analysis”

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  1.7

  	
  “Effective Date”

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  1.8

  	
  “GMP”

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  1.9

  	
  “License Agreement”

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  1.10

  	
  “Master Cell Bank (MCB)”

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  1.11

  	
  “Manufacturers Working Cell Bank(s) (MWCB)”

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  1.12

  	
  “Phase I”

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  1.13

  	
  “Phase II”

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  1.14

  	
  “Process”

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  1.15

  	
  “Product”

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  1.16

  	
  “Project”

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  1.17

  	
  “Project Fee”

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  1.18

  	
  “Project Manager”

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  1.19

  	
  “Project Team”

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  1.20

  	
  “Start Date”

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  1.21

  	
  “Sublicensee”

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  1.22

  	
  “BI Pharma KG Confidential Information”

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  1.23

  	
  “Specifications”

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  2.

  	
  COOPERATION BETWEEN THE PARTIES IN THE
  COURSE OF THE PROJECT

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  2.1

  	
  Designation of Project Manager

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  2.2

  	
  Cooperation

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  3.

  	
  BIOMEDICINES RESPONSIBILITIES

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  3.1

  	
  General

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  3.2

  	
  Specific

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  4.

  	
  BI PHARMA KG RESPONSIBILITIES

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  4.1

  	
  Master Projectplan including Project
  Timeline

  	
   

  

 

[ * ] = 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.

 

i

 

	
   

  	
  4.2

  	
  Documentation

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  4.3

  	
  Additional Work

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  5.

  	
  PROJECT TO BE CONDUCTED ON FIXED-FEE BASIS

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  6.

  	
  PROJECT FEE

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  7.

  	
  PROGRESS TO PHASE II

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  7.1

  	
  Start of a Possible Phase II

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  8.

  	
  OWNERSHIP OF / LICENSE TO PROJECT DATA

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  8.1

  	
  Transfer of Project Data

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  8.2

  	
  Interim Reports

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  8.3

  	
  License for the Use of Project Data

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  9.

  	
  COMMERCIAL PRODUCTION AND SUPPLY

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  9.1

  	
  BI Pharma KG’s Right and Obligation to Commercial
  Production and Supply

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  9.2

  	
  Terms and Conditions

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  9.3

  	
  BI Pharma KG’s Inability to Manufacture

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  9.4

  	
  BioMedicines Forecast / Capacities /
  Exceeding Quantities

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  9.5

  	
  Pricing

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  10.

  	
  REPRESENTATIONS, WARRANTIES AND INDEMNIFICATION.

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  10.1

  	
  BioMedicines

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  10.2

  	
  BI Pharma KG

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  10.3

  	
  No Additional Warranty

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  11.

  	
  LIABILITY

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  11.1

  	
  Limitation of Liability

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  11.2

  	
  Special Limitation of Liability

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  11.3

  	
  Maximum Amount

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  12.

  	
  CONFIDENTIALITY

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  12.1

  	
  BI Pharma KG

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  12.2

  	
  BioMedicines

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  12.3

  	
  Exceptions to Confidentiality

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  12.4

  	
  Others

  	
   

  

 

[ * ] = 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.

 

ii

 

	
  13.

  	
  TERM AND TERMINATION

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  13.1

  	
  Term

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  13.2

  	
  Right to Terminate

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  13.3

  	
  Termination with Immediate Effect

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  13.4

  	
  Effect of Termination

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  14.

  	
  FORCE MAJEURE

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  15.

  	
  PUBLICITY

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  16.

  	
  NOTICES

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  17.

  	
  APPLICABLE LAW

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  18.

  	
  COMPLIANCE WITH LAWS

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  19.

  	
  INDEPENDENT CONTRACTORS

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  20.

  	
  WAIVER

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  21.

  	
  SEVERABILITY

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  22.

  	
  ENTIRETY

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  23.

  	
  ASSIGNMENT

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  APPENDICES

  	
   

  

 

[ * ] = 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.

 

iii

 

This Contract
Research And Development Agreement (“Agreement”) is
made effective as of 17 July, 1998 (“Effective Date”), by and among BioMedicines, Inc. (“BioMedicines),
a incorporated in the state of Delaware in the United States of America, having
its principal business offices at 909 Marina Village Parkway No. 583, Alameda,
CA 94501, and Boehringer
Ingelheim Pharma KG (“BI Pharma KG”) a German corporation having a
place of business at Birkendorfer Strabe 65, 88397
Biberach an der Riss, Federal Republic of Germany.

 

Background

 

BioMedicines has a license to certain proprietary rights in
INTERFERON-OMEGA (“IFN-OMEGA”) from Boehringer Ingelheim International GmbH (“BII”),
a German corporation, under a separate agreement dated 17 July, 1998 and which
is referenced in toto hereby.

 

BI Pharma KG owns all of the appropriate and specialized cell culture,
processing, protein purification aseptic filling and lyophilisation equipment,
as well as suitable packaging and labeling facilities that are necessary and
sufficient for the production of IFN-OMEGA, and, furthermore, employs personnel
who have the requisite experience, knowledge, and expertise in production of
proteins by cell culture and purification processes, as well as in the
development and registration of biopharmaceutical products.

 

BioMedicines desires to have BI Pharma KG personnel evaluate the
performance of the IFN-OMEGA production processes and sterile liquid filling of
the resulting product in BI Pharma KG’s facilities and according to the
provisions of this Agreement hereinafter to manufacture IFN-OMEGA for clinical
trial and commercial purposes.

 

Agreement

 

In
Consideration Of the mutual covenants set forth in
this Agreement, BI Pharma KG and BioMedicines hereby agree as follows:

 

1.             Definitions

 

1.1          “Affiliate” shall mean any
corporation or business entity controlled by, controlling or under common
control with either BI or B/M, as the case may be.  For this purpose, control shall mean any of
the following:

 

(a)           direct or indirect beneficial ownership
of more than fifty percent (50%) of the voting stock of such entity;

 

(b)           a fifty percent (50%) or greater
interest in the income of such entity;

 

(c)           a fifty percent (50%) or greater
management control over a joint venture; or

 

(d)           any other relationship that, in fact,
constitutes actual control.

 

1.2          “BioMedicines” shall mean
BioMedicines Inc. as laid down first above.

 

[ * ] = 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

 

1.3          “BI Pharma KG” shall mean
Boehringer Ingelheim Pharma KG as laid down first above.

 

1.4          “BioMedicines Confidential
Information” shall mean all technical and other
information relating to the Product that is disclosed or supplied to BI Pharma
KG by BioMedicines pursuant to this Agreement whether patented or unpatented,
including, without limitation, trade secrets, know-how, processes, concepts,
experimental methods and results and business, scientific plans and financial
information or data and shall retroactively include similar such BioMedicines
confidential information previously provided to BII under confidentiality
obligation that BII subsequently disclosed verbally or in writing to BI Pharma
KG.

 

1.5          “Cell Line(s)” shall mean a CHO DX B11-SS cell line
currently designated 2-1C4 (or any similar cell line designated differently)
and any other cell line(s) developed pursuant to this Agreement.

 

1.6          “Certificate of Analysis”
shall mean a document describing testing methods and results, the accuracy of
which has been certified by a party, to be agreed upon between the parties in
due time.

 

1.7          “Effective Date”
shall mean the date first above written, which shall be the effective date of
this Agreement.

 

1.8          “GMP” shall
mean the regulatory requirements for good manufacturing practices promulgated
by the United States Food and Drug Administration (FDA) under the Federal Food,
Drug and Cosmetic Act, as amended, 21 C.F.R, § 210 et seq.  and 21 C.F.R. § 600-610, as applicable, or
any manufacturing standards set now or in the future by the FDA or by the currently
applicable regulations, directives, or decisions of the European Union (as now
published in the Official Journal of the
European Community (EC) or its successor publication or directed
specifically to BI Pharma KG by the appropriate regulatory authorities.  Moreover, GMP shall be understood to be the
higher or more stringent of the FDA or EC standards as mutually agreed by BI
Pharma KG and BioMedicines.

 

1.9          “License Agreement”
Shall mean the License Agreement concluded between BioMedicines and BII
regarding IFN- OMEGA.

 

1.10        “Master Cell Bank (MCB)”
shall mean reference deposit or collection of ampoules of the Cell Line 2-1C4
(or other cell lines as described above in Section 1.5) and that has currently
been designated MCB 054 Th, and any successor or substantially similar but
differently designated cell line and cell lines created pursuant to the
Agreement.

 

1.11        “Manufacturers Working Cell Bank(s)
(MWCB)” shall mean BI Pharma KG’s collection of [*] serially subcultivated cells that will
be derived from the MCB. The MWCB’(s) will be used to establish seed cultures
of the Cell Line to initiate the Process.

 

[ * ] =
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

 

1.12        “Phase I” shall
mean all activities and work to be performed as laid down in the Master Project
plan attached hereto as Appendix 1 (“Master Project Plan Interferon Omega;
Proposed Development Plan”) which shall include manufacturing for purposes of
commercialisation.

 

1.13        “Phase II”
shall mean the future research and development activities and work to be performed
according to a future agreement of the parties hereto, but excluding
manufacturing for purposes of commercialisation.

 

1.14        “Process” shall
refer to a BI Pharma KG developed and owned process for using the Cell Line,
including defined procedures, equipment and analytical methodologies for
in-process control, release testing and Product characterization, that has been
used by BI Pharma KG to produce the Product at the [*] fermentation scale, or, if and when applicable, the
modified process after adaptation to serum-free production by BI Pharma KG.

 

1.15        “Product” shall
mean drug substance or final product of IFN-OMEGA produced by the Cell Line(s)
in accordance with the Process.

 

1.16        “Project” shall
mean the Phase I program described herein, in which BI Pharma KG will
establish, implement, upscale and evaluate the serum-free Process at the
respective fermentation scale in BI Pharma KG’s facility and equipment.  The primary objectives of the Project will be
to perform registration runs at commercial scale in the BI Pharma KG facility,
successfully demonstrate that equivalent Product (i. e. Product meeting the
Specifications) can be reproducibly manufactured in BI Pharma KG’s facilities,
and prepare the CMC part of a BLA registration dossier with all relevant data
generated in the Project.  A proposed
timeline for the Project is included in Appendix 1.

 

1.17        “Project Fee”
shall have the meaning specified in Section 6 hereof.

 

1.18        “Project Manager”
shall have the meaning specified in Section 2.1 hereof.

 

1.19        “Project Team”
shall have the meaning specified in Section 2.2 hereof.

 

1.20        “Start Date”
shall mean the date mutually agreed by BI Pharma KG and BioMedicines, which is
anticipated to be on or about 1 August 1998.

 

1.21        “Sublicensee”
shall mean a person or legal entity to which BioMedicines grants a sublicense
of some or all of the rights granted to BioMedicines according to the License
Agreement.

 

1.22        “BI Pharma KG Confidential
Information” shall mean all technical and other
information relating to the Cell Line, Process, Product and BI Pharma KG’s
facilities and associated technologies that is disclosed or supplied to, or
used on behalf of, BioMedicines by BI Pharma KG pursuant to this Agreement,
whether patented or unpatented, including, without limitation, trade secrets,
know-how, processes, concepts, experimental methods and results and business
and scientific plans.

 

[ * ] =
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

 

1.23        “Specifications”
shall mean the specifications for the Product and the respective test methods
for release of drug substance and drug product as mutually agreed by the
Project Team, as such specifications may be amended from time to time by mutual
agreement of BioMedicines and BI Pharma KG according to the further development
of the Process and Product.

 

2.             Cooperation between the Parties in the Course
of the Project

 

2.1          Designation
of Project Manager.  BI Pharma
KG and BioMedicines shall each identify a Project Manager who will be
responsible for communicating all instructions and information concerning the
Project to the other party.  Each Project
Manager will be available on an agreed upon regular basis for consultation at
pre-arranged times during the course of the Project.  In the absence of the Project Manager, a
substitute shall be appointed. 
Additional modes or methods of communication and decision making may be
implemented with the mutual consent of each party.

 

2.2          Cooperation.  In the course of the Project, BI Pharma KG
will at all times take into consideration and implement the recommendations of
BioMedicines as long as they do not unreasonably and adversely influence other
BI Pharma KG biotech operations; in the absence of explicit instructions from
BioMedicines, BI Pharma KG shall be entitled to employ its reasonable judgment
in carrying out the Project.  BI Pharma
KG shall be entitled to rely upon any instructions or directives provided by
any BioMedicines representative and BI Pharma KG shall not be responsible for
the failure to achieve any objective or the inability to adhere to any
guideline if such failure or inability is caused by events beyond the
reasonable control of BI Pharma KG or by instructions or directives provided by
BioMedicines, if any.

 

BI Pharma KG shall permit BioMedicines, from time to time upon at least
thirty (30) days’ prior notice to BI Pharma KG to conduct audits at BI Pharma
KG’s facilities used for the Project during BI Pharma KG’s normal business
hours and at a reasonable frequency. 
While at any BI Pharma KG facility, BioMedicines personnel shall comply
with all applicable BI Pharma KG security and safety policies and procedures.

 

3.             BioMedicines Responsibilities.

 

3.1          General.  BioMedicines will periodically and
appropriately keep BI Pharma KG informed of the status of its activities around
the Product as long as the same facilitate the development and manufacture of
the Product according to this Agreement.

 

3.2          Specific.  As far as not specified herein the responsibilities
of BioMedicines are defined in the License Agreement and possibly other
separate agreements between BioMedicines and Boehringer Ingelheim International
GmbH (BII), BI Pharma KG, or other BII Affiliates as appropriate.

 

4.             BI Pharma KG Responsibilities

 

4.1          Master
Projectplan including Project Timeline.  In the course of this Agreement BI Pharma KG
shall perform the work and tasks as laid down and detailed in the Master

 

[ * ] =
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

 

Projectplan including Project Timeline, attached as Appendix 1
hereto.  Any third party contractors that
BI Pharma KG intends to hire for the Project need the approval of BioMedicines,
except for single quality control tasks. 
Such quality control tasks and vendors will be identified to BioMedicines.

 

4.2          Documentation.  As soon as the data and documents are
available to BI Pharma KG and needed for registration, as mutually agreed upon
in the project plan, BI Pharma KG shall provide BioMedicines with all CMC-parts
of a United States FDA Biologics License Application (BLA) or similar
document(s) for European Registration as may be required to enable and
facilitate regulatory approval(s) to market IFN-OMEGA: Such CMC-documents shall
be provided to BioMedicines in English, shall be complete and accurate, and
shall contain all data required to enable and facilitate regulatory
approval(s).  The format(s) for such
documents will be appropriate for the regulatory agency in question and
mutually agreed.

 

4.3          Additional
Work.  On request of
BioMedicines BI Pharma KG shall perform additional work to sustain the progress
of the Project on conditions in terms of money, time and scope to be subject to
mutual agreement of the parties hereto.

 

5.             Project to be Conducted on Fixed-Fee Basis

 

The Project shall be conducted by BI Pharma KG for BioMedicines on
fixed fee basis, in consideration of payment by BioMedicines of the Project Fee
according to the Master Projectplan as laid down in Appendix 1.

 

BioMedicines acknowledges that the Project is experimental in nature
and that no favorable or useful result can be assured by BI Pharma KG.
Accordingly, BI Pharma KG shall not be responsible to BioMedicines for any
failure of fermentations except for

 

contamination of (a) batch(es) due to BI Pharma KG’s mishandling or inability
to obtain useful yields (Definition) of Product

 

and the Project Fee shall be payable in full regardless of result
unless the Project is terminated prior to its scheduled completion pursuant to
Section 13 hereof.

 

6.             Project Fee

 

Subject to Section 5 above, BioMedicines shall pay BI Pharma KG a
Project Fee of [*] for the
services provided in carrying out the Project. 
This fee includes all fees for BI Pharma KG’s work according to Article
4 hereof.

 

Disposal of organic and hazardous waste is included in the Project
Fee.  The Project Fee shall be payable in
installments, each non-refundable when paid, as provided for in the Master
Projectplan (Appendix 1).

 

Each invoice shall be payable within 30 days following receipt thereof.

 

[ * ] =
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.

 

5

 

7.             Progress to Phase II

 

7.1          Start
of a Possible Phase II.  If
BioMedicines decides to conduct a Phase II the parties will have to agree on
the conditions thereof (in terms of time and commercial conditions) in due time
depending on the then prevailing capacity of BI Pharma KG.

 

8.             Ownership of / License to Project Data

 

8.1          Transfer
of Project Data.  In
consideration of the Project Fee, BI Pharma KG shall execute the Project in a
timely manner (as further detailed in the Appendices) and shall make available
to BioMedicines in a timely manner all information, data, or materials obtained
or developed in the course of the Project necessary to evaluate, test, develop,
register, market, or sell the Product.

 

8.2          Interim
Reports.  BI Pharma KG agrees
to provide interim reports to BioMedicines on a reasonable basis (max.  quarterly basis).

 

8.3          License
for the Use of Project Data. 
BioMedicines, its Affiliates or Sublicensees shall have a worldwide,
royalty-free, exclusive license, with the right to sublicense, to
Product-specific information and a non-exclusive license to otherwise
non-Product-specific information (i.e., information that may also apply to
other projects/products) to use BI Pharma KG Confidential Information that is
used in carrying out the Process to evaluate, test, develop, register, market,
and sell the Product.  These licenses,
and sublicenses if any, shall expire automatically at the same time when the
License Agreement expires.

 

9.             Commercial Production and Supply

 

9.1          BI
Pharma KG’s Right and Obligation to Commercial Production and Supply.  The parties acknowledge and agree that, in
case BioMedicines decides to commercialize the Product, BI Pharma KG has an
exclusive right and obligation to produce and supply commercial quantities of
Product (in bulk drug, final product and/or finished product form) for
BioMedicines within the respective capacity of BI Pharma KG and the parties
shall negotiate in good faith and consummate a supply agreement at the earliest
reasonable opportunity for the supply by BI Pharma KG of commercial quantities
of the respective Product for the term of the License Agreement.

 

9.2          Terms
and Conditions.  Such supply
agreement shall contain terms and conditions customary for such a supply
agreement and shall be concluded between BioMedicines and BI Pharma KG or, at
the sole discretion of BI PHARMA KG, with BII or any other Affiliate of BI
Pharma KG as the case may be, provided however, that the main production
activities shall remain at BI Pharma KG.

 

9.3          BI
Pharma KG’s Inability to Manufacture.  Should BI Pharma KG be unable for any reason
to manufacture sufficient quantities of Product, BI Pharma KG will take all
necessary or desirable steps to facilitate the manufacture of Product by
BioMedicines or by a third party.

 

[ * ] =
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.

 

6

 

9.4          BioMedicines
Forecast / Capacities / Exceeding Quantities.  In Appendix 2 BioMedicines has laid down its
present forecast estimation of its, its Affiliates and Sublicensees total
requirements of Product.  This forecast
is non-binding; however, BI Pharma KG’s capacity planning for commercial supply
is based on and limited by BioMedicines’s forecast.

 

If, for good reason, BI Pharma KG cannot produce and supply all
requested commercial quantities of Product as outlined in BioMedicines forecast
referenced above for whatever reason, BioMedicines will have the right to have
the missing quantities, as long as BI Pharma KG is not able to produce and
supply the respective quantities, produced elsewhere.

 

Moreover, the supply agreement shall provide for minimum quantities as
follows:

 

	
  per order for commercial supplies:

  	
   

  	
  [*] of Product and

  
	
   

  	
   

  	
   

  
	
  Per calendar year:

  	
   

  	
  [*] of Product (to
  be agreed upon between the parties at a later stage of the cooperation at the
  earliest reasonable opportunity and depending on BioMedicines’s forecast for
  commercial supply and BI Pharma KG’s capacity planning resulting therefrom.

  

 

BI Pharma KG’s will provide a reserved capacity for BioMedicines for a
certain amount of Product per calendar year based on the product
assumptions.  This capacity may be
increased by mutual agreement between the parties with a lead time of no more
than [*].

 

9.5          Pricing.  The pricing for the Product manufactured and
supplied under the supply agreement to be concluded (see Section 9.1 above)
shall take place in accordance with the License Agreement.

 

10.          Representations, Warranties and
Indemnification.

 

10.1        BioMedicines.  BioMedicines hereby represents, warrants and
agrees that:

 

(a)           BioMedicines has full corporate
authority to enter into this Agreement and this Agreement is binding upon
BioMedicines in accordance with its terms; and

 

(b)           BioMedicines shall indemnify, defend and
hold BI Pharma KG, its affiliates, and their respective officers, employees and
agents harmless from and against all losses, damages, costs and expenses
(including, without limitation, reasonable attorneys’ fees), including injury
to persons or damage to property resulting from any breach of the
representations and warranties made by BioMedicines under this Section, or as a
result of any claim, except for willful or knowing violation of third party
intellectual property rights by BI Pharma KG, of infringement of the
intellectual property rights of a third party based upon BI Pharma KG’s
activities

 

[ * ] =
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.

 

7

 

in implementing the Process or producing the Product in accordance with
the instructions and documentation provided by BioMedicines or developed in the
course of the Project.

 

10.2        BI
Pharma KG.  BI Pharma KG
hereby represents, warrants and agrees that:

 

(a)           BI Pharma KG is the owner of the
facilities and BI Pharma KG Confidential Information to be used for purposes
set forth in this Agreement;

 

(b)           BI Pharma KG is not aware of any special
or unusual hazards that would arise as a result of its carrying out of the
Project as planned;

 

(c)           BI Pharma KG has full corporate
authority to enter into this Agreement and this Agreement is binding upon BI
Pharma KG in accordance with its terms; and

 

(d)           BI Pharma KG shall indemnify, defend and
hold BioMedicines and its officers, employees and agents harmless from and
against all losses, damages, costs and expenses (including, without limitation,
reasonable attorneys’ fees), including injury to persons or damage to property,
resulting from any breach of the representations and warranties made by BI
Pharma KG under this Section, or as a result of any claim that BI Pharma KG has
violated any local law, ordinance, or guideline in carrying out its
biotechnical manufacturing responsibilities under this Agreement or as a result
deliberate misconduct or gross negligence in the duties of BI Pharma KG under
the terms of the Agreement.

 

(e)           BI Pharma KG will not knowingly infringe
upon the intellectual property rights of BioMedicines or any third party.

 

(f)            BI Pharma KG will conduct all
manufacture of Product for clinical phase III trials according to manufacturing
standards set by the currently applicable regulations, directives or decisions
of the European Union (as now published in the Official Journal of the European
Community or its successor publication).

 

(g)           BI Pharma KG has conducted the positive
preliminary work with regard to the serum-free process.

 

(h)           BI Pharma KG will conduct the Project as
described to BioMedicines and that any documentation of Project results or
procedures provided to BioMedicines by BI Pharma KG shall be accurate in all
material respects.

 

10.3        No
Additional Warranty.  BI
Pharma KG shall provide the results of the Project to BioMedicines without any
additional warranty of any kind, express or implied, including, without
limitation, any warranties of merchantability or fitness for a particular
purpose.

 

11.          Liability

 

11.1        Limitation
of Liability.  Other than BI
Pharma KG generally knowing that BioMedicines will be using the Product in
clinical trials, BI Pharma KG has no

 

[ * ] =
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.

 

8

 

knowledge or awareness of or control over the manner in which
BioMedicines intends to use any Product or results obtained in the
Project.  BI Pharma KG shall not be
liable to BioMedicines for any losses, damages, costs or expenses of any nature
incurred or suffered by BioMedicines or by a third party, arising out of any
dispute or other claims or proceedings made by or brought against BioMedicines
in respect of the results of the Project, or the use of any Product by
BioMedicines or by a third party (including, without limitation, product
liability claims and claims by a third party alleging infringement of its
intellectual property rights), nor shall BI Pharma KG be responsible in any way
for dealing with any such disputes, claims or proceedings except insofar as
such losses, damages, costs, expenses, claims or dealings shall be the result
of actions by BI Pharma KG, its personnel, or its agents that represent
deliberate misconduct or constitute gross negligence.

 

Notwithstanding the foregoing, BI Pharma KG shall remain liable for its
actions and the consequences thereof in the event that BI Pharma KG knowingly
infringes upon the intellectual property rights of BioMedicines or any third
party.

 

BioMedicines shall indemnify, defend and hold BI Pharma KG, its
Affiliates and their respective officers, employees and agents harmless from
and against all such losses, damages, costs and expenses (including, without
limitation, reasonable attorneys’ fees) except insofar as such losses, damages,
costs, expenses, claims or dealings shall be the result of actions by BI Pharma
KG, its personnel, or its agents that represent deliberate misconduct or
constitute gross negligence.

 

11.2        Special
Limitation of Liability. 
Notwithstanding Art. 10.2/10.3 above, BI Pharma KG shall in no way be
liable for the correctness, usefulness and operatability of material and data
(such as cellbanks, reagents etc.) received from BioMedicines, if any.

 

11.3        Maximum
Amount.  BI Pharma KG
undertakes to use its best efforts to perform the Project under the Master
Projectplan and to meet the target dates set forth in Appendix 1 hereto.  However, due to the biological nature of the
work to be performed hereunder BI Pharma KG’s liability under this Agreement
shall in no event amount to more than [*]
of the Project Fee due for the entire Project according to Articles 5 and 6
above.  The maximum of [*] shall not apply to liabilities
resulting from deliberate misconduct by BI Pharma KG.

 

12.          Confidentiality

 

12.1        BI
Pharma KG.  BI Pharma KG shall
not disclose BioMedicines Confidential Information to any person other than its
employees or employees of its Affiliates who have a need to know such
information in order to perform their duties in carrying out the Project
hereunder.  All other disclosures need
the prior approval of BioMedicines.

 

12.2        BioMedicines.  BioMedicines shall not disclose any BI Pharma
KG Confidential Information to any person other than its employees, directors,
or consultants who are bound by similar obligations of confidentiality and who
have a need to know such

 

[ * ] =
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.

 

9

 

information in order to provide direction to
BI Pharma KG or evaluate the results of the Project.

 

12.3        Exceptions
to Confidentiality.  The
obligations of confidentiality applicable to BioMedicines Confidential
Information and BI Pharma KG Confidential Information shall not apply to any
information that is:

 

(a)           known publicly or becomes known publicly
through no fault of the recipient;

 

(b)           learned by the recipient from a third
party entitled to disclose it;

 

(c)           developed by the recipient independently
of information obtained from the disclosing party;

 

(d)           already known to the recipient before
receipt from the disclosing party, as shown by its prior written records;

 

(e)           required to be disclosed by law,
regulation or the order of a judicial or administrative authority (e.g. regulatory authorities, for example,
the FDA, that require such information in order to review an IND or other
regulatory filing); or

 

(f)            released with the prior written consent
of the disclosing party.

 

12.4        Others.
 No right or license, either
express or implied, under any patent or proprietary right is granted hereunder
by virtue of the disclosure of BioMedicines Confidential Information or BI
Pharma KG Confidential Information. 
Either party shall be entitled to injunctive relief in the event of a
breach of this Agreement by the other party. 
The obligations of both parties under this Section 11 shall survive the
expiration or termination of this Agreement. 
Both BioMedicines and BI Pharma KG shall use reasonable and customary
precautions to safeguard BioMedicines Confidential Information and BI Pharma KG
Confidential Information, including ensuring that all employees, consultants,
directors, agents, or the like who are provided access to such information are
informed of the confidential and proprietary nature of such information and
understand that all such information is required to be maintained confidential.

 

13.          Term and Termination

 

13.1        Term.  This Agreement shall, unless terminated
earlier, commence as of the Effective Date and shall expire upon the date of
payment of the last sum due hereunder, or upon the date when the last services required
to be performed hereunder are performed, whichever date shall last occur.

 

[ * ] =
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.

 

10

 

13.2        Right
to Terminate.  If it becomes
apparent to either party at any stage of the Project that it will not be
possible to carry out the Project for scientific or technical reasons or as a
result of Force Majeure, the parties shall permit thirty (30) days for
discussion to resolve, if possible, the scientific or technical issue giving
rise to the problem.  If the parties fail
to resolve the problem, either party shall have the right to terminate this
Agreement, effective upon written notice to the other.  In the event of such termination, the amount
due to BI Pharma KG hereunder shall include all expenses reasonably incurred by
BI Pharma KG prior to such termination in respect of the purchase of supplies
or raw materials, and an allocation of the balance of the Project Fee for the
period prior to receipt of such termination by BI Pharma KG and for a period of
[*] weeks thereafter.  The amount to be paid per week in this case
shall be calculated separately Phase by Phase by dividing the amount to be paid
by BioMedicines for the respective entire Phase by the number of weeks of the
respective Phase.  Such the amount per
week may vary if the six week period reaches into the next Phase.  However, under no circumstances BioMedicines
shall be obliged to pay more than the amount that would have been due
ordinarily for the respective Phase.

 

13.3        Termination
with Immediate Effect.  Either
party may terminate this Agreement effective upon written notice if either of
the following events occurs.

 

(a)           The other party commits a breach of this
Agreement and the breach is not remedied within 30 days after the receipt of
notice identifying the breach and requiring its remedy; or

 

(b)           The other party (I) becomes unable to
pay its debts as they become due, (II) suspends payment of its debts, (III)
enters into or becomes subject to corporate rehabilitation or bankruptcy
proceedings or liquidation or dissolution, (IV) makes an assignment for the
benefit of its creditors or (V) seeks relief under any similar laws for debtor’s
relief.

 

(c)           If the License Agreement terminates for
whatsoever reason.

 

13.4        Effect
of Termination.  Upon the
expiration or termination of this Agreement:

 

(a)           At the request of BioMedicines, BI
Pharma KG shall promptly return all BioMedicines Confidential Information to
BioMedicines; except for a single copy and/or sample of each material for
documentation purposes only.  BI Pharma
KG’s responsibility to keep and store the Cell Line and any other material
shall terminate 6 (six) months after expiration or termination of this
Agreement; and

 

(b)           BioMedicines shall promptly return all
BI Pharma KG Confidential Information to BI Pharma KG, except for a single copy
and/or sample for documentation purposes only.

 

The respective rights of BI Pharma KG and BioMedicines to
indemnification as set forth in Section 9 hereof shall survive termination of
this Agreement with respect to any claims that relate to or derive from the
Project, or any acts or failures to act, of either BI Pharma KG or BioMedicines
in connection with the Project that occur prior to termination.

 

[ * ] =
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.

 

11

 

14.          Force
Majeure.  Neither party shall
be in breach of this Agreement if there is any failure of performance under
this Agreement (except for payment of any amounts due hereunder) occasioned by
any act of God, fire, act of government or state, war, civil commotion,
insurrection, embargo, prevention from or hindrance in obtaining energy or
other utilities, labor disputes of whatever nature or any other reason beyond
the control of either party.

 

15.          Publicity.
 No press release or other form of
publicity regarding the Project or this Agreement shall be permitted by either
party to be published unless both parties have indicated their consent to the
form of the release in writing.

 

16.          Notices.  Any notice required or permitted to be given
hereunder by either party shall be in writing and shall be (a) delivered
personally, (b) sent by registered mail, return receipt requested, postage
prepaid or (c) delivered by facsimile with immediate telephonic confirmation of
receipt, to the addresses or facsimile numbers set forth below:

 

	
  If to BI Pharma KG:

  	
  Boehringer Ingelheim Pharma KG

  
	
   

  	
  Birkendorfer Straβe 65

  
	
   

  	
  88397 Biberach an der Riss

  
	
   

  	
  Federal Republic of Germany

  
	
   

  	
  Attention: Prof. Dr. Rolf G. Werner

  
	
   

  	
  Fax: 0 73 51/54-51 31

  
	
   

  	
  Phone 0 73 51/54-48 00

  
	
   

  	
   

  
	
  If to BioMedicines:

  	
  BioMedicines, Inc.

  
	
   

  	
  909 Marina Village Parkway, No. 583

  
	
   

  	
  Alameda, CA 94501 USA

  
	
   

  	
  Fax:                                    

  
	
   

  	
  Phone:                                

  

 

Each notice shall be deemed given (a) on the
date it is received if it is delivered personally, (b) 1 day after the date it
is postmarked if it is sent by certified United States mail, return receipt
requested, postage prepaid or by other commercial carrier such as DHL (c) on
the date it is received if it is sent by facsimile with immediate telephonic
confirmation of receipt.  Notice to
BioMedicines shall be deemed to constitute notice to and for purposes of this
Agreement.

 

17.          APPLICABLE
LAW

 

This Agreement shall be governed by and
construed in accordance with the laws of the place of domicile of BI Pharma KG
and the courts of the place of domicile of BI Pharma KG shall have exclusive
jurisdiction over all legal matters and proceedings hereunder.

 

18.          COMPLIANCE
WITH LAWS

 

BI Pharma KG shall perform the work hereunder
in conformance with GMP, as applicable, and all German laws, ordinances and
governmental rules or regulations pertaining thereto.

 

[ * ] = 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.

 

12

 

19.          INDEPENDENT
CONTRACTORS

 

Each of the parties hereto is an independent
contractor and nothing herein contained shall be deemed to constitute the
relationship of partners, joint ventures, nor of principal and agent between
the parties hereto.  Neither party shall
hold itself out to third persons as purporting to act on behalf of, or serving
as the agent of, the other party.

 

20.          WAIVER

 

No waiver of any term, provision or condition
of this Agreement whether by conduct or otherwise in any one or more instances
shall be deemed to be or construed as a further or continuing waiver of any
such term, provision or condition or of any other term, provision or condition
of this Agreement.

 

21.          SEVERABILITY

 

If any provision of this Agreement is held to
be invalid or unenforceable by a court of competent jurisdiction all other
provisions shall continue in full force and effect.

 

22.          ENTIRETY

 

This Agreement, including any exhibits and
appendices attached hereto and referenced herein, constitutes the full
understanding of the parties and a complete and exclusive statement of the
terms of their agreement, and no terms, conditions, understandings or
agreements purporting to modify or vary the terms thereof shall be binding
unless it is hereafter made in writing and signed by both parties.

 

23.          ASSIGNMENT

 

This Agreement shall be binding upon the
successors and assigns of the parties and the name of a party appearing herein
shall be deemed to include the names of its successors and assigns provided
always that nothing herein shall permit any assignment by either party.  However, BI Pharma KG may assign this
Agreement to any suitably qualified Affiliate of BII.

 

[ * ] = 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.

 

13

 

IN WITNESS WHEREOF,
the parties have caused this Agreement to be executed as of the Effective Date.

 

	
  BIOMEDICINES, INC.

  	
  BOEHRINGER INGELHEIM PHARMA KG

  
	
   

  
	
  By:

  	
  /s/ S. M. Moran

  	
   

  	
  ppa.

  	
  ppa.

  
	
   

  	
  /s/ Rolf Werner

  	
   

  	
  /s/ Michelberger

  	
   

  
	
  Title:

  	
   

  	
  S.M. Moran, M.D.

  	
   

  	
   

  
	
   

  	
  Chief Executive Officer

  	
  Prof. Dr. Rolf G. Werner 

  	
  Dr. Michelberger

  
	
   

  	
   

  	
  (Head of Biotechnical

  Manufacture)

  	
  (Head of Legal Dept)

  
	
   

  
	
  Date

  	
  23 July 1998

  	
  Date

  	
  July 17, 1998

  	
   

  
										

 

 

Appendices:

Appendix 1            Master
Projectplan including Project Timeline

Appendix 2            BioMedicines
present forecast estimation of its Affiliates and Sublicensees total
requirements of Product

 

[ * ] = 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.

 

14

 

 

Appendix
1

 

Cost estimate of the Master Project Plan
Interferon Omega

 

	
  Establishing and Testing [*]

  	
   

  	
  [*]

  
	
  [*]

  	
   

  	
  –,–

  
	
  [*]

  	
   

  	
  [*]

  
	
  [*]

  	
   

  	
  [*]

  
	
  [*]

  	
   

  	
  [*]

  
	
  [*]

  	
   

  	
  [*]

  
	
  [*]

  	
   

  	
  [*]

  
	
  [*]

  	
   

  	
  [*]

  
	
  Total amount

  	
   

  	
  [*]

  

 

[ * ] = 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.

 

15

 

[*]

 

[ * ] = 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.

 

 

[*]

 

[ * ] = 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.

 

 

 

Appendix
2

 

BioMedicines present forecast estimation of
its, its Affiliates and

Sublicensees total requirements of Product

 

	
  1.

  	
   

  	
  [*] μg/[*] 

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  2.

  	
   

  	
  [*] per week per [*]-week treatment cycle

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  3.

  	
   

  	
  [*] cycle per year
  per patient

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  4.

  	
   

  	
  year 1:

  	
   

  	
  [*] patients

  	
   

  	
  =

  	
   

  	
  [*] cycles

  	
   

  	
  =

  	
   

  	
  [*]

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  5.

  	
   

  	
  year 2:

  	
   

  	
  [*] patients

  	
   

  	
  =

  	
   

  	
  [*] cycles

  	
   

  	
  =

  	
   

  	
  [*]

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  6.

  	
   

  	
  year 3:

  	
   

  	
  [*] patients

  	
   

  	
  =

  	
   

  	
  [*] cycles

  	
   

  	
  =

  	
   

  	
  [*]

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  7.

  	
   

  	
  In year 1, an additional

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
  [*]

  
	
   

  	
   

  	
  will be needed to provide a reserve of drug
  in the pharmacies; 

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
  in year 2 an additional

  	
   

  	
   

  	
   

  	
   

  	
   

  	
  [*]

  
	
   

  	
   

  	
  will be needed to provide a reserve of drug
  in the pharmacies; and 

  	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
  in year 3 an additional

  	
   

  	
   

  	
   

  	
   

  	
   

  	
  [*]

  
	
   

  	
   

  	
  will be needed to provide a reserve of drug
  in the pharmacies 

  	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  8.

  	
   

  	
  phase IV testing will require an additional
  [*] per year

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  

 

[ * ] = 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.

 

 

Amendment No. 1

 

to the Contract Research and Development
Agreement

on Interferon-Omega

dated July 17th/23rd,
1998

 

(hereinafter referred to as the “R&D-Agreement”)

 

 

between

 

BioMedicines,
Inc.

2000 Powell Street, Suite 1640

Emeryville, CA 94541

 

U.S.A.

 

	
   

  	
   

  	
  (hereinafter referred to as “BioMedicines”)

  

 

and

 

Boehringer Ingelheim Pharma GmbH & Co. KG

Birkendorfer Straβe 65

D-88397 Biberach an der Riss

 

Federal Republic of Germany

 

	
   

  	
   

  	
  (hereinafter
  referred to as “BI Pharma”)

  
	
   

  	
   

  	
   

  
	
   

  	
   

  	
  (hereinafter
  individually and/or collectively referred

  to as the “Party/Parties”)

  

 

PREAMBLE

 

Whereas, the R&D-Agreement
has been concluded between BioMedicines and BI Pharma (formerly doing business
as “Boehringer Ingelheim Pharma KG”) and which has been updated as regards the
Project by letter agreement of the Parties; and

 

[ * ] = 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.

 

 

 

Whereas, the BioMedicines wishes
BI Pharma to supply certain quantities of drug substance to BioMedicines for
non-commercial development purposes before having a supply agreement in place
as intended by the License Agreement (as defined); and

 

Whereas, BI Pharma is willing to
supply BioMedicines with such quantities under the additional conditions laid
down hereinafter.

 

Now Therefore, the Parties agree
as follows.

 

1.              General

 

All
capitalized terms in this Agreement shall have the meaning laid down in the
R&D-Agreement unless otherwise defined in this Amendment No.1 or in the
Appendices hereto.

 

2.              Section 1
(Definitions)

 

In Section 1
of the R&D-Agreement a new Section 1.24 is added to read as follows:

 

“1.24                      Agreement on
Release Responsibility

shall mean the special agreement between the Parties with regard to
certain quantities of the drug substance in a certain form to be provided by BI
Pharma to BioMedicines for non-commercial development purposes at certain
conditions agreed upon by the Parties in that Agreement on Release
Responsibility.”

 

3.              Section 4

 

(1)                                      The existing Section 4.3 is made
Section 4.4.

 

(2)                                      A new Section 4.3 is inserted to
read as follows:

 

“4.3                            Agreement on
Release Responsibility

The Parties have agreed on the Agreement on Release Responsibility
attached hereto as Appendix Amend- No.1 — 1, according to which
drug substance in a certain form will be provided by BI Pharma to BioMedicines
for non-commercial development purposes at certain conditions agreed upon by
the Parties in that Agreement on Release Responsibility. The quantities itself
and the price for such quantities shall be agreed upon by the Parties in due
time in good faith negotiations before the respective order.”

 

4.              Section 4

This Amendment
No. 1 shall be effective as of the last signature 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.

 

 

5.              Validity of the
R&D-Agreement

 

As far as not amended herein,
the R&D-Agreement shall remain in full force and effect.

 

IN WITNESS HEREOF, the parties
hereto have executed this Amendment No.1 as of the last day and year written
below.

 

 

	
  Biberach, 19. December 2003

  	
   

  	
  Emeryville, 22 March 2004

  
	
   

  	
   

  	
   

  
	
  Boehringer Ingelheim

  	
   

  	
  BioMedicines,
  Inc.

  
	
   

  	
   

  	
   

  
	
  Pharma GmBH & Co. KG

  	
   

  	
   

  
	
   

  	
   

  	
  ppa.

  	
   

  	
   

  
	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  
	
  Dr. Wolfram Carius

  	
   

  	
  Dr. H. Michelberger

  	
   

  	
  Thomas A. Alessi

  

 

 

Appendix:

 

Appendix Amend- No.1 – 1:                                            Agreement on Release Responsibility
(including Appendices)

 

[ * ] =
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.

 

 

APPENDIX AMEND- NO.1 — 1: 

Agreement on Release Responsibility (including
Appendices)

 

Agreement on Release Responsibility

 

(including Release Procedure and Definition of Responsibilities for

Product Release

between

BioMedicines and BI Pharma)

 

TABLE OF CONTENTS

 

	
  1.

  	
  DEFINITIONS

  	
   

  
	
   

  	
   

  	
   

  
	
  2.

  	
  ORDER

  	
   

  
	
   

  	
   

  	
   

  
	
  3.

  	
  SPECIFICATIONS

  	
   

  
	
   

  	
   

  	
   

  
	
  4.

  	
  LABELLING

  	
   

  
	
   

  	
   

  	
   

  
	
  5.

  	
  DOCUMENTATION

  	
   

  
	
   

  	
   

  	
   

  
	
  6.

  	
  RESPONSIBILITIES

  	
   

  
	
   

  	
   

  	
   

  
	
  7.

  	
  LIABILITY

  	
   

  

 

[ * ] =
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.                                      Definitions

 

	
  “Bulk Drug Substance”:

  	
   

  	
  means under cGMP produced Interferon Omega
  processed to the bulk step;

  
	
   

  	
   

  	
   

  
	
  “Drug Product”

  	
   

  	
  means Bulk Drug Substance formulated and
  aseptically filled [*].
  Labelling will occur on the packaging boxes for shipment and storage;

  
	
   

  	
   

  	
   

  
	
  “Finished Product”

  	
   

  	
  means Drug Product after labelling of
  individual [*] and final
  release;

  
	
   

  	
   

  	
   

  
	
  “Certificate
  of Analysis”

  	
   

  	
  or
  “CoA” means a batch specific document, signed by an authorized representative
  of BI Pharma, describing specifications and testing methods and the results
  thereof for Bulk Drug Substance, Drug Product and Finished Product, as the
  case may be;

  
	
   

  	
   

  	
   

  
	
  “Certificate
  of Compliance”

  	
   

  	
  means
  a batch specific document, signed by an authorized representative of BI
  Pharma, confirming GMP compliance of production of a given batch signed by a
  Qualified Person.

  

 

2.                                      ORDER

 

BioMedicines
shall deliver to BI Pharma, in writing, a binding purchase to order for Bulk
Drug Substance or Drug Product. Such a purchase order will be based on an
agreed-upon planning basis for manufacturing of Bulk Drug Substance and Drug
Product considering the lead time for manufacturing at BI Pharma (3[*] months for Bulk Drug Substance and [*] months for Drug Product).

 

Delivery shall
take place by BI Pharma on the base of EXW (Incoterms 2000). Further delivery
terms (i.e. primary container, detailed quantities, shipment address, etc.)
will be agreed upon by the parties on a case by case basis and are subject to a
purchase order.

 

Bulk Drug
Product or Drug Product will be delivered to BioMedicines and will be shipped
based on BI Release

 

3.                                      SPECIFICATIONS

 

All Bulk Drug Substance or Drug Product supplied to BioMedicines
hereunder will comply with the specifications shown in Appendix 1 or 2
to this Release Procedure at

 

[ * ] =
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.

 

 

the time of manufacture and be
in accordance with the current batch record and cGMP.

 

4.                                      LABELLING

 

The labels for the Bulk Drug Substance or Drug Product shipment
containers should contain at least the following:

•                                          name
of the Bulk Drug Substance or Drug Product;

•                                          batch
number;

•                                          manufacturer;

•                                          amount
of the Bulk Drug Substance or Drug Product;

•                                          storage
instructions;

•                                          manufacturing
date;

 

5.                                      DOCUMENTATION

 

Each delivery
of the Bulk Drug Substance or Drug Product to BioMedicines will be accompanied by a CoC and CoA, provided by
the competent Quality and Compliance department of BI Pharma.

 

6.                                      RESPONSIBILITIES

 

6.1                                 General:

 

BI Pharma will
be responsible for manufacturing, manufacturer’s release and stability testing
of Bulk Drug Substance, Drug Product and Finished Product, as the case may be.

 

6.2                                 Only
Bulk Drug Substance Shipped:

 

If only Bulk Drug Substance is shipped to BioMedicines, BI Pharma will
be responsible for manufacturing of Bulk Drug Substance, manufacturer’s release
and stability testing of Bulk Drug Substance. BioMedicines will be responsible
for manufacturing, final release for clinics and/or market supplies and
stability testing of Drug Product and Finished Product.

 

7.                                      LIABILITY

 

7.1                                 No
Warranty of Merchantability or Fitness. 

 

BI Pharma makes no warranty that the Bulk Drug Substance/Drug
Product/Finished Product (the “Product”) will be merchantable or fit for any
particular purpose, nor does BI Pharma make any other warranties with respect
to the Product, except as expressly stated in this Agreement.

 

[ * ] =
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.

 

 

7.2                                 Limitation
of Liability as regards Amount and Consequential Damages

 

BI Pharma undertakes to use commercially reasonable efforts to provide
the Product as foreseen in this Agreement. However, due to [*] BI Pharma’s liability under this
Agreement shall in no event exceed the amount to be paid by BioMedicines for
the respective delivery.  Any liability
of BI Pharma for consequential damages is excluded.

 

7.3                                 Limitation
of Liability regarding Use of Product/any Formulations thereof

 

As BI Pharma has no knowledge or awareness of or control over the manner
in which BioMedicines intends to use any Product obtained according to this
Agreement and in particular does not know or control how BioMedicines intends
to use such Product or results in pre-clinical or clinical studies or
commercially, BI Pharma shall not be liable to BioMedicines for any losses,
damages, costs or expenses of any nature incurred or suffered by BioMedicines
or by a third party, arising out of any dispute or other claims or proceedings
made by or brought against BioMedicines in respect of the use of the Product by
BioMedicines or by a third party (including, without limitation, product
liability claims), nor shall BI Pharma be responsible in any way for dealing
with any such disputes, claims or proceedings.

 

BioMedicines shall indemnify, defend and hold BI Pharma, its affiliates
and their respective officers, employees and agents harmless from and against
all such losses, damages costs and expenses (including, without limitation,
reasonable attorneys’ fees).

 

Appendices:

 

Appendix 1:                                           Release
relevant Analytical Methods and Specifications for Interferon Omega Bulk Drug Substance at BI Pharma:

 

Appendix 2:                                           Release
relevant Analytical Methods and Specifications for Interferon Omega Drug Product at BI Pharma:

 

[ * ] =
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.

 

 

Appendix
1

 

to the
Agreement on Release Responsibility

by and between
BioMedicines and BI Pharma:

 

Release relevant Analytical
Methods and Specifications for Interferon Omega Bulk Drug Substance at BI
Pharma:

 

BuIk Drug
Substance:

 

In-process
Specifications for Bulk Drug Substance

 

	
  Test

  	
   

  	
  Specification

  	
   

  	
  Process Step

  
	
  [*]

  	
   

  	
  [*]

  	
   

  	
  [*]

  
	
  [*]

  	
   

  	
  [*]

  	
   

  	
  [*]

  
	
  [*]

  	
   

  	
  [*]

  	
   

  	
  [*]

  

 

Release
Specifications for Bulk Drug Substance

 

Concentration [*] mg/mL and [*]
mg/mL

 

	
  Test

  	
   

  	
  Doc.-No.

  	
   

  	
  Specification

  
	
  [*]

  	
   

  	
  [*]

  	
   

  	
  [*]

  
	
  [*]

  	
   

  	
  [*]

  	
   

  	
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  [*]

  	
   

  	
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  [*]

  
	
  [*]

  	
   

  	
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  [*]

  	
   

  	
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  [*]

  	
   

  	
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  [*]

  	
   

  	
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  [*]

  
	
  [*]

  	
   

  	
  [*]

  	
   

  	
  [*]

  
	
  [*]

  	
   

  	
  [*]

  	
   

  	
  [*]

  

 

[ * ] =
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.

 

 

Final
formulated bulk after sterile filtration

 

	
  Test

  	
   

  	
  Doc.-No.

  	
   

  	
  Specification

  
	
  [*]

  	
   

  	
  [*]

  	
   

  	
  [*]

  

 

Appendix
2

 

to the
Agreement on Release Responsibility

by and between BioMedicines
and BI Pharma:

 

Release relevant Analytical
Methods and Specifications for Interferon Omega Drug Product at BI Pharma:

 

Drug Product:

 

	
  Test

  	
   

  	
  Doc.-No.

  	
   

  	
  Specification

  
	
  [*]

  	
   

  	
   

  	
   

  	
   

  
	
  [*]

  	
   

  	
  [*]

  	
   

  	
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  [*]

  	
   

  	
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[*]

 

[ * ] =
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.EXHIBIT 10.9

 

[ * ] = 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 EXCHANGE ACT OF 1933, AS AMENDED.

 

ALZA Contract #
20001780

 

INTERIM
DEVELOPMENT AGREEMENT

 

This INTERIM
DEVELOPMENT AGREEMENT (“Agreement”) is entered into as of this 8th
day of November, 2000 between ALZA CORPORATION (“ALZA”)
and BIOMEDICINES, INC. (“BioMedicines”).

 

RECITALS

 

A.                                   ALZA
and BioMedicines have entered into discussions with respect to the development
of a product utilizing proprietary technology of ALZA for the controlled
delivery of BioMedicines’ proprietary Interferon Omega recombinant protein and
have signed a Confidentiality Agreement dated May 10, 2000 (the “Confidentiality
Agreement”) in that regard.

 

B.                                     The
parties wish to commence the development of such product while negotiating the
definitive agreement covering the development, manufacture and marketing of
such product.

 

NOW THEREFORE, in
consideration of the mutual covenants and agreements provided herein, the
parties hereby agree as follows:

 

1.                                      DEFINITIONS.  For the purposes of this Agreement, the
following terms shall have the respective meanings set forth below:

 

1.1                               “Confidential
Information” shall mean (i) in the case of BioMedicines, information
disclosed by BioMedicines to ALZA on or after the Effective Date hereof
concerning Drug (as defined herein) as such, or the use or manufacture thereof,
owned by or licensed to BioMedicines prior to the date of the Confidentiality
Agreement or developed by BioMedicines after the date of the Confidentiality
Agreement outside the Program (as defined herein) and without reference to or
use of any Program Information (as defined herein) or ALZA Confidential
Information, and (ii) in the case of ALZA, information disclosed by ALZA to
BioMedicines on or after the Effective Date hereof concerning the System, or
the use or manufacture thereof, or otherwise useful to the Program, owned by or
licensed to ALZA prior to the date of the Confidentiality Agreement or
developed by ALZA after the date of the Confidentiality Agreement outside the
Program and without reference to or use of any Program Information or
BioMedicines Confidential Information. 
Confidential Information will not include any information which is (i)
now in the public domain or subsequently enters the public domain without fault
on the part of the receiving party; (ii) known by the receiving party from its
own sources, as evidenced by the receiving party’s written records made prior
to the date of the Confidentiality Agreement; or (iii) received from any third
party not under any obligation to keep such information confidential.

 

1

 

1.2                               “Development
Costs” shall mean the costs of the Program incurred by ALZA pursuant to
this Agreement and determined in accordance with Exhibit A hereto.

 

1.3                               “Drug”
shall mean BioMedicines’ proprietary Interferon Omega recombinant protein in
its pure form or in the formulation originally provided to ALZA by BioMedicines
hereunder.

 

1.4                               “Effective
Date” shall mean November 8, 2000.

 

1.5                               “Product”
shall mean the product developed under the Program which combines Drug with
System or another product combining Drug with System that is substantially
identical to the Product.

 

1.6                               “Program”
shall mean all activities undertaken on or after the Effective Date by either
or both parties in accordance with the terms hereof for the development of a
Product, including regulatory and clinical activities.

 

1.7                               “Program
Information” shall mean any Technical Information and Regulatory Data
developed or acquired by either party under or as a result of the Program.

 

1.8                               “Regulatory
Data” shall mean regulatory filings (but not any Program Information owned
by ALZA or any of ALZA’s Confidential Information contained therein, which
shall remain the property of ALZA) resulting from the Program and clinical
study results resulting from activities under the Program.

 

1.9                               “System”
shall mean an implantable osmotic system which is intended to function by
releasing the active agent or agents on a controlled basis. The term “System”
will include anything incorporated in or used in connection with, or which is
an attribute of, the Product, or the development thereof, including anything
which affects or may affect the pharmacodynamics, pharmacokinetics, stability
or absorption of a therapeutic agent or the formulation, stabilization or use
of a therapeutic agent in the System (in each case other than the Drug itself,
any formulation of the Drug itself provided to ALZA by BioMedicines created by
BioMedicines not under or as a result of the Program or any other therapeutic
agent not physically incorporated into or onto the System).

 

1.10                        “Technical
Information” shall mean know-how, ideas, trade secrets, inventions
(including patents covering such inventions), data, technology and information,
including improvements and modifications to any thereof, processes and
analytical methodology used in development, testing, analysis and manufacture,
and medical, clinical, toxicological and other scientific data developed or
acquired by either party under or as a result of the Program.  Notwithstanding the foregoing, Technical
Information will not include trademarks or Regulatory Data.

 

2.                                      PRODUCT
DEVELOPMENT PROGRAM.

 

2.1                               Promptly
after execution of this Agreement and receipt from BioMedicines of Drug and the
materials described in Section 2.3, the parties will commence the
Program.  In connection with the Program,
the parties will make available appropriate scientific,

 

[ * ] = 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 EXCHANGE ACT OF 1933, AS AMENDED.

 

2

 

engineering
and other personnel to perform tasks under the Program.  The parties will use diligent efforts to
carry out the Program, will participate in periodic conferences to review its
status and will cooperate in the prompt preparation and review of, and
discussion concerning, work plans and cost estimates and revisions thereto as
further described in Section 2.2.

 

2.2                               The
initial work plan for, and the initial cost estimate for ALZA’s activities
under the Program is attached hereto as Exhibit B.  The parties understand and agree that it is
difficult to accurately predict the activities that will be necessary to
develop the Product, or the cost thereof, and significant uncertainties exist
in any product development effort.  As a
result, any such work plan and cost estimate will be diligently reviewed and
revised from time to time in order that it remain a faithful best-estimate of
work to be done by the parties under the Program and, with regard to ALZA’s
activities, the Development Costs thereof.

 

2.3                               In
connection with the Program, BioMedicines will provide to ALZA, at no charge to
ALZA, such quantities of Drug which ALZA may reasonably require to carry out
its duties hereunder.  BioMedicines will
provide ALZA with a Material Safety Data Sheet for the Drug and will complete
and return ALZA’s Safety and Environmental Evaluation Questionnaire prior to
commencement of the Program.  BioMedicines
will also provide ALZA with all relevant information available and known to
BioMedicines concerning the safety, handling, use, disposal and environmental
effects of the Drug or as may be necessary to conduct the Program.  ALZA will provide BioMedicines with all
relevant information available and known to ALZA concerning the safety,
handling, use, disposal and environmental effects on the System or as may be
necessary to conduct the Program.

 

BioMedicines will
indemnify, defend and hold ALZA harmless from and against all liabilities,
claims, demands, damages, losses, costs, expenses or money judgments (including
reasonable attorneys’ fees) incurred by or rendered against ALZA and resulting
from the use, storage or handling of the Drug under the Program, except to the
extent that ALZA has not complied with written materials provided in advance by
BioMedicines as described above. 
Notwithstanding the foregoing, BioMedicines shall not be required to
indemnify ALZA for actions by ALZA that represent willful misconduct, gross
negligence or a material violation of the law.

 

2.4                               BioMedicines
will pay to ALZA, on a monthly basis, all Development Costs incurred by ALZA in
connection with the activities carried out under the Program.  ALZA will invoice BioMedicines on or before
the fifteenth day of each month for the preceding month’s Development
Costs.  All payments will be made within
30 days after the date of the invoice. 
Notwithstanding the foregoing, BioMedicines will not be obligated to pay
Development Costs in excess of those provided for in approved work plans and
cost estimates, and ALZA will not be obligated to perform any work which would
result in Development Costs exceeding such approved cost estimates.

 

2.5                               Each
party will, for the term of this Agreement and for [ * ]
after its expiration or termination for any reason, keep confidential and not
disclose to others, and use only as permitted hereunder in connection with the
Program, (a) all clinical study results resulting from activities under the
Program (unless such results fall within the exceptions set forth in
subsections (i), (ii) and (iii) in the last sentence of Section 1.1
above), (b) all of the other 

 

[ * ] = 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 EXCHANGE ACT OF 1933, AS AMENDED.

 

3

 

party’s
Confidential Information and (c) all Program Information (other than such
clinical study results) owned by the other party.  Notwithstanding the foregoing, such
information may be (i) disclosed to government and regulatory agencies where
such information may be required to be included in patent applications or
regulatory filings permitted under the terms of this Agreement; (ii) provided
to third parties under agreements including appropriate confidentiality
provisions for consulting, market research, manufacturing, development, and
clinical testing with respect to the Product and similar activities under the
Program; (iii) published if and to the extent such publication has been
approved in writing by each of the parties (provided, however, results of
clinical studies of the Product may be published without the prior written
approval of both parties if and to the extent any such publication has been
reviewed to ensure that no Confidential Information or Program Information
(other than the results of clinical studies of the Product) has been disclosed
and each party has been given at least 60 days to file a patent application to
protect any patentable invention owned by it which would otherwise be disclosed
in such publication); or (iv) disclosed to the extent required by applicable
laws or regulations or as ordered by a court or other regulatory body having
competent jurisdiction.  In each of the
foregoing cases, the other party will use diligent efforts to limit the
disclosure and maintain confidentiality to the extent reasonably possible.

 

2.6                               As
part of the Program, BioMedicines may conduct clinical studies of the Product,
at its sole cost and expense.  In such
instances:

 

(a)                                  ALZA
will have the right to review and comment upon all proposed protocols, forms of
informed consent forms, investigator brochures and all forms of investigator
agreements and contract research organization agreements (other than with
respect to the financial arrangements under such agreements) for any clinical
studies to be conducted by or on behalf of BioMedicines with respect to the
Product.  ALZA agrees to provide its
comments to BioMedicines in writing as soon as reasonably practicable but in
any event within 30 days of receipt of such documents.  BioMedicines will make such changes in any
such documents as may be reasonably requested by ALZA in writing with respect
to the use of the System or any reference to or description of ALZA or to
otherwise protect the rights or intellectual property interests of ALZA as
described herein.

 

(b)                                  Clinical
supplies shall be supplied by ALZA on a Development Cost basis and shall be
manufactured in accordance with current Good Manufacturing Practices as defined
from time to time by the Act (as defined in Section 2.8) or any successor
laws or regulations governing the manufacture of clinical supplies of Product
in the United States (“GMPs”).

 

(c)                                  In
order to assist in obtaining patent protection for the Product outside the
United States, unless otherwise agreed in writing by ALZA, prior to conducting
any clinical study, BioMedicines will obtain from each participating subject or
patient, a confidentiality agreement in the form attached hereto as Exhibit C
and will deliver an executed copy thereof to ALZA.  If ALZA requires BioMedicines to obtain such
an agreement, ALZA shall pay the cost of any translation thereof as required by
applicable law or regulations.

 

(d)                                  Within
a reasonable time after completion or termination of each clinical study,
BioMedicines will deliver a final report concerning the study to ALZA.

 

[ * ] = 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 EXCHANGE ACT OF 1933, AS AMENDED.

 

4

 

Publication
of any data or information derived from the study, or any reports thereof, will
be subject to the mutual agreement of the parties, (provided, however, results
of clinical studies of the Product may be published without the prior written
approval of both parties if and to the extent any such publication has been
reviewed to ensure that no Confidential Information or Program Information
(other than the results of clinical studies of the Product) has been disclosed
and each party has been given at least 60 days to file a patent application to
protect any patentable invention owned by it which would otherwise be disclosed
in such publication).

 

(e)                                  If
and to the extent that any clinical studies are undertaken pursuant to this
Agreement, BioMedicines will indemnify, defend and hold ALZA harmless from and
against any and all liabilities, claims, demands, damages, losses, costs,
expenses or money judgments (including reasonable attorneys’ fees) incurred by
or rendered against ALZA, and which arise out of or result from the clinical
studies or the use, design or labeling of the Product in connection therewith,
except as may arise from the gross negligence or willful misconduct of
ALZA.  ALZA will give BioMedicines prompt
notice in writing, in the manner set forth in Section 5.3 below, of any
claim or demand made against ALZA for which ALZA may be entitled to indemnity
under this Section 2.6.

 

(f)                                    If
and to the extent that any clinical studies are undertaken pursuant to this
Agreement, ALZA will indemnify, defend and hold BioMedicines harmless from and
against any and all liabilities, claims, demands, damages, losses, costs,
expenses or money judgments (including reasonable attorneys’ fees) incurred by
or rendered against BioMedicines, which arise out of or result from the gross
negligence or willful misconduct of ALZA or the failure by ALZA to deliver
clinical supplies manufactured in accordance with GMPs as described in Section 2.6(b).  BioMedicines will give ALZA prompt notice in
writing, in the manner set forth in Section 5.3 below, of any claim or
demand made against BioMedicines for which BioMedicines may be entitled to
indemnity under this Section 2.6.

 

2.7                               As
part of the Program, ALZA will have the right, but not the obligation, to
review and comment upon all regulatory filings proposed to be made by
BioMedicines with respect to the Product, and BioMedicines will include any
changes reasonably requested by ALZA with respect to the use of the System or
any reference to or description of ALZA or to otherwise protect the rights or
intellectual property interests of ALZA as described herein.  Such changes must be provided within 10
business days after ALZA’s receipt of the proposed filing from
BioMedicines.  ALZA will have the right,
but not the obligation, to participate in any meetings to be held with
regulatory authorities with respect to the Product, and BioMedicines will
promptly provide ALZA with copies of all correspondence from or to regulatory
authorities concerning the Product.  If
ALZA does elect to participate in any meeting, then ALZA shall promptly inform
BioMedicines of its decision and agrees to coordinate its activities with
BioMedicines in preparation for said meeting(s).  Notwithstanding the foregoing, unless
otherwise agreed subsequently, BioMedicines shall be responsible for the
conduct of all meetings with regulatory authorities regarding the Product.

 

2.8                               Each
party will promptly notify the other party of any information that it obtains
or develops regarding the efficacy or safety of the Product or the System but
only insofar as such System-related information bears on the safety or efficacy
of the Product.  ALZA and BioMedicines
also agree to exchange adverse drug reaction reports in a manner and time frame

 

[ * ] = 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 EXCHANGE ACT OF 1933, AS AMENDED.

 

5

 

that
will allow compliance with regulatory reporting requirements, including any
requirements of the U.S. Food, Drug and Cosmetic Act, 21 U.S.C. 312 et seq.,
and regulations promulgated thereunder (the “Act”) (and, if applicable, the ICH
guidelines) and ongoing safety review of the Product.  After execution of this Agreement but prior
to the initiation of any clinical trial of the Product, the parties will agree
in writing upon standard operating procedures for reporting adverse events to
regulatory authorities and to each other. 
BioMedicines agrees and acknowledges that ALZA may provide information
it obtains under this Section 2.8 to ALZA’s other clients developing
and/or marketing other products incorporating the System or similar delivery
systems.

 

2.9                               Prior
to [ * ], BioMedicines will not conduct
(by itself or with a third party) any material development or commercialization
activities with respect to any product (other than the Product) which
incorporates any [ * ] into any drug delivery
system for the controlled or sustained release of such [ * ] and
intended for commercialization in any subterritory in which BioMedicines
retains exclusive commercialization rights to the Product (as described in
Exhibit D attached hereto).  Prior to [ * ], ALZA will not conduct (by itself or with any third
party) any material development or commercialization activities with respect to
any product (other than the Product) which incorporates any [ * ]) into any [ * ] drug
delivery system and intended for commercialization in any subterritory in which
BioMedicines retains exclusive commercialization rights to the Product (as
described in Exhibit D attached hereto) so long as BioMedicines is using
diligent efforts to carry out the Program and is not otherwise in material
breach of this Agreement.  Thereafter,
neither party will conduct (by itself or with a third party) any material
development or commercialization activities with respect to any product (other
than the Product) incorporating [ * ] drug delivery
system and intended for commercialization in any subterritory in which
BioMedicines retains exclusive commercialization rights to the Product (as
described in Exhibit D attached hereto).

 

3.                                      OWNERSHIP.

 

3.1                               Technical
Information will be (a) the property of BioMedicines if and to the extent (i) [ * ] or (ii) [ * ], and (b)
the property of ALZA [ * ].  [ * ] will be
the property of BioMedicines, subject to the confidentiality obligations set
forth in Section 2.5.

 

3.2                               Each
party has the right, with respect to Program Information owned by the other
party under Section 3.1, to use such information to carry out the Program
during the term of this Agreement.  Each
party has the right, with respect to Program Information owned by it under Section 3.1,
to disclose and to license such Program Information to third parties; provided,
however, that during the term of this Agreement, no such use will be
inconsistent with the terms of this Agreement.

 

3.3                               In
addition, if BioMedicines terminates this Agreement or determines not to
proceed with the Program for any reasons other than (i) an uncured material
breach of this Agreement by ALZA or (ii) the failure of the parties to enter
into a definitive development and commercialization agreement on the terms in
Exhibit D attached hereto (unless such failure is based on BioMedicines’
failure to negotiate such an agreement in good faith), BioMedicines hereby
grants ALZA a worldwide, royalty-free, nonexclusive license in perpetuity to
use all 

 

[ * ] = 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 EXCHANGE ACT OF 1933, AS AMENDED.

 

6

 

Regulatory
Data (including the right to cross-reference the Regulatory Data contained in
the regulatory filings made in connection with the Program).

 

3.4                               Nothing
in this Agreement shall provide or imply under any circumstance (i) the right
of BioMedicines to use or license the System from ALZA; (ii) the right of ALZA
to use or license [ * ] from
BioMedicines; or (iii) the right of either party to otherwise use or license
any intellectual property owned by the other party except as specifically
provided in this Agreement concerning Program Information.

 

3.5                               Each
party agrees to enter promptly into good faith negotiations with the other
party for a definitive development and commercialization agreement, consistent
with the terms set forth on Exhibit D attached hereto, and such additional
terms and conditions as the parties will agree, covering the development and
manufacture by ALZA and marketing by BioMedicines of the Product.

 

4.                                      TERM
AND TERMINATION.

 

4.1                               This
Agreement will remain in effect until such time as work is no longer being
carried out under the Program in accordance with mutually approved work plans
and cost estimates.

 

4.2                               BioMedicines
may terminate this Agreement at any time upon not less than sixty (60) days’
written notice to ALZA.  ALZA may
terminate this Agreement upon not less than thirty (30) days’ written notice to
BioMedicines but only if BioMedicines fails to pay any amounts due to ALZA
under this Agreement within thirty (30) days after the date of invoice or if
BioMedicines is not proceeding diligently with the Program in accordance with Section 2.1
hereof.

 

4.3                               Termination
of this Agreement will be without prejudice to ALZA’s right to receive from
BioMedicines (i) payment of all Development Costs incurred prior to the effective
date of the termination and (ii) all Program Information owned by it.  Termination of this Agreement by BioMedicines
will be without prejudice to BioMedicines’ right to receive from ALZA all
Program Information owned by it.  After
termination of this Agreement by BioMedicines or termination by ALZA due to a
breach of this Agreement by BioMedicines, BioMedicines will reimburse ALZA,
within thirty (30) days after invoice, for any uncancellable obligations and
expenses incurred by ALZA prior to such termination in connection with the
Program and all costs incurred by ALZA in terminating the Program.

 

4.4                               Upon
termination of this Agreement, ALZA will return all unused Drug to
BioMedicines, if requested by BioMedicines in writing within thirty (30) days
after termination, or otherwise will dispose of it at BioMedicines’ expense.

 

5.                                      MISCELLANEOUS.

 

5.1                               This
Agreement will be governed by and construed in accordance with the laws of the
State of California, excluding any choice of law rules which may direct the
application of the laws of another jurisdiction.

 

[ * ] = 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
EXCHANGE ACT OF 1933, AS AMENDED.

 

7

 

5.2                               This
Agreement will not be amended or modified except in a writing signed by each of
the parties hereto.

 

5.3                               All
notices, requests and other communications required or permitted to be given
hereunder or with respect hereto will be in writing, and may be given by (i)
personal delivery, (ii) registered first-class United States mail, postage
prepaid by the sender, return receipt requested, (iii) overnight delivery
service, charges prepaid by the sender, or (iv) via facsimile and, in each
case, addressed to the other party at the address for such party as set forth
below, and will be effective upon receipt in the case of (i) (iii) or (iv)
above, and five days after mailing in the case of (ii) above.

 

If to ALZA:                                                                                 ALZA
Corporation

1900 Charleston Road

Mountain View, CA  94043

Fax #: 650-564-7848

Attention:  General Counsel

 

If to BioMedicines:                                          BioMedicines,
Inc.

1301 Marina Village
Parkway

Suite 200

Alameda, CA  94501

Fax #: 510-814-0170

Attention:  Vice President, Chemical Development

 

Any party may
change its address at which notice is to be received by written notice provided
pursuant to this Section 5.3.

 

5.4                               Each
party will be responsible for assuring that all applicable rules, laws and
regulations are met in the performance of its respective duties hereunder.

 

5.5                               This
Agreement, together with the exhibits hereto, sets forth the entire agreement
and understanding between the parties with respect to the subject matter
hereof, and supersedes all prior agreements and understandings between the
parties with respect to the subject matter hereof, whether oral or in writing;
provided, however, that the provisions of the Confidentiality Agreement (other
than with respect to the term of confidentiality which is hereby amended to
extend to the term of this Agreement and for [ * ]
after its expiration or termination for any reason) will remain in full force
and effect with respect to Confidential Information (as such term is defined
therein) disclosed prior to the date hereof.

 

5.6                               Neither
party will originate any publicity, news release or public announcement,
written or oral, whether to the public, the press, stockholders or otherwise,
referring to the existence or terms of this Agreement, including its existence,
the subject matter to which it relates, the performance under it or any of its
specific terms and conditions, except such announcements, as in the opinion of
the counsel for the party making such announcement, are required by law,
including United States securities laws, rules or regulations, without the
prior written consent of the other party, such consent not to be unreasonably
withheld.  If a party decides to make an
announcement it believes to be required by law with respect to this 

 

[ * ] = 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 EXCHANGE ACT OF 1933, AS AMENDED.

 

8

 

 

Agreement, it will give
the other party such notice as is reasonably practicable and an opportunity to
comment upon the announcement.  In
addition, neither party will disclose the existence of this Agreement, any of the
subject matter hereof, or any of the terms hereof to any third party without
the prior written consent of the other party, except as otherwise provided in
Section 2.5.

 

5.7                               The
provisions of Sections 1, the last sentence of 2.3, 2.5, 2.6(d), (e) and (f),
the first sentence of 2.8, 3.1, the second sentence of Section 3.2, 3.3, 3.4,
4.3, 4.4, 5.1, 5.3, 5.4, 5.5 , 5.6, 5.8, 5.9, 5.10, 5.11 and 5.12 and this
Section 5.7 will survive the termination for any reason of this Agreement.  Except as specifically provided in this
Agreement, neither party will be liable to the other due to the termination of
this Agreement as provided herein, whether in loss of good will, anticipated
profits or otherwise.

 

5.8                               In
the event that any provision of this Agreement (other than any provision
regarding confidentiality of the ownership of intellectual property) shall be
invalid or unenforceable under any controlling body of the law, the validity or
enforceability of the remaining provisions shall remain unaffected.

 

5.9                               This
Agreement may be executed in any number of counterparts, each of which shall be
deemed an original but all of which together shall constitute one and the same
instrument.

 

5.10                        The
failure of either ALZA or BioMedicines to assert a right hereunder or to insist
upon compliance with any term or condition of this Agreement shall not
constitute a waiver of that right or excuse a subsequent failure to perform any
term or condition by BioMedicines or ALZA, respectively.

 

5.11                        The
titles or headings of various numbered or un-numbered Sections in this Agreement
are for reference only and do not limit or modify the substance of the
Agreement in any way.

 

5.12                        Neither
party shall be held liable or responsible to the other party nor be deemed to
have defaulted under or breached this Agreement for failure or delay in
fulfilling nor performing any term of this Agreement, other than an obligation
to make a payment, when such failure or delay is caused by or results from
fire, floods, embargoes, government regulations, prohibitions or interventions,
war, insurrections, riots, civil commotions, lockouts, acts of God or any other
cause beyond the reasonable control of such party.

 

In Witness Whereof, the
parties have executed this Agreement as of the date first set forth above. 

 

[ * ] =
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 Exchange Act of
1933, as amended.

 

9

 

	
  Alza
  Corporation

  	
  Biomedicines,
  Inc.  

  
	
   

  	
   

  
	
   

  	
   

  
	
  By:

  	
  /s/ Robert M. Myers

  	
   

  	
  By:

  	
  /s/ Mark Moran

  	
   

  
	
   

  	
  Robert M. Myers

  	
   

  
	
   

  	
  Title: Senior Vice President,

  	
   

  	
  Title: 

  	
  Chief Executive Officer

  	
   

  
	
   

  	
  Commercial Development

  	
   

  
							

 

[ * ] =
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 Exchange Act of
1933, as amended.

 

10

 

Exhibit
A

 

Development
Costs

 

Development Costs are
equal to the sum of (i) research expenses, (ii) general and administrative
expenses and (iii) capital asset expenditures.

 

(i)                                    Research
expenses include both direct expenses and indirect expenses.

 

(a)                                  Direct
expenses include direct [ * ] in
connection with the Program.

 

(b)                                  Indirect
expenses include [ * ].

 

Examples of items included in direct and indirect
expenses are listed on Exhibit A-1

 

(ii)                                General
and administrative expenses are allocated among the [ * ] organizations.  The portion allocated to the research and
product development organization is then allocated to all [ * ]

 

Examples of items included in general and
administrative expenses are listed on Exhibit A-1.

 

(iii)                            Capital
asset expenditures are the actual costs of new capital assets acquired
specifically for the project.

 

*  This fixed
billing rate will not be changed prior to [ * ] and, if
changed on or after [ * ], such
changes will be limited to not more than [ * ] change
per calendar year and shall be a maximum of [ * ] of
the rate in effect at the time of the increase.

 

[ * ] =
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 Exchange Act of
1933, as amended.

 

 

Exhibit
A-1

 

Examples of

Research Expenses

 

Direct Expenses

 

[ * ]

 

Indirect Expenses

 

[ * ]

 

Examples of

General and Administrative Expense

 

[ * ]

 

[ * ]

 

[ * ] =
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 Exchange Act of
1933, as amended.

 

 

Exhibit
B

 

Work
Plan And Cost Estimates

 

[ * ] =
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 Exchange Act of
1933, as amended.

 

 

Exhibit
C

 

Form of
(Patient) (Subject) Letter of Confidentiality

 

Dear Volunteer:

 

I would like to discuss
with you the possibility of you participating in a clinical study to evaluate
the safety and efficacy of a new product. 
This study is being sponsored by the company that is developing the new
product, and I will be participating in this study as an investigator.  I believe, based on your medical records,
that you would qualify as a participant in this study although a final
determination of your qualification cannot be made until a screening evaluation
is done.

 

At this time, information
about this new product and the study is being kept confidential by the company
sponsoring the study in order to protect the sponsor’s early work in the
development of this product.  I therefore
ask that you confirm by signing this letter that you will respect the sponsor’s
desire to keep any information relating to the new product and the clinical
study confidential until the sponsor releases the information to the public.

 

The sponsor recognizes
that your health and well-being are of primary importance and does not want to
prevent you from discussing information about the study, the product and its
effect on you with your health care providers and other persons involved in the
study.  Instead, what you are agreeing to
do is not to disclose any information about the product or this study to anyone
else.

 

Signing this letter does
not mean that you are required to participate in the study, or that you must
stay in the study if you begin to participate in the study.  It merely means that you will keep
information relating to the product or this study confidential, whether or not
you participate in the study.

 

If you are willing to
agree to maintain the confidentiality of this information, please return this
letter fully signed (including the date and your full name) to me.  I will then be free to discuss this matter in
greater detail with you.

 

 

	
  Very truly yours,

  
	
   

  
	
   

  	
   

  
	
  (Investigator)

  
	
   

  
	
  I agree with the
  confidential treatment of information as discussed above:

  
	
   

  
	
   

  	
   

  
	
  Signature

  
	
   

  
	
   

  	
   

  
	
  (Type in
  Patient/Subject Name)

  

 

[ * ] =
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 Exchange Act of 1933, as
amended.

 

 

	
  Date:

  	
   

  	
   

  

 

[ * ] =
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 Exchange Act of 1933, as
amended.

 

2

 

Exhibit
C-1a

 

(Alternative
Form for Minor Patients/Subjects)

 

Form of
(Patient) (Subject) Letter of Confidentiality

 

Dear Volunteer:

 

I would like to discuss
with you the possibility of you testing a new type of medicine. The sponsor of
this test has not made any public announcement about this new medicine so I am
asking you and your parent or guardian to agree not to discuss with other
people the information I may give you about the new medicine.

 

If you would like me to
tell you about this new medicine, you should talk with your parents or
guardian.  If you and your parents or
guardian agree that you would like to be a part of this test, please sign this
letter for me.

 

	
  Very truly yours,

  
	
   

  
	
   

  	
   

  
	
  (Investigator)

  
	
   

  
	
  I agree with the
  confidential treatment of information as discussed above:

  
	
   

  
	
   

  	
   

  
	
  Signature

  
	
   

  
	
   

  	
   

  
	
  (Type in
  Patient/Subject Name)

  
	
   

  
	
   

  
	
  Date:

  	
   

  	
   

  
			

 

[ * ] =
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 Exchange Act of
1933, as amended.

 

 

Exhibit
C-1b

 

Form of
Parent or Guardian Letter of Confidentiality

 

Dear Parent or Guardian:

 

I would like to discuss
with you the possibility of your minor child/ward participating as a volunteer
in a clinical study to evaluate the safety and efficacy of a new product.  This study is being sponsored by the company
that is developing the new product, and I will be participating in this study
as an investigator.  I believe, based on
the child’s medical records, that (s)he would qualify as a participant in this
study although a final determination of qualification cannot be made until a
screening evaluation is done.

 

At this time, information
about this new product and the study is being kept confidential by the company
sponsoring the study in order to protect the sponsor’s early work in the
development of this product.  I therefore
ask that you confirm by signing this letter that you will respect the sponsor’s
desire to keep any information relating to the new product and the clinical
study confidential until the sponsor releases the information to the public.

 

The sponsor recognizes
that the health and well-being of the child are of primary importance and does
not want to prevent the discussion of information about the study, the product
and its effect on the child with his/her health care providers and other
persons involved in the study.  Instead,
what you are agreeing to do is not to disclose any information about the
product or this study to anyone else.

 

Signing this letter does
not mean that the child is required to participate in the study, or that (s)he
must stay in the study if (s)he begins to participate in the study.  It merely means that you will keep
information relating to the product or this study confidential as described
above, whether or not the child participates in the study.

 

If you are willing to
agree to maintain the confidentiality of this information, please return this
letter fully signed (including date and your full name) to me. The child has
been asked to sign a separate letter.  
When you sign this letter and the child signs his/her letter, I will be
free to discuss this matter in greater detail with you and the child.

 

	
  Very truly yours,

  
	
   

  
	
   

  	
   

  
	
  (Investigator)

  
	
   

  
	
  I agree with the
  confidential treatment of information as discussed above:

  
	
   

  
	
   

  	
   

  
	
  Signature (Parent or
  Guardian)

  
	
   

  
	
   

  	
   

  
	
  (Type in Name
  of Parent or Guardian)

  

 

[ * ] =
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 Exchange Act of
1933, as amended.

 

 

Exhibit
D

 

Term
Sheet

 

[ * ] =
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 Exchange Act of 1933, as
amended.

 

 

Key Terms For

Product Development and Commercialization Agreement

DUROS® Interferon-omega

 

	
  Parties:

  	
   

  	
  ALZA Corporation (together with its affiliates,
  “ALZA”) and BioMedicines, Inc. (“BioMedicines”).

  
	
   

  	
   

  	
   

  
	
  Product:

  	
   

  	
  A product (the “Product”) combining BioMedicines’
  proprietary Interferon-omega (the “Drug”) and ALZA’s proprietary DUROS® drug
  delivery system (the “System”).

  
	
   

  	
   

  	
   

  
	
  Territory:

  	
   

  	
  Worldwide, divided into four Subterritories:

  
	
   

  	
   

  	
   

  
	
   

  	
   

  	
  Subterritory A: [ * ]

  
	
   

  	
   

  	
  Subterritory B: [ * ]

  
	
   

  	
   

  	
  Subterritory C: [ * ]

  
	
   

  	
   

  	
  Subterritory D: [ * ]

  
	
   

  	
   

  	
   

  
	
  Agreement:

  	
   

  	
  Product Development and Commercialization Agreement.

  
	
   

  	
   

  	
   

  
	
  Product Development Program:

  	
   

  	
  ALZA will undertake the development of the Product
  in accordance with work plans and cost estimates approved by BioMedicines.
  BioMedicines will have the right to pre-approve all work plans and cost
  estimates and will reimburse ALZA on a monthly basis for its Development
  Costs. The development program will proceed with diligence through product
  development and regulatory approval of the Product in Major Market Countries*
  in accordance with a reasonable regulatory strategy communicated by
  Biomedicines to ALZA.

  
	
   

  	
   

  	
   

  
	
  Commercialization Rights and Term:

  	
   

  	
  Upon receipt of regulatory approvals, BioMedicines
  will proceed with diligence to commence and continue diligent
  commercialization of the Product during the term of the Agreement as follows:

  
	
   

  	
   

  	
   

  
	
   

  	
   

  	
  Basic Term: BioMedicines will be
  granted the exclusive right to market the Product until (i) in each of
  Subterritories A, B, and C, [ * ] after
  the first commercial sale of the Product in the first Major Market Country of
  such Subterritory, and (ii) in Subterritory D, [ * ]
  after the first commercial sale of the Product in the first Major Market
  Country anywhere in the Territory. BioMedicines shall have the right to
  assign or transfer such right to a third party, subject to ALZA’s approval,
  such approval not to be unreasonably withheld (it being understood that
  reasonable bases for withholding such approval shall include, without
  limitation, a transfer to a competitor of ALZA in the drug delivery business,
  a transfer to a company with whom ALZA is engaged in significant litigation,
  or any other legitimate business reason).

  

 

*France, Germany, Italy,
Japan, United Kingdom and United States.

 

[ * ] = 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 Exchange Act of 1933, as amended.

 

2

 

	
   

  	
   

  	
  Extended Term:  At its election, BioMedicines may continue
  its commercialization rights on an exclusive basis, or convert to
  nonexclusive commercialization rights, after the Basic Term, on a
  Subterritory-by-Subterritory basis. 
  Such election will be made on an annual basis, at least 90 days before
  the end of each calendar year (beginning with the last year of the Basic Term).  Once BioMedicines has elected to convert to
  nonexclusive rights for any Subterritory, BioMedicines may not reconvert to
  exclusive rights for such Subterritory.

  
	
   

  	
   

  	
   

  
	
  Upfront Payments:

  	
   

  	
  None.

  
	
   

  	
   

  	
   

  
	
  Milestone Payments:

  	
   

  	
  [ * ], due upon initiation of
  the first [ * ] .

  
	
   

  	
   

  	
   

  
	
   

  	
   

  	
  [ * ] , due upon submission of
  first application for regulatory approval to market the Product in the [ * ].

  
	
   

  	
   

  	
   

  
	
   

  	
   

  	
  [ * ] , due upon first
  regulatory approval to market the Product in the [ * ].

  
	
   

  	
   

  	
   

  
	
   

  	
   

  	
  [ * ], due upon the first
  commercial sale of the Product in a Major Market Country.

  
	
   

  	
   

  	
   

  
	
   

  	
   

  	
  [ * ], due when cumulative
  worldwide Net Sales** in four consecutive calendar quarters first exceed [ * ].

  
	
   

  	
   

  	
   

  
	
   

  	
   

  	
  [ * ], due when cumulative
  worldwide Net Sales in four consecutive calendar quarters first exceed [ * ]; provided, however, that if such milestone is
  reached within 12 months of the prior milestone being reached, such milestone
  shall not be due until 12 months after the prior milestone payment of [ * ] became due.

  

 

**        “Net Sales” will mean the total
amount billed or invoiced in United States dollars (or converted thereto in
accordance with the Definitive Agreement) on sales of the Product by
BioMedicines or any of its affiliates, assignees, transferees, distributors or
marketing partners (or their affiliates) to independent, unrelated third
parties such as wholesalers, hospitals, and others, in bona fide arm’s length
transactions, less the following deductions, in each case related specifically
to the Product and actually allowed and taken by such third parties and not
otherwise recovered by or reimbursed to BioMedicines or any of its affiliates,
assignees, transferees, distributors or marketing partners (or their
affiliates):  (i) trade, cash and
quantity discounts; (ii) taxes on sales (such as sales or use taxes) to the
extent added to the sale price and set forth separately as such in the total
amount invoiced; (iii) freight, insurance and other transportation charges to
the extent added to the sale price and set forth separately as such in the
total amount invoiced; and (iv) amounts repaid or credited by reason of
rejections, defects, recalls or returns or because of retroactive price
reductions or wholesaler chargebacks. Net Sales will also include the fair
market value of all other consideration received by BioMedicines in respect of
the Product or by any of its affiliates, assignees, transferees, 

 

[ * ] =
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 Exchange Act of
1933, as amended.

 

3

 

distributors or marketing partners (or their
affiliates) with respect to the Product, in each case whether such
consideration is in cash, payment in kind, exchange or other form.

 

	
   

  	
   

  	
  [ * ], due when cumulative
  worldwide Net Sales in four consecutive calendar quarters first exceed [ * ]; provided, however, that if such milestone is
  reached within 12 months of the prior milestone being reached, such milestone
  shall not be due until 12 months after the prior milestone payment of [ * ] became due.

  
	
   

  	
   

  	
   

  
	
  Exclusivity:

  	
   

  	
  Prior to [ * ],
  BioMedicines will not conduct (by itself or with a third party) any material
  development or commercialization activities with respect to any product
  (other than the Product) which incorporates any [ * ]
  into any [ * ] for the controlled or
  sustained release of such [ * ] and
  intended for commercialization in any Subterritory in which BioMedicines
  retains exclusive commercialization rights to the Product.

  
	
   

  	
   

  	
   

  
	
   

  	
   

  	
  Prior to [ * ] , ALZA
  will not conduct (by itself or with a third party) any material development
  or commercialization activities with respect to any product (other than the
  Product) which incorporates any [ * ] into
  any [ * ] and intended for
  commercialization in any Subterritory in which BioMedicines retains exclusive
  commercialization rights to the Product so long as BioMedicines is not in
  material breach of this Agreement. In negotiations for the Agreement, the
  parties will discuss, without obligation on either side, incentives for ALZA
  to extend the foregoing exclusivity period.

  
	
   

  	
   

  	
   

  
	
   

  	
   

  	
  Thereafter, neither party will [ * ] with
  respect to any product (other than the Product) incorporating [ * ] and intended for commercialization in any
  Subterritory in which BioMedicines retains exclusive commercialization rights
  to the Product.

  
	
   

  	
   

  	
   

  
	
  Product Payments:

  	
   

  	
  During the Basic Term: In addition
  to the supply price for the Product described below, BioMedicines will make
  quarterly payments (“Product Payments”) to ALZA in each calendar year based
  on Net Sales of the Product, at a percentage rate, determined as provided
  below, of the aggregate worldwide Net Sales of the Product for the
  immediately preceding calendar year:

  

 

	
  If Worldwide Net Sales 

  of the Product in 

  Year X are ($ U.S. million):

  	
   

  	
  The Payment Rate 

  For Year X + 1 will 

  be the following% of Net Sales:

  
	
   

  	
   

  	
   

  
	
  Less than [ * ]

  	
   

  	
  [ * ]

  
	
  [ * ]

  	
   

  	
  [ * ]

  
	
  [ * ]

  	
   

  	
  [ * ]

  
	
  [ * ]

  	
   

  	
  [ * ]

  
	
  [ * ] or more

  	
   

  	
  [ * ]

  

 

[ * ] = 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 Exchange Act of 1933, as amended.

 

4

 

	
   

  	
   

  	
  For clarification, for the calendar year in which
  the Product is first sold commercially, the payment rate will be [ * ] of Net Sales.

  
	
   

  	
   

  	
   

  
	
   

  	
   

  	
  During the Extended Term:  For any Subterritory for which BioMedicines
  elects to maintain exclusive commercialization rights after the Basic Term,
  Product Payments will continue to be determined in the same manner as during
  the Basic Term.  For any Subterritory
  for which BioMedicines elects to convert to nonexclusive commercialization
  rights after the Basic Term, Product Payments will be reduced by [ * ] of the rates for the Basic Term.  For example, assuming worldwide Net Sales
  in Year X were less than [ * ],
  the payment rate would be [ * ] of
  Net Sales in Year X + 1 for any Subterritory as to which BioMedicines elects
  nonexclusive rights.

  
	
   

  	
   

  	
   

  
	
  Minimum Payments:

  	
   

  	
  On a Subterritory by Subterritory basis,
  BioMedicines will make quarterly Minimum Payments to ALZA equal to [ * ] of projected quarterly Net Sales of Product in each
  of Subterritories A, B, and C (such projected Net Sales to be based on
  reasonably anticipated timing of regulatory approvals and sales
  projections).  Such quarterly Minimum
  Payments will be established no later than the date of submission of the
  first application for regulatory approval to market the Product, and will be
  fully creditable against quarterly Product Payments due for the quarter in
  which the Minimum Payments are made. 
  No minimum payments will be due for Subterritory D.

  
	
   

  	
   

  	
   

  
	
  Manufacture and Supply:

  	
   

  	
  ALZA will manufacture BioMedicines’ requirements of
  the Product.  The parties will begin to
  negotiate in good faith fixed supply prices (which may include annual price
  increases in accordance with the U.S. Producers’ Price Index) promptly after
  the manufacture and acceptance by BioMedicines of three batches of the
  Product which meet the then-current guidelines of the International Committee
  on Harmonization (“ICH”), or successor organization, or regulatory
  requirements of the U.S. Food and Drug Administration, whichever are more
  stringent.  Until the parties agree
  upon a supply price, the supply price will be [ * ] of
  ALZA’s standard manufacturing cost. BioMedicines will supply Drug to ALZA at [ * ].

  
	
   

  	
   

  	
   

  
	
  Proprietary Rights:

  	
   

  	
  The provisions regarding ownership of Program
  Information will be identical to those in Article 3 of the Interim
  Development Agreement between the parties, including a license to Regulatory
  Data for ALZA under the terms set forth in Section 3.3 of the Interim
  Development Agreement in each Subterritory in which BioMedicines no longer
  retains exclusive commercialization rights to the Product.

  
	
   

  	
   

  	
   

  
	
  Indemnification:

  	
   

  	
  BioMedicines will indemnify ALZA for claims arising
  from the use or sale of the Product, except to the extent due to ALZA’s gross
  negligence or intentional misconduct, illegal act or failure to manufacture
  Product in accordance with cGMP.  ALZA
  will warrant that, at the time of shipment, Product manufactured by ALZA will
  meet the NDA or BLA

  

 

[ * ] = 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 Exchange Act of 1933, as amended.

 

5

 

	
   

  	
   

  	
  specifications, will be manufactured in accordance
  with cGMP, and will not be adulterated or misbranded due to any action, or
  failure to act, of ALZA.  ALZA will
  indemnify BioMedicines for breach of this warranty, subject to certain
  limitations to be negotiated in good faith and included in the Agreement.
  BioMedicines will make parallel warranties with respect to Drug and will
  indemnify ALZA for breach of these warranties, subject to certain limitations
  to be negotiated in good faith and included in the Agreement.

  
	
   

  	
   

  	
   

  
	
  Termination:

  	
   

  	
  BioMedicines may terminate the Agreement at any time
  upon [ * ] written notice to ALZA.

  

 

THIS DOCUMENT OUTLINES THE GENERAL BUSINESS TERMS FOR THE
AGREEMENT.  OTHER TERMS AND CONDITIONS
WILL APPLY.

 

[ * ] = 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 Exchange Act of 1933, as amended.

 

6

 

COMPANY
LETTERHEAD

 

 

May 10, 2002

 

BioMedicines, Inc.

2000 Powell Street, Suite
1640

Emeryville, CA 94608

 

Re:          Amendment
No. 1 to lnterim Development Agreement Effective November 8, 2000

ALZA Contract # 20001780-1

 

Ladies and Gentlemen:

 

ALZA Corporation (“ALZA”)
and BioMedicines, Inc. (“BioMedicines”) desire to amend the Interim Development
Agreement between the parties effective November 8, 2000 (the “Agreement”).  Accordingly, effective immediately, Section
2.5 of the Agreement is hereby amended by adding the following sentence at the
end of that section: “Additionally, ALZA may disclose Confidential Information
to affiliated companies controlling, under the control of, or under common
control with ALZA, if such companies are bound by obligations of
confidentiality at least as stringent as those set forth herein.”

 

Capitalized terms used
but not otherwise defined herein shall have the meanings ascribed to them in
the Agreement. Except as expressly amended herein, the Agreement shall remain
unchanged and in full force and effect.

 

If the foregoing is
acceptable, please have both copies of this Amendment executed and dated by an
authorized corporate officer and return one fully executed original to ALZA.

 

	
  Very truly yours,

  	
   

  
	
   

  	
   

  
	
  ALZA Corporation

  	
   

  
	
   

  	
   

  
	
  /s/ Erik Wiberg

  	
   

  	
   

  
	
   

  	
   

  
	
  Erik D. Wiberg

  	
   

  
	
  Vice President,
  Business Development

  	
   

  
	
   

  	
   

  
	
  AGREED TO AND ACCEPTED
  THIS 20th DAY OF May , 2002

  	
   

  
	
   

  	
   

  
	
  BioMedicines, Inc.

  	
   

  
	
   

  	
   

  
	
  By:

  	
  /s/ S. M. Moran

  	
   

  
	
   

  
	
  Title:

  	
  CEO

  	
   

  
					

 

 

COMPANY
LETTERHEAD

 

August 6, 2002

 

BioMedicines, Inc.

2000 Powell Street, Suite
1640

Emeryville, CA 94608

 

Re:          Amendment
No. 2 to lnterim Development Agreement Effective November 8, 2000

ALZA Contract # 20001780-2

 

Ladies and Gentlemen:

 

ALZA Corporation (“ALZA”)
and BioMedicines, Inc. (“BioMedicines”) desire to amend the Interim Development
Agreement dated November 8, 2000 between the parties (as amended, the “Agreement”)
to revise the description of “Development Costs” in Exhibit A, to extend the
period of expanded exclusivity and to provide for a milestone payment.
Accordingly, effective immediately, the Agreement is hereby amended as follows:

 

1.             Beginning
on the first full monthly invoicing cycle following ALZA’s receipt of this
fully executed Amendment No. 2, Exhibits A and A-1 will be replaced with
Schedule A attached hereto, and all references to “Exhibit A” in the Agreement
will be to Schedule A.

 

2.             Section
2.9 of the Agreement is deleted in its entirety and replaced with the
following:

 

“2.9         Until the
first to occur of: (i) ALZA’s first shipment of Product for the [ * ] of the Product, (ii) the [ * ]
of the [ * ] of a [ * ]
for the Product by [ * ] or (iii) [ * ], BioMedicines will not conduct (by itself or with a
third party) any material development or commercialization activities with
respect to any product (other than the Product) which incorporates any [ * ] into any drug delivery system for the controlled or
sustained release of such [ * ] and
intended for commercialization in any subterritory in which BioMedicines
retains exclusive commercialization rights to the Product (as described in
Exhibit D attached to the Agreement).

 

Until the first to occur of: (i) ALZA’s first shipment
of Product for the [ * ] of the
Product, (ii) the [ * ] of the [ * ] of [ * ] for the
Product by [ * ] or (iii) [ * ], ALZA will not conduct (by itself or with any third
party) any material development or commercialization activities with respect to
any product (other than the Product) which incorporates any [ * ] into any [ * ] drug
delivery system and intended for commercialization in any subterritory in which
BioMedicines retains exclusive commercialization rights to the Product (as
described in Exhibit D attached to the Agreement) so long as BioMedicines is
using diligent efforts to carry out the Program and is not otherwise in
material breach of this Agreement.

 

[ * ] =
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 Exchange Act of 1933, as
amended.

 

 

 

Thereafter, neither party will conduct (by itself or
with a third party) any material development or commercialization activities
with respect to any product (other than the Product) incorporating [ * ] drug delivery system and intended for
commercialization in any subterritory in which BioMedicines retains exclusive
commercialization rights to the Product (as described in Exhibit D attached to
the Agreement).”

 

3.             The “Exclusivity”
section of Exhibit D of the Agreement is deleted in its entirety and replaced
with the following:

 

“Exclusivity: Until
the first to occur of: (i) ALZA’s first shipment of Product for the [ * ] of the Product, (ii) the [ * ]
of the [ * ] of [ * ]
for the Product by [ * ] or (iii) [ * ],
BioMedicines will not conduct (by itself or with a third party) any material
development or commercialization activities with respect to any product (other
than the Product) which incorporates any [ * ] into any
drug delivery system for the controlled or sustained release of such [ * ] and intended for commercialization in any Subterritory
in which BioMedicines retains exclusive commercialization rights to the
Product.

 

Until the first to occur of: (i) ALZA’s first shipment
of Product for the [ * ] of the
Product, (ii) the [ * ] of the [ * ] of [ * ] for the
Product by [ * ] or (iii) [ * ], ALZA will not conduct (by itself or with any third
party) any material development or commercialization activities with respect to
any product (other than the Product) which incorporates any [ * ] into any [ * ] drug
delivery system and intended for commercialization in any Subterritory in which
BioMedicines retains exclusive commercialization rights to the Product, so long
as BioMedicines is not in material breach of this Agreement.

 

Thereafter, neither party will conduct (by itself or
with a third party) any material development or commercialization activities
with respect to any product (other than the Product) incorporating [ * ] drug delivery system and intended for
commercialization in any Subterritory in which BioMedicines retains exclusive
commercialization rights to the Product.”

 

4.             A new
Section 6 is added to the Agreement to read as follows:

 

“6.           Milestone
Payment. BioMedicines will make a one-time, noncreditable, nonrefundable
milestone payment to ALZA of $1,500,000 (One Million, Five Hundred Thousand
Dollars) within 30 days of BioMedicines first entering into an agreement with
any third party under which such third party obtains the right to market the
Product in any one or more of the following major market countries:   [ * ].”

 

Except as expressly
amended hereinabove, the Agreement shall remain unchanged and in full force and
effect.

 

If the foregoing is acceptable,
please have both copies of this Amendment No. 2 executed and dated by an
authorized corporate officer and return one fully executed original to ALZA.

 

[ * ] =
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 Exchange Act of
1933, as amended.

 

2

 

	
  Very truly yours,

  	
   

  
	
   

  	
   

  
	
  ALZA Corporation

  	
   

  
	
   

  	
   

  
	
  /s/ Erik Wiberg

  	
   

  	
   

  
	
   

  	
   

  
	
  Erik D. Wiberg

  	
   

  
	
  Vice President, Business
  Development

  	
   

  
	
   

  	
   

  
	
  APPROVED AND ACCEPTED
  THIS  8 th DAY OF August , 2002

  	
   

  
	
   

  	
   

  
	
  BioMedicines, Inc.

  	
   

  
	
   

  	
   

  
	
   

  	
   

  
	
  By:

  	
  /s/ S. M. Moran

  	
   

  
	
   

  	
   

  
	
  Title:

  	
  CEO

  	
   

  
					

 

[ * ] =
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 Exchange Act of
1933, as amended.

 

3

 

SCHEDULE A

 

DEVELOPMENT COSTS

 

Development Costs are
equal to the sum of (i) direct labor and overhead costs and (ii) out-of-pocket
expenses and (iii) capital asset expenditures.

 

(i) Direct labor and overhead costs include [ * ]. Direct labor and overhead costs are billed using an
all inclusive FTE rate as follows:

 

The annual rate will be based upon a fixed rate* of [ * ].

 

(ii) Out-of-pocket expenses include [ * ].

 

(iii) Capital asset expenditures are the actual costs
of new capital assets acquired specifically for the Program.

 

* This fixed billing rate
will not be changed prior to [ * ] and, if
changed on or after [ * ], such
changes will be limited to not more than [ * ] per
calendar year and shall be a maximum of [ * ] of the
rate in effect at the time of the increase.

 

[ * ] =
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 Exchange Act of
1933, as amended.

 

 

COMPANY
LETTERHEAD

 

 

December 30, 2002

 

BioMedicines, Inc.

2000 Powell Street, Suite
1640

Emeryville, CA 94608

 

Re:          Amendment
No. 3 to Interim Development Agreement

Effective November 8, 2000

ALZA Contract # 20001780-3

 

Ladies and Gentlemen:

 

ALZA Corporation (“ALZA”)
and BioMedicines, Inc. (“BioMedicines”) desire to amend the Interim Development
Agreement effective November 8, 2000 between the parties (as amended, the “Agreement”).
Accordingly, effective immediately, the Agreement is hereby amended as follows:

 

5.             (a)           Notwithstanding
Section 2.4 of the Agreement, beginning on [ * ] and
continuing until the end of the month in which the first subject is dosed in
the first [ * ] human clinical study of the
Product, but in any event no later than [ * ],
BioMedicines shall pay to ALZA, on a monthly basis, [ * ] of
the Development Costs invoiced consisting of [ * ] and
[ * ] of the Development Costs invoiced
consisting of [ * ] .

 

(b)           After
the end of the month in which the first subject is dosed in the first     [ * ] human
clinical study of the Product, but in any event no later than [ * ], BioMedicines will again pay to ALZA, on a monthly
basis, [ * ] of all Development Costs
invoiced, as described in Section 2.4 of the Agreement.

 

6.             A new
Section 7 is added to the Agreement to read as follows:

 

“7.           Milestone
Payment.  BioMedicines will make a
one-time, noncreditable, nonrefundable milestone payment to ALZA equal to [ * ] of the Development Costs consisting of [ * ] invoiced for the period described in Section 1(a) of
Amendment No. 3 within thirty days of the first to occur of (i) ALZA’s first
shipment of Product meeting the specifications agreed to by the parties for the
[ * ] of the Product or (ii) the [ * ] of the [ * ] of [ * ] for the Product by [ * ].”

 

Except as expressly
amended hereinabove, the Agreement shall remain unchanged and in full force and
effect.

 

If the foregoing is
acceptable, please have both copies of this Amendment No. 3 executed and dated
by an authorized corporate officer and return one fully executed original to
ALZA.

 

[ * ] =
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 Exchange Act of
1933, as amended.

 

 

 

	
  Very truly yours,

  	
   

  
	
   

  	
   

  
	
  /s/ Erick Wiberg

  	
   

  	
   

  
	
   

  	
   

  
	
  Erik D. Wiberg

  	
   

  
	
  Vice President,
  Business Development

  	
   

  
	
   

  	
   

  
	
  APPROVED AND ACCEPTED
  THIS  30 DAY OF December , 2002.

  	
   

  
	
   

  	
   

  
	
  BioMedicines, Inc.

  	
   

  
	
   

  	
   

  
	
   

  	
   

  
	
  By:

  	
  /s/ S. M. Moran

  	
   

  
	
   

  	
   

  
	
  Title:

  	
  CEO

  	
   

  
					

 

[ * ] =
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 Exchange Act of
1933, as amended.

 

2

 

Amendment No. 4 to
Interim Development Agreement

 

ALZA
Corporation (“ALZA”) and BioMedicines, Inc. (“BioMedicines”) desire to amend
the Interim Development Agreement dated November 8, 2000 between the parties
(as amended the “Agreement”). 
Accordingly, effective immediately, the Agreement is hereby amended as
follows:

 

1.             The
references in Section 2.9 and in Exhibit D of the Agreement to “[ * ]”, describing the periods during which the parties will
deal with each other exclusively in certain defined areas, are deleted and
replaced with “[ * ].”

 

2.             Section
7 of the Agreement, providing for a milestone payment from BioMedicines to
ALZA, is deleted in its entirety.

 

Except as expressly amended herein above, the
Agreement shall remain unchanged and in full force and effect.

 

ALZA Corporation

 

 

	
  /s/ Erick. D.
  Wiberg

  	
   

  	
  Dated: 

  	
  May 19, 2004

  
	
  Erick D. Wiberg

  	
   

  	
   

  
	
  Vice President,
  Pharmaceutical Group

  	
   

  	
   

  
	
  Business
  Development

  	
   

  	
   

  
	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  
	
  BioMedicines,
  Inc.

  	
   

  	
   

  
	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  
	
  By:

  	
  /s/ K. Alice
  Leung

  	
   

  	
  Dated:

  	
   May 26, 2004

  
	
   

  	
   

  	
   

  
	
  Title:

  	
  K. Alice Leung,
  President & CEO

  	
   

  	
   

  	
   

  
						

 

[ * ] =
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 Exchange Act of
1933, as amended.

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