Exhibit 10.3
PUBLIC HEALTH SERVICE
COOPERATIVE RESEARCH AND DEVELOPMENT AGREEMENT
This Cooperative Research and Development Agreement, hereinafter referred to as
the "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 NATIONAL CANCER INSTITUTE, hereinafter referred to as
the "NCI"; and (2) PROTARGA, INC. (formerly known as Neuromedica, Inc.), which
has offices at 0000 Xxxx Xxxxxx Xxxxxx, Xxxxx 000, Xxxxxxxxxxxx, XX 00000,
hereinafter referred to as the "Collaborator."
* Confidential treatment requested: material has been omitted and filed
separately with the Commission.
COOPERATIVE RESEARCH AND DEVELOPMENT AGREEMENT
ARTICLE 1. INTRODUCTION
This Cooperative Research and Development Agreement (CRADA) between NCI 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.
This CRADA is made under the authority of the Federal Technology Transfer Act,
15 U.S.C. Section 3710a and is governed by its terms.
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 NCI 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 NCI 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.
* Confidential treatment requested: material has been omitted and filed
separately with the Commission.
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 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. NCI research work under this CRADA will be
performed by the NCI laboratory identified in the RP, and the NCI
Principal Investigator (PI) designated in the RP will be responsible
for the scientific and technical conduct of this project on behalf of
NCI. 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.
* Confidential treatment requested: material has been omitted and filed
separately with the Commission.
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 twelve (12) months after this CRADA becomes effective and at
least within every twelve (12) months 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 four (4) months 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 NCI AND COLLABORATOR CONTRIBUTIONS. The contributions of the Parties,
including payment schedules, if applicable, are set forth in Appendix
B. NCI 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. NCI 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 one
(1) year 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. NCI 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 NCI with funds provided by
the Collaborator shall be the property of NCI. 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 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
* Confidential treatment requested: material has been omitted and filed
separately with the Commission.
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 NCI pursuant to Article 6.5. If NCI
declines such assignment, the Collaborator may release its IP rights as
it may determine.
6.3 NCI EMPLOYEE INVENTIONS. NCI on behalf of the U.S. Government may elect
to retain IP rights to each Subject Invention made solely by NCI
employees. If NCI does not elect to retain IP rights, NCI 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,
NCI 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 NCI and
Collaborator employees shall be jointly owned by NCI and the
Collaborator. The Collaborator may elect to file the joint patent or
other IP application(s) thereon and shall notify NCI 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), NCI 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 NCI 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 NCI inventors will share in any royalty distribution that
the Collaborator pays to its own inventors.
* Confidential treatment requested: material has been omitted and filed
separately with the Commission.
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.
However, the Government shall retain a nonexclusive, non-transferable,
irrevocable, royalty-free license to practice any such Subject
Invention or have it practiced throughout the world by or on behalf of
the Government.
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 Collaborator, the Collaborator shall be responsible for
all 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 NCI 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, NCI 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, NCI
hereby grants to the Collaborator an EXCLUSIVE option to elect an
exclusive or nonexclusive commercialization license, which is
substantially in the form of the appropriate model NCI 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, NCI 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
* Confidential treatment requested: material has been omitted and filed
separately with the Commission.
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 three (3) months after either (i)
Collaborator receives written notice from NCI that the patent or other
IP application has been filed; or (ii) the date Collaborator files such
IP application. Exercise of this option by the Collaborator initiates a
negotiation period that expires nine (9) months after the exercise of
the option. If the last proposal by the Collaborator has not been
responded to in writing by NCI within this nine (9) month period, the
negotiation period shall be extended to expire one (1) month after NCI
so responds, during which month the Collaborator may accept in writing
the final license proposal of NCI. In the absence of such acceptance,
or an extension of the time limits by NCI, NCI will be free to license
such IP rights to others. In the event that the Collaborator elects the
option for an exclusive license, but no such license is executed during
the negotiation period, NCI agrees not to make an offer for an
exclusive license on more favorable terms to a third party for a period
of six (6) months without first offering Collaborator those more
favorable terms. These times may be extended at the sole discretion of
NCI upon good cause shown in writing by the Collaborator.
7.3 LICENSE FOR NCI EMPLOYEE INVENTIONS AND JOINT INVENTIONS. Pursuant to
15 U.S.C. Section 3710a(b)(1)(A), for Subject Inventions made under
this CRADA by a NCI employee(s) or jointly by such employee(s) and
employees of the Collaborator pursuant to Articles 6.3 and 6.4 and
licensed pursuant to the option of Article 7.1, the Collaborator grants
to the Government 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. Section
3710a(b)(2), for inventions made solely by Collaborator employees under
this CRADA pursuant to Article 6.2, the Collaborator grants to the
Government 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. Section 3710a(b)(1)(B), if
NCI grants an exclusive license to a Subject Invention made wholly by
NCI employees or jointly with a Collaborator under this CRADA, pursuant
to Articles 6.3 and 6.4, the Government shall
* Confidential treatment requested: material has been omitted and filed
separately with the Commission.
retain the right to require the Collaborator to grant to a responsible
applicant a nonexclusive, partially exclusive, or exclusive sublicense
to use the invention in Collaborator's licensed field of use on terms
that are reasonable under the circumstances; or if the Collaborator
fails to grant such a license, to grant the license itself. 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. NCI and the Collaborator agree to exchange all Subject
Data produced in the course of research under this CRADA. 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
permitted by law, the Collaborator and NCI 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. To the extent permitted by
law, the 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 NCI 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.
* Confidential treatment requested: material has been omitted and filed
separately with the Commission.
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 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 NCI 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. 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 seek 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 2.7 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 Invention, Subject Data or Research
Materials, the other Party shall be provided thirty (30) days to review
the proposed publication or disclosure to assure that
Proprietary/Confidential Information is
* Confidential treatment requested: material has been omitted and filed
separately with the Commission.
protected. The publication or other disclosure shall be delayed for up
to thirty (30) additional days upon written request by any Party as
necessary to preserve U.S. or foreign patent or other IP rights.
ARTICLE 9. REPRESENTATIONS AND WARRANTIES
9.1 REPRESENTATIONS AND WARRANTIES OF NCI. NCI hereby represents and
warrants to the Collaborator that the official signing this CRADA has
authority to do so.
9.2 REPRESENTATIONS AND WARRANTIES OF THE COLLABORATOR.
(a) The Collaborator hereby represents and warrants to NCI that the
Collaborator has the requisite power and authority to enter into this
CRADA and to perform according to its terms, and that the
Collaborator's official signing this CRADA has authority to do so. The
Collaborator further represents that it is financially able to satisfy
any funding commitments made in Appendix B.
(b) The Collaborator certifies that the statements herein are true,
complete, and accurate to the best of its knowledge. The Collaborator
is aware that any false, fictitious, or fraudulent statements or claims
may subject it to criminal, civil, or administrative penalties.
ARTICLE 10. TERMINATION
10.1 TERMINATION BY MUTUAL CONSENT. NCI and the Collaborator may terminate
this CRADA, or portions thereof, at any time by mutual written consent.
In such event the Parties shall specify the disposition of all
property, inventions, patent or other IP applications and other results
of work accomplished or in progress, arising from or performed under
this CRADA, all in accordance with the rights granted to the Parties
under the terms of this Agreement.
10.2 UNILATERAL TERMINATION. Either NCI or the Collaborator may unilaterally
terminate this entire CRADA at any time by giving written notice at
least thirty (30) days prior to the desired termination date, and any
rights accrued in property, patents or other IP rights shall be
disposed of as provided in paragraph 10.1.
10.3 STAFFING. If this CRADA is mutually or unilaterally terminated prior to
its expiration, funds will nevertheless remain available to NCI for
continuing any staffing commitment made by the Collaborator pursuant to
Article 5.1 above and Appendix B, if applicable, for a period of six
(6) months after such termination. If there are insufficient funds to
cover this expense, the Collaborator agrees to pay the difference.
* Confidential treatment requested: material has been omitted and filed
separately with the Commission.
10.4 NEW COMMITMENTS. No Party shall make new commitments related to this
CRADA after a mutual termination or notice of a unilateral termination
and shall, to the extent feasible, cancel all outstanding commitments
and contracts by the termination date.
10.5 TERMINATION COSTS. Concurrently with the exchange of final reports
pursuant to Articles 4.2 and 5.2, NCI shall submit to the Collaborator
for payment a statement of all costs incurred prior to the date of
termination and for all reasonable termination costs including the cost
of returning Collaborator property or removal of abandoned property,
for which Collaborator shall be responsible.
ARTICLE 11. DISPUTES
11.1 SETTLEMENT. Any dispute arising under this CRADA which is not disposed
of by agreement of the Principal Investigators shall be submitted
jointly to the signatories of this CRADA. If the signatories are unable
to jointly resolve the dispute within thirty (30) days after
notification thereof, the Assistant Secretary for Health (or his/her
designee or successor) shall propose a resolution. Nothing in this
Article shall prevent any Party from pursuing any additional
administrative remedies that may be available and, after exhaustion of
such administrative remedies, pursuing all available judicial remedies.
11.2 CONTINUATION OF WORK. Pending the resolution of any dispute or claim
pursuant to this Article, the Parties agree that performance of all
obligations shall be pursued diligently in accordance with the
direction of the NCI signatory.
ARTICLE 12. LIABILITY
12.1 PROPERTY. The U.S. Government shall not be responsible for damages to
any Collaborator property provided to NCI, where Collaborator retains
title to the property, or any property acquired by Collaborator for its
own use pursuant to this CRADA.
12.2 NO WARRANTIES. EXCEPT AS SPECIFICALLY STATED IN ARTICLE 9, THE PARTIES
MAKE NO EXPRESS OR IMPLIED WARRANTY AS TO ANY MATTER WHATSOEVER,
INCLUDING THE CONDITIONS OF THE RESEARCH OR ANY INVENTION OR PRODUCT,
WHETHER TANGIBLE OR INTANGIBLE, MADE, OR DEVELOPED UNDER THIS CRADA, OR
THE OWNERSHIP, MERCHANTABILITY, OR FITNESS FOR A PARTICULAR PURPOSE OF
THE RESEARCH OR ANY INVENTION OR PRODUCT.
12.3 INDEMNIFICATION. The Collaborator agrees to hold the U.S. Government
harmless and to indemnify the Government for all liabilities, demands,
damages, expenses and losses arising out of the use by the Collaborator
for any purpose of the Subject Data, Research Materials and/or Subject
Inventions produced in whole or part by NCI employees under
* Confidential treatment requested: material has been omitted and filed
separately with the Commission.
this CRADA, unless due to the negligence or willful misconduct of NCI,
its employees, or agents. The Collaborator shall be liable for any
claims or damages it incurs in connection with this CRADA. NCI has no
authority to indemnify the Collaborator.
12.4 FORCE MAJEURE. Neither Party shall be liable for any unforeseeable
event beyond its reasonable control not caused by the fault or
negligence of such Party, which causes such Party to be unable to
perform its obligations under this CRADA, and which it has been unable
to overcome by the exercise of due diligence. In the event of the
occurrence of such a FORCE MAJEURE event, the Party unable to perform
shall promptly notify the other Party. It shall further use its best
efforts to resume performance as quickly as possible and shall suspend
performance only for such period of time as is necessary as a result of
the FORCE MAJEURE event.
ARTICLE 13. MISCELLANEOUS
13.1 GOVERNING LAW. The construction, validity, performance and effect of
this CRADA shall be governed by Federal law, as applied by the Federal
Courts in the District of Columbia. Federal law and regulations will
preempt any conflicting or inconsistent provisions in this CRADA.
13.2 ENTIRE AGREEMENT. This CRADA constitutes the entire agreement between
the Parties concerning the subject matter of this CRADA and supersedes
any prior understanding or written or oral agreement.
13.3 HEADINGS. Titles and headings of the articles and subarticles of this
CRADA are for convenient reference only, do not form a part of this
CRADA, and shall in no way affect its interpretation. The NCI component
that is the Party for all purposes of this CRADA is the Bureau(s),
Institute(s), Center(s) or Division(s) listed on the Cover Page herein.
13.4 WAIVERS. None of the provisions of this CRADA shall be considered
waived by any Party unless such waiver is given in writing to the other
Party. The failure of a Party to insist upon strict performance of any
of the terms and conditions hereof, or failure or delay to exercise any
rights provided herein or by law, shall not be deemed a waiver of any
rights of any Party.
13.5 SEVERABILITY. The illegality or invalidity of any provisions of this
CRADA shall not impair, affect, or invalidate the other provisions of
this CRADA.
13.6 AMENDMENTS. If either Party desires a modification to this CRADA, the
Parties shall, upon reasonable notice of the proposed modification or
extension by the Party desiring the change, confer in good faith to
determine the desirability of such modification or extension. Such
modification shall not be effective until a written amendment is signed
* Confidential treatment requested: material has been omitted and filed
separately with the Commission.
by the signatories to this CRADA or by their representatives duly
authorized to execute such amendment.
13.7 ASSIGNMENT. Neither this CRADA nor any rights or obligations of any
Party hereunder shall be assigned or otherwise transferred by either
Party without the prior written consent of the other Party.
13.8 NOTICES. All notices pertaining to or required by this CRADA shall be
in writing and shall be signed by an authorized representative and
shall be delivered by hand or sent by certified mail, return receipt
requested, with postage prepaid, to the addresses indicated on the
signature page for each Party. Notices regarding the exercise of
license options shall be made pursuant to Article 7.2. Any Party may
change such address by notice given to the other Party in the manner
set forth above.
13.9 INDEPENDENT CONTRACTORS. The relationship of the Parties to this CRADA
is that of independent contractors and not agents of each other or
joint venturers or partners. Each Party shall maintain sole and
exclusive control over its personnel and operations. Collaborator
employees who will be working at NCI facilities may be asked to sign a
Guest Researcher or Special Volunteer Agreement appropriately modified
in view of the terms of this CRADA.
13.10 USE OF NAME OR ENDORSEMENTS. By entering into this CRADA, NCI does not
directly or indirectly endorse any product or service provided, or to
be provided, whether directly or indirectly related to either this
CRADA or to any patent or other IP license or agreement which
implements this CRADA by its successors, assignees, or licensees. The
Collaborator shall not in any way state or imply that this CRADA is an
endorsement of any such product or service by the U.S. Government or
any of its organizational units or employees. Collaborator issued press
releases that reference or rely upon the work of NCI under this CRADA
shall be made available to NCI at least 7 days prior to publication for
review and comment.
13.11 EXCEPTIONS TO THIS CRADA. Any exceptions or modifications to this CRADA
that are agreed to by the Parties prior to their execution of this
CRADA are set forth in Appendix C.
13.12 REASONABLE CONSENT. Whenever a Party's consent or permission is
required under this CRADA, such consent or permission shall not be
unreasonably withheld.
ARTICLE 14. DURATION OF AGREEMENT
14.1 DURATION. It is mutually recognized that the duration of this project
cannot be rigidly defined in advance, and that the contemplated time
periods for various phases of the RP
* Confidential treatment requested: material has been omitted and filed
separately with the Commission.
are only good faith guidelines subject to adjustment by mutual
agreement to fit circumstances as the RP proceeds. In no case will the
term of this CRADA extend beyond the term indicated in the RP unless it
is revised in accordance with Article 13.6.
14.2 SURVIVABILITY. The provisions of Articles 4.2, 5-8, 10.3-10.5, 11.1,
12.2-12.4, 13.1, 13.10 and 14.2 shall survive the termination of this
CRADA.
SIGNATURES BEGIN ON THE NEXT PAGE
* Confidential treatment requested: material has been omitted and filed
separately with the Commission.
FOR NCI:
/s/ Xxxx Xxxxxx Date: 1/10/00
-------------------------------------------- ------------------
Xxxx X. Xxxxxx, M.D.
Deputy Director, National Cancer Institute
Mailing Address for Notices:
National Cancer Institute
Technology Development and
Commercialization Branch
Executive Plaza South, Ste 450
0000 Xxxxxxxxx Xxxx.
Xxxxxxxxx, XX 00000
FOR THE COLLABORATOR:
/s/ X. X. Xxxx Date: January 6, 2000
-------------------------------------------- ------------------
Xxxxx X. Xxxx, Ph.D.
President and Chief Executive Officer, Protarga, Inc.
Mailing Address for Notices:
Protarga, Inc.
0000 Xxxx Xxxxxx Xxxxxx - Xxxxx 000
Xxxxxxxxxxxx, XX 00000
* Confidential treatment requested: material has been omitted and filed
separately with the Commission.
APPENDIX A
RESEARCH PLAN
TITLE OF CRADA: Fatty Acid Mediated Delivery of
Anti-neoplastic Agents for the
Treatment of Cancer
NCI PRINCIPAL INVESTIGATORS: Xxxxxx Xxxxxxxxx, M.D., Ph.D.
Xxxxx Xxxxx
COLLABORATOR PRINCIPAL INVESTIGATORS: Xxxxx X. Xxxx, Ph.X.
Xxxxxxxx X. Xxxxxxx, Ph.D.
TERM OF CRADA: Three (3) years.
I. GOALS STATEMENT
The overall goal of this research project is to develop fatty acid conjugates of
anti-neoplastic agents (supplied by the Developmental Therapeutics Program, NCI)
for targeted cancer therapeutic purposes.
II. SUMMARY AND SCIENTIFIC BACKGROUND
Protarga, Inc. ("Protarga") has developed the Targaceutical-TM- Technology for
drug targeting, in order to increase the proportion of administered therapeutic
molecules that reach medically-important cells. This technology involves
chemically linking the pharmaceutical agent of interest to a natural molecule
that is accumulated by the class of cell being targeted. Protarga has employed
this technology to conjugate fatty acids to anti-cancer drugs, with a view to
increasing anti-tumor activity and reducing systemic toxicity. Tumor cells, with
their higher growth rate and intrinsically higher rate of metabolism possess a
greater nutritional need for fatty acids and thus take them up at a greater rate
than surrounding normal tissues. Extensive preclinical studies have shown that
high and stable concentrations of cytotoxic agents may be sustained within
tumors, with a concomitant increase in efficacy. For example, when the fatty
acid docosahexaenoic acid (DHA) was covalently linked to paclitaxel, the cure
rate of paclitaxel-sensitive, syngeneic M109 tumors in mice increased from 0/8
mice using paclitaxel alone, to 8/8 mice with DHA-paclitaxel.
Protarga's Targaceutical-TM- Technology may significantly reduce the systemic
toxicity of many anti-neoplastic agents. Toxicology studies with DHA-paclitaxel
in mice, rats and dogs have shown that the Maximum Tolerated Dose for
DHA-paclitaxel was more than three times higher than that for paclitaxel alone
(calculated on a molar basis). This reduction in systemic toxicity may be due,
in part, to a significant increase in the proportion of drug retained within the
plasma and tumor compartments. Therefore, the use of this technology may allow
for a reduction in toxicity, while allowing for greater efficacy.
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separately with the Commission.
Protarga owns more than 50 patents and patent applications in the U.S. and
abroad that are related to its Targaceutical(TM) Technology and is recognized by
the field as an expert in fatty acid conjugation. Protarga was chosen as the
collaborator on this CRADA project because of its expertise and unique
proprietary position concerning fatty acid conjugation. The following is a list
of patents and patent applications that Protarga owns related to its
Targaceutical(TM) Technology:
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SERIAL/ ISSUE
COUNTRY PATENT NUMBER FILING DATE DATE
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USA 4,939,174 02/26/88 07/03/90
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USA 4,933,324 02/24/89 06/12/90
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AUSTRALIA 635203 02/24/89 07/12/93
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EP 0401301 02/24/89 1/27/99
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JAPAN 503859/89 02/24/89
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KOREA 701965/89 02/24/89
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WO US89/00757 02/24/89
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USA 5,284,876 06/11/92 02/08/94
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USA 5,545,719 02/24/93 08/13/96
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USA 5,919,815 05/22/96 7/6/99
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WO US97/08792 05/22/97
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AUSTRALIA 34734/97 05/22/97
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EP 97930990.3 11/26/98
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USA 08/651,429 05/22/96
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WO US97/08866 05/22/97
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AUSTRALIA 31424/97 05/22/97
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EP 97926722.6 11/26/98
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USA 5,795,909 05/22/96 08/18/98
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WO US97/08867 05/22/97
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SERIAL/ ISSUE
COUNTRY PATENT NUMBER FILING DATE DATE
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AUSTRALIA 31425/97 11/6/98
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USA 08/868,476 06/03/97
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USA 09/021,247 02/10/98
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USA 08/979,313 11/26/97
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WO W099/26620 11/12/98
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USA 08/978,541 11/26/97
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WO W099/26661 11/12/98
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WO W099/26958 11/12/98
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USA 5,955,459 11/26/97 9/21/97
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The Developmental Therapeutics Program (DTP) has operated a repository of
synthetic and pure natural products, which have been evaluated as potential
anti-cancer agents, for more than 40 years. The repository has an historic
inventory of greater than 600,000 compounds that have been supplied over the
years to DTP from a variety of sources world-wide. The repository has sufficient
quantities of approximately 140,000 samples believed to be non-proprietary that
are offered to extramural research community for the discovery and development
of new agents for the treatment of cancer. Subject to the conditions of Article
7.7, it is the intention of the NCI to provide the Collaborator with synthetic
compounds under this CRADA that are non-proprietary and are not subject to third
party rights.
With respect to Natural Product Compounds, the Collaborator acknowledges that a
majority of natural product materials or isolates in the NCI's repository have
been obtained from foreign countries (source country) under the principles of
the model NCI Letter of Collection Agreement ("LOC"). As such, Collaborator is
aware that its access to Natural Product Compounds is subject to Article 7.8.
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III. RESEARCH STRATEGY
The DTP of the National Cancer Institute (NCI) will supply selected Biological
Evaluation Committee or Decision Network (DN) approved anti-neoplastic agents
(NCI Provided Compunds) to Protarga with the desired properties for conjugation.
Protarga will perform the initial conjugation using its Targaceutical-TM-
Technology. Protarga will characterize the derived Targaceutical-TM- Conjugates.
The DTP will conduct the initial IN VITRO and IN VIVO evaluations of the
Targaceutical-TM- Conjugates. For those Targaceutical-TM- Conjugates judged by
the NCI and the CRADA Steering Committee to possess potential anti-tumor
activity the DTP will conduct further preclinical development, subject to NCI DN
approval.
IV. RESPECTIVE CONTRIBUTIONS OF THE PARTIES
COLLABORATOR RESPONSIBILITIES
Protarga's contributions to the collaborative research and development of the
agent will include the following:
o Protarga has an active research program in fatty acid conjugate
chemistry and will contribute expertise towards this collaboration;
o Protarga will conjugate agents supplied by the Pharmaceutical Resources
Branch of the DTP with the appropriate fatty acid using their
proprietary Targaceutical-TM- Technology;
o Protarga will characterize the initial purity and stability of the
Targaceutical-TM- Conjugates; and
o Protarga will provide initial supplies of the conjugated drug
sufficient for preclinical testing of the Targaceutical-TM- Conjugates.
NCI RESPONSIBILITIES
NCI's contribution to the collaborative research and development of the
compounds will include the following:
o NCI, based on their expertise, in conjunction with the CRADA Steering
Committee (described below), will select up to twelve agents per month
from its repository, to be linked to fatty acids. These agents will
exhibit a novel mechanism of action, a need to reduce toxicity or
increase efficacy, an appropriate chemical group for conjugation, and
the presence of sufficient compound in the NCI repository. The quantity
supplied of any agent selected will not exceed 50% of NCI's current
inventory;
o NCI will supply the agent for all preclinical efficacy
toxicology/pharmacology studies set forth under the scope of this
CRADA. If there is insufficient compound remaining in the NCI
repository to complete these studies it shall be the responsibility of
the NCI to resynthesize additional compound, where practicable and
feasible;
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o NCI will collaborate solely with Protarga for the development of
Targaceutical-TM- Conjugates based on Protarga's proprietary technology
for attaching anti-neoplastic molecules to fatty acids for therapeutic
effectiveness in cancer; and
o NCI will evaluate each of the active studies as they progress to ensure
that the appropriate questions are being addressed and to ensure that
the studies are modified as required based on the developing data.
If there are Targaceutical-TM- Conjugates emerging from these studies which
exhibit enough initial IN VIVO and IN VITRO activity as to warrant further
preclinical development, the results of the studies will be presented to the NCI
DN for approval to conduct studies at the DNIIA level of preclinical
development. If approved by the DN and the CRADA Steering Committee, the DTP
will conduct the following preclinical studies:
o Determine or develop the optimal formulation for the agent to allow
preclinical and anticipated clinical use;
o Determine stability of drug as bulk substances; dilution stability;
stability in clinical dosage forms;
o Develop a detailed assay for the bulk drug, as well as drug dissolved
in vehicles, body fluids, and possibly tissues;
o Determine schedule dependence for demonstration of anti-tumor activity,
and to demonstrate the feasibility for administration of the agent to
at least two animal species at a dose likely to have therapeutic
effect; and
o Develop assays that allow for pharmacokinetic monitoring of the drug in
initial clinical trials.
Following completion of studies at the DNIIA level, the compound will be
presented to the DN again, for review at the DNIIB level of preclinical
development. If approved by the DN and the CRADA Steering Committee, DTP will
conduct IND-directed toxicology evaluation in at least two animal species (one
not a rodent) optimally using the same lot of Targaceutical-TM- Conjugates as
formulated for clinical trials. These studies will be carried out using a
schedule that simulates the schedule projected for the initial clinical trials.
Further, this effort will be conducted with correlative histopathologic and
pharmacologic studies.
Evaluation of a range of compound concentrations that encompasses the maximum
tolerated dose, and includes at least one dose level with evidence of reversible
toxicity and one dose level of nonreversible toxicity will be accomplished.
These studies will be carried out under recognized Good Laboratory Practice
regulations. The results of DNIIB studies will allow for the definition of
initial dose, route and schedule, for the design of Phase I clinical trials.
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JOINT RESPONSIBILITIES
Both Parties will work closely together to ensure that the proposed preclinical
studies move forward expeditiously. The ultimate goal of this collaboration is
to determine whether drug-fatty acid conjugates created using Protarga's
proprietary Targaceutical-TM- technology are effective as therapeutic agents
against cancer. If efficacy can be demonstrated without unacceptable toxicity,
the clinical development will proceed, with mutual consent of the parties, and
amendment of this CRADA in accordance with Article 13.6
Compound Selection: The Steering Committee (described below) will jointly select
and prioritize those compounds from the NCI repository for use in conjunction
with the Protarga technology, and determine which Targaceutical-TM- Carrier or
Carriers might be most appropriate. Compound selection will be based on at least
the following criteria: novel mechanism of compound action, need to reduce
toxicity or increase efficacy of the compound based on prior data, appropriate
chemical group on the compound for conjugating to a chosen carrier, availability
of sufficient compound in the NCI library, and whether the compound is synthetic
or natural.
The NCI and Protarga will decide on an appropriate plan for initial IN VITRO and
IN VIVO testing of the Targaceutical-TM- Conjugates.
STEERING COMMITTEE
A joint steering committee will be established, with equal participation by NCI
and Protarga (Steering Committee). The Steering Committee shall be comprised of
the Principal Investigators on the CRADA plus appropriate staff, as needed.
These Investigators will be authorized by NCI and Protarga, respectively, to
determine such things as, but not limited to, which Targaceutical-TM- Conjugates
are synthesized and tested under the CRADA and which testing protocols will be
used. The Investigators would be encouraged to elicit expert recommendations
from their respective organizations prior to each Steering Committee meeting.
The Steering Committee will determine the frequency and location of its
meetings. NCI and Protarga contemplate that the scope and type of synthesis and
testing will evolve commensurate with scientific progress, and the Committee
will be encouraged to harness the resources of both organizations.
V. DESCRIPTION OF OTHER NIH AND PROTARGA AGREEMENTS
Other than this CRADA, no agreements between the parties are currently effective
or under negotiations. However, the National Institute of Mental Health
conducted a CRADA project with Protarga (formerly known as Neuromedica)
entitled, Therapeutic and Diagnostic Research Using a Novel Carrier System for
the Delivery of Compounds to the Brain, from October 31, 1994 to October 31,
1999.
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VI. ABSTRACT OF RESEARCH PLAN FOR PUBLIC RELEASE
This abstract of the CRADA Research Plan may be released to the public:
The National Cancer Institute and Protarga, Inc. have entered into a
Cooperative
Research and Development Agreement (CRADA) for the development of cancer
therapeutics. It is the objective of the CRADA to accelerate discovery of new
cancer therapies by chemically linking promising anti-neoplastic drugs to fatty
acids using Protarga's proprietary Targaceutical-TM- Technology and evaluating
the resulting conjugates both IN VITRO and in animal tumor models for tumor
specificity and therapeutic efficacy.
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APPENDIX B
FINANCIAL AND STAFFING CONTRIBUTIONS OF THE PARTIES
For NIH:
The NCI, DTP estimates that two to three person years of effort will be required
to conduct a range of studies necessary for the preclinical development of
Targaceutical(TM) Conjugates identified as leads under the CRADA NCI shall, in
addition to its Principal Investigators, provide sufficient staffing to execute
and fulfill the obligations of the CRADA.
NCI will provide no funding to Collaborator for collaborative research and
development pursuant to this CRADA, inasmuch as financial contributions by the
U.S. government to non-Federal parties under a CRADA is prohibited under the
Federal Technology Transfer Act of 1986 (15 U.S.C. 3710a(d)(1)).
For Collaborator:
PERSONNEL:
Collaborator intends to commit 4.6 person-years per year of effort to permit the
timely execution of the studies implemented under this CRADA. More specifically,
this staffing shall include Collaborator full-time employees, consultants to the
company, external contract agencies and contract research organizations.
FUNDING:
Collaborator agrees to fund up to [*] per year for transportation and lodging
costs to support the participation of NCI staff at selected scientific or
development meetings where such participation will substantially xxxxxx
development under this CRADA. Collaborator and NCI must mutually agree to the
activities that are appropriate under this Agreement. Travel arrangements
will be made in accordance with the Federal Travel Rules and Regulations for
all government staff whether paid for by government or private Collaborator
funds.
If additional funding to support additional preclinical studies is determined to
be necessary and agreed upon by the Parties hereto, an appropriate written
amendment pursuant to Article 13.6 will be executed.
No funds provided under this CRADA by Collaborator will be used by NCI to pay
the salary of any full-time tenured federal employees.
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PAYMENT SCHEDULE:
Payments by the Collaborator shall be made annually. The first payment will be
due within thirty(30)days of the signing of this CRADA. Subsequent payment for
years two and three should be made within 30 days of the anniversary date of the
execution of the CRADA. A check in the amount of [*] should be deposited in
the CRADA account. Checks should be made payable to the National Cancer
Institute and sent via express mail to:
CRADA Funds Coordinator;
Technology Development and Commercialization Branch,
National Cancer Institute
0000 Xxxxxxxxx Xxxx., Xxxxx. 000
Xxxxxxxxx, XX 00000
with a clear reference to the NCI CRADA Number and Title: #888, Fatty Acid
Mediated Delivery of Anti-Neoplastic Agents for the Treatment of Cancer. A copy
of the check and letter should be faxed to Xxxxx Xxxxx at 000-000-0000.
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APPENDIX C
EXCEPTIONS OR MODIFICATIONS TO THIS CRADA
ARTICLE 2. DEFINITIONS
Add: 2.12 "Targaceutical(TM) Technology" means Protarga's proprietary
information and property relating to chemical conjugates of
fatty acids with natural and synthetic agents, including, but
not limited to, trade secrets, technology, know-how,
patentable and unpatentable inventions, discoveries, formulae,
synthetic methods, specifications, processes, test procedures,
samples, specimens, results, data, computer programs, and
manufacturing, toxicology, regulatory and clinical information
and other valuable information that relates thereto. Protarga
is the owner of the patents and patent applications related to
Targaceutical(TM) Technology listed in Appendix A, Section II
of this CRADA.
2.13 "Targeceutical Conjugate" means an NCI Provided Compound
linked to a "Targaceutical Carrier" using Targaceutical(TM)
Technology.
2.14 "NCI Provided Compound" means any and all compounds, materials
and data, other than collaborator compounds, and including
both synthetic and Natural Product Compounds, that are
supplied to Collaborator by the NCI pursuant to this CRADA.
2.15 "Targaceutical Carrier" means a fatty acid which will be
linked to any NCI Provided Compound
2.16 "Natural Product Compound" means a NCI Provided Compound that
was obtained from a foreign country under a Letter of
Collection or any natural compound provided to the
Collaborator by the NCI from the NCI Natural Products
Repository.
2.17 "Steering Committee" means the committee, comprised of the
Principal Investigators on the CRADA and any appropriate
staff, that will determine such things as, but not limited to,
which Targaceutical(TM) Conjugates are synthesized, which
testing protocols will be used and whether an NCI Contractor
will be used under the CRADA.
ARTICLE 6. INTELLECTUAL PROPERTY RIGHTS AND PATENT APPLICATIONS
Replace old 6.2 with new 6.2:
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6.2 COLLABORATOR EMPLOYEE, CONTRACTORS AND CONSULTANT INVENTIONS.
The Collaborator shall retain IP rights to any Subject
Invention made solely by Collaborator employees, its
contractors, or its consultants.
Add: 6.9 CONTRACTOR INTELLECTUAL PROPERTY RIGHTS. In conducting a
portion of the CRADA research, it may be necessary for NCI to
utilize the services of a contractor under a funding agreement
as defined by 35 U.S.C.sec.201(b) ("NCI Contractor"). The
Collaborator is aware that such a NCI Contractor is not a
party to this CRADA, and that under the Xxxx-Xxxx Act (see 35
U.S.C. 200 et seq.) and 37 Code of Federal Regulations Part
401, such a contractor has the right to elect title to any
invention discovered solely or jointly by its employee in the
performance of a funding agreement.
The NCI may utilize the services of a NCI Contractor under
this CRADA only after the Steering Committee has approved such
use. In determining whether a NCI Contractor will be utilized,
the NCI will provide to the Steering Committee the name and
contact information for the proposed contractor and a draft
work scope for the proposed contract services.
If the Steering Committee determines that such a contractor
will be utilized, prior to the NCI sending a
Targacuetical(TM) Conjugate to the contractor for study, the
contractor must agree to the terms of Appendix E attached
hereto. Pursuant to Appendix E, the Collaborator may approach
the contractor or contractor employee to secure a license to
commercialize the invention.
If the Steering Committee determines that it is not in the
best interest of the Parties to use a NCI Contactor to perform
a specific task under the CRADA research plan, or if such a
contractor refuses to agree to the terms of Appendix E, the
Collaborator may elect to perform the proposed studies at its
own expense or may elect to waive the obligations of the NCI
Contractor set forth herein, whereupon the NCI Contractor will
be utilized.
Add: 6.10 TRADEMARKS. The Collaborator has adopted, and has registered
or intends to register, a number of trademarks, including
"Protarga", "Targaceutical", "T2000", and "Taxoprexin", that
it considers to be valuable property, and intends to adopt or
register additional trademarks in the future. In any
communication by NCI that includes a trademark adopted by
Collaborator, including the trademarks listed above, NCI will
acknowledge that Collaborator is the owner of such trademark.
No license to NCI or the U.S. Government for such trademarks
is intended or implied by this paragraph.
ARTICLE 7. LICENSING
Add as a new 7.7
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7.7 REASONABLE INQUIRY. Before any NCI Provided Compound is sent
to the Collaborator for research under the CRADA, NCI will
perform a reasonable inquiry into whether patent or license
rights owned or granted by NCI exist in the compound which
could preclude the Collaborator from performing its
obligations under the CRADA or block the Collaborator from
exercising its rights in a Subject Invention. NCI will inform
the Collaborator of any such findings prior to providing said
compound to Collaborator.
However, the NCI makes no representation that the use of a NCI
Provided Compound will not infringe any patent or proprietary
rights of third parties. Nonetheless, if it is known to the
NCI that a third party has a proprietary interest in a NCI
Provided Compound, the NCI will provide notice to the
Collaborator of such interest and provide any information, in
the possession of the NCI, that would allow that Collaborator
to contact the third party in order to conduct its own inquiry
concerning the third party's rights.
To the extent that a license in an NCI Provided Compound is
necessary to commercialize a Subject Invention, NCI will in
good faith consider in accordance with 37 CFR 404 an
application submitted by Collaborator for an exclusive or
nonexclusive license to that NCI Compound owned compound.
Add a new 7.8
7.8 Policy Related to Natural Product Compounds. Collaborator is
put on notice, and agrees to the following NCI guideline for
access to Natural Product Compounds from the NCI Natural
Products Repository:
(A) Collaborator acknowledges that the majority of
Natural Product Compounds or isolates in the NCI Natural
Products Repository have been obtained from foreign countries
under the principles of the model NCI Letter of Collection
Agreement ("LOC"), which appears under Appendix F. Articles
8-10 and 13 of the LOC stipulate that NCI require a commercial
licensee of an invention derived from a Natural Product
Compound to enter into an agreement with the Source Country of
the Natural Product Compound (or an appropriate organization
thereof). This agreement will address the reasonable concerns
of the signatory Source Country Government ("SCG") agency or
Source County Organization ("SCO") related to (a) ensuring a
long-term source of supply of the Natural Product Compound and
other conservation measures and (b) sharing in commercial
benefits that arise from development of the Natural Product
Compound. In the case of a Natural Products Repository
material not covered under a formal LOC, Collaborator agrees
to negotiate and execute such an agreement with the SCG agency
that issued the collection permit for the Natural Product
Compound. These steps are necessary for NCI to comply with (a)
the mutual understandings between NCI, NCI's contract
collectors and the SCG permit-issuing-agencies, under which
the Natural Product Compounds were collected, and (b) the
NCI's policy of adhering to the principles of the United
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Nations Convention on Biological Diversity ("U.N. CBD"), which
calls for "sharing in a fair and equitable way the results of
research and development and the benefits arising from the
commercial and other utilization of genetic resources with the
[source country] providing such resources." (U.N. CBD; Article
15.7). Therefore:
(B) Should NIH license or assign to Collaborator NCI
rights in any CRADA Subject Invention derived from material
from the Natural Products Repository, Collaborator agrees, as
a condition for obtaining the license or assignment, that it
will negotiate in good faith and enter into an agreement with
the appropriate SCG agency and/or SCO which will address
concerns on the part of the SGC or SCO that pertinent
agencies, institutions, and/or persons in the Source Country
receive royalties and other forms of compensation, as
appropriate. If NIH in consultation with SCG/SCO deem it
appropriate, Collaborator's obligation to negotiate such an
agreement may be suspended until Collaborator is prepared to
commercialize the invention or to (sub)license its rights in
the invention to a third party that will pursue final
development and commercialization. In this latter case, NIH
may, at its discretion, transfer the obligation to conclude
such an agreement from Collaborator to Collaborator's
(sub)licensee. However, Collaborator agrees that, in any
event, negotiations between either Collaborator or
Collaborator's (sub)licensee and the SCG/SCO must commence
prior to the start of any human clinical trials using
inventions derived from material from the Natural Products
Repository. Negotiations must be completed and an agreement
executed prior to the commercial sale of any product or
process derived from such Natural Product Compound. This
agreement must be binding upon the SCG/SCO, Collaborator and
any licensee(s) or assignees of Collaborator with respect to
any intellectual property rights relating to inventions
derived from the Natural Product Compound.
(C) Similarly, Collaborator agrees that, should an
invention by Collaborator employees derived from material from
the Natural Products Repository eventually be developed and
marketed by Collaborator, or licensed or assigned by
Collaborator to a third party for development and
commercialization, Collaborator or Collaborator's
licensee/assignee will negotiate in good faith and enter into
an agreement with the appropriate SCG agency or SCO. This
agreement will address concerns on the part of the SCG or SCO
that pertinent agencies, institutions, and/or persons in the
Source Country receive royalties and other forms of
compensation, as appropriate. Collaborator agrees that
negotiations between either Collaborator or Collaborator's
licensee/assignee and the SCG/SCO must commence prior to the
start of any human clinical trials using inventions derived
from material from the Natural Products Repository.
Negotiations must be completed and an agreement executed prior
to the commercial sale of any product or process derived from
such Natural Product Compound. This agreement must be binding
upon the SCG/SCO, Collaborator and any licensees) or assignees
of Collaborator with respect to any intellectual property
rights relating to inventions derived from the Natural Product
Compound.
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(D) The provisions of Subsections (B) and (C) above will
apply equally to instances where an invention is directed to a
direct isolate from a Natural Product Compound, a product
structurally based upon an isolate from the Natural Product
Compound, a synthetic material for which the Natural Product
Compound provided a key development lead, or a method of
synthesis or use of any aforementioned isolate, product or
material; although the percentage of royalties or the type and
amount of other appropriate negotiated compensation may vary
depending upon the relationship of the final commercial
product to the Natural Product Compound originally obtained
from the Source Country. It is understood that the eventual
development of a drug to the stage of marketing is a long term
process which may require 10-15 years.
(E) In obtaining additional sources of a material from the
Natural Products Repository (or extracts thereof),
Collaborator agrees to seek as its first source of supply
natural products from the Source Country and to require any
licensee or assignee of Collaborator's interests in inventions
derived from the Natural Product Compound to do the same. If
Collaborator or Collaborator's licensee/assignee, after a
good-faith attempt or inquiry, decides it cannot use the
Natural Product Compounds available from the Source Country,
or if the SCG or SCO cannot provide adequate amounts of raw
materials at a mutually agreeable fair price, then
Collaborator agrees (a) to pay the appropriate SCG agency or
SCO an amount of money (to be negotiated) to be used for
expenses associated with the cultivation of medicinal plant
species that are endangered by deforestation, or for other
appropriate conservation measures, or (b) to require its
licensee/assignee to do the same. These provisions will also
apply in the event that Collaborator or a licensee/assignee of
Collaborator begins to market a synthetic material for which a
material from the Natural Product Repository provided a key
development lead.
(F) Subsection E will not apply to Natural Product Compounds
which are freely available from different countries (i.e.,
common weeds, agricultural crops, ornamental plants, fouling
organisms) unless information indicating a particular use of
the Natural Product Compound (e.g., medicinal, pesticidal) was
provided by local residents to guide the collection of such an
organism from the Source Country, or unless other
justification acceptable to the SCG or SCO and the NCI is
provided. In the case where a Natural Product Compound is
freely available from different countries, but a genotype
producing an active agent is found only in the Source Country,
Section E will apply.
(G) Collaborator will not transfer materials from the Natural
Products Repository to any third party
ARTICLE 8. PROPRIETARY RIGHTS AND PUBLICATION
Add to the end of Article 8.1 the following sentence:
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In the event that the NCI elects that it has no further
interest in the development of a Targaceutical(TM) Conjugate
at any stage of development, Protarga will be provided copies
of all data, within NCI's possession and control, generated
under the CRADA with the Targaceutical(TM) Conjugates and will
be free to pursue development of that Targaceutical(TM)
Conjugates with its own resources.
Add to the end of Article 8.7 the following sentence:
In any written scientific publication concerning the research
findings from the CRADA, the publishing party will acknowledge
the contributions of the non-publishing party where
appropriate.
ARTICLE 10. TERMINATION
Add as a new 10.6
10.6 DISPOSITION OF RESEARCH MATERIALS. NCI shall use any
and all compounds, materials and data that are
supplied to NCI by the Collaborator pursuant to this
CRADA, only for work conducted under this CRADA and
shall return unused compounds, materials and data
supplied by the Collaboratortor to the Collaborator
within 30 days of expiration or termination of this
CRADA. Notwithstanding the previous sentence, if a
Targaceutical Compound supplied to NCI by the
Collaborator pursuant to this CRADA constitutes a
joint Subject Invention, NCI shall have the right to
retain such a compound which is in its possession at
the time of termination or expiration of this CRADA
and NCI shall retain all its rights to such a
compound subject to the terms and conditions of this
CRADA.
ARTICLE 13. MISCELLANEOUS
Add to the end of 13.6 the following sentence:
If Collaborator elects to perform any portion of the Research
Plan through a contractor or consultant, Collaborator agrees
to incorporate into such contracts all provisions necessary to
ensure that the work of such contractors or consultants is
governed by the terms of the CRADA, including, but not limited
to a provision for the assignment of inventions of the
contractor or consultant to Collaborator.
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APPENDIX D
MODEL OF THE NCI
LETTER OF COLLECTION
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separately with the Commission.
LETTER OF COLLECTION
Agreement Between
[Source Country Institution]
and/or [Source Country Organization]
and the
Developmental Therapeutics Program
Division of Cancer Treatment and Diagnosis
National Cancer Institute
The Developmental Therapeutics Program (DTP), Division of
Cancer Treatment and Diagnosis (DCTD), National Cancer Institute (NCI)
is currently investigating plants, microbes, and marine macro-organisms
as potential sources of novel anticancer and AIDS-antiviral drugs. The
DTP is the drug discovery program of the NCI which is an Institute of
the National Institutes of Health (NIH), an arm of the Department of
Health and Human Services of the United States Government. While
investigating the potential of natural products in drug discovery and
development, NCI wishes to promote the conservation of biological
diversity, and recognizes the need to compensate [Source Country]
organizations and peoples in the event of commercialization of a drug
developed from an organism collected within their borders.
As part of the drug discovery program, DTP has contracts with
various organizations for the collection of plants, microbes and marine
macro-organisms worldwide. DTP has an interest in investigating plants,
microbes and marine macro-organisms from [Source Country], and wishes
to collaborate with the [Source Country Government ("SCG") or Source
Country Organization(s) (SGO) as appropriate in this investigation. The
collection of plants, microbes, and marine macro-organisms will be
within the framework of the collection contract between the NCI and the
NCI Contractor (Contractor) which will collaborate with the appropriate
agency in the [SCG or SCO]. The NCI will make sincere efforts to
transfer knowledge, expertise, and technology related to drug discovery
and development to the [appropriate Source Country Institution ("SCI")]
in [Source Country] as the agent appointed by the [SCG or SCO], subject
to the provision of mutually acceptable guarantees for the protection
of intellectual property associated with any patented technology. The
[SCG or SCO], in turn, desires to collaborate closely with the DTP/NCI
in pursuit of the investigation of its plants, microbes and marine
macro-organisms, subject to the conditions and stipulations of this
agreement.
THE ROLE OF DTP, DCTD, NCI IN THE COLLABORATION WILL INCLUDE THE
FOLLOWING:
1) DTP/NCI will screen the extracts of all plants, microbes
and marine macro-organisms provided from [Source Country] for
anticancer and AIDS-antiviral activity, and will provide the
test results to [SCI] on a quarterly basis. Such results will
be channeled via Contractor.
2) The test results will be kept confidential by all parties,
with any publication delayed until DTP/NCI has an opportunity
to file a patent application in the
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United States of America on any active agents isolated. Such
application will be made according to the terms stated in
Article 6.
3) Any extracts exhibiting significant activity will be
further studied by bioassay-guided fractionation in order to
isolate the pure compounds(s) responsible for the observed
activity. Since the relevant bioassays are only available at
DTP/NCI, such fractionation will be carried out in DTP/NCI
laboratories. A suitably qualified scientist designated by
[SCI] may participate in this process subject to the terms
stated in Article 4. In addition, in the course of the
contract period, DTP/NCI will assist the [SCG or SCO], in
conjunction with [SCI], to develop the capacity to undertake
drug discovery and development, including capabilities for the
screening and isolation of active compounds from plants,
microbes and marine organisms.
4) Subject to the provision that suitable laboratory space and
other necessary resources are available, DTP/NCI agrees to
invite a senior technician or scientist designated by [SCI] to
work in the laboratories of DTP/NCI or, if the parties agree,
in laboratories using technology which would be useful in
furthering work under this agreement. The duration of such a
visit would not exceed one year except by prior agreement
between [SCI] and DTP/NCI. The designated Guest Researcher
will be subject to provisions usually governing Guest
Researchers at NIH, except when carrying out research on
materials provided through collections in [Source Country].
Salary and other conditions of exchange will be negotiated in
good faith.
5) In the event of the isolation of a promising agent from a
plant, microbe or marine macro-organism collected in [Source
Country], further development of the agent will be undertaken
by DTP/NCI in collaboration with [SCI]. Once an active agent
is approved by the DTP/NCI for preclinical development, [SCI]
and the DTP/NCI will discuss participation by SCI scientists
in the development of the specific agent.
The DTP/NCI will make a sincere effort to transfer any
knowledge, expertise, and technology developed during such
collaboration in the discovery and development process to
[SCI], subject to the provision of mutually acceptable
guarantees for the protection of intellectual property
associated with any patented technology.
6) DTP/NCI will, as appropriate, seek patent protection on all
inventions developed under this agreement by DTP/NCI employees
alone or by DTP/NCI and [SCG or SCO] employees jointly, and
will seek appropriate protection abroad, including in [Source
Country], if appropriate.
7) All licenses granted on any patents arising from this
collaboration shall contain a clause referring to this
agreement and shall indicate that the licensee has been
apprized of this agreement.
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8) Should the agent eventually be licensed to a pharmaceutical
company for production and marketing, DTP/NCI, will require
the successful licensee to negotiate and enter into
agreement(s) with the [SCG] agency(ies) or [SCO] as
appropriate. This agreement(s) will address the concern on the
part of the [SCG or SCO] that pertinent agencies, institutions
and/or persons receive royalties and other forms of
compensation, as appropriate.
9) Such terms shall apply equally to instances where an
invention is directed to a direct isolate from a natural
product material, a product structurally based upon an isolate
from the natural product material, a synthetic material for
which the natural product material provided a key development
lead, or a method of synthesis or use of any aforementioned
isolate, product or material; though the percentage of
royalties negotiated as payment might vary depending upon the
relationship of the marketed drug to the originally isolated
product. It is understood that the eventual development of a
drug to the stage of marketing is a long term process which
may require 10- 15 years.
10) In obtaining licensees, the DTP/NCI will require the
license applicant to seek as its first source of supply the
natural products from [Source Country]. If no appropriate
licensee is found that will use natural products available
from [Source Country], or if the [SCG] or [SCO] as
appropriate, or its suppliers cannot provide adequate amounts
of raw materials at a mutually agreeable fair price, the
licensee will be required to pay the [SCG] or [SCO] as
appropriate, an amount of money (to be negotiated) to be used
for expenses associated with cultivation of medicinal plant,
microbe or marine macro-organism species that are endangered
by deforestation, or for other appropriate conservation
measures. These terms will also apply in the event that the
licensee begins to market a synthetic material for which a
material from [Source Country] provided a key development
lead.
11) Section 10 shall not apply to organisms which are freely
available from different countries (i.e., common weeds,
agricultural crops, ornamental plants, fouling organisms)
unless information indicating a particular use of the organism
(e.g., medicinal, pesticidal) was provided by local residents
to guide the collection of such an organism from [Source
Country], or unless other justification acceptable to both the
[SCG or SCO] and the DTP/NCI is provided. In the case where an
organism is freely available from different countries, but a
phenotype producing an active agent is found only in [Source
Country], Article 10 shall apply.
12) DTP/NCI will test any pure compounds submitted by the [SCG
or SCO] and [SCI] scientists for antitumor and anti HIV/AIDS
activity, provided such compounds have not been tested
previously in the DTP/NCI screens. If significant antitumor or
anti HIV/AlDS activity is detected, further development of the
compound and investigation of patent rights will, as
appropriate, be undertaken by DTP/NCI in consultation with
[SCI] and the [SCG or SCO].
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Should an agent derived from the compound eventually be
licensed to a pharmaceutical company for production and
marketing, DTP/NCI will require the successful licensee to
negotiate and enter into agreement(s) with the appropriate
[SCG agency(ies) or SCO]. This agreement will address the
concern on the part of the [SCG or SCO] that pertinent
agencies, institutions and/or persons receive royalties and
other forms of compensation, as appropriate.
13) DTP/NCI may send selected samples to other organizations
for investigation of their anti-cancer, anti-HIV or other
therapeutic potential. Such samples will be restricted to
those collected by NCI contractors unless specifically
authorized by the [SCG or SCO]. Any organization receiving
samples must agree to compensate the [SCG or SCO] and
individuals, as appropriate, in the same fashion as described
in Articles 8-10 above, notwithstanding anything to the
contrary in Section 11.
THE ROLE OF THE SOURCE COUNTRY GOVERNMENT ("SCG") OR SOURCE COUNTRY
ORGANIZATION(S) ("SCO") IN THE COLLABORATION WILL INCLUDE THE
FOLLOWING:
1) The appropriate agency in [SCG or SCO] will collaborate
with Contractor in the collection of plants, microbes and
marine macro-organisms, and will work with Contractor to
arrange the necessary permits to ensure the timely collection
and export of materials to DTP/NCI.
2) Should the appropriate agency in [SCG or SCO] have any
knowledge of the medicinal use of any plants, microbes and
marine macro-organisms by the local population or traditional
healers, this information will be used to guide the collection
of plants, microbes or marine macro-organisms on a priority
basis where possible. Details of the methods of administration
(e.g., hot fusion, etc.) used by the traditional healers will
be provided where applicable to enable suitable extracts to be
made. All such information will be kept confidential by
DTP/NCI until both parties agree to publication.
The permission of the traditional healer or community will be
sought before publication of their information, and proper
acknowledgment will be made of their contribution.
3) The appropriate agency in [SCG or SCO] and Contractor will
collaborate in the provision of further quantities of active
raw material if required for development studies.
4) In the event of large amounts of raw material being
required for production, the appropriate agency of the [SCG or
SCO] and Contractor
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will investigate the mass propagation of the material in
[Source Country]. Consideration should also be given to
sustainable harvest of the material while conserving the
biological diversity of the region, and involvement of the
local population in the planning and implementation stages.
5) [SCG or SCG] and SCI scientists and their collaborators may
screen additional samples of the same raw materials for other
biological activities and develop them for such purposes
independently of this agreement.
This agreement shall be valid as of the date of the final
authorized signature below for an initial period of three (3) years,
after which it can be renewed by mutual agreement. It may be amended at
any time subject to the written agreement of both parties. Copies of
such amendments will be kept on file at both of the addresses indicated
below.
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separately with the Commission.
FOR THE NATIONAL CANCER INSTITUTE: For [SCI] or [SCO]:
-----------------------------
Xxxxxxx Xxxxxxxx, M.D. Name: (typed)
Director, National Cancer Institute Title: (typed)
-----------------------------
Date Date
Mailing and contact address: Mailing and contact address:
Technology Development &
Commercialization branch
National Cancer Institute
Executive Plaza South, Suite 450
0000 Xxxxxxxxx Xxxx.
Xxxxxxxxx, Xxxxxxxx 00000 X.X.X.
Telephone: 000-000-0000
Facsimile: 000-000-0000
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separately with the Commission.
APPENDIX E
TERMS OF AWARD ADDITIONS
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TERMS OF AWARD ADDITIONS
INTELLECTUAL PROPERTY OPTION TO COLLABORATOR
Contractor agrees to promptly notify the NCI and "Collaborator" in
writing of any inventions, discoveries or innovations made by the
Contractor's principal investigator or any other employees or agents of
Contractor, whether patentable or not, which are conceived and/or first
actually reduced to practice in the performance of this study using a
Targaceutical(TM) Conjugate (hereinafter "Contractor Inventions").
Contractor agrees to grant to Collaborator: (i) a paid-up nonexclusive,
nontransferable, royalty-free, world-wide license to all Contractor
Inventions for research purposes only; and (ii) a time-limited first
option to negotiate an exclusive, world-wide royalty-bearing license
for all commercial purposes, including the right to grant sub-licenses,
to all Contractor Inventions on terms to be negotiated in good faith by
Collaborator and Contractor. Collaborator shall notify Contractor, in
writing, of its interest in obtaining an exclusive license to any
Contractor Invention within six (6) months of Collaborator's receipt of
notice of such Contractor Invention(s). In the event that Collaborator
fails to so notify Contractor, or elects not to obtain an exclusive
license, then Collaborator's option shall expire with respect to that
Contractor Invention, and Contractor will be free to dispose of its
interests in such Contractor Invention in accordance with Contractor's
policies. If Contractor and Collaborator fail to reach agreement within
ninety (90) days, (or such additional period as Collaborator and
Contractor may agree) on the terms for an exclusive license for a
particular Contractor Invention, then for a period of six (6) months
thereafter Contractor shall not offer to license the Contractor
Invention to any third party on materially better terms than those last
offered to Collaborator without first offering such terms to
Collaborator, in which case Collaborator shall have a period of thirty
(30) days in which to accept or reject the offer.
Contractor agrees that notwithstanding anything herein to the contrary,
any inventions, discoveries or innovations, whether patentable or not,
which are not Subject Inventions as defined in 35 USC 201(e),*
[footnote] arising out of any unauthorized use of the Collaborator's
Study drug and/or any modifications to the Study Drug, shall be the
property of the Collaborator (hereinafter "Collaborator Inventions").
Contractor will promptly notify the Collaborator in writing of any
such Collaborator Inventions and, at Collaborator's request and
expense, Contractor will cause to be assigned to Collaborator all
right, title and interest in and to any such Collaborator Inventions
and provide Collaborator with reasonable assistance to obtain patents
(including causing the execution of any invention assignment or
other documents).
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separately with the Commission.
* [footnote] 35 USC(e): (e) The term "subject invention" means any
invention of the contractor conceived or first actually reduced to
practice in the performance of work under a funding agreement:
Provided, That in the case of a variety of plant, the date of
determination (as defined in section 41(d) (FOOTNOTE 1) of the Plant
Variety Protection Act (7 U.S.C. 2401(d)) must also occur during the
period of contract performance.
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separately with the Commission.
PROTECTION OF PROPRIETARY DATA
Data generated using a Targaceutical(TM) Conjugate will be kept
confidential and shared only with the NCI, the FDA and the
Collaborator. The Contractor retains the right to publish research
results subject to the terms of the Collaborator/NCI CRADA.
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