Exhibit 10.22
[CERTAIN MATERIAL (INDICATED BY A [*CON*]) HAS BEEN OMITTED FROM THIS
DOCUMENT PURSUANT TO A REQUEST FOR CONFIDENTIAL TREATMENT. THE OMITTED
MATERIAL HAS BEEN FILED SEPARATELY WITH THE SECURITIES AND EXCHANGE COMMISSION]
COLLABORATIVE RESEARCH AND DEVELOPMENT AGREEMENT
This COLLABORATIVE RESEARCH AGREEMENT ("Agreement") is entered into as of
November 4, 1998 by and between PFIZER INC, and its Affiliates ("Pfizer"), a
Delaware corporation, having an office at ▇▇▇ ▇▇▇▇ ▇▇▇▇ ▇▇▇▇▇▇, ▇▇▇ ▇▇▇▇, ▇▇▇
▇▇▇▇ ▇▇▇▇▇, and MITOKOR, and its Affiliates ("Mitokor"), a California
corporation, having an office at ▇▇▇▇▇ ▇▇▇▇▇▇▇▇ ▇▇▇▇▇▇ ▇▇▇▇, ▇▇▇ ▇▇▇▇▇,
▇▇▇▇▇▇▇▇▇▇ ▇▇▇▇▇;
WHEREAS, Mitokor has expertise in biology, biochemistry, proteomics and
molecular sciences focused on the mitochondria ; and
WHEREAS, Mitokor owns the patents and patent applications set forth in Exhibit A
attached to and made part of this Agreement with respect to cybrid cell line
technology and mitochondrial research reagents; and
WHEREAS, Pfizer has the capability to undertake research for the discovery and
evaluation of agents for treatment of disease and also the capability for
clinical analysis, manufacturing and marketing with respect to therapeutic
agents; and
WHEREAS, Pfizer and Mitokor enter into this Agreement to discover and develop
patentable small molecules that affect mitochondrial biochemical targets useful
in the treatment, prevention or diagnosis of disease in human and animal health;
NOW, THEREFORE, the parties agree as follows:
1. DEFINITIONS
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Whenever used in this Agreement, the terms defined in this Section 1 shall have
the meanings specified.
1.1 "AFFILIATE" means any corporation or other legal entity owning,
directly or indirectly, fifty percent (50%) or more of the voting capital shares
or similar voting securities of Pfizer or Mitokor; any corporation or other
legal entity fifty percent (50%) or more of the voting capital shares or similar
voting rights of which is owned, directly or indirectly, by Pfizer or Mitokor or
any corporation or other legal entity fifty percent (50%) or more of the voting
capital shares or similar voting rights of which is owned, directly or
indirectly, by a corporation or other legal entity which owns, directly or
indirectly, fifty percent (50%) or more of the voting capital shares or similar
voting securities of Pfizer or Mitokor.
1.2 "RESEARCH PLAN" means the written plan describing the research and
development in the Area to be carried out by Pfizer and Mitokor pursuant to this
Agreement. The initial Research Plan is attached to and made a part of this
Agreement as Exhibit B.
1.3 "RESEARCH PROGRAM" is the collaborative research program in the Area
conducted by Pfizer and Mitokor pursuant to the Research Plan.
1.4 "EFFECTIVE DATE" is November 4, 1998.
1.5 "CONTRACT PERIOD" means the period beginning on the Effective Date and
ending on the date on which this Agreement terminates.
1.6 "AREA" means research and development of small molecules directed to
Molecular Targets with respect to therapeutic agents directed to the treatment
or prevention or both of mitochondrial dysfunction in neurodegenerative disease
and [ * CON * ] in the course of the research or development as specified in the
Research Plan.
1.7 "TECHNOLOGY" means and includes all materials, technology, technical
information, know-how, expertise and trade secrets within the Area.
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1.8 "MITOKOR TECHNOLOGY" means Technology that is or was developed by
employees of or consultants to Mitokor alone or jointly with third parties prior
to the Effective Date, but, in the case of consultants or third parties, only to
the extent Mitokor has the right to grant rights to such Technology.
1.9 "PROGRAM TECHNOLOGY" means Technology that is or was developed by
employees of or consultants to Pfizer or Mitokor solely or jointly with each
other in the course of performing the Research Program including (i) Molecular
Targets (ii) associated assays, research reagents and high throughput screens;
provided, however that Cybrid Cell Lines shall not be Program Technology and
shall be owned by Mitokor and deemed to be Mitokor Technology.
1.10 "PFIZER TECHNOLOGY" means Technology that is or was developed by
employees of or consultants to Pfizer alone or jointly with third parties prior
to the Effective Date, but, in the case of consultants or third parties, only to
the extent Pfizer has the right to grant rights to such Technology.
1.11 "MITOKOR CONFIDENTIAL INFORMATION" means all information about any
element of the Mitokor Technology or Program Technology which is disclosed by
Mitokor to Pfizer and designated "Confidential" in writing by Mitokor at the
time of disclosure or within thirty (30) days following disclosure, to the
extent that such information as of the date of disclosure to Pfizer is not (i)
known to Pfizer other than by virtue of a prior confidential disclosure to
Pfizer by Mitokor; or (ii) disclosed in published literature, or otherwise
generally known to the public through no fault or omission of Pfizer; or (iii)
obtained from a third party free from any obligation of confidentiality to
Mitokor.
1.12 "PFIZER CONFIDENTIAL INFORMATION" means all information about any
element of Pfizer or Program Technology which is disclosed by Pfizer to Mitokor
and designated "Confidential" in writing by Pfizer at the time of disclosure or
within thirty (30) days following disclosure to the extent that such information
as
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of the date of disclosure to Mitokor is not (i) known to Mitokor other than by
virtue of a prior confidential disclosure to Mitokor by Pfizer; or (ii)
disclosed in published literature, or otherwise generally known to the public
through no fault or omission of Mitokor; or (iii) obtained from a third party
free from any obligation of confidentiality to Pfizer.
1.13 "VALID CLAIM" means a claim within Patent Rights so long as such
claim shall not have been disclaimed by Pfizer (in the case of Patent Rights
within the Pfizer Technology) or by Mitokor (in the case of Patent Rights within
the Mitokor Technology) or both (in the case of Patent Rights within the Program
TECHNOLOGY) and shall not have been held invalid in a final decision rendered by
a tribunal of competent jurisdiction from which no appeal has been or can be
taken.
1.14 "PATENT RIGHTS" shall mean all patent rights in and to inventions
within Pfizer Technology, Mitokor Technology or Program Technology including all
the Valid Claims of patent applications, whether domestic or foreign, claiming
such patentable inventions, including all continuations, continuations-in-part,
divisions, and renewals, all letters patent granted thereon, and all reissues,
reexaminations and extensions thereof, including but not limited to, as to
Mitokor Technology, those listed in Exhibit A.
1.15 "MOLECULAR TARGET " shall mean one of the specific proposed molecular
targets that both parties agree to include in the collaborative Research
Program.
1.16 " DIAGNOSTIC PRODUCT" means any product within the Area useful for
the identification or quantification of the propensity toward or actual
existence of a disease state in a human or animal patient or any other human or
animal diagnostic utility identified in the course of research the manufacture,
use, sale, offer for sale or import of which would infringe any Valid Claim
within the Patent Rights.
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1.17 "THERAPEUTIC PRODUCT" means any product directed to a Molecular
Target for the management of any disease or pre-disease state in a patient or
[ * CON * ] in the course of the Research Program the manufacture, use, sale,
offer for sale or import of which would infringe any Valid Claim within the
Patent Rights.
1.18 "HTS" means a primary assay supplied by Mitokor to Pfizer in a format
suitable for Pfizer to prepare an automated high throughput screen against a
Molecular Target for the purpose of initially identifying small molecules that
affect the Molecular Target.
1.19 "CYBRID CELL LINES" are cybrid cell lines developed by Mitokor prior
to the Research Program or in the course of conducting the Research Program.
1.20 "PFIZER'S COMPOUND LIBRARY" are those compounds in Pfizer's
possession which may be screened by Pfizer using the HTS assays provided to
Pfizer pursuant to this Agreement.
2. COLLABORATIVE RESEARCH PROGRAM
2.1 PURPOSE. Mitokor and Pfizer shall conduct the Research Program
throughout the Contract Period. All Technology in the Area developed in the
course of performing the Research Plan will become part of the Program
Technology. The objective of the Research Program is to discover and develop
Therapeutic Products.
2.2 RESEARCH PLAN. The initial Research Plan is described in the attached
Exhibit B. Each new Research Plan, for the addition of each succeeding Molecular
Target in the Area, or otherwise, shall be appended to Exhibit B and made part
of this Agreement.
2.3 EXCLUSIVITY. Mitokor agrees that during the Contract Period, Mitokor
shall not conduct research itself or sponsor any other research, or engage
6
in any research sponsored by any third party for any Molecular Target, with the
exception of any research and development necessary for Diagnostic Products,
without Pfizer's consent.
2.4 RESEARCH COMMITTEE
2.4.1 PURPOSE. Pfizer and Mitokor shall establish a Research
Committee (the "Research Committee"):
(a) to review and evaluate progress under the Research Plan;
(b) to prepare the Research Plan, and any amendments; and
(c) to propose, discuss, select and document in writing, the mutual
acceptance of Molecular Targets in the Area to be included in the Research Plan;
and
(d) to coordinate and monitor publication of research results
obtained from the Research Program as specified in Section 4.2 and to coordinate
and monitor the exchange of information and materials that relate to the
Research Program (this function shall survive the termination of this
Agreement).
2.4.2 MEMBERSHIP. Pfizer and Mitokor each shall appoint, in its sole
discretion, three members to the Research Committee. Substitutes may be
appointed at any time.
The members initially shall be:
Pfizer Appointees: Dr. [ * CON * ] (co-Chair)
To be named
Dr. [ * CON * ]
Mitokor Appointees: Dr. [ * CON * ] (co-Chair)
To be named
Dr. [ * CON * ]
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2.4.3 CHAIR. The Research Committee shall be chaired by two
co-chairpersons, one appointed by Pfizer and the other appointed by Mitokor.
2.4.4 MEETINGS. The Research Committee shall meet at least
quarterly, at places selected by each party in turn and on dates mutually agreed
by the parties. The location of the first meeting of the Research Committee
shall be at Pfizer's election. Representatives of Pfizer or Mitokor or both, in
addition to members of the Research Committee, may attend such meetings at the
invitation of either party.
2.4.5 MINUTES. The Research Committee shall keep accurate minutes of
its deliberations which record all proposed decisions and all actions
recommended or taken. Drafts of the minutes shall be delivered to all Research
Committee members within five (5) business days after each meeting. The party
choosing the location for the meeting shall be responsible for the preparation
and circulation of the draft minutes. Draft minutes shall be edited by the
co-chairpersons and shall be issued in final form only with their approval and
agreement.
2.4.6 DECISIONS. All decisions of the Research Committee shall be
made by a majority of the members. Notwithstanding the foregoing or any other
provision of this Agreement, Research Plans may only be amended (and Research
Plans for an additional Molecular Targets adopted) as mutually agreed by the
Research Committee and approved by Pfizer's and Mitokor's managements.
2.4.7 EXPENSES. Pfizer and Mitokor shall [ * CON * ], related to the
participation of their designated members of the Research Committee,
respectively.
2.5 REPORTS AND MATERIALS.
2.5.1 REPORTS. During the Contract Period, Pfizer and Mitokor each
shall furnish to the Research Committee:
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(a) summary written reports within fifteen (15) days after the end
of each stage of the Research Plan, commencing on the Effective Date, describing
the progress under the Research Plan; and
(b) comprehensive written reports within thirty (30) days after the
end of each contract year, describing in detail the work accomplished by it
under the Research Plan during the year and discussing and evaluating the
results of such work.
2.5.2 MATERIALS. Mitokor and Pfizer shall, during the Contract
Period, as a matter of course as described in the Research Plan, or upon each
other's written or oral request, furnish to each other samples of biochemical,
biological or synthetic chemical materials which are part of Pfizer Technology,
Mitokor Technology or Program Technology and which are necessary for each party
to carry out its responsibilities under the Research Plan; provided, however,
that Mitokor shall, upon request, deliver to Pfizer samples of any material made
pursuant to the Research Plan; and, further provided that such material will not
include the transfer of Cybrid Cell Lines by Mitokor. To the extent that Pfizer
requests [ * CON * ] under the Research Plan, Pfizer shall [ * CON * ].
2.6 LABORATORY FACILITIES AND PERSONNEL. Mitokor shall provide suitable
laboratory facilities, equipment and personnel for the work to be done by
Mitokor in carrying out the Research Program.
2.7 DILIGENT EFFORTS. Pfizer and Mitokor each shall use reasonably
diligent efforts to achieve the objectives of the Research Program. Mitokor will
use reasonably diligent efforts to achieve the objectives listed in the Research
Plan and Pfizer will use reasonably diligent efforts to assist Mitokor in each
Research Plan.
3. PAYMENTS.
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3.1 RESEARCH PROGRAM FUNDING. Pfizer will fund the research to be
performed by Mitokor, pursuant to this Agreement, according to the following
schedule:
Commitment Year Annual Commitment
--------------- -----------------
1 $ [ * CON * ]
2 $ [ * CON * ]
3 $ [ * CON * ]
The funding payments are expected to support the work of [ * CON * ]
([ * CON * ]) full time equivalents (FTEs).
3.1.1 All funding payments shall be made quarterly in advance for
work scheduled to be performed by Mitokor during any three (3) month period,
against Mitokor's invoice for such three (3) month period. Adjustments as
necessary to reflect the work actually performed by Mitokor shall be made at the
end of each three (3) month period and shall be reflected in Mitokor's invoice
for the next three (3) month period. It is understood that all payments pursuant
to this Section are noncreditable and nonrefundable.
3.1.2 The amount of the Funding Payment for each quarter shall be
based on the work in progress pursuant to the applicable Research Plan and the
associated annual budget; provided, however, that the aggregate amount of
Funding Payments made in any Commitment Year shall not exceed the Annual
Commitment for such Commitment Year.
3.2 OTHER PAYMENTS.
3.2.1 INITIAL PAYMENT. Within ten (10) days of the execution of this
Agreement, Pfizer will pay to Mitokor a one time, non refundable, noncreditable
payment of $[ * CON * ].
3.2.2 As set forth in the initial Research Plan and subsequent
amendments, Mitokor will provide to Pfizer [ * CON * ] ([ * CON * ]) HTS,
reasonably acceptable to Pfizer . For each additional HTS
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provided by Mitokor and accepted by Pfizer, after the [ * CON * ] ([ * CON * ])
described above and included in the Research Plan, Pfizer will pay to Mitokor
the sum of $[ * CON * ] for each HTS which contains a [ * CON * ], or the sum of
$[ * CON * ] for an HTS that does not contain a [ * CON * ]. These payments are
in addition to the Research Funding in Section 3.1 and are noncreditable and
non-refundable.
3.2.3 ADDITIONAL EQUITY PURCHASE. Concurrently with the execution of
this Agreement, Pfizer has made an initial investment in Mitokor in accordance
with the Stock Purchase Agreement attached as Exhibit D. At such time as
[ * CON * ] ([ * CON * ]) HTS have been accepted by the Research Committee and
added to the Research Plan, as described above, Pfizer shall purchase from
Mitokor $ [ * CON * ] in additional shares of capital stock in Mitokor at a
[ * CON * ] percent ([ * CON * ]%) premium to the then current price for such
shares. Such purchase shall be, at Mitokor's sole discretion, by means of
Pfizer's participation in a further round of private financing or a public
offering. Such purchase shall be in accordance with the terms and conditions of
a stock purchase agreement to be entered into between Mitokor and Pfizer, which
agreement shall contain substantially the same terms, conditions and
registration rights for shares as in the Stock Purchase Agreement.
3.2.4 Pfizer will pay to Mitokor the sum of $[ * CON * ] when Pfizer
issues a [ * CON * ] with respect to a compound derived from the Research
Program. This payment will be made one time only for each compound directed
against a Molecular Target and a specific indication and will not include
back-up compounds directed against the same Molecular Target and indication.
These payments are noncreditable and non-refundable.
3.3 US FUNDS. Each payment pursuant to this Agreement shall be paid by
Pfizer in U.S. currency by wire transfer in immediately available funds to an
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account designated by Mitokor, or by other mutually acceptable means within
thirty (30) days after receipt and acceptance by Pfizer of the invoice from
Mitokor.
3.4 RECORDS. Mitokor shall keep for three (3) years from the conclusion of
each year complete and accurate records of its expenditures of efforts from
payments received by it from Pfizer under Section 3.1. The records shall conform
to good accounting principles as applied to a similar company similarly
situated. Pfizer shall have the right at its own expense during the term of this
Agreement and during the subsequent three-year period to appoint an independent
certified public accountant reasonably acceptable to Mitokor to inspect said
records to verify the accuracy of such expenditures of efforts, pursuant to each
Research Plan. Upon reasonable notice by Pfizer, Mitokor shall make its records
available for inspection by the independent certified public accountant during
regular business hours at the place or places where such records are customarily
kept, to verify the accuracy of the expenditures of efforts. This right of
inspection shall not be exercised more than once in any calendar year and not
more than once with respect to records covering any specific period of time. All
information concerning such expenditures of efforts, and all information learned
in the course of any audit or inspection, shall be deemed to be Mitokor
Confidential Information, except to the extent that it is necessary for Pfizer
to reveal the information in order to enforce any rights it may have pursuant to
this Agreement or if disclosure is required by law. The failure of Pfizer to
request verification of any expenditures of efforts before or during the
three-year period shall be considered acceptance by Pfizer of the accuracy of
such expenditures of efforts, and Mitokor shall have no obligation to maintain
any records pertaining to such report or statement beyond such three-year
period. The findings of such inspection, if any, shall be binding on the
parties.
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4. TREATMENT OF CONFIDENTIAL INFORMATION
4.1 CONFIDENTIALITY
4.1.1 Pfizer and Mitokor each recognize that the other's
Confidential Information constitutes highly valuable, confidential information.
Subject to the terms and conditions of the License Agreement between the parties
of even date with this Agreement (the "License Agreement"), the obligations set
forth in Section 4.3 and the publication rights set forth in Section 4.2, Pfizer
and Mitokor each agree that during the term of this Agreement and for
[ * CON * ] ([ * CON * ]) years thereafter, it will keep confidential, and will
cause its Affiliates and sublicensees to keep confidential, all Mitokor
Confidential Information or Pfizer Confidential Information, as the case may be,
that is disclosed to it, or to any of its Affiliates or sublicensees pursuant to
this Agreement. Neither Pfizer nor Mitokor nor any of their respective
Affiliates or sublicensees shall use such Confidential Information of the other
party except as expressly permitted in this Agreement. For the purposes of this
Section 4, it is understood that Program Technology shall be deemed Confidential
Information of both parties.
4.1.2 Pfizer and Mitokor each agree that any disclosure of the
other's Confidential Information to any officer, employee or agent of the other
party or of any of its Affiliates shall be made only if and to the extent
necessary to carry out its responsibilities under this Agreement and shall be
limited to the maximum extent possible consistent with such responsibilities.
Pfizer and Mitokor each agree not to disclose the other's Confidential
Information to any third parties under any circumstance without written
permission from the other party. Each party shall take such action, and shall
cause its Affiliates and sublicensees to take such action, to preserve the
confidentiality of each other's Confidential Information as it would customarily
take to preserve the confidentiality of its own Confidential Information. Each
party, upon the other's request, will return all the Confidential
13
Information disclosed to it by the other party pursuant to this Agreement,
including all copies and extracts of documents, within sixty (60) days of the
request upon the termination of this Agreement except for one (1) copy which may
be kept for the purpose of complying with continuing obligations under this
Agreement.
4.1.3 Mitokor and Pfizer each represent that all of its employees,
and any consultants to such party, participating in the Research Program who
shall have access to Program Technology, the Technology of the other (Pfizer
Technology or Mitokor Technology, as the case may be) or Confidential
Information of the other (Pfizer Confidential Information or Mitokor
Confidential Information, as the case may be) are bound by agreement to maintain
such information in confidence.
4.2 PUBLICATION. Notwithstanding any matter set forth with particularity
in this Agreement to the contrary, results obtained in the course of the
Research Program may be submitted for publication following scientific review by
the Research Committee and subsequent written approval by Mitokor's and Pfizer's
managements, which approval shall not be unreasonably withheld. After receipt of
the proposed publication by both Pfizer's and Mitokor's managements written
approval or disapproval shall be provided within thirty (30) days for a
manuscript, and within fourteen (14) days for an abstract for presentation at,
or inclusion in the proceedings of a scientific meeting, and within fourteen
(14) days for presentation materials to be used at a scientific meeting.
4.3 PUBLICITY. Except as required by law, and except for a mutually
approved press release to be issued upon the signing of this Agreement, neither
party may disclose the terms of this Agreement nor the research described in it
without the written consent of the other party, which consent shall not be
unreasonably withheld; provided, however, that Mitokor may disclose the terms,
14
or provide copies, of this Agreement as necessary in the normal course of
business to bankers, investors and others in order to obtain financing.
4.4 PERMITTED DISCLOSURE.
4.4.1 DISCLOSURE REQUIRED BY LAW. If either party is requested to
disclose the Confidential Information in connection with a legal or
administrative proceeding or is otherwise required by law to disclose the
Confidential Information, such party will give the other party prompt notice of
such request. The disclosing party may seek an appropriate protective order or
other remedy or waive compliance with the provisions of this Agreement. If such
party seeks a protective order or other remedy, the other party will cooperate.
If such party fails to obtain a protective order or waive compliance with the
relevant provisions of this Agreement, the other party will disclose only that
portion of Confidential Information which its legal counsel determines it is
required to disclose.
4.4.2 DISCLOSURE OF INVENTIONS. Each party shall promptly inform the
other about all inventions in the Area within the Program Technology that are
made in the course of carrying out the Research Program by employees of, or
consultants to, either of them solely, or jointly with employees of, or
consultants to the other.
4.5 RESTRICTIONS ON TRANSFERRING MATERIALS. Mitokor and Pfizer recognize
that the biological, biochemical and chemical materials which are part of
Program Technology, represent valuable commercial assets. Therefore, throughout
the Contract Period and for [ * CON * ] ([ * CON * ]) years thereafter, Mitokor
and Pfizer agree not to transfer such materials to any third party, unless prior
written consent for any such transfer is obtained from the other party.
5. INTELLECTUAL PROPERTY RIGHTS. The following provisions relate to intellectual
property rights in the Program Technology.
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5.1 OWNERSHIP. All Mitokor Confidential Information and Mitokor Technology
shall be owned by Mitokor. All Pfizer Confidential Information and Pfizer
Technology shall be owned by Pfizer. All Program Technology shall be jointly
owned by Mitokor and Pfizer except for the Cybrid Cell Lines which shall be
owned by Mitokor.
5.2 GRANTS OF RESEARCH LICENSES.
5.2.1 Mitokor and Pfizer each grants to the other a nonexclusive,
irrevocable, worldwide, royalty-free, perpetual license, including the right to
grant sublicenses to Affiliates, to make and use Confidential Information,
Program Technology and Patent Rights for all research purposes other than the
sale or manufacture for sale of products or processes; provided, however, that
this license does not include and the other party shall not acquire, by virtue
of this Section 5.2 , any rights in the following:
(i) Cybrid Cell Lines ; or
(ii) Pfizer's Compound Library; or
(iii) any compounds active in HTS which Pfizer chooses, in its sole,
unfettered discretion, not to develop or otherwise include in the Program
Technology.
5.2.2 Any Section in this Agreement to the contrary notwithstanding,
if Pfizer employs an HTS subsequent to the termination of this Agreement, to
identify a product lead, Pfizer shall develop such lead subject to all terms and
conditions of this Agreement and the License Agreement.
6. PROVISIONS CONCERNING THE FILING, PROSECUTION AND MAINTENANCE OF PATENT
RIGHTS. The following provisions relate to the filing, prosecution and
maintenance of Patent Rights during the term of this Agreement:
16
6.1 FILING, PROSECUTION AND MAINTENANCE BY MITOKOR. With respect to
Patent Rights in which Mitokor employees or consultants, alone or together
with Pfizer employees, or consultants are named as inventors, Mitokor shall
have the exclusive right and obligation:
(a) to file applications for letters patent on patentable inventions
included in Patent Rights; provided, however, that Mitokor shall consult with
Pfizer regarding countries in which such patent applications should be filed and
shall file patent applications in those countries where Pfizer requests that
Mitokor file such applications; and, further provided, that Mitokor, at its
option and expense, may file in countries where Pfizer does not request that
Mitokor file such applications;
(b) to take all reasonable steps to prosecute all pending and new
patent applications included within Patent Rights;
(c) to respond to oppositions, nullity actions, re-examinations,
revocation actions, interference proceedings and similar proceedings filed by
third parties against the grant of letters patent for such applications;
(d) to maintain in force any letters patent included in Patent
Rights by duly filing all necessary papers and paying any fees required by the
patent laws of the particular country in which such letters patent were granted;
and
(e) to cooperate fully with, and take all necessary actions
requested by, Pfizer in connection with the preparation, prosecution and
maintenance of any letters patent included in Patent Rights.
Mitokor shall notify Pfizer in a timely manner of any decision to not
pursue an action or to abandon a pending patent application or an issued patent
included in Patent Rights. Thereafter, Pfizer shall have the option, at its
expense, of taking such action or continuing to prosecute any such pending
patent application or of keeping the issued patent in force, or all of these.
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6.1.1 COPIES OF DOCUMENTS. Mitokor and Pfizer shall provide to each
other copies of all patent applications that are part of Patent Rights prior to
filing, for the purpose of obtaining substantive comment of the other party's
patent counsel. Mitokor and Pfizer shall also provide to the other copies of all
material documents relating to prosecution of all such patent applications in a
timely manner and shall provide to the other every six (6) months a report
detailing the status of all patent applications that are a part of Patent
Rights.
6.1.2 REIMBURSEMENT OF COSTS FOR FILING PROSECUTING AND MAINTAINING
PATENT RIGHTS. Within thirty (30) days of receipt of invoices from Mitokor,
Pfizer shall reimburse Mitokor for all the costs of filing, prosecuting,
responding to opposition and maintaining patent applications and patents in
countries where Pfizer consents to or requests that patent applications be
filed, prosecuted and maintained. Such reimbursement shall be in addition to
other funding payments under this Agreement and shall include such costs of all
activities described in 6.1 (a)-(e) above. However, Pfizer may, upon sixty (60)
days notice, request that Mitokor discontinue filing or prosecution of certain
patent applications in any country and discontinue reimbursing Mitokor for the
costs of filing, prosecuting, responding to opposition or maintaining such
patent application or patent in any country. Mitokor shall pay all costs in
those countries in which Pfizer requests that Mitokor not file, prosecute or
maintain patent applications and patents, but in which Mitokor, at its option,
elects to do so.
6.2 FILING, PROSECUTION AND MAINTENANCE BY PFIZER. With respect to Patent
Rights in which Pfizer employees or consultants alone are named as inventors,
Pfizer shall have those rights and duties ascribed to Mitokor in Section 6.1.,
except that Pfizer will bear all related expenses.
6.3 Neither party may disclaim a Valid Claim within Patent Rights without
the written consent of the other.
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7. ACQUISITION OF RIGHTS FROM THIRD PARTIES. During the Contract Period, Mitokor
and Pfizer shall each promptly notify each other of any appropriate
opportunities to acquire in any manner from third parties, technology or patents
or information which it elects to use in the course of performing the Research
Program. Mitokor and Pfizer shall decide if such rights should be acquired in
connection with the Research Program and, if so, whether by Mitokor, Pfizer or
both, it being understood that nothing herein shall obligate either party to
obtain such rights or, if it does acquire such rights, to make such rights
available for use in the Research Program. If acquired such rights shall become
part of the Confidential Information, Technology or Patent Rights, whichever is
appropriate, of the acquiring party or Program Technology, as the case may be.
8. OTHER AGREEMENTS. Concurrently with the execution of this Agreement, Mitokor
and Pfizer shall enter into the License Agreement of even date appended to and
made part of this Agreement as Exhibit C and the Stock Purchase Agreement
appended to and made a part of this Agreement as Exhibit D. This Agreement, the
Stock Purchase Agreement and the License Agreement are the sole agreements with
respect to the subject matter and supersede all other agreements and
understandings between the parties with respect to same.
9. TERM, TERMINATION AND DISENGAGEMENT.
9.1 TERM. Unless sooner terminated, as provided below or extended, by
mutual agreement of the parties, this Agreement shall expire on November 3,
2001.
9.2 EVENTS OF TERMINATION. The following events shall constitute events of
termination ("Events of Termination"):
19
(a) if any written representation or warranty by Mitokor or Pfizer,
or any of its officers, made under or in connection with this Agreement shall
prove to have been incorrect in any material respect when made;
(b) Mitokor or Pfizer shall fail in any material respect to perform
or observe any term, covenant or understanding contained in this Agreement or in
any of the other documents or instruments delivered pursuant to, or concurrently
with, this Agreement, and any such failure shall remain unremedied for thirty
(30) days after written notice to the failing party.
9.3 TERMINATION.
9.3.1 UPON EVENT OF TERMINATION BY PFIZER OR MITOKOR. Upon the
occurrence of any Event of Termination, the party not responsible may, by
written notice to the other party, terminate this Agreement. 9.3.2 If Pfizer
terminates this Agreement pursuant to Section 9.3.1, the License Agreement shall
not terminate, but instead shall terminate or expire in accordance with its
terms. If Mitokor terminates this Agreement pursuant to Section 9.3.1, the
License Agreement shall terminate immediately.
9.4 TERMINATION BY PFIZER. Between June 1 and August 1, 2000, Pfizer may
terminate this Agreement, with or without cause, by delivering written notice of
termination to Mitokor, for a termination effective November 3, 2000. Upon
Mitokor's receipt of such notice of termination by Pfizer, Mitokor may, at its
sole option, terminate all work under the Research Plan unless otherwise agreed
with Pfizer. If Pfizer terminates this Agreement pursuant to this Section, it
will make funding payments which would have otherwise been due through November
3, 2000 and Pfizer will retain all rights and obligations as set forth in the
License Agreement.
9.5 Termination of this Agreement by either party, with or without cause,
will not terminate the licenses granted pursuant to Section 5.2.
20
9.6 Termination of this Agreement for any reason shall be without
prejudice to:
(a) the rights and obligations of the parties provided in Sections
4, 5, 6, and 12 and any Sections which provide by its terms performance by
either party subsequent to termination;
(b) Mitokor's right to receive all payments accrued under Section 3;
or
(c) any other remedies which either party may otherwise have.
10. REPRESENTATIONS AND WARRANTIES. Mitokor and Pfizer each represents and
warrants as follows:
10.1 It is a corporation duly organized, validly existing and is in good
standing under the laws of the States of California and Delaware, respectively,
is qualified to do business and is in good standing as a foreign corporation in
each jurisdiction in which the conduct of its business or the ownership of its
properties requires such qualification; and it has all requisite power and
authority, corporate or otherwise, to conduct its business as now being
conducted, to own, lease and operate its properties and to execute, deliver and
perform this Agreement.
10.2 The execution, delivery and performance by it of this Agreement have
been duly authorized by all necessary corporate action and do not and will not
(a) require any consent or approval of its stockholders beyond the approvals
already obtained, (b) violate any provision of any law, rule, regulations,
order, writ, judgment, injunction, decree, determination or award presently in
effect having applicability to it or any provision of its certificate of
incorporation or by-laws or (c) result in a breach of or constitute a default
under any material agreement, mortgage, lease, license, permit or other
instrument or obligation to which it is a party or by which it or its properties
may be bound or affected.
21
10.3 This Agreement is a legal, valid and binding obligation of it
enforceable against it in accordance with its terms and conditions, except as
such enforceability may be limited by applicable bankruptcy, insolvency,
moratorium, reorganization or similar laws, from time to time in effect,
affecting creditor's rights generally.
10.4 It is not under any obligation to any person, or entity, contractual
or otherwise, that is conflicting or inconsistent in any respect with the terms
of this Agreement or that would impede the diligent and complete fulfillment of
its obligations.
10.5 It has good and marketable title to or valid leases or licenses for,
all of its properties, rights and assets necessary for the fulfillment of its
responsibilities under the Research Program, subject to no claim of any third
party other than any relevant lessors or licensors.
11. COVENANTS OF MITOKOR AND PFIZER OTHER THAN REPORTING REQUIREMENTS.
Throughout the Contract Period, Mitokor and Pfizer each shall:
11.1 maintain and preserve its corporate existence, rights, franchises and
privileges in the jurisdiction of its incorporation, and qualify and remain
qualified as a foreign corporation in good standing in each jurisdiction in
which such qualification is from time to time necessary or desirable in view of
their business and operations or the ownership of their properties.
11.2 comply in all material respects with the requirements of all
applicable laws, rules, regulations and orders of any government authority to
the extent necessary to conduct the Research Program, except for those laws,
rules, regulations, and orders it may be contesting in good faith.
12. INDEMNIFICATION. Pfizer and Mitokor will indemnify, defend and hold each
other harmless for any and all damages, settlements, costs, legal fees and other
22
expenses incurred in connection with a claim by a third party against either
party based on any action or omission of the indemnifying party's agents,
employees, or officers related to its obligations under this Agreement;
provided, however, that the foregoing shall not apply (i) if the claim is found
to be based upon the negligence, recklessness or willful misconduct of the party
seeking indemnification; or (ii) if such party fails to give the other party
prompt notice of any claim it receives and such failure materially prejudices
the other party with respect to any claim or action to which its obligation
pursuant to this Section applies. Notwithstanding the foregoing, Pfizer hereby
expressly agrees to indemnify, defend and hold harmless Mitokor (and all
officers, directors, agents and Affiliates of Mitokor) for any and all claims
arising from clinical trials pursued by Pfizer or its Affiliates and/or
sublicensees, the sale of Licensed Products, the exercise of rights granted to
Pfizer under Section 5.2 or the License Agreement (including without limitation
product liability claims) and/or claims arising from Patent Rights, Pfizer
Patent Rights, Program Technology and Pfizer Technology except for intellectual
property claims with respect to Mitokor Patent Rights, or Mitokor Technology.
The indemnifying party, in its sole discretion, shall choose legal counsel,
shall control the defense of such claim or action and shall have the right to
settle same on such terms and conditions it deems advisable.
13. NOTICES. All notices shall be in writing mailed via certified mail, return
receipt requested, courier, or facsimile transmission addressed as follow, or to
such other address as may be designated from time to time:
If to Pfizer: Pfizer Central Research
▇▇ ▇▇▇▇ ▇▇▇▇ ▇▇▇▇▇▇
▇▇▇ ▇▇▇▇, ▇▇ ▇▇▇▇▇
Attention: ▇▇. ▇▇▇▇▇▇ ▇▇▇▇▇, President
with copy to: General Counsel
23
If to Mitokor: MitoKor
▇▇▇▇▇ ▇▇▇▇▇▇▇▇ ▇▇▇▇▇▇ ▇▇▇▇
▇▇▇ ▇▇▇▇▇, ▇▇ ▇▇▇▇▇
Attention: ▇▇. ▇▇▇▇▇▇ ▇▇▇▇, CEO
Notices shall be deemed given as of the date received at the above specified
address.
14. GOVERNING LAW. This Agreement shall be governed by and construed in
accordance with the laws of the State of New York.
15. MISCELLANEOUS.
15.1 BINDING EFFECT. This Agreement shall be binding upon and inure to the
benefit of the parties and their respective legal representatives, successors
and permitted assigns.
15.2 HEADINGS. Paragraph headings are inserted for convenience of
reference only and do not form a part of this Agreement.
15.3 COUNTERPARTS. This Agreement may be executed simultaneously in two or
more counterparts, each of which shall be deemed an original. Signatures may be
transmitted via facsimile, thereby constituting the valid signature and delivery
of this Agreement.
15.4 AMENDMENT, WAIVER. This Agreement may be amended, modified,
superseded or canceled, and any of the terms may be waived, only by a written
instrument executed by each party or, in the case of waiver, by the party or
parties waiving compliance. The delay or failure of any party at any time or
times to require performance of any provisions shall in no manner affect the
rights at a later time to enforce the same. No waiver by any party of any
condition or of the
24
breach of any term contained in this Agreement, whether by conduct, or
otherwise, in any one or more instances, shall be deemed to be, or considered
as, a further or continuing waiver of any such condition or of the breach of
such term or any other term of this Agreement.
15.5 NO THIRD PARTY BENEFICIARIES. No third party including any employee
of any party to this Agreement, shall have or acquire any rights by reason of
this Agreement. Nothing contained in this Agreement shall be deemed to
constitute the parties partners with each other or any third party.
15.6 ASSIGNMENT AND SUCCESSORS. This Agreement may not be assigned by
either party, except that each party may assign this Agreement and the rights
and interests of such party, in whole or in part, to any of its Affiliates, any
purchaser of all or substantially all of its assets or to any successor
corporation resulting from any merger or consolidation of such party with or
into such corporations.
15.7 FORCE MAJEURE. Neither Pfizer nor Mitokor shall be liable for failure
of or delay in performing obligations set forth in this Agreement, and neither
shall be deemed in breach of its obligations, if such failure or delay is due to
natural disasters or any causes reasonably beyond the control of Pfizer or
Mitokor.
15.8 SEVERABILITY. If any provision of this Agreement is or becomes
invalid or is ruled invalid by any court of competent jurisdiction or is deemed
unenforceable, it is the intention of the parties that the remainder of the
Agreement shall not be affected so long as the essential benefits of this
Agreement remain enforceable and obtainable.
25
IN WITNESS WHEREOF, the parties have caused this Agreement to be executed by
their duly authorized representatives.
PFIZER INC
By:
-----------------------------
Title:
---------------------------
MITOKOR
By:
-----------------------------
Title:
---------------------------
EXHIBIT A
MITOKOR PATENTS AND PATENT APPLICATIONS RELATED
TO DRUG DISCOVERY AND SCREENING OF THERAPEUTICS
TITLE: [ * CON * ]
-----
COUNTRY FILING DATE DOCKET NO.1 (SERIAL NO.) FAMILY HISTORY; STATUS
------- ----------- ------------------------ -----------------------------------------
U.S.A. [ * CON * ] 401C1 ([ * CON * ]) [ * CON * ] ; Pending
TITLE: [ * CON * ]
-----
COUNTRY FILING DATE DOCKET NO. (SERIAL NO.) FAMILY HISTORY; STATUS
------- ----------- ----------------------- -----------------------------------------
U.S.A. [ * CON * ] 401C2 ([ * CON * ]) [ * CON * ]; Pending
TITLE: [ * CON * ]
-----
COUNTRY FILING DATE DOCKET NO. (SERIAL NO.) FAMILY HISTORY; STATUS
------- ----------- ----------------------- -----------------------------------------
PCT [ * CON * ] 401PC ([ * CON * ]) [ * CON * ]; Converted,
Published [ * CON * ]
2
(NATIONAL STAGE APPLICATIONS BASED ON 401PC):
Australia 401AU ([ * CON * ]) Natl. Stage of 401PC; Pending
Brazil 401BR ([ * CON * ]) Natl. Stage of 401PC; Pending
Canada 401CA ([ * CON * ]) Natl. Stage of 401PC; Pending
China 401CN ([ * CON * ]) Natl. Stage of 401PC; Pending
Europe 401EP ([ * CON * ]) Natl. Stage of 401PC; Pending
Finland 401FI ([ * CON * ]) Natl. Stage of 401PC; Pending
Japan 401JP ([ * CON * ]) Natl. Stage of 401PC; Pending
Korea 401KR ([ * CON * ]) Natl. Stage of 401PC; Pending
Mexico 401MX ([ * CON * ]) Natl. Stage of 401PC; Pending
Norway 401NO ([ * CON * ]) Natl. Stage of 401PC; Pending
New Zealand 401NZ ([ * CON * ]) Natl. Stage of 401PC; Pending,
Published in New Zealand Patent Office
Journal [ * CON * ]
Singapore 401SG ([ * CON * ]) Natl. Stage of 401PC; Pending
Vietnam 401VN ([ * CON * ]) Natl. Stage of 401PC; Pending
TITLE: [ * CON * ]
-----
COUNTRY FILING DATE DOCKET NO. (SERIAL NO.) FAMILY HISTORY; STATUS
------- ----------- ----------------------- -----------------------------------------
U.S.A. [ * CON * ] 409 ([ * CON * ]) Pending
3
TITLE: [ * CON * ]
-----
COUNTRY FILING DATE DOCKET NO. (SERIAL NO.) FAMILY HISTORY; STATUS
------- ----------- ----------------------- -----------------------------------------
U.S.A. [ * CON * ] 417 ([ * CON * ]) Pending
TITLE: [ * CON * ]
-----
COUNTRY FILING DATE DOCKET NO. (SERIAL NO.) FAMILY HISTORY; STATUS
------- ----------- ----------------------- -----------------------------------------
U.S.A. [ * CON * ] 418 ([ * CON * ]) Pending
TITLE: [ * CON * ]
-----
COUNTRY FILING DATE DOCKET NO. (SERIAL NO.) FAMILY HISTORY; STATUS
------- ----------- ----------------------- -----------------------------------------
U.S.A. [ * CON * ] 420 ([ * CON * ]) Pending
NOTES:
-----
1 For brevity's sake, only the Docket No. suffix is included; the full
Docket No. includes the prefix 660088. For example, the first listed
application's full Docket No. is 660088.401C1.
2 USP = U.S. Patent No.
Confidential page 1
EXHIBIT B
RESEARCH PLAN
SUMMARY
o It is proposed to enter a candidate-generating collaboration with Mitokor
with a primary focus in the Neurodegeneration area.
o The collaboration will place Pfizer at the leading edge of novel
discoveries relating mitochondrial dysfunction to neuronal damage and
validate a new class of therapeutic targets, which will contribute to
meeting our Discovery productivity goals.
o The collaboration will provide Pfizer with privileged access to new
technology, targets and world-renowned scientists.
INTRODUCTION
Strong experimental evidence supports the role of oxidative toxicity in sporadic
Alzheimer's disease (AD) and ▇▇▇▇▇▇▇▇▇'▇ disease (PD). A prominent source of the
chemical species responsible for this damage is the compromised mitochondrion.
Therefore, amelioration of mitochondrial dysfunction is a rational therapeutic
goal for both of these chronic, neurodegenerative diseases. Alzheimer's disease
(AD) is associated with disturbances in cytochrome C oxidase (complex IV in the
mitochondrial electron transport chain), while PD is associated with defects in
NADH ubiquinone oxidoreductase (Complex I) enzymatic activity. The exact genetic
mechanisms causing these enzymatic defects are not known. Disturbances in either
of these enzyme complexes results in disrupted intracellular calcium metabolism
and elevated reactive oxygen species (ROS), outcomes known to be neurotoxic.
Indeed, inhibitors of complex I, such as MPP+, induce PD symptoms in humans.
Thus, limiting mitochondrial dysfunction is a compelling therapeutic goal for AD
and PD.
In addition, mitochondria play a critical role in the execution of apoptosis and
perhaps necrosis, which, in turn may be responsible for the neuronal cell death,
observed in ischemia and peripheral neuropathies. Thus, limiting mitochondrial
dysfunction also provides an attractive target for abrogating neuronal loss in
these indications.
Finally, there is emerging evidence that mitochondrial dysfunction, and
associated increases in ROS, are a general feature of aging. Therefore,
compounds which limit mitochondrial dysfunction may have utility in other
diseases associated with aging, Indeed, preclinical data suggests that NIDDM and
cardiovascular pathologies may be improved by drug therapy which limits
mitochondrial dysfunction.
Mitokor has established an important new technology for characterizing
mitochondrial dysfunction termed cybrids (cytoplasmic hybrids). Cybrids are
human, neuron-derived, clonal cell lines depleted of native mtDNA, but
containing mtDNA from human donor cells. For
Confidential page 2
example, fusion of mitochondria isolated from Alzheimer's disease patients with
SH-SY5Y cells depleted of endogenous mtDNA, produces a cybrid line with
defective intracellular calcium metabolism, elevated ROS and increased
propensity to undergo apoptosis. Cybrids appear to represent a particularly
relevant system to study oxidative toxicity associated with AD, PD and
mitochondrial-induced apoptosis, and are a novel tool for screening compounds
meant to reverse the oxidative toxicity in neurodegeneration. Additionally, the
observation that AD and PD cybrids display these defects supports the hypothesis
that mitochondrial dysfunction plays a role in these two diseases.
In addition to the cybrids, Mitokor are also actively seeking novel targets
(differential display, proteomics and [ * CON * ]) which may play a role in
[ * CON * ] and/or the defects observed in the cybrid cells.
The major benefits from a collaboration with Mitokor are fourfold; 1) access to
cybrid technology 2) novel, proprietary targets associated with mitochondrial
dysfunction and apoptosis, 3) general expertise in measuring mitochondrial
function/dysfunction and 4) CAN-production.
RESEARCH PLAN
A. INITIAL TARGET/SCREENING SEQUENCE
The research plan for the collaboration will follow a standard drug discovery
sequence beginning with an HTS (performed at Pfizer), followed by IN VITRO
selectivity assays, assessment of activity in whole cell assays (the cybrids)
and finish with IN VIVO experiments in rodents. We have outlined the screening
strategy below using the first proposed target. Novel targets that emerge during
the collaboration are expected to follow a similar sequence.
The initial HTS will be performed at Pfizer (Groton) with a novel proprietary
target provided by Mitokor and disclosed to us under confidentiality,
[ * CON * ] ([ * CON * ]). [ * CON * ] have been identified so far: [ * CON * ],
brain and other tissues, [ * CON * ], differentiated muscle and [ * CON * ],
other tissues. [ * CON * ], will be the first Molecular Target in the Research
Plan as of the Effective Date, and selectivity against [ * CON * ] will also be
studied. [ * CON * ] is believed to be a component of [ * CON * ] ([ * CON * ]).
The physiological function of [ * CON * ] is unclear, but may be implicated in
[ * CON * ], induction of [ * CON * ] and [ * CON * ] of the mitochondria.
[ * CON * ] is activated by a number of stimuli associated with [ * CON * ]
including increases in [ * CON * ] levels, decrease in mitochondrial [ * CON * ]
and elevated levels of [ * CON * ]. The [ * CON * ] results in mitochondrial
[ * CON * ], [ * CON * ] of the mitochondrial [ * CON * ] and loss of [ * CON *
] including [ * CON * ]. In some systems, the [ * CON * ] of [ * CON * ] from
mitochondria appears to be required for [ * CON * ] via subsequent activation of
[ * CON * ] followed by [ * CON * ] ([ * CON * ]). The HTS is a [ * CON * ]
assay using a proprietary [ * CON * ] developed by Mitokor and recombinant human
[ * CON * ] (provided by Mitokor). Preventing the [ * CON * ] of [ * CON * ] to
[ * CON * ] may [ * CON * ] the [ * CON * ] in a [ * CON * ] that [ * CON * ] of
the [ * CON * ]. Selectivity of hits for [ * CON * ] vs. other mitochondrial
[ * CON * ] (e.g., the [ * CON * ], [ * CON * ], [ * CON * ] - all functional
assays) and [ * CON * ] and [ * CON * ] will be assessed.
Confidential page 3
Compounds with the desired selectivity will be tested in AD cybrids at MitoKor.
AD cybrids display increased sensitivity to toxic insults such as the amyloid
beta (A(beta)) peptide, the predominant protein in the amyloid plaques of AD
brain. The ability of compounds to prevent A(beta)-induced mitochondrial
[ * CON * ] (measured with a [ * CON * ] to estimate mitochondrial [ * CON * ])
and the [ * CON * ] of [ * CON * ] that [ * CON * ] subsequent [ * CON * ] of
the [ * CON * ] will be assessed. Efficacious compounds in these assays will be
tested to insure that they do not interfere with normal mitochondrial function
(e.g., [ * CON * ], [ * CON * ] production). The final whole cell assay will
determine if active compounds can protect [ * CON * ] from [ * CON * ] from
[ * CON * ] and [ * CON * ].
Once a lead has fulfilled all IN VITRO criteria, it will be tested at MitoKor in
two IN VIVO models of neuronal mitochondrial dysfunction. In the first,
[ * CON * ] ([ * CON * ]), an [ * CON * ] inhibitor of mitochondrial [ * CON * ]
that is neurotoxic will be [ * CON * ] into the [ * CON * ]. Preferred compounds
will limit neuronal death after oral administration in this model. The second
model is [ * CON * ] of [ * CON * ] ([ * CON * ]), an inhibitor of [ * CON * ]
in the mitochondrial [ * CON * ]. [ * CON * ] increases [ * CON * ] production
and is particularly neurotoxic to the [ * CON * ], an area of the brain
[ * CON * ]. Preferred compounds will limit [ * CON * ] and [ * CON * ] in the
[ * CON * ] as well as decrease [ * CON * ] production and [ * CON * ]
accumulation in these animals.
Leads meant to limit [ * CON * ] will be tested in the following cell based
assays: [ * CON * ]- and [ * CON * ]-induced [ * CON * ] in [ * CON * ] and
[ * CON * ] cultures, respectively. Compounds that block [ * CON * ] in the
above models and meet our lead criteria will be tested for efficacy in
appropriate animal models e.g. [ * CON * ] for [ * CON * ] and [ * CON * ] for
[ * CON * ] (Pfizer Sandwich).
B. FUTURE TARGETS
All future Molecular Targets will be added to the Research Plan by proposal and
discussion by either Mitokor or Pfizer at the Research Committee and the mutual
acceptance of the Molecular Target by the Research Committee and Pfizer's and
Mitokor's managements. Future targets will derive from two sources. First, there
is evidence from the literature that modulation of known mitochondrial proteins
can limit mitochondrial dysfunction. These potential targets include [ * CON * ]
([ * CON * ]), [ * CON * ], [ * CON * ] and [ * CON * ] ([ * CON * ]). Since
there are known [ * CON * ] for [ * CON * ] and [ * CON * ], one approach is to
validate these targets in the cybrids. Validation of one of these targets could
result in rapid application of chemistry staffing and "jump start" the
collaboration.
The second potential source is a genomic/proteomic target discovery effort at
Mitokor. Mitokor is using differential display, high density cDNA arrays and
quantitative PCR to identify genes and proteins whose expression is altered in
the cybrids vs. control cells. Thus far, they have been able to detect 2-15-fold
increases in mRNA for several relevant genes including those encoding
[ * CON * ] (e.g., [ * CON * ]) and [ * CON * ] proteins (e.g., [ * CON * ]).
Confidential page 4
Pfizer will have the ability to add to the Research Plan any potential target
mutually agreed by Mitokor within the field identified by this effort.
C. DIVISION OF LABOR
The division of labor will be discussed and modified as needed during the term
of the Agreement by discussion of the Research Committee.
MITOKOR
o Molecular biologists to deliver quantities of all target proteins required for
HTS ([ * CON * ])
o Molecular biologists to pursue novel targets ([ * CON * ])
o IN VITRO pharmacologists to perform selectivity assays and characterize leads
in cybrids ([ * CON * ])
o TOTAL PROPOSED MITOKOR STAFFING: [ * CON * ]
(SCIENTISTS/TECHNICIANS, RESPECTIVELY; [ * CON * ] TOTAL FTES)
PFIZER
o HTS ([ * CON * ])
o Chemistry (up to [ * CON * ])
o Drug Metabolism (up to [ * CON * ])
o IN VITRO [ * CON * ] assays, IN VIVO [ * CON * ] model (Sandwich, up to
[ * CON * ])
o TOTAL PROPOSED PFIZER STAFFING (MAXIMUM [ * CON * ])
CONCLUSION
[ * CON * ], perturbations in [ * CON * ] and [ * CON * ] are known regulators
of neuronal degeneration. Mitochondria play a major role in the generation or
execution of these processes and extensive preclinical evidence supports the
role of this organelle in the neurodegeneration observed in AD, PD, stroke and
peripheral neuropathies. Thus, amelioration of mitochondrial dysfunction is a
compelling therapeutic goal for these disorders. We feel that collaboration with
Mitokor is favored for five reasons. First, we believe the approach is valid,
i.e., there are solid experimental data which show that limiting
mitochondrial-mediated [ * CON * ] and [ * CON * ] will likely provide
neuroprotection in both AD, PD, stroke and peripheral neuropathies. Second,
Mitokor possess a proprietary technology, the cybrid, which links mitochondrial
dysfunction directly to AD and PD. Third, the approach is complementary with our
[ * CON * ] and [ * CON * ] programs. For example, it is believed that
[ * CON * ] also plays a role in [ * CON * ] via the combination of [ * CON * ]
with [ * CON * ] derived from mitochondria and resultant [ * CON * ] of
[ * CON * ], a [ * CON * ] and [ * CON * ]. As we will soon have
Confidential page 5
candidates that selectively inhibit [ * CON * ], limiting the production of
[ * CON * ] by mitochondria will [ * CON * ] the [ * CON * ] and combination
therapy may be synergistic. Fourth, Mitokor clearly possess the expertise to
both move forward in this area and identify novel, proprietary targets,
including novel [ * CON * ] targets which has been an important goal of the
Sandwich Neurodegeneration team and would become a front line project. Fifth, we
will be working with academic leaders in the mitochondrial field and will have
privileged access to validated targets and reagents for HTS as they emerge from
the research and enter into the collaboration.
In addition, Mitokor is working to provide surrogate markers of efficacy for
limiting mitochondrial function in AD clinical trials. They are currently
exploring the potential of measuring [ * CON * ] levels in human and animal
brains by [ * CON * ]. In a proof of concept study, Mitokor has shown that brain
(striatal) [ * CON * ] levels are elevated in Huntington's disease. Determining
if brain [ * CON * ] concentrations are elevated in AD and testing of prototype
compounds reduce these concentrations represent studies which may identify a
surrogate marker in a Phase II trial. Furthermore, since platelets are the
source of compromised mitochondrial function in the cybrids, a second potential
surrogate marker might be mitochondrial function in platelets from treated and
controls patients.
In conclusion, we find that limiting mitochondrial dysfunction is a compelling
therapeutic goal for AD, PD, stroke and peripheral neuropathies and that
collaboration with Mitokor represents a rapid and scientifically sound fashion
to pursue that goal.
Confidential page 6
Following are guidelines for the first [ * CON * ] months of the collaboration,
outlining the anticipated activities and division of labor between MitoKor and
Pfizer.
MITOKOR TIMELINES
[ * CON * ]
AMENDMENT NO. 1 TO COLLABORATIVE RESEARCH AGREEMENT BETWEEN MITOKOR AND PFIZER
This Amendment No. 1, effective as of November 4, 2001 (the "Amendment Effective
Date"), is by MitoKor and its Affiliates ("MitoKor") and Pfizer Inc and its
Affiliates ("Pfizer").
I. BACKGROUND
1.1 WHEREAS MitoKor and Pfizer entered into a
Collaborative Research and
Development Agreement ("Research Agreement") and a License and Royalty Agreement
("License Agreement") as of November 4, 1998, to discover and develop patentable
small molecules that affect mitochondrial biochemical targets useful in the
treatment, prevention or diagnosis of disease in human and animal health;
1.2 WHEREAS the Research Agreement expires on November 3, 2001;
1.3 WHEREAS MitoKor and Pfizer wish to extend the term of the Research Agreement
for a further six (6) months beyond the original expiration date (the "Extension
Period") and to provide for, during the Extension Period, funding payments to be
made by Pfizer to MitoKor and a revised Research Plan attached hereto;
1.4 WHEREAS MitoKor and Pfizer also wish to amend certain payment provisions in
the Research Agreement;
1.5 NOW THEREFORE, Pfizer and MitoKor hereby amend the Research Agreement as
follows:
II AMENDMENTS
2.1 Section 9.1 of the Research Agreement is deleted in its entirety and
replaced with the following:
9.1 TERM.
9.1.1 Unless sooner terminated, as provided below or extended, by
mutual agreement of the parties as provided in this Section 9.1,
this Agreement shall expire on May 5, 2002.
9.1.2 At Pfizer's sole discretion, the term of the Agreements may be
further extended for up to an additional eighteen (18) months beyond
May 5, 2002 on terms and conditions to be agreed upon at that time
by the Parties.
page 1 of 3
2.2 The following sections are added to Section 3 of the Research Agreement:
3.1.3 During the Extension Period Pfizer will fund the research to
be performed by MitoKor, pursuant to this Agreement, for a total
amount of [ * CON * ] dollars ($[ * CON * ]). The sum of [ * CON * ]
dollars ($[ * CON * ]) shall be paid on or before December 4, 2001.
The sum of [ * CON * ] dollars ($[ * CON * ]) shall be paid on or
about February 4, 2002, following MitoKor's invoice to Pfizer in
such amount. It is understood that all payments pursuant to this
Section are noncreditable and nonrefundable.
3.1.4 The above amounts are expected to support the work performed
[ * CON * ] ([ * CON * ]) FTEs for the Extension Period. The work
performed shall be in accordance with the revised Research Plan,
attached to and made part of this Research Agreement as Exhibit E.
2.3 Section 3.2.3 of the Research Agreement, which contemplates an Additional
Equity Stock purchase of MitoKor by Pfizer, is deleted in its entirety and is of
no further force and effect.
2.4 Section 3.2.2 of the Research Agreement is deleted in its entirety and
replaced with the following:
3.2.2 MitoKor will provide to Pfizer [ * CON * ] ([ * CON * ]) HTS,
reasonably acceptable to Pfizer.
2.5 Except as expressly set forth in this Amendment No. 1, all terms and
conditions of the Research Agreement, and the Licensing Agreement shall remain
in full force and effect.
Signatures begin on next page
page 2 of 3
IN WITNESS WHEREOF, Pfizer and MitoKor have caused the Research Agreement to be
amended by duly authorized representatives of both Pfizer and MitoKor as of the
Amendment Effective Date:
Agreed: Pfizer Inc Agreed: MitoKor
By: By:
----------------------------- --------------------------------
Name: Name:
--------------------------- ------------------------------
Title: Title:
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Confidential
AMENDED RESEARCH PROTOCOL
Pfizer and MitoKor Collaboration
Subject: Extension of Collaboration with MitoKor for Inhibitors of
Mitochondrial Dysfunction and Neuroprotective Agents
Date: November 4, 2001 - May 5, 2002
A. INTRODUCTION
Strong experimental evidence supports the role of oxidative toxicity in sporadic
Alzheimer's disease (AD) and ▇▇▇▇▇▇▇▇▇'▇ disease (PD). A prominent source of the
chemical species responsible for this damage is the compromised mitochondrion.
Therefore, amelioration of mitochondrial dysfunction is a rational therapeutic
goal for these diseases. Alzheimer's disease is associated with disturbances in
cytochrome C oxidase (complex IV in the mitochondrial electron transport chain),
while PD is associated with defects in NADH ubiquinone oxidoreductase (Complex
I) enzymatic activity. The exact genetic mechanisms causing these enzymatic
defects are not known. Disturbances in either of these enzyme complexes results
in disrupted intracellular calcium metabolism and elevated reactive oxygen
species (ROS), outcomes known to be toxic to neurons. Indeed, inhibitors of
complex I, such as MPP+, induce PD-like symptoms in humans. Therefore, limiting
mitochondrial dysfunction is a compelling therapeutic goal for AD and PD.
Finally, there is emerging evidence that mitochondrial dysfunction, and
associated increases in ROS, is a general feature of aging and compounds that
limit mitochondrial dysfunction may have utility in other age-related diseases.
Indeed, preclinical data suggests that NIDDM and cardiovascular pathologies may
be improved by drug therapy that limits mitochondrial dysfunction.
Thus the body of evidence that implicates mitochondrial dsyfunction and energy
metabolism in the pathophysiology of several diseases across therapeutic areas
is compelling. The collaboration with MitoKor provides a unique opportunity to
develop mitochondrial targets for therapeutic utility.
Over the past 3 years, our collaboration with MitoKor has yielded [ * CON * ]
novel targets ([ * CON * ]% of contracted deliverables), [ * CON * ]
([ * CON * ]), [ * CON * ] and [ * CON * ] ([ * CON * ]). HTS on [ * CON * ]
and [ * CON * ] have been completed.
The major benefits derived from a extension of the collaboration with MitoKor
are: 1) validation of novel, proprietary targets associated with mitochondrial
function for neurodegenerative diseases; 2) access to mitochondrial
function/dysfunction and energy metabolism scientific expertise along with
relevant assay development.
B. RESEARCH PLAN
[ * CON * ]
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[ * CON * ] is believed to [ * CON * ] the mitochondrial [ * CON * ], a
[ * CON * ] activity that [ * CON * ], results in the [ * CON * ] of the
mitochondrial [ * CON * ] and [ * CON * ]. There are [ * CON * ] and [ * CON * ]
predominates in mammalian brain. The [ * CON * ] HTS completed in [ * CON * ].
Secondary characterization of [ * CON * ] HTS hits and analogs is complete.
There are [ * CON * ] attractive leads, [ * CON * ]. [ * CON * ] of these
compounds display neuroprotective activity in a variety of in vitro assays
utilizing primary cultured neurons or clonal human cells. The potency of the
compounds for these activities is in the [ * CON * ] range. These compounds have
no effect on [ * CON * ] or [ * CON * ]. Data presented at the [ * CON * ]
meeting appeared to clarify the molecular mechanism of the neuroprotective
activity displayed by the compounds, i.e., that these compounds act [ * CON * ]
to [ * CON * ] of [ * CON * ] by mitochondria isolated from rodent brain.
However, the link between the molecular mechanism, inhibition of [ * CON * ] and
the [ * CON * ] activity of the compounds has been [ * CON * ].
Because of the novelty of this target and the broad range of neuroprotective
activity of the HTS hits, the team wishes to extend the collaboration in order
to complete the confidence in mechanism experiments that will drive a decision
on the target. The team will construct a decision tree comprising a focused
series of experiments using available assays that will lead to a GO/NO GO
decision in 6 months.
[ * CON * ]
[ * CON * ] is responsible for the [ * CON * ] of [ * CON * ] of [ * CON * ] the
mitochondria that result in mitochondrial [ * CON * ], [ * CON * ] of the
mitochondrial [ * CON * ], inhibition of [ * CON * ] and [ * CON * ]. Since
large increases in intramitochondrial [ * CON * ] are known to be neurotoxic,
inhibition of [ * CON * ] is hypothesized to be [ * CON * ]. The HTS is
complete. Confirmed hits have been identified and re-testing will be
[ * CON * ]. A screening sequence utilizing isolated mitochondria and whole cell
assays has been established.
The next steps for this target are to confirm the activity and structure of the
HTS hits and determine if they display neuroprotective activity in primary
cultured neurons. In parallel, we will identify analogs of the HTS hits in our
file in order to assess if any preliminary SAR trends are apparent.
[ * CON * ]
Association of [ * CON * ] ([ * CON * ]) with [ * CON * ] is believed to
facilitate or provoke [ * CON * ] of the mitochondrial [ * CON * ] in both
neurons and cardiac tissue. This interaction is inhibited by association of [ *
CON * ] ([ * CON * ]) with [ * CON * ].
Initially this target was to be pursued by the [ * CON * ] therapeutic area in [
* CON * ] with the HTS based on an [ * CON * ] format sponsored by [ * CON * ]
group. In anticipation of this screen, MitoKor developed a [ * CON * ] assay.
However, due to [ * CON * ] in the [ * CON * ] group, this target will not be
pursued. Since this target is also relevant for Neurodegeneration, we propose
that the [ * CON * ] HTS be run in Groton. As "benchtop" development of the
screen at MitoKor is complete, transfer of the
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technology to the Groton New Leads group and implementation of the HTS should be
straightforward.
C. DIVISION OF LABOR
MITOKOR
o In vitro pharmacologists to drive the [ * CON * ] project to a GO/NO GO
decision based on confidence in mechanism ([ * CON * ])
o In vitro pharmacologists to characterize the hits derived from the
[ * CON * ] HTS ([ * CON * ])
o Management of collaboration ([ * CON * ])
o TOTAL PROPOSED MITOKOR STAFFING OF [ * CON * ] FTEs ([ * CON * ] PhDs,
[ * CON * ] ASSOCIATES)
PFIZER
o Re-testing [ * CON * ] HTS hits ([ * CON * ])
o [ * CON * ] ([ * CON * ])
o Management of the collaboration ([ * CON * ])
o TOTAL PROPOSED PFIZER STAFFING OF [ * CON * ] FTEs ([ * CON * ])
CONCLUSION
[ * CON * ] and perturbations in [ * CON * ] are known regulators of neuronal
cell death. Mitochondria play a major role in the generation or execution of
these processes and extensive preclinical evidence supports the role of this
organelle in the neurodegeneration observed in AD and PD. Thus, amelioration of
mitochondrial dysfunction is a compelling therapeutic goal for these disorders.
The goal of this renewal is to provide proof of mechanism for the hits
identified in the [ * CON * ] HTS, characterize the hits that emerged in the [ *
CON * ] HTS and run the [ * CON * ] HTS. Realization of these goals will provide
the Neurodegenerative disease therapeutic area with [ * CON * ] novel molecular
targets that will provide opportunities for developing compounds that are
intended to slow the progression of AD and PD.