Collaborative Research And Development Agreement

COOPERATIVE RESEARCH AND
DEVELOPMENT AGREEMENT


(CACR-352)


CLINICAL DEVELOPMENT OF Adp53


[*]
[*]
CTEP
DCTD


[*]
RHONE-POULENC RORER PHARMACEUTICALS, INC.


[*]
INTROGEN THERAPEUTICS, INC.


PREPARED BY
TECHNOLOGY DEVELOPMENT AND COMMERCIALIZATION BRANCH
NATIONAL CANCER INSTITUTE


[*] Certain information on this page has been omitted and filed
separately with the Commission. Confidential treatment has been
requested with respect to the omitted portions. 2


PUBLIC HEALTH SERVICE


COOPERATIVE RESEARCH AND DEVELOPMENT AGREEMENT


This Cooperative Research and Development Agreement, hereinafter referred to as "CRADA," consists of this Cover Page, an attached Agreement, and various Appendices referenced in the Agreement. This Cover Page serves to identify the Parties to this CRADA:


(1) the following Bureau(s), Institute(s), Center(s) or Division(s) of the National Institutes of Health ("NIH"), the Food and Drug Administration ("FDA"), and the Centers for Disease Control and Prevention ("CDC"):


THE CANCER THERAPY EVALUATION PROGRAM
DIVISION OF CANCER TREATMENT AND DIAGNOSIS
THE NATIONAL CANCER INSTITUTE


, hereinafter singly or collectively referred to as the Public Health Service ("PHS"); and


(2) RHONE-POULENC RORER PHARMACEUTICALS, INC.,


which has offices at 500 ARCOLA ROAD
COLLEGEVILLE, PENNSYLVANIA 19426


, hereinafter referred to as "RPRP" and


(3) INTROGEN THERAPEUTICS, INC.,


which has offices at 301 CONGRESS AVENUE, SUITE 1850
AUSTIN, TEXAS 78701


, hereinafter referred to as "Introgen"


PHS CRADA CACR-0352 3


COOPERATIVE RESEARCH AND DEVELOPMENT AGREEMENT


ARTICLE 1. INTRODUCTION


This Cooperative Research and Development Agreement (CRADA) between PHS and the Collaborator will be effective when signed by all Parties. The research and development activities which will be undertaken by each of the Parties in the course of this CRADA are detailed in the Research Plan (RP) which is attached as Appendix A. The funding and staffing commitments of the Parties are set forth in Appendix B. Any exceptions or changes to the CRADA are set forth in Appendix C.


ARTICLE 2. DEFINITIONS


As used in this CRADA, the following terms shall have the indicated meanings:


2.1 "AFFILIATE" means any corporation or other business entity controlled
by, controlling, or under common control with Collaborator. For this
purpose, "control" means direct or indirect beneficial ownership of at
least fifty (50) percent of the voting stock or at least fifty (50)
percent interest in the income of such corporation or other business.


2.2 "Cooperative Research and Development Agreement" or "CRADA" means this
Agreement, entered into by PHS pursuant to the Federal Technology
Transfer Act of 1986, as amended, 15 U.S.C. 3710a et seq. and
Executive Order 12591 of October 10, 1987.


2.3 "GOVERNMENT" means the Government of the United States as represented
through the PHS agency that is a Party to this agreement.


2.4 "IP" means intellectual property.


2.5 "INVENTION" means any invention or discovery which is or may be
patentable or otherwise protected under title 35, United States Code,
or any novel variety or plant which is or may be protectable under the
Plant Variety Protection Act (7 U.S.C. 2321 et seq.).


2.6 "PRINCIPAL INVESTIGATOR(S)" or "PIS" means the persons designated
respectively by the Parties to this CRADA who will be responsible for
the scientific and technical conduct of the RP.


2.7 "PROPRIETARY/CONFIDENTIAL INFORMATION" means confidential scientific,
business, or financial information provided that such information does
not include:


2.7.1 information that is publicly known or available from other
sources who are not under a confidentiality obligation to the
source of the information;


2.7.2 information which has been made available by its owners to
others without a confidentiality obligation;


2.7.3 information which is already known by or available to the
receiving Party without a confidentiality obligation; or


2.7.4 information which relates to potential hazards or cautionary
warnings associated with the production, handling or use of
the subject matter of the Research Plan of this CRADA.


2.8 "RESEARCH MATERIALS" means all tangible materials other than Subject
Data first produced in the


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performance of this CRADA.


2.9 "RESEARCH PLAN" or "RP" means the statement in Appendix A of the
respective research and development commitments of the Parties to this
CRADA.


2.10 "SUBJECT INVENTION" means any Invention of the Parties, conceived or
first actually reduced to practice in the performance of the Research
Plan of this CRADA.


2.11 "SUBJECT DATA" means all recorded information first produced in the
performance of this CRADA by the Parties.


ARTICLE 3. COOPERATIVE RESEARCH


3.1 PRINCIPAL INVESTIGATORS. PHS research work under this CRADA will be
performed by the PHS laboratory identified in the RP, and the PHS
Principal Investigator (PI) designated in the RP will be responsible
for the scientific and technical conduct of this project on behalf of
PHS. Also designated in the RP is the Collaborator PI who will be
responsible for the scientific and technical conduct of this project on
behalf of the Collaborator.


3.2 RESEARCH PLAN CHANGE. The RP may be modified by mutual written consent
of the Principal Investigators. Substantial changes in the scope of the
RP will be treated as amendments under Article 13.6.


ARTICLE 4. REPORTS


4.1 INTERIM REPORTS. The Parties shall exchange formal written interim
progress reports on a schedule agreed to by the PIs, but at least
within [*] after this CRADA becomes effective and at least within [*]
thereafter. Such reports shall set forth the technical progress made,
identifying such problems as may have been encountered and establishing
goals and objectives requiring further effort, any modifications to the
Research Plan pursuant to Article 3.2, and all CRADA-related patent
applications filed.


4.2 FINAL REPORTS. The Parties shall exchange final reports of their
results within [*] after completing the projects described
in the RP or after the expiration or termination of this CRADA.


ARTICLE 5. FINANCIAL AND STAFFING OBLIGATIONS


5.1 PHS AND COLLABORATOR CONTRIBUTIONS. The contributions of the Parties,
including payment schedules, if applicable, are set forth in Appendix
B. PHS shall not be obligated to perform any of the research specified
herein or to take any other action required by this CRADA if the
funding is not provided as set forth in Appendix B. PHS shall return
excess funds to the Collaborator when it sends its final fiscal report
pursuant to Article 5.2, except for staffing support pursuant to
Article 10.3. Collaborator acknowledges that the U.S. Government will
have the authority to retain and expend any excess funds for up to
[*] subsequent to the expiration or termination of the CRADA to
cover any costs incurred during the term of the CRADA in undertaking
the work set forth in the RP.


5.2 ACCOUNTING RECORDS. PHS shall maintain separate and distinct current
accounts, records, and other evidence supporting all its obligations
under this CRADA, and shall provide the Collaborator a final fiscal
report pursuant to Article 4.2.


5.3 CAPITAL EQUIPMENT. Equipment purchased by PHS with funds provided by
the Collaborator shall be the property of PHS. All capital equipment
provided under this CRADA by one party for the use of another Party
remains the property of the providing Party unless other disposition is
mutually agreed upon by in


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requested with respect to the omitted portions. 5
writing by the Parties. If title to this equipment remains with the
providing Party, that Party is responsible for maintenance of the
equipment and the costs of its transportation to and from the site
where it will be used.


ARTICLE 6. INTELLECTUAL PROPERTY RIGHTS AND PATENT APPLICATIONS


6.1 REPORTING. The Parties shall promptly report to each other in writing
each Subject Invention resulting from the research conducted under this
CRADA that is reported to them by their respective employees. Each
Party shall report all Subject Inventions to the other Party in
sufficient detail to determine inventorship. Such reports shall be
treated as Proprietary/Confidential Information in accordance with
Article 8.4.


6.2 COLLABORATOR EMPLOYEE INVENTIONS. If the Collaborator does not elect to
retain its IP rights, the Collaborator shall offer to assign these IP
rights to the Subject Invention to PHS pursuant to Article 6.5. If PHS
declines such assignment, the Collaborator may release its IP rights as
it may determine.


6.3 PHS EMPLOYEE INVENTIONS. PHS on behalf of the U.S. Government may elect
to retain IP rights to each Subject Invention made solely by PHS
employees. If PHS does not elect to retain IP rights, PHS shall offer
to assign these IP rights to such Subject Invention to the Collaborator
pursuant to Article 6.5. If the Collaborator declines such assignment,
PHS may release IP rights in such Subject Invention to its employee
inventors pursuant to Article 6.6.


6.4 JOINT INVENTIONS. Each Subject Invention made jointly by PHS and
Collaborator employees shall be jointly owned by PHS and the
Collaborator. The Collaborator may elect to file the joint patent or
other IP application(s) thereon and shall notify PHS promptly upon
making this election. If the Collaborator decides to file such
applications, it shall do so in a timely manner and at its own expense.
If the Collaborator does not elect to file such application(s), PHS on
behalf of the U.S. Government shall have the right to file the joint
application(s) in a timely manner and at its own expense. If either
Party decides not to retain its IP rights to a jointly owned Subject
Invention, it shall offer to assign such rights to the other Party
pursuant to Article 6.5. If the other Party declines such assignment,
the offering Party may release its IP rights as provided in Articles
6.2, 6.3, and 6.6.


6.5 FILING OF PATENT APPLICATIONS. With respect to Subject Inventions made
by the Collaborator as described in Article 6.2, or by PHS as described
in Article 6.3, a Party exercising its right to elect to retain IP
rights to a Subject Invention agrees to file patent or other IP
applications in a timely manner and at its own expense and after
consultation with the other Party. The Party shall notify the other
Party of its decision regarding filing in countries other than the
United States in a timely manner. The Party may elect not to file a
patent or other IP application thereon in any particular country or
countries provided it so advises the other Party ninety (90) days prior
to the expiration of any applicable filing deadline, priority period or
statutory bar date, and hereby agrees to assign its IP right, title and
interest in such country or countries to the Subject Invention to the
other Party and to cooperate in the preparation and filing of a patent
or other IP applications. In any countries in which title to patent or
other IP rights is transferred to the Collaborator, the Collaborator
agrees that PHS inventors will share in any royalty distribution that
the Collaborator pays to its own inventors.


6.6 RELEASE TO INVENTORS. In the event neither of the Parties to this CRADA
elects to file a patent or other IP application on a Subject Invention,
either or both (if a joint invention) may retain or release their IP
rights in accordance with their respective policies and procedures.
[*]


6.7 PATENT EXPENSES. The expenses attendant to the filing of patent or
other IP applications generally shall be paid by the Party filing such
application. If an exclusive license to any Subject Invention is
granted to the


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separately with the Commission. Confidential treatment has been
requested with respect to the omitted portions. 6
Collaborator, the Collaborator shall be responsible for [*] past and
future out-of-pocket expenses in connection with the preparation,
filing, prosecution and maintenance of any applications claiming such
exclusively-licensed inventions and any patents or other IP grants that
may issue on such applications. The Collaborator may waive its
exclusive license rights on any application, patent or other IP grant
at any time, and incur no subsequent compensation obligation for that
application, patent or IP grant.


6.8 PROSECUTION OF INTELLECTUAL PROPERTY APPLICATIONS. Within one month of
receipt or filing, each Party shall provide the other Party with copies
of the applications and all documents received from or filed with the
relevant patent or other IP office in connection with the prosecution
of such applications. Each Party shall also provide the other Party
with the power to inspect and make copies of all documents retained in
the patent or other IP application files by the applicable patent or
other IP office. Where licensing is contemplated by Collaborator, the
Parties agree to consult with each other with respect to the
prosecution of applications for PHS Subject Inventions described in
Article 6.3 and joint Subject Inventions described in Article 6.4. If
the Collaborator elects to file and prosecute IP applications on joint
Subject Inventions pursuant to Article 6.4, PHS will be granted an
associate power of attorney (or its equivalent) on such IP
applications.


ARTICLE 7. LICENSING


7.1 OPTION FOR COMMERCIALIZATION LICENSE. With respect to Government IP
rights to any Subject Invention not made solely by the Collaborator's
employees for which a patent or other IP application is filed, PHS
hereby grants to the Collaborator an option to elect an exclusive or
nonexclusive commercialization license, which is substantially in the
form of the appropriate model PHS license agreement. This option does
not apply to Subject Inventions conceived prior to the effective date
of this CRADA that are reduced to practice under this CRADA, if prior
to that reduction to practice, PHS has filed a patent application on
the invention and has licensed it or offered to license it to a third
party. The terms of the license will fairly reflect the nature of the
invention, the relative contributions of the Parties to the invention
and the CRADA, the risks incurred by the Collaborator and the costs of
subsequent research and development needed to bring the invention to
the marketplace. The field of use of the license will be commensurate
with the scope of the RP.


7.2 EXERCISE OF LICENSE OPTION. The option of Article 7.1 must be exercised
by written notice mailed within [*] after either (i) Collaborator
receives written notice from PHS that the patent or other IP
application has been filed; or (ii) the date Collaborator files such IP
application; whichever comes first. Exercise of this option by the
Collaborator initiates a negotiation period that expires [*] after the
exercise of the option. If the last proposal by the Collaborator has
not been responded to in writing by PHS within this [*] period, the
negotiation period shall be extended to expire [*] after PHS
so responds, during which month the Collaborator may accept in writing
the final license proposal of PHS. [*]. In the event that the
Collaborator elects the option for an exclusive license, but no such
license is executed during the negotiation period, PHS agrees not to
make an offer for an exclusive license on more favorable terms to a
third party for a period of [*] without first offering Collaborator
those more favorable terms.


7.3 LICENSE FOR PHS EMPLOYEE INVENTIONS AND JOINT INVENTIONS. Pursuant to
15 U.S.C. 3710a(b)(1)(A), for inventions made by PHS employees or
jointly with a Collaborator under this CRADA, pursuant to Articles 6.3
and 6.4, the Collaborator grants to PHS a nonexclusive,
nontransferable, irrevocable, paid-up license to practice the invention
or have the invention practiced throughout the world by or on behalf of
the Government. In the exercise of such license, the Government shall
not publicly disclose trade secrets or commercial or financial
information that is privileged or confidential within the meaning of 5
U.S.C. 552(b)(4) or which would be considered as such if it had been
obtained from a non-Federal party.


7.4 LICENSE IN COLLABORATOR INVENTIONS. Pursuant to 15 U.S.C. 3710a(b)(2),
for inventions made solely by


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separately with the Commission. Confidential treatment has been
requested with respect to the omitted portions. 7
Collaborator employees under this CRADA, pursuant to Article 6.2, the
Collaborator grants to PHS a nonexclusive, nontransferable,
irrevocable, paid-up license to practice the invention or have the
invention practiced throughout the world by or on behalf of the
Government for research or other Government purposes.


7.5 THIRD PARTY LICENSE. Pursuant to 15 U.S.C. 3710a(1)(B), if PHS grants
an exclusive license to a Subject Invention made wholly by PHS
employees or jointly with a Collaborator under this CRADA, pursuant to
Articles 6.3 and 6.4, the Government shall [*] to use the invention in
Collaborator's licensed field of use on terms that are [*]; or if the
Collaborator fails to [*], to [*]. The exercise of such rights by the
Government shall only be in exceptional circumstances and only if the
Government determines (i) the action is necessary to meet health or
safety needs that are not reasonably satisfied by Collaborator, (ii)
the action is necessary to meet requirements for public use specified
by Federal regulations, and such requirements are not reasonably
satisfied by the Collaborator; or (iii) the Collaborator has failed to
comply with an agreement containing provisions described in 15 U.S.C.
3710a(c)(4)(B). The determination made by the Government under this
Article is subject to administrative appeal and judicial review under
35 U.S.C. 203(2).


7.6 JOINT INVENTIONS NOT EXCLUSIVELY LICENSED. In the event that the
Collaborator does not acquire an exclusive commercialization license to
IP rights in all fields in joint Subject Inventions described in
Article 6.4, then each Party shall have the right to use the joint
Subject Invention and to license its use to others in all fields not
exclusively licensed to Collaborator. The Parties may agree to a joint
licensing approach for such IP rights.


ARTICLE 8. PROPRIETARY RIGHTS AND PUBLICATION


8.1 RIGHT OF ACCESS. PHS and the Collaborator agree to exchange all Subject
Data produced in the course of research under this CRADA, whether
developed solely by PHS or jointly with the Collaborator. Research
Materials will be shared equally by the Parties to the CRADA unless
other disposition is agreed to by the Parties. All Parties to this
CRADA will be free to utilize Subject Data and Research Materials for
their own purposes, consistent with their obligations under this CRADA.


8.2 OWNERSHIP OF SUBJECT DATA AND RESEARCH MATERIALS. Subject to the
sharing requirements of Paragraph 8.1 and the regulatory filing
requirements of Paragraph 8.3, the producing Party will retain
ownership of and title to all Subject Inventions, all Subject Data and
all Research Materials produced solely by their investigators. Jointly
developed Subject Inventions, Subject Data and Research Materials will
be jointly owned.


8.3 DISSEMINATION OF SUBJECT DATA AND RESEARCH MATERIALS. To the extent
allowed under law, the Collaborator and PHS agree to use reasonable
efforts to keep Subject Data and Research Materials confidential until
published or until corresponding patent applications are filed. Any
information that would identify human subjects of research or patients
will always be maintained confidentially. Collaborator shall have the
exclusive right to use any and all CRADA Subject Data in and for any
regulatory filing by or on behalf of Collaborator, except that PHS
shall have the exclusive right to use Subject Data for that purpose,
and authorize others to do so, if the CRADA is terminated or if
Collaborator abandons its commercialization efforts.


8.4 PROPRIETARY/CONFIDENTIAL INFORMATION. Each Party agrees to limit its
disclosure of Proprietary/Confidential Information to the amount
necessary to carry out the Research Plan of this CRADA, and shall place
a confidentiality notice on all such information. Confidential oral
communications shall be reduced to writing within 30 days by the
disclosing Party. Each Party receiving Proprietary/Confidential
Information agrees that any information so designated shall be used by
it only for the purposes described in the attached Research Plan. Any
Party may object to the designation of


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separately with the Commission. Confidential treatment has been
requested with respect to the omitted portions. 8
information as Proprietary/Confidential Information by another Party.
Subject Data and Research Materials developed solely by the
Collaborator may be designated as Proprietary/Confidential Information
when they are wholly separable from the Subject Data and Research
Materials developed jointly with PHS investigators, and advance
designation of such data and material categories is set forth in the
RP. The exchange of other confidential information, e.g., patient-
identifying data, should be similarly limited and treated. Jointly
developed Subject Data and Research Material derived from the
Research Plan may be disclosed by Collaborator to a third party under a
confidentiality agreement for the purpose of possible sublicensing
pursuant to the Licensing Agreement and subject to Article 8.7.


8.5 PROTECTION OF PROPRIETARY/CONFIDENTIAL INFORMATION. Proprietary/
Confidential Information shall not be disclosed, copied, reproduced or
otherwise made available to any other person or entity without the
consent of the owning Party except as required under court order or the
Freedom of Information Act (5 U.S.C. Section 552). Each Party agrees to
use its best efforts to maintain the confidentiality of
Proprietary/Confidential Information. Each Party agrees that the other
Party is not liable for the disclosure of Proprietary/Confidential
Information which, after notice to and consultation with the concerned
Party, the other Party in possession of the Proprietary/Confidential
Information determines may not be lawfully withheld, provided the
concerned Party has been given an opportunity to obtain a court order
to enjoin disclosure.


8.6 DURATION OF CONFIDENTIALITY OBLIGATION. The obligation to maintain the
confidentiality of Proprietary/Confidential Information shall expire at
the earlier of the date when the information is no longer Proprietary
Information as defined in Article 2.5 or three (3) years after the
expiration or termination date of this CRADA. The Collaborator may
request an extension to this term when necessary to protect
Proprietary/Confidential Information relating to products not yet
commercialized.


8.7 PUBLICATION. The Parties are encouraged to make publicly available the
results of their research. Before either Party submits a paper or
abstract for publication or otherwise intends to publicly disclose
information about a Subject ...