Collaborative Research and License Agreement - Pfizer Inc. and Rigel Pharmaceuticals Inc.
COLLABORATIVE RESEARCH AND LICENSE AGREEMENT
THIS COLLABORATIVE RESEARCH AND LICENSE AGREEMENT ("the Agreement") is
entered into as of January 31, 1999 ("Effective Date") by and between PFIZER
INC, a Delaware corporation, having an office at 235 East 42nd Street, New
York, New York 10017-5755 ("Pfizer") and RIGEL PHARMACEUTICALS, INC., a
Delaware corporation, having an address at 772 Lucerne Drive, Sunnyvale,
California 94086 ("Rigel"). Pfizer and Rigel and their Affiliates may be
referred to herein individually as a "Party" or collectively as the "Parties."
WHEREAS, Rigel has the capability and expertise to undertake research
for the discovery of novel and selective elements of the IL-4 signaling
pathway involved in the modulation of IgE synthesis that are suitable targets
for an IgE synthesis-inhibitor, lead identification program;
WHEREAS, Rigel owns the patents, patent applications and licenses with
third parties set forth in Exhibit A attached to and made a part of this
Agreement with respect to retroviral expression technology and cell lines
engineered for identifying components of the IL-4 pathway; and
WHEREAS, Pfizer has the capability to undertake research for the
discovery and evaluation of biosynthetic, biochemical and organic matter for
treatment of disease and also the capability for clinical analysis,
manufacturing and marketing with respect to a wide variety of drugs for
medicinal use in human and animal health; and
WHEREAS, the Parties plan to seek patent protection for biological
elements that regulate IgE synthesis which will serve as molecular targets
for compounds from Pfizer's chemical library and patent protection for
Licensed Products which make up the subject matter of this Agreement;
NOW, THEREFORE, the Parties agree as follows:
1. DEFINITIONS
Whenever used in this Agreement, the terms defined in this Section 1
shall have the meanings specified.
1.1 "AFFILIATE" means (a) 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 a Party; (b) 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 Party; or (c) 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
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entity which owns, directly or indirectly, fifty percent (50%) or more of the
voting capital shares or similar voting securities of such Party.
1.2 "ANIMAL HEALTH PRODUCT" shall mean any Licensed Product intended
for animal patients.
1.3 "AREA" means research directed to the discovery of cDNA, peptides
or proteins within the IL-4 signaling pathway that selectively regulate IgE
synthesis further described in the Research Plan.
1.4 "DISCOVERY MILESTONE" shall have the meaning given to that term
in Section 3.3.
1.5 "EFFECTIVE DATE" is January 31, 1999.
1.6 "HIGH THROUGHPUT SCREEN" or "HTS" means a primary assay performed
by or under the direction of Pfizer that incorporates a Molecular Target for
the purpose of identifying potential Licensed Products.
1.7 "HUMAN HEALTH PRODUCT" shall mean any Licensed Product intended
for human patients.
1.8 "LICENSED PRODUCT" means any chemical or biological entity that
(a) directly, selectively and specifically modulates the activity of a
Molecular Target; (b) was identified by Pfizer in HTS; (c) is to be used for
the management of any disease or any therapeutic indication in human or
animal patients; and (d) the manufacture, use or sale of which would infringe
Valid Claims.
1.9 "MOLECULAR TARGET" shall mean any cDNA, peptide or protein
identified in the Research Program.
1.10 "NET SALES" means the gross amount invoiced by Pfizer, its
Affiliates, or any sublicensee of Pfizer for sales to a third party or third
parties of Licensed Products, less normal and customary trade discounts
actually allowed, rebates, returns, credits, taxes the legal incidence of
which is on the purchaser and separately shown on Pfizer's or any sublicensee
of Pfizer's invoices and transportation, insurance and postage charges, if
prepaid by Pfizer or any sublicensee of Pfizer and billed on Pfizer's or any
sublicensee of Pfizer's invoices as a separate item.
1.11 "PRODUCT PATENT RIGHTS" shall mean all the Valid Claims covering
Licensed Products, whether domestic or foreign, including all continuations,
continuations-in-part, divisions, and renewals, all letters patent granted
thereon, and all reissues, re-examinations and extensions thereof.
1.12 "PFIZER COMPOUND LIBRARY" means those Pfizer compounds which it
may use for HTS.
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1.13 "PFIZER CONFIDENTIAL INFORMATION" means all information about any
element of Pfizer Technology or Program Technology, except for Program
Technology assigned to Rigel pursuant to Section 5.1, which is disclosed by
Pfizer to Rigel and designated "Confidential" in writing by Pfizer at the
time of disclosure or within thirty (30) days following disclosure to Rigel
to the extent that such information as of the date of disclosure to Rigel is
not (i) demonstrably known to Rigel other than by virtue of a prior
confidential disclosure to Rigel by Pfizer; (ii) disclosed in published
literature, or otherwise generally known to the public through no fault or
omission of Rigel; or (iii) obtained from a third party free from any
obligation of confidentiality to Pfizer prior to disclosure to Rigel by
Pfizer.
1.14 "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.
1.15 "PROGRAM INVENTIONS" shall have the meaning given to it in
Section 5.1.
1.16 "PROGRAM TECHNOLOGY" means Technology within the Area that is or
was developed by employees of or consultants to Pfizer or Rigel solely or
jointly with each other in the course of performing the Research Program;
PROVIDED, HOWEVER, that Rigel's peptide library, Phoenix cell line and Felix
cell line shall not be Program Technology and are owned by or exclusively
licensed to Rigel and deemed to be Rigel Technology and that the Pfizer
Compound Library shall not be Program Technology and is owned by or
exclusively licensed and deemed to be Pfizer Technology.
1.17 "RECOMMENDED FOR DEVELOPMENT NOTICE" or "RFD" shall have the
meaning provided in the Research Plan.
1.18 "RESEARCH COMMITTEE" shall have the meaning given to that term in
Section 2.5.1.
1.19 "RESEARCH PERIOD" means the period beginning on the Effective
Date and ending on the date the Research Program terminates as provided in
Section 8.1.
1.20 "RESEARCH PLAN" means the written plan describing the research
and development to be carried out by Rigel and Pfizer pursuant to this
Agreement, as amended from time to time. The initial Research Plan is
appended to this Agreement as Exhibit B.
1.21 "RESEARCH PROGRAM" is the collaborative research program in the
Area conducted by Pfizer and Rigel pursuant to the Research Plan.
1.22 "RIGEL CONFIDENTIAL INFORMATION" means all information about any
element of the Rigel Technology or Program Technology, except for Program
Technology assigned to Pfizer pursuant to Section 5.1, which is disclosed by
Rigel to Pfizer and designated "Confidential" in writing by Rigel at the time
of disclosure or within thirty (30) days following disclosure to Pfizer to
the extent that such information as of the date of disclosure to Pfizer is
not (i) demonstrably known to Pfizer other than by virtue of a prior
confidential disclosure to Pfizer
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by Rigel; (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 Rigel prior
to disclosure to Pfizer by Rigel.
1.23 "RIGEL PATENT RIGHTS" shall mean the Valid Claims in Rigel's
patents and patent applications, listed in Exhibit A, any patents granted
thereon, including any divisions, continuations, continuations-in-part,
renewals, extensions, reexaminations, reissues or foreign counterparts
thereof.
1.24 "RIGEL TECHNOLOGY" means Technology that is or was developed by
employees of or consultants to Rigel alone or jointly with, or licensed to
Rigel from, third parties prior to the Effective Date, but, in the case of
consultants or third parties, only to the extent Rigel has the right to grant
rights to such Technology.
1.25 "TARGET PATENT RIGHTS" shall have the meaning given to it in
Section 6.1.1.
1.26 "TECHNOLOGY" means and includes all unpatented materials,
technology, technical information, know-how, expertise and trade secrets.
1.27 "VALID CLAIM" means a claim within a patent or patent application
so long as such claim shall not have been disclaimed by the Parties or 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.
2. COLLABORATIVE RESEARCH PROGRAM
2.1 PURPOSE. Rigel and Pfizer shall conduct the Research Program
throughout the Research Period. The objective of the Research Program is to
discover Molecular Targets and to discover and develop Licensed Products.
2.2 AMENDMENT TO RESEARCH PLAN. The Research Plan may be amended
from time to time by unanimous agreement of the Research Committee. Exhibit
B shall be revised as necessary to reflect each such amendment.
2.3 CONTINGENT LICENSE. If during the Research Period Rigel ceases
to do business or is unable to perform its duties and obligations as set
forth in the Research Plan, whether due to insolvency, bankruptcy or any
other reason, Pfizer shall have a non-exclusive license in the Area under the
Rigel Technology and under Rigel Patent Rights to carry out and complete the
Research Plan.
2.4 EXCLUSIVITY. Rigel agrees, during the Research Period, not to
conduct research itself or sponsor any other research, or engage in any
research sponsored with any third party in the Area except pursuant to the
Research Program.
2.5 RESEARCH COMMITTEE.
2.5.1 PURPOSE. Pfizer and Rigel shall establish a Research
Committee (the "Research Committee"):
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(a) to review and evaluate progress of the Research
Program throughout the Research Period under the Research Plan;
(b) to prepare any amendments to the Research Plans;
(c) to coordinate and monitor publication of research
results obtained from and the exchange of information and materials that
relate to the Research Program (This function will survive the termination of
Research Period for a period of three (3) years).
2.5.2 Membership. Within ten (10) days of the Effective Date
each Party shall appoint, in its sole discretion, four (4) members to the
Research Committee. Substitutes may be appointed at any time. The members
initially shall be:
Pfizer Appointees: Rigel Appointees:
1. Dr. Scott Kennedy 1. Dr. Donald Payan
2. Dr. Edward D. Pagani 2. Dr. David Ferrick
3. Dr. Phil Vickers 3. Dr. Jeremy Caldwell
4. Dr. John Watson 4. To be determined.
2.5.3 Co-Chairs. The Research Committee shall be chaired by two
(2) chairpersons, one appointed by Rigel and the other by Pfizer. The
Co-Chairs will have the responsibility to ensure that a Research Committee
meeting agenda is distributed to the Research Committee prior to the meeting.
2.5.4 Meetings. The Research Committee shall meet in person at
least quarterly, at places and on dates suggested by Pfizer and by Rigel in
turn. The location of the first meeting of the Research Committee shall be at
Pfizer's election. Representatives of Pfizer or Rigel or both, in addition
to members of the Research Committee, may attend such meetings at the
invitation of either Party.
2.5.5 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 fifteen (15) business days after each
meeting. The Party choosing the location of 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.
2.5.6 Decisions. All decisions of the Research Committee shall
be by the unanimous vote of its members.
2.5.7 Expenses. Pfizer and Rigel shall each bear all expenses,
including reasonable travel, related to the participation of their designated
members of the Research Committee, respectively.
2.6 REPORTS AND MATERIALS.
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2.6.1 Reports. Pfizer and Rigel each shall furnish to the
Research Committee:
(a) summary written reports within fifteen (15) days
after the end of each three (3) month period during the Research Period,
describing its progress under the Research Plan; and
(b) a comprehensive written report within thirty (30)
days after the end of the Research Period, describing in detail the work
accomplished by it under the Research Plan during and discussing and
evaluating the results of such work.
2.6.2 Materials. Rigel shall provide the following Program
Technology to Pfizer:
(a) all Molecular Targets identified in the course of
the Research Program;
(b) all other Program Technology, including biological
materials, which is: specific to a Molecular Target which has been delivered
to Pfizer by Rigel pursuant to Section 2.6.2(a); necessary for Pfizer to
perform its obligations under the Research Program; or necessary for Pfizer
to perform HTS with delivered Molecular Targets;
PROVIDED, HOWEVER, that such Program Technology will not include the
transfer of any portion of Rigel's peptide libraries or Rigel Technology to
Pfizer or the transfer of the Pfizer compound library or any portion of it to
Rigel. Rigel agrees to supply reasonable quantities of Molecular Targets and
biological materials specific to such Molecular Targets to Pfizer for the
performance of the Research Program; and Pfizer agrees to supply reasonable
quantities of Molecular Targets to perform HTS; PROVIDED, HOWEVER, that if
either Party needs quantities of such materials which quantities are larger
than would otherwise be anticipated by the supplying Party, the Parties will
meet and discuss in good faith appropriate compensation to the supplying
Party for such supply.
2.6.3 Pfizer's Selection of Molecular Targets. Pfizer may, in
its sole, unfettered discretion, select for HTS during the Research Program
and the three (3) year period immediately following the Research Period, any
Molecular Target identified in the Research Program. To prevent the
reversion of a Molecular Target to Rigel pursuant to Section 2.6.5, Pfizer
must commence HTS on a Molecular Target within a period of two (2) years
after its selection of such Molecular Target for HTS.
2.6.4 Exclusivity of Molecular Targets. Molecular Targets for
which Pfizer has initiated HTS shall be exclusive to Pfizer and shall not be
conveyed to a third party in any manner by Rigel.
2.6.5 Reversion to Rigel. The following shall become Rigel
Technology, and Rigel shall have no obligations to Pfizer with respect to:
Molecular Targets which are not selected pursuant to Section 2.6.3; and any
Molecular Target for which Pfizer has failed to satisfy the due diligence
obligations set forth in Section 2.6.3; PROVIDED, HOWEVER, that no Molecular
Target for which Pfizer has initiated HTS shall revert to Rigel.
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2.7 LABORATORY FACILITIES AND PERSONNEL. Pfizer and Rigel shall
provide suitable laboratory facilities, equipment and personnel for the work
to be done under the Research Program.
2.8 DILIGENT EFFORTS. Rigel and Pfizer each shall use reasonably
diligent efforts to achieve the objectives of the Research Program.
2.9 KEY INVESTIGATOR. If during the Research Period Dr. Donald
Payan's association with Rigel, in the capacity as chief scientific officer
or a similar role ends for any reason and the Parties are unable to agree on
a successor acceptable to Pfizer, in its sole and unfettered discretion,
within one hundred eighty (180) days of his dissociation, Pfizer may
terminate this Agreement pursuant to Section 8.3.1.
3. PAYMENTS.
3.1 RESEARCH PROGRAM FUNDING.
3.1.1 Pfizer will fund the research to be performed by Rigel,
pursuant to the Agreement, according to the following schedule:
COMMITMENT YEAR ANNUAL COMMITMENT
1 $2,350,000.00
2 $2,350,000.00
The funding payments of two million three hundred and fifty thousand dollars
($2,350,000.00) shall support the work of the equivalent of ten (10) full
time employees ("FTEs") of Rigel.
3.1.2 All funding payments shall be made quarterly in advance
for work scheduled to be performed by Rigel during any three (3) month
period, against Rigel's invoice for the FTEs allocated to the Research
Program for such three (3) month period. Adjustments as necessary to reflect
the work actually performed by Rigel shall be made at the end of each three
(3) month period and shall be reflected in Rigel's invoice for the next three
(3) month period. It is understood that all payments pursuant to this Section
are non-creditable and non-refundable. Rigel shall also furnish to Pfizer
the name and percent effort of each Rigel employee assigned to perform the
Research Plan during each three (3) month period.
3.1.3 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 for Research Program personnel (FTEs); provided,
however, that the aggregate amount of funding payments made in any commitment
year shall not exceed the annual commitment for such commitment year.
3.1.4 Rigel shall keep for three (3) years from the conclusion
of the Research Period complete and accurate records of its expenditures of
payments received by it pursuant to
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this Research Agreement. The records shall conform to generally accepted
accounting practices (GAAP) as applied to similar companies similarly
situated. Pfizer shall have the right at its own expense during the Research
Period and during the subsequent three-year period to appoint an independent
certified public accountant reasonably acceptable to Rigel to inspect said
records to verify the accuracy of the FTE allocation, pursuant to the
Research Plan. Upon reasonable notice by Pfizer, Rigel 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 FTE allocation.
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, and
all information learned in the course of any audit or inspection, shall be
deemed to be Rigel's Confidential Information. The failure of Pfizer to
request verification of any expenditures before or during the three-year
period shall be considered acceptance by Pfizer of the accuracy of such FTE
allocation, and Rigel shall have no obligation to maintain any records
pertaining to such report or statement beyond such three year period. The
results of such inspection, if any, shall be binding on the parties.
3.1.5 If Pfizer, in its sole, unfettered discretion, extends the
Research Program for a third year as set forth in Section 8.4, Pfizer shall
pay Rigel two million five hundred thousand dollars ($2,500,000.00) with
respect to the extension period on the same terms and conditions set forth in
this Section 3. The funding payments shall support the work of ten (10) Rigel
FTEs.
3.2 INITIAL PAYMENT. Within fifteen (15) days of the execution of
this Agreement, Pfizer will pay to Rigel a one time, non refundable,
noncreditable payment of two million dollars ($2,000,000.00).
3.3 DISCOVERY MILESTONE PAYMENTS. Within sixty (60) days after
Rigel's delivery to Pfizer of Molecular Targets meeting the D3/D4 criteria
set forth in Exhibit B and within thirty (30) days after Pfizer's selection,
in its sole, unfettered discretion, of a Molecular Target for HTS ("Discovery
Milestones"), as the case may be, Pfizer shall pay Rigel according to the
following schedule:
DISCOVERY STAGE DELIVERABLE MILESTONE PAYMENT
D3 Molecular Targets No. 1-3 $75,000.00 each
D3 Molecular Targets No. 4-6 $100,000.00 each
D3 Molecular Targets No. 7+ $150,000.00 each
D4a/D4b Molecular Targets No.1-3 $150,000.00 each
D4a/D4b Molecular Targets No.4-6 $200,000.00 each
D4a/D4b Molecular Targets No.7+ $250,000.00 each
HTS Molecular Target No.1 $200,000.00
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HTS Molecular Target No.2 $250,000.00
HTS Molecular Target No.3 $300,000.00
HTS Molecular Target No.4 $350,000.00
HTS Molecular Target No.5 $400,000.00
HTS Molecular Target No.6 $450,000.00
HTS Molecular Target No.7+ No Additional Payments
3.4 DISCOVERY MILESTONE PAYMENT CHARACTERISTICS. Discovery Milestone
payments are in addition to the other payments in this Section 3 and are
noncreditable and non-refundable. If Pfizer in its sole, unfettered
discretion, selects a Molecular Target for HTS which does not meet the
criteria for D3 or D4, such Molecular Target shall be deemed to have met both
D3 and D4 criteria for the purposes of the payment for Discovery Milestones
to Rigel under Section 3.3.
3.5 LIMITATION OF DISCOVERY MILESTONE PAYMENTS. Irrespective of the
number of Molecular Targets meeting the criteria or the number of Molecular
Targets selected by Pfizer for HTS, the aggregate amount which Pfizer shall
pay to Rigel for Discovery Milestones shall not exceed (a) one million three
hundred fifty thousand dollars ($1,350,000.00) in the case of Molecular
Targets meeting the D3 criteria; (b) one million eight hundred thousand
dollars ($1,800,000.00) in the case of Molecular Targets which meet the
D4a/D4b criteria; and (c) one million nine hundred fifty thousand dollars
($1,950,000.00) in the case of Molecular Targets selected for HTS in Pfizer's
sole, unfettered discretion.
3.6 RECOMMENDED FOR DEVELOPMENT. Pfizer will pay to Rigel the sum of
five hundred thousand dollars ($500,000.00) each time Pfizer issues a
Recommended for Development Notice for a Human Health Product and a sum of
two hundred fifty thousand dollars ($250,000.00) each time Pfizer issues a
RFD notice for a Animal Health Product; PROVIDED, HOWEVER, that such payment
will be made only once for each compound identified in a specific Pfizer HTS
for a specific indication and will not include back-up compounds identified
in the same HTS for the same indication. These payments are noncreditable
and non-refundable, and shall be paid to Rigel within thirty (30) days of
Pfizer's issuance of the applicable RFD notice.
3.7 ROYALTIES ON NET SALES OF LICENSED PRODUCTS.
3.7.1 Pfizer shall pay Rigel a royalty based on the Net Sales of
each Licensed Product. Such royalty shall be paid with respect to each
country of the world from the date of the first commercial sale (the date of
the invoice of Pfizer or any sublicensee of Pfizer with respect to such sale)
of such Licensed Product in each such country until the expiration of the
last Product Patent Right to expire with respect to each such country and
each such Licensed Product. If the manufacture and sale of a Licensed
Product takes place in countries where there are no Product Patent Rights,
Pfizer will pay to Rigel a royalty based on the Net Sales of each Licensed
Product in each such country for ten (10) years after the first commercial
sale of such Licensed Product in such country.
3.7.2 Unpatented Products. Pfizer will commercialize only those
products derived or resulting from HTS which are covered by Product Patent
Rights. If, in the unlikely
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event, Pfizer determines in its absolute,
unfettered discretion to commercialize an unpatented product, it will meet with
Rigel to discuss additional compensation, if any, to Rigel, for use of the
Molecular Target on the basis of which Pfizer conducted HTS to identify such
product given Pfizer's advancement and commercialization of an unpatented
product will have involved extraordinary development costs to Pfizer.
3.8 ROYALTY RATES. The royalty paid each year shall be based on
increments of world-wide Net Sales with respect to each of the Licensed Products
according to the following schedule:
HUMAN HEALTH PRODUCT ANIMAL HEALTH PRODUCT
Annual Net Sales (Dollars) Royalty Rate Royalty Rate
--------------------------- ------------ ------------
$0-$500MM
2% 1%
> $500MM < $750MM
-- 2%
> $500MM < 1B
3% --
> = $750MM
-- 3%
> = $1B
4% --
3.9 PAYMENT DATES FOR ROYALTIES. Royalties shall be paid by Pfizer on
Net Sales within sixty (60) days after the end of each calendar quarter in which
such Net Sales are made. Such payments shall be accompanied by a statement
showing the Net Sales of each Licensed Product by Pfizer or any sublicensee of
Pfizer in each country, the applicable royalty rate for such Licensed Product,
and a calculation of the amount of royalty due, including any offsets.
3.10 ACCOUNTING FOR ROYALTIES. The Net Sales used for computing the
royalties payable to Rigel by Pfizer shall be computed in U.S. dollars, and
royalties shall be paid in U.S. dollars by wire transfer in immediately
available funds to a U.S. account designated by Rigel, or by other mutually
acceptable means. For purposes of determining the amount of royalties due, the
amount of Net Sales in any foreign currency shall be computed by (a) converting
such amount into U.S. dollars at the prevailing commercial rate of exchange for
purchasing dollars with such foreign currency as published in the Wall Street
Journal for the close of the last business day of the calendar quarter for which
the relevant royalty payment is to be made by Pfizer; and (b) deducting the
amount of any governmental tax, duty, charge, or other fee actually paid in
respect of such conversion into, and remittance of U.S. dollars.
3.11 RECORDS FOR ROYALTIES. Pfizer shall keep for three (3) years from
the date of each payment of royalties complete and accurate records of sales by
Pfizer, its Affiliates or sublicensees of each Licensed Product in sufficient
detail to allow the accruing royalties to be determined accurately. Rigel shall
have the right for a period of three (3) years after receiving any report or
statement with respect to royalties due and payable to appoint at its expense
(except as otherwise provided in this Section 3.11), an independent certified
public accountant reasonably acceptable to Pfizer to inspect the relevant
records of Pfizer, its Affiliates or
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sublicensees to verify such report or statement. Pfizer, its Affiliates or
sublicensees shall make its records available for inspection by such
independent certified public accountant during regular business hours at such
place or places where such records are customarily kept, upon reasonable
notice from Rigel, to verify the accuracy of the reports and payments. Such
inspection right shall not be exercised more than once in any calendar year
nor more than once with respect to sales in any given period. Rigel agrees
to hold in strict confidence all information concerning royalty payments and
reports, and all information learned in the course of any audit or
inspection, except to the extent necessary for Rigel to reveal such
information in order to enforce its rights under this Agreement or if
disclosure is required by law. The failure of Rigel to request verification
of any report or statement during said three (3) year period shall be
considered acceptance of the accuracy of such report, and Pfizer shall have
no obligation to maintain records pertaining to such report or statement
beyond said three (3) year period. The findings of each inspection, if any,
shall be binding on both Parties.
3.12 MILESTONE PAYMENTS FOR LICENSED PRODUCTS. Pfizer shall pay
Rigel, within sixty (60) days of the completion of each event set forth below
("Event"), the payment listed opposite that Event. Payments shall be made in
U.S. dollars by wire transfer in immediately available funds to a U.S. bank
account designated by Rigel, or other mutually acceptable means. Pfizer
shall be obligated to make each payment only once with respect to each
Licensed Product affected by an Event and such payment for such Event shall
not be due with respect to any subsequent Licensed Product directed to a
Molecular Target and indication which has previously been the subject of the
same Event. With the exception of any such milestone paid to Rigel for the
occurrence of the earlier of Submission of IND or initiation of human
(Section 3.12.1(i)) or animal (Section 3.12.2(i)) clinical trials, payments
made by Pfizer pursuant to this Section 3.12 with respect to a Licensed
Product shall be credited against sums due to Rigel pursuant to Section 3.8
of this Agreement with respect to Net Sales of such Licensed Product. Fifty
percent (50%) of the milestone payment paid to Rigel for commencement of
Phase III human clinical trials (Section 3.12.1(ii)) and submission of NADA
for animal use (Section 3.12.2 (ii)) shall be credited against royalty
payments and one hundred percent (100%) of milestone payments paid to Rigel
for NDA/PLA filing for human use (Section 3.12.1 (iii)) and for NADA/PLA
approval in any country for animal use (Section 3.12.2 (iii)); PROVIDED,
HOWEVER, that the sums due pursuant to Section 3.8 in any calendar year with
respect to such Licensed Product shall not be reduced by virtue of this
credit by more than fifty percent (50%):
3.12.1 HUMAN HEALTH PRODUCT
EVENT AMOUNT (DOLLARS)
----- ----------------
$1,000,000.00
(i) Submission of INDA or initiation of human
clinical testing in any country (whichever
occurs first)
(ii) Commencement of Phase III human clinical $2,000,000.00
trials in any country
(iii) NDA/PLA Filing in any country for human $4,000,000.00
use
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3.12.2 ANIMAL HEALTH PRODUCT
EVENT AMOUNT (DOLLARS)
----- ----------------
(i) Submission of INAD or initiation of $ 500,000.00
animal clinical testing in any country
(whichever occurs first)
(ii) Submission of NADA in any country for $1,000,000.00
animal use
(iii) NADA/PLA Approval in any country for $2,000,000.00
animal use
For the purposes of the foregoing, "IND" "INAD" or "INDA" shall mean an
Investigational New Drug Application filed with the U.S. Food and Drug
Administration (FDA), or a similar filing made with a counterpart health
regulatory authority in another country; "NDA/PLA" or "NADA/PLA" shall mean a
New Drug Application, Product License Application, or other application for
authority to market a Licensed Product filed with the U.S. FDA or a counterpart
health regulatory agency in another country.
3.13 U.S. 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
account designated by Rigel, or by other mutually acceptable means. If a
payment due date is not otherwise specified in this Agreement, payment shall be
made within thirty (30) days after receipt and acceptance by Pfizer of the
invoice from Rigel.
4. TREATMENT OF CONFIDENTIAL INFORMATION
4.1 CONFIDENTIALITY
4.1.1 Pfizer and Rigel each recognize that the other's Confidential
Information constitutes highly valuable, confidential information. Subject to
the terms and conditions of the Agreement, Pfizer and Rigel each agree that
during the Research Period and for five (5) years thereafter, it will keep
confidential, and will cause its Affiliates to keep confidential, all Rigel
Confidential Information or Pfizer Confidential Information, as the case may be,
that is disclosed to it, or to any of its Affiliates pursuant to this Agreement.
Neither Pfizer nor Rigel nor any of their respective Affiliates shall use such
Confidential Information except as expressly permitted in this Agreement.
4.1.2 Pfizer and Rigel 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 Rigel 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
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 similar Confidential Information. Each Party, upon
the other's request, will return all
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the Confidential Information disclosed to 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 Rigel and Pfizer each represent that all of its employees,
Affiliates and any consultants to such Party, participating in the Research
Program who shall have access to Pfizer Technology, Rigel Technology or Program
Technology and Pfizer Confidential Information and Rigel Confidential
Information are bound by agreement to maintain such information in confidence
with the same degree of care each Party holds it own confidential information.
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 approval by Rigel's and Pfizer's
managements, which approval shall not be unreasonably withheld. After receipt
of the proposed publication by both Pfizer's and Rigel's managements, written
approval or disapproval shall be provided within thirty (30) days for a
manuscript, 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 a transcript of an oral presentation to be given at a scientific
meeting.
4.3 PUBLICITY. Except as required by law, and except for approved press
releases which may be issued by each Party upon the signing of this Agreement,
neither Party may disclose the terms of this Agreement without the prior written
consent of the other Party; PROVIDED, HOWEVER, that Rigel may disclose the
terms, or provide copies, of this Agreement as necessary in the normal course of
business to bankers, investors and others bound by obligations of
confidentiality not to disclose such information to other third parties in order
to obtain financing.
4.4 PERMITTED DISCLOSURE.
4.4.1 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 that are conceived, made or developed
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.
5. INTELLECTUAL PROPERTY RIGHTS.
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5.1 OWNERSHIP. All Rigel Confidential Information, Rigel Technology and
Rigel Patent Rights shall be owned by Rigel. All Pfizer Confidential
Information, Pfizer Technology and Pfizer Patent Rights shall be owned by
Pfizer. Program Technology (including, without limitation, any patentable
invention or discovery) acquired, developed or made solely or jointly by
employees or agents of either Party during the course of the Research Program
("Program Inventions") shall be the property of Pfizer and deemed to be Pfizer
Confidential Information if it pertains to or is an improvement upon its HTS
compound library or a Licensed Product and shall be the property of Rigel and
deemed to be Rigel Confidential Information if it pertains to or is an
improvement upon Rigel Patents, Rigel Technology or pertains to or is an
improvement upon Molecular Targets which are not selected for HTS by Pfizer.
Each Party shall cooperate with the other in completing any patent applications
relating to Program Inventions, and in executing and delivering any instrument
required to assign, convey or transfer to such other Party its interest, as
provided in the preceding sentence.
5.2 GRANTS OF RESEARCH LICENSES.
5.2.1 Program License. Rigel and Pfizer each grants to the other a
nonexclusive, worldwide, royalty-free license during the Research Period,
including the right to grant sublicenses to Affiliates, to make and use
Confidential Information, Program Technology and Product Patent Rights for the
purpose of performing the Research Program; provided, however, that the other
Party shall not acquire, by virtue of this Section or any other Section, any
rights in the following:
(a) Rigel's peptide libraries;
(b) the Pfizer Compound Library; or
(c) any compounds active in the HTS which Pfizer chooses,
in its sole, unfettered discretion, not to develop or otherwise include in
Program Technology.
5.2.2 Research License.
(a) Rigel grants Pfizer an irrevocable, nonexclusive,
worldwide license under its interest in Program Technology, except Rigel Core
Technology, and under all intangible technology, technical information,
know-how, expertise and trade secrets within Rigel Technology disclosed to
Pfizer during the course of the Research Program, solely for the purpose of
conducting research.
(b) Pfizer grants Rigel an irrevocable, nonexclusive,
worldwide license under Pfizer's interest in all intangible technology,
technical information, know-how, expertise and trade secrets within Program
Technology, and under all intangible technology, technical information,
know-how, expertise and trade secrets within Pfizer Technology disclosed to
Rigel during the course of the Research Program, solely for the purpose of
conducting research.
(c) For purposes of this Section 5.2.2, Rigel Core
Technology shall mean:
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(i) Rigel's peptide libraries
(ii) Rigel's Phoenix cell lines
(iii) Felix cell lines
5.3 GRANT OF COMMERCIALIZATION LICENSE, TERM, RIGHTS AND OBLIGATIONS.
5.3.1 Grant to Pfizer. Rigel hereby grants to Pfizer an exclusive,
world-wide license, including the right to grant sublicenses, to research,
manufacture, use, sell, offer for sale and import Licensed Products under
Rigel's interest in the Product Patent Rights and the Molecular Targets.
5.3.2 Term of License. The term of the grant to Pfizer set forth
in Section 5.3.1 shall begin on the Effective Date. The duration of the term of
the grant shall be determined on a country-by-country basis. For any country in
which there are Product Patent Rights, the term shall end on the date of the
last to expire of the Product Patent Rights in such country. For all other
countries, the term shall expire on the tenth (10th) anniversary of the first
commercial sale of such Licensed Product in such country.
5.3.3 Paid-Up License. Upon the expiration of Pfizer's obligation
to pay royalties on Net Sales of Licensed Products as provided in Section 3.7.1,
the license granted in Section 5.3.1 shall become an irrevocable, nonexclusive
paid-up license.
5.3.4 Pfizer Obligations.
(a) Pfizer shall use reasonably diligent efforts to
exploit Licensed Products commercially employing similar effort to that applied
to other products similarly situated; provided, however, Pfizer may, in its
sole, unfettered judgement, discontinue the development or sale of any Licensed
Product in any country in the world or all of them.
(b) If Pfizer grants a sublicense pursuant to this Section
5, Pfizer shall guarantee that any sublicensee fulfills all of Pfizer's
obligations under this Agreement; PROVIDED, HOWEVER, that Pfizer shall not be
relieved of its obligations pursuant to this Agreement.
5.3.5 Technical Assistance. Rigel shall provide to Pfizer or any
sublicensee of Pfizer, at Pfizer's request and expense, any agreed technical
assistance reasonably necessary to enable Pfizer or such sublicensee to
manufacture, use, sell, offer for sale or import each Licensed Product and to
enjoy fully all the rights granted to Pfizer pursuant to this License Agreement;
provided, however, that Rigel is reasonably capable of providing that
assistance. Pfizer shall reimburse Rigel's costs of providing such assistance.
6. PROVISIONS CONCERNING THE FILING, PROSECUTION AND MAINTENANCE OF PATENT
RIGHTS.
The following provisions relate to the filing, prosecution and maintenance
of patents and patent applications during the term of this Agreement:
6.1 FILING, PROSECUTION AND MAINTENANCE BY RIGEL.
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6.1.1 With respect to any Rigel interest in patents and patent
applications which claim a Molecular Target ("Target Patent Rights"), Rigel
shall have the obligation:
(a) to file applications for letters patent on any
invention included in Target Patent Rights; PROVIDED, HOWEVER, that Rigel 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 Rigel file such applications; and, further provided, that Rigel,
at its option and expense, may file in countries where Pfizer does not request
that Rigel file such applications;
(b) to take all reasonable steps to prosecute all pending
and new patent applications included within Target Patent Rights;
(c) to respond to oppositions, nullity actions,
re-examinations, revocation actions 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
Target 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 reasonable and
necessary actions requested by, Pfizer in connection with the preparation,
prosecution and maintenance of any letters patent included in Target Patent
Rights.
Rigel shall notify Pfizer in a timely manner of any decision to abandon
a pending patent application or an issued patent included in Target Patent
Rights. Thereafter, Pfizer shall have the option, at its expense, of
continuing to prosecute any such pending patent application or of keeping the
issued patent in force.
6.1.2 Copies of Documents. Rigel shall provide to Pfizer copies
of all patent applications that are part of Target Patent Rights prior to
filing, for the purpose of obtaining substantive comment of Pfizer patent
counsel. Rigel shall also provide to Pfizer copies of all documents relating
to prosecution of all such patent applications in a timely manner and shall
provide to Pfizer every six (6) months a report detailing their status.
6.1.3 Reimbursement of Costs for Filing Prosecuting and
Maintaining Target Patent Rights. Within ninety (90) days of rendered patent
services and thirty (30) days of receipt of invoices from Rigel, Pfizer shall
reimburse Rigel for all the costs of writing, filing, prosecuting, responding
to opposition and maintaining patent applications and patents in countries
where Pfizer requests that patent applications be filed, prosecuted and
maintained. Such reimbursement shall be in addition to payments described in
Section 3. However, Pfizer may, upon sixty (60) days notice, request that
Rigel discontinue filing or prosecution of patent applications in any country
and discontinue reimbursing Rigel for the costs of filing, prosecuting,
responding to opposition or maintaining such patent application or patent in
any country. Rigel shall pay all costs in those countries in which Pfizer
does not request that Rigel file, prosecute or maintain patent applications
and patents, but in which Rigel, at its option, elects to do so.
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6.1.4 Pfizer shall have the right to file on behalf of and as an
agent for Rigel all applications and take all actions necessary to obtain patent
extensions pursuant to 35 USC Section 156 and foreign counterparts for Target
Patent Rights described in Section 6.1 licensed to Pfizer. Rigel agrees, to
sign, at Pfizer's expense, such further documents and take such further actions
as may be requested by Pfizer in this regard.
6.2 FILING, PROSECUTION AND MAINTENANCE BY PFIZER. With respect to
Product Patent Rights claiming compounds in the Pfizer Compound Library or
Licensed Products, Pfizer shall have those rights and duties ascribed to Rigel
in Section 6.1, except that Pfizer will bear all related expenses.
6.3 DISCLAIMING A VALID CLAIM. Neither Party may disclaim a Valid Claim
within Target Patent Rights or Product Patent Rights without the consent of the
other.
6.4 ACTUAL OR THREATENED DISCLOSURE OR INFRINGEMENT. When information
comes to the attention of Pfizer to the effect that any Target Patent Rights or
Product Patent Rights relating to a Licensed Product have been or are threatened
to be unlawfully infringed, Pfizer shall have the right at its expense to take
such action as it may deem necessary to prosecute or prevent such unlawful
infringement, including the right to bring or defend any suit, action or
proceeding involving any such infringement. Pfizer shall notify Rigel promptly
of the receipt of any such information and of the commencement of any such suit,
action or proceeding. If Pfizer determines that it is necessary or desirable
for Rigel to join any such suit, action or proceeding, Rigel shall, at Pfizer's
expense, execute all papers and perform such other acts as may be reasonably
required to permit Pfizer to commence such action, suit or proceeding in which
case Pfizer shall hold Rigel free, clear and harmless from any and all costs and
expenses of litigation, including attorneys fees. If Pfizer brings a suit, it
shall have the right first to reimburse itself out of any sums recovered in such
suit or in its settlement for all costs and expenses, including attorney's fees,
related to such suit or settlement, and twenty percent (20%) of any funds that
shall remain from said recovery shall be paid to Rigel and the balance of such
funds shall be retained by Pfizer. Each Party shall always have the right to be
represented by counsel of its own selection and at its own expense in any suit
instituted by the other for infringement under the terms of this Section. If
Pfizer lacks standing and Rigel has standing to bring any such suit, action or
proceeding, then Rigel shall do so at the request of Pfizer and at Pfizer's
expense.
6.5 DEFENSE OF INFRINGEMENT CLAIMS. Rigel will cooperate with Pfizer at
Pfizer's expense in the defense of any suit, action or proceeding against Pfizer
or any sublicensee of Pfizer alleging the infringement of the intellectual
property rights of a third party by reason of the use of Target Patent Rights or
Product Patent Rights in the manufacture, use or sale of the Licensed Product.
Pfizer shall give Rigel prompt written notice of the commencement of any such
suit, action or proceeding or claim of infringement and will furnish Rigel a
copy of each communication relating to the alleged infringement. Rigel shall
give to Pfizer all authority (including the right to exclusive control of the
defense of any such suit, action or proceeding and the exclusive right after
consultation with Rigel, to compromise, litigate, settle or otherwise dispose of
any such suit, action or proceeding), at Pfizer's expense, including by
providing information and assistance necessary to defend or settle any such
suit, action or proceeding; PROVIDED, HOWEVER, Pfizer shall obtain Rigel's prior
consent to such part of any settlement which contemplates payment or other
action by Rigel or has a material adverse effect on Rigel's
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business. If the Parties agree that Rigel should institute or join any suit,
action or proceeding pursuant to this Section, Pfizer may, at Pfizer's
expense, join Rigel as a defendant if necessary or desirable, and Rigel shall
execute all documents and take all other actions, including giving testimony,
which may reasonably be required in connection with the prosecution of such
suit, action or proceeding.
7. ACQUISITION OF RIGHTS FROM THIRD PARTIES. During the Research Period, each
Party which acquires technology, patents or information in the Area from third
parties during the course of the Research Program and wants to use such
technology, patents or information in its performance of the Research Program
shall obtain the prior written consent of the other Party, such consent not to
be unreasonably withheld, prior to using such technology, patents or information
in its performance of the Research Program. If the other Party gives the
acquiring Party consent to use such third party technology, patents or
information in the performance of the Research Program, such technology, patents
or information shall be deemed either the Confidential Information or the
Technology of the acquiring Party, as appropriate.
8. TERM, TERMINATION AND RENEWAL.
8.1 TERM. Unless sooner terminated or extended, the Research Period
shall expire two (2) calendar years from the Effective Date. Unless sooner
terminated or extended, the Agreement shall expire upon the expiration of
Pfizer's financial obligations under this Agreement.
8.2 EVENTS OF TERMINATION. The following events shall constitute an
event of termination ("Events of Termination"):
8.2.1 Rigel or Pfizer shall fail in any material respect to perform
or observe any term, covenant or understanding contained in this Agreement, and
any such failure shall remain unremedied for sixty (60) days after written
notice to the failing Party; or
8.2.2 If any written representation or warranty by Rigel or Pfizer,
or any of its officers, made under or in connection with this Agreement or any
other contemporaneous written agreement between the Parties shall prove to have
been incorrect in any material respect when made.
8.3 TERMINATION.
8.3.1 Upon the occurrence of any Event of Termination, the Party
not responsible may, by written notice to the other Party, terminate this
Agreement.
8.3.2 If Pfizer terminates this Agreement pursuant to Section
8.3.1, the terms and conditions of the Agreement, shall not terminate, but
instead shall terminate or expire according to its terms. If Rigel terminates
this Agreement pursuant to Section 8.3.1, the terms and conditions of the
Agreement shall terminate immediately.
8.3.3 Termination of this Agreement for any reason, with or without
cause, will not terminate the license granted pursuant to Section 5.2.2.
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8.3.4 Termination of this Agreement for any reason shall be without
prejudice to:
(a) the rights and obligations of the Parties in any
Section which provide by its terms for performance by either Party subsequent to
termination;
(b) Rigel's right to receive all royalty, milestone or
other payments accrued hereunder; or
(c) any other remedies which either Party may otherwise
have.
8.4 RENEWAL. Pfizer shall have the option, in its sole, unfettered
discretion, of renewing the Research Program for a one (1) year extension period
on the same terms and conditions set forth in this Agreement by written notice
to Rigel. This option shall expire if not exercised by Pfizer at least three (3)
months prior to the termination date described in Section 8.1. If Pfizer
exercises this option, the Parties shall adopt an annual Research Plan during
the ensuing ninety (90) day period, including a budget. All other terms and
conditions of this Agreement shall otherwise remain in full force and effect
except as set forth in Section 3.1.5.
9. REPRESENTATIONS AND WARRANTIES.
9.1 REPRESENTATIONS AND WARRANTIES OF BOTH PARTIES. Rigel and Pfizer
each represents and warrants as follows:
9.1.1 It is a corporation duly organized, validly existing and is
in good standing under the laws of the State of Delaware, 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 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.
9.1.2 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 (i) require any additional consent or approval of its stockholders
beyond the approvals already obtained; (ii) violate any provision of any law,
rule, regulations, order, writ, judgment, injunctions, decree, determination
award presently in effect having applicability to it or any provision of its
certificate of incorporation or by-laws; or (iii) 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.
9.1.3 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.
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9.1.4 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.
9.1.5 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 the relevant lessors or licensors.
9.2 REPRESENTATIONS AND WARRANTIES OF RIGEL.
9.2.1 LICENSES GRANTED. Rigel represents and warrants to Pfizer
that it has the right to grant the licenses granted pursuant to this Agreement,
and that the licenses so granted do not conflict with or violate the terms of
any agreement between Rigel and any third party.
9.2.2 FINANCIAL STABILITY. Rigel represents and warrants as of the
Effective Date that it has received subsequent to October 31, 1998 cash
aggregating at least $7 million from equity investment and at least $3 million
from license fees and research support which, together with other cash on hand
and projected cash receipts, is sufficient to meet its projected cash expenses
during the next following 18 months exclusive, in each case, respectively, of
cash received or to be received from Pfizer and of cash Rigel is required to
expend to perform fully its obligations under the Research Program. Rigel
further represents and warrants that during the Research Period it will continue
to maintain sufficient financial resources to perform fully its obligations
under the Research Program and will furnish to Pfizer, not earlier than January
31, 1999 or more often than annually thereafter, within sixty (60) days after
receipt of Pfizer's written request therefor, reasonable evidence of sufficient
financial resources to perform fully its remaining obligations under the
Research Program; provided, however, the information contained in, and any
information furnished pursuant to Pfizer's request under, this Section 9.2.2 is
Confidential Information of Rigel and is subject to the requirements of Article
4 of this Agreement.
9.2.3 GOVERNMENTAL CONSENTS. No consent, approval, qualification,
order or authorization of, or filing with, any local, state, or federal
governmental authority is required on the part of Rigel in connection with
Rigel's valid execution, delivery, or performance of this Agreement.
9.2.4 CAPITALIZATION AND VOTING RIGHTS. The authorized capital of
Rigel consists, or will consist immediately prior to the Effective Date, of:
(a) Preferred Stock. 22,000,000 shares of Preferred Stock,
par value $.001, of which 665,000 shares have been designated Series A Preferred
Stock, all of which are issued and outstanding; 7,675,000 shares have been
designated Series B Preferred Stock, of which 7,500,000 are issued and
outstanding; 8,000,000 shares have been designated Series C Preferred Stock, of
which 7,386,843 are issued and outstanding; and 5,660,000 shares of Series D
Preferred Stock, of which 3,481,864 are issued and outstanding (before giving
effect to any transactions with Pfizer). The rights, privileges and preferences
of the Series A, Series B, Series C and Series D Preferred Stock are as stated
in the restated certificate of incorporation.
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(b) Common Stock. 35,000,000 shares of common stock, par
value $.001 ("Common Stock"), of which 2,675,333 shares are issued and
outstanding.
(c) The outstanding shares of Series A Preferred Stock,
Series B Preferred Stock, Series C Preferred Stock, and Common Stock have been
duly authorized and validly issued, are fully paid and nonassessable, and were
issued in accordance with the registration or qualification provisions of the
Securities Act and any relevant state securities laws or pursuant to valid
exemptions therefrom.
(d) Except for (i) the conversion privileges of the Series
A, Series B, Series C, and Series D Preferred Stock, (ii) the rights provided in
paragraph 2.3 of a certain Investor Rights Agreement separately furnished to
Pfizer, (iii) a warrant to purchase 175,000 shares of Series B Preferred Stock,
(iv) a warrant to purchase 131,578 shares of Series C Preferred Stock, and (v)
shares to be issued to Pfizer under a certain stock purchase agreement executed
on even date herewith, there are not outstanding any options, warrants, rights
(including conversion or preemptive rights and rights of first refusal), proxy
or stockholder agreements or agreements of any kind for the purchase or
acquisition from Rigel of any of its securities. In addition, Rigel has
reserved 5,325,000 shares of its Common Stock for purchase upon exercise of
options to be granted in the future under Rigel's 1997 Stock Option Plan (the
"Option Plan"). Rigel is not a party or subject to any agreement or
understanding, and, to the best of Rigel's knowledge, there is no agreement or
understanding between any persons that affects or relates to the voting or
giving of written consents with respect to any security or the voting by a
director of Rigel.
9.2.5 SUBSIDIARIES. As of the Effective Date, Rigel does not own
or control, directly or indirectly, any interest in any other corporation,
partnership, limited liability company, association, or other business entity.
Rigel is not a participant in any joint venture, partnership, or similar
arrangement.
9.2.6 PERMITS. Rigel has all franchises, permits, licenses, and
any similar authority necessary for the conduct of its business as now being
conducted by it, the lack of which could materially and adversely affect the
business, properties, prospects, or financial condition of Rigel, and believes
it can obtain, without undue burden or expense, any similar authority for the
conduct of its business as presently planned to be conducted. Rigel is not in
default in any material respect under any of such franchises, permits, licenses
or other similar authority.
9.2.7 COMPLIANCE WITH OTHER INSTRUMENTS. Rigel is not in violation
or default in any material respect of any provision of its restated certificate
of incorporation or bylaws or in any material respect of any provision of any
mortgage, indenture, agreement, instrument, or contract to which it is a party
or by which it is bound or, to the best of its knowledge, of any federal or
state judgment, order, writ, decree, statute, rule, regulation or restriction
applicable to Rigel. The execution, delivery, and performance by Rigel of this
Agreement and the consummation of the transactions contemplated hereby and
thereby, will not result in any such violation or be in material conflict with
or constitute, with or without the passage of time or giving of notice, either a
material default under any such provision or an event that results in the
creation of any material lien, charge, or encumbrance upon any assets of Rigel
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or the suspension, revocation, impairment, forfeiture, or nonrenewal of any
material permit, license, authorization, or approval applicable to Rigel, its
business or operations, or any of its assets or properties.
9.2.8 LITIGATION. There is no action, suit, proceeding, or
investigation pending or currently threatened against Rigel that questions the
validity of this Agreement or the right of Rigel to enter into this Agreement,
or to consummate the transactions contemplated hereby, or that might result,
either individually or in the aggregate, in any material adverse change in the
assets, business, properties, prospects, or financial condition of Rigel, or in
any material change in the current equity ownership of Rigel. The foregoing
includes, without limitation, any action, suit, proceeding, or investigation
pending or currently threatened involving the prior employment of any of Rigel's
employees, their use in connection with Rigel's business of any information or
techniques allegedly proprietary to any of their former employers, their
obligations under any agreements with prior employers, or negotiations by Rigel
with potential backers of, or investors in, Rigel or its proposed business.
Rigel is not a party to or, to the best of its knowledge, named in or subject to
any order, writ, injunction, judgment, or decree of any court, government
agency, or instrumentality. There is no action, suit, proceeding or
investigation by Rigel currently pending or that Rigel currently intends to
initiate.
9.2.9 DISCLOSURE. Rigel has provided Pfizer with all the
information reasonably available to it without undue expense that Pfizer has
requested for deciding whether to enter into this Agreement. This Agreement
does not contain any untrue statement of a material fact or, to the best of
Rigel's knowledge, omits to state a material fact necessary to make the
statements made by Rigel herein not misleading.
9.2.10 FINANCIAL STATEMENTS. Rigel has delivered to Pfizer its
unaudited balance sheet as at August 31, 1998 and unaudited statement of income
and cash flows for the eight months ending August 31, 1998 (collectively, the
"Financial Statements"). The Financial Statements, have been prepared in
accordance with generally accepted accounting principles applied on a consistent
basis throughout the periods indicated, except as disclosed therein, and present
fairly the financial condition and position of Rigel as of August 31, 1998;
provided, however, that the unaudited financial statements are subject to normal
recurring year-end audit adjustments (which are not expected to be material),
and do not contain all footnotes required under generally accepted accounting
principles.
9.2.11 CHANGES. Since August 31, 1998 there has not been:
(a) any damage, destruction or loss, whether or not
covered by insurance, materially and adversely affecting the business,
properties, prospects, assets, liabilities or financial condition of Rigel (as
such business is presently conducted and as it is presently proposed to be
conducted);
(b) any waiver or compromise by Rigel of a valuable right
or of a material debt owed to it;
(c) any satisfaction or discharge of any lien, claim, or
encumbrance or payment of any obligation by Rigel, except in the ordinary course
of business and that is not
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material to the business, properties, prospects, or financial condition of
Rigel (as such business is presently conducted and as it is presently
proposed to be conducted);
(d) any sale, assignment, or transfer of any patents,
trademarks, copyrights, trade secrets, or other intangible assets;
(e) any resignation or termination of employment of any
key officer of Rigel and Rigel, to the best of its knowledge, does not know of
the impending resignation or termination of employment of any such officer;
(f) any mortgage, pledge, transfer of a security interest
in, or lien, created by Rigel, with respect to any of its material properties or
assets, except liens for taxes not yet due or payable;
(g) any loans or guarantees made by Rigel to or for the
benefit of its employees, stockholders, officers, or directors, or any members
of their immediate families, other than travel advances and other advances made
in the ordinary course of its business;
(h) any declaration, setting aside, or payment of any
dividend or other distribution of Rigel's assets in respect of any of Rigel's
capital stock, or any direct or indirect redemption, purchase, or other
acquisition of any of such stock by Rigel;
(i) any material adverse change in the business, property,
assets, liabilities, financial condition or results of operations of Rigel;
(j) any change (individually or in the aggregate), except
in the ordinary course of business, in the contingent obligations of Rigel by
way of guarantee, endorsement, indemnity, warranty or otherwise;
(k) except in the ordinary course of business, any
material change in the compensation arrangement of any of Rigel's employees,
officers or directors; or
(l) to the best of Rigel's knowledge, any other event or
condition of any character that might materially and adversely affect the
business, properties, prospects, or financial condition of Rigel (as such
business is presently conducted and as it is presently proposed to be
conducted).
9.2.12 PATENTS AND TRADEMARKS. To the best of its knowledge (but
without having conducted any special investigation), Rigel owns or possesses
sufficient legal rights to all patents, trademarks, service marks, trade names,
copyrights, trade secrets, licenses, information, and proprietary rights and
processes (including technology currently licensed from Stanford University)
necessary for its business as now conducted and as proposed to be conducted
without any conflict with, or infringement of the rights of, others. Rigel
currently licenses certain technology from Stanford University (the "Licensed
Technology") on an "as is" basis, with no representation or warranty from
Stanford University that such technology does not infringe the proprietary
rights of others. To Rigel's knowledge, Rigel has not, as of the date hereof,
received any claims from any third party alleging that the use of the Licensed
Technology infringes the
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proprietary rights of such party. Except for agreements with its own
employees or consultants and standard end-user license agreements, there are
no outstanding options, licenses, or agreements of any kind relating to the
foregoing, nor is Rigel bound by or a party to any options, licenses, or
agreements of any kind with respect to the patents, trademarks, service
marks, trade names, copyrights, trade secrets, licenses, information, and
proprietary rights and processes of any other person or entity, other than
the license agreements with Janssen Pharmaceutica N.V., Stanford University,
SUNY, and BASF. Rigel has not received any communications alleging that
Rigel has violated or, by conducting its business as proposed, would violate
any of the patents, trademarks, service marks, trade names, copyrights, trade
secrets, or other proprietary rights or processes of any other person or
entity. Rigel is not aware that any of its employees is obligated under any
contract (including licenses, covenants, or commitments of any nature) or
other agreement, or subject to any judgment, decree, or order of any court or
administrative agency, that would interfere with the use of such employee's
best efforts to promote the interests of Rigel or that would conflict with
Rigel's business as proposed to be conducted. Neither the execution nor
delivery of this Agreement, nor the carrying on of Rigel's business by the
employees of Rigel, nor the conduct of Rigel's business as proposed, will, to
the best of Rigel's knowledge, conflict with or result in a breach of the
terms, conditions, or provisions of, or constitute a default under, any
contract, covenant, or instrument under which any of such employees is now
obligated. Rigel is not aware of any violation by a third party of any of
Rigel's patents, licenses, trademarks, service marks, tradenames, copyrights,
trade secrets or other proprietary rights.
9.2.13 EMPLOYEES; EMPLOYEE COMPENSATION. There is no strike, labor
dispute or union organization activities pending or, to the best of Rigel's
knowledge, threatened between it and its employees. None of Rigel's employees
belongs to any union or collective bargaining unit. To the best of its
knowledge, Rigel has complied in all material respects with all applicable state
and federal equal opportunity and other laws related to employment. To the best
of Rigel's knowledge, no employee of Rigel is or will be in violation of any
judgment, decree, or order, or any term of any employment contract, patent
disclosure agreement, or other contract or agreement relating to the
relationship of any such employee with Rigel, or any other party because of the
nature of the business conducted or presently proposed to be conducted by Rigel
or to the use by the employee of his or her best efforts with respect to such
business. Rigel is not a party to or bound by any currently effective employment
contract, deferred compensation agreement, bonus plan, incentive plan, profit
sharing plan, retirement agreement, or other employee compensation agreement,
except as entered into in the ordinary course of business. Rigel is not aware
that any officer or key employee, or that any group of key employees, intends to
terminate their employment with Rigel, nor does Rigel have a present intention
to terminate the employment of any of the foregoing. Subject to general
principles related to wrongful termination of employees, the employment of each
officer and employee of Rigel is terminable at the will of Rigel.
9.2.14 PROPRIETARY INFORMATION AND INVENTIONS AGREEMENTS. Each
employee and officer of Rigel has executed a Proprietary Information and
Inventions Agreement. Each consultant to Rigel has executed a Consulting
Agreement containing confidentiality and assignment of inventions provisions
similar to those included in the Proprietary Information and Inventions
Agreement.
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9.2.15 TAX RETURNS, PAYMENTS, AND ELECTIONS. Rigel has timely filed
all tax returns and reports (federal, state and local) as required by law.
These returns and reports are true and correct in all material respects. Rigel
has paid all taxes and other assessments due, except those contested by it in
good faith. Rigel has not elected pursuant to the Internal Revenue Code of
1986, as amended ("Code"), to be treated as an S corporation or a collapsible
corporation pursuant to Section 1362(a) or Section 341(f) of the Code, nor has
it made any other elections pursuant to the Code (other than elections that
relate solely to methods of accounting, depreciation, or amortization) that
would have a material effect on the business, properties, prospects, or
financial condition of Rigel. Rigel has never had any tax deficiency proposed
or assessed against it and has not executed any waiver of any statute of
limitations on the assessment or collection of any tax or governmental charge.
None of Rigel's federal income tax returns and none of its state income or
franchise tax or sales or use tax returns has ever been audited by governmental
authorities.
9.2.16 INSURANCE. Rigel has in full force and effect fire and
casualty insurance policies, with extended coverage, in amounts customary for
companies similarly situated to Rigel.
9.2.17 ENVIRONMENTAL AND SAFETY LAWS. Rigel is not in violation of
any applicable statute, law, or regulation relating to the environment or
occupational health and safety, and to the best of its knowledge, no material
expenditures are or will be required in order to comply with any such existing
statute, law, or regulation.
9.2.18 REAL PROPERTY HOLDING CORPORATION. Rigel is not a real
property holding corporation within the meaning of Code section 897(c)(2) and
any regulations promulgated thereunder.
9.2.19 FDA APPROVAL. The U.S. Food and Drug Administration has not
delivered a letter of nonapproval, nor threatened to deliver such a letter, with
respect to any product manufactured, marketed, licensed or developed by Rigel,
or any product which Rigel intends to manufacture, market, license or develop.
9.2.20 INVESTMENT COMPANY ACT. Rigel is not an "investment
company", or a company "controlled" by an "investment company", within the
meaning of the Investment Company Act of 1940, as amended.
10. COVENANTS OF RIGEL AND PFIZER OTHER THAN REPORTING REQUIREMENTS.
Throughout the term of the Agreement, Rigel and Pfizer each shall:
10.1 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.
10.2 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
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Research Program, except for those laws, rules, regulations, and orders it
may be contesting in good faith.
11. INDEMNIFICATION.
Pfizer will indemnify Rigel for damages, settlements, costs, legal fees and
other expenses incurred in connection with a claim against Rigel based on a
Licensed Product or any action or omission of Pfizer, its agents or employees
whether such claims allege negligence, willful misconduct or strict liability,
related to the obligations of Pfizer under this Agreement. Pfizer, 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.
12. NOTICES.
All notices and invoices shall be in writing mailed via certified mail,
return receipt requested, courier, or facsimile transmission with transmission
confirmed addressed as follow, or to such other address as may be designated
from time to time:
IF TO PFIZER: To Pfizer at its address as set forth at the beginning of
this Agreement.
Attention: President, Central Research
with copy to: Office of the General Counsel
Fax:
IF TO RIGEL: Rigel at its address as set forth at the beginning of this
Agreement.
Attention: President
Fax: (408) 736-1588
Notices shall be deemed given as of the date received or five (5) days after
dispatch.
13. GOVERNING LAW.
This Agreement shall be governed by and construed in accordance with the
laws of the State of New York.
14. MISCELLANEOUS.
14.1 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.
14.2 HEADINGS. Paragraph headings are inserted for convenience of
reference only and do not form a part of this Agreement.
14.3 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.
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14.4 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 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.
14.5 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.
14.6 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.
14.7 FORCE MAJEURE. Neither Pfizer nor Rigel 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
Rigel.
14.8 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.
14.9 INTEGRATION. This Agreement supersedes all other agreements and
understandings between the parties with respect to the subject matter discussed
herein.
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IN WITNESS WHEREOF, the Parties have caused this Agreement to be executed
by their duly authorized representatives.
Agreed: Pfizer Inc and Affiliates Agreed: Rigel Pharmaceuticals, Inc. and
Affiliates
By: /s/ George M. Milne Jr. By: /s/ James M. Gower
------------------------------ --------------------------
George M. Milne, Jr. James M. Gower
President Chief Executive Officer
Pfizer Central Research Rigel Pharmaceuticals, Inc.
Date: 1/29/99 Date 1/26/99
--------------------------- -------------------------
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EXHIBIT A
RIGEL PATENT RIGHTS
LICENSED TITLE/MATERIAL INVENTOR PATENT
TECHNOLOGIES FILING
DATE
1. Phoenix and 293T Garry Nolan, - Non-Exclusive
cells lines Stanford University license 10/7/96
2. Phoenix and 293T Garry Nolan, - Exclusive
cells lines Stanford University license 8/18/97
3A. USSN Methods for Garry Nolan & 1/23/96 Technology licensed
08,589,109 Screening for Michael Rothenberg, by Rigel 10/7/96
Transdominant assigned to Stanford
Effector Peptides University
and RNA Molecules
3B. USSN Methods for Garry Nolan & 1/23/97 CIP
08,787,738 Screening for Michael Rothenberg,
Transdominant assigned to Stanford
Effector Peptides University
and RNA Molecules
3C. PCT Methods for Garry Nolan & 1/23/97 PCT
US97/01048 Screening for Michael Rothenberg,
Transdominant assigned to Stanford
Effector Peptides University
and RNA Molecules
4. A Genetic System to Stanley Fields & 1/24/90; Technology licensed
US patents # Detect Protein-Protein Ok-Kyu Song, assigned continued 1/12/98
5,283,173 Interactions to the Research 2/1/94;
5,468,614 Foundation of SUNY continued
5,667,973 (Stonybrook) 9/16/97
5. Provisional Detection of Helen Blau, assigned 4/2/97 Technology licensed
application # Molecular Interactions to Stanford University 8/4/97 by Rigel 3/27/98
60,042,576, and by Reporter Subunit
60,054,623; Complementation
(replaced by
application
09,053,614) 4/1/98
6. (TET system Tetracycline Regulated BASF Bioresearch Corp. Technology licensed
includes 16 Expression Technology: 5/1/98
patents) The TET System
<PAGE>
PATENTS TITLE AUTHOR PATENT
FILING
DATE
1A. USSN Methods for Garry Nolan 1/23/96 Assigned to
08,589,911 Screening for Rigel 10/20/97
Transdominant
Intracellular Effector
Peptides and RNA
Molecules
1B. USSN Methods for Garry Nolan 1/23/97 CIP
08,789,333 Screening for
Transdominant
Intracellular Effector
Peptides and RNA
Molecules
1C. USSN Methods for Garry Nolan 11/3/97 divisional
08,963,368 Screening for
Transdominant
Intracellular Effector
Peptides and RNA
Molecules
1D. PCT Methods for Garry Nolan 1/23/97 PCT
US97/01019 Screening for
Transdominant
Intracellular Effector
Peptides and RNA
Molecules
2. USSN Combinatorial Garry Nolan & 6/12/97 Assigned to
08,873,601 Enzymatic Complexes Donald Payan Rigel 9/9/97
3. USSN Small Molecule Donald Payan 3/24/98
09,047,119 Library Screening
Using FACS
4. 09,050,863 Mammalian Protein Ying Luo, Betty 3/30/98
Interaction Cloning Huang, & Donald
System Payan
5. 60,080,444 Peptides Causing Dave Anderson 4/2/98
Formation of Compact
Structures
6. 09,076,624 Methods and Compositions Dave Ferrick, 5/12/98
for Screening for Susan Swift,
Modulators of IgE Randy Armstrong,
Synthesis, Secretion and Bryan Fox
Switch
Rearrangement
7A. 09,133,944 Shuttle Vectors Ying Luo, Peiwen 8/14/98
Yu, Jim Lorens
7B. Shuttle Vectors Ying Luo, Peiwen In process CIP
Yu, Jim Lorens
8. Green Fluorescent David Anderson 10/9/98
Protein Fusions with
Random Peptides
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EXHIBIT B
RESEARCH PLAN
1. GOALS
The goal of this collaboration between Rigel and Pfizer is to identify
novel and selective elements of the IL-4 signaling pathway that are suitable
targets for an IgE synthesis inhibitor, lead identification program.
2. RESEARCH PLAN
The research strategy for the first two years of the Pfizer-Rigel
collaboration is shown in FIGURE 1. During this time, research activities
will take place primarily at Rigel towards the goal of discovering novel
Molecular Targets in the IL-4 signaling pathway that can be further developed
by Pfizer into high throughput screens (HTS) at Pfizer to find agents to
inhibit IL-4 signaling and IgE synthesis for the treatment of allergic
disease and asthma. In brief, Rigel uses intracellular retrovirus expression
of peptide libraries in an IL-4 responsive reporter cell line to discover
peptide inhibitors of the IL-4 signaling pathway. The peptide inhibitors are
validated by showing their selectivity in inhibiting IL-4 directed IgE
synthesis over IL-10 directed IgG synthesis. The peptide inhibitors are used
to isolate their protein ligands using Yeast Two Hybrid (YTH) technology, and
then these ligands will be valided for their effect on IgE synthesis at Rigel
using a combination of IN VITRO mutagenesis and further YTH pathway mapping.
2.1 DELIVERABLES AND TIMELINE
2.1.1 RESEARCH ACTIVITIES, 0-12 MONTHS:
DELIVERABLE 1 (D1)--ISOLATION AND CONFIRMATION OF INHIBITORY
PEPTIDES:
(a) (8 MONTHS) Rigel will endeavor to isolate specific
peptide inhibitors of IL-4-induced, B cell germline epsilon transcription,
from stem loop peptide libraries (2x10(9) component complexity) using a
Fas-mediated apoptosis cell survival assay. The greater the number of
peptides actually expressed in the reporter cell line, the greater the
chances of finding novel Molecular Targets, so every reasonable effort will
be made to maximize the representation of the peptide library in the reporter
cell line. However, taking transfection efficiency into account, no less than
10(8) components will be have been expressed in the B-cell reporter cell
line. The iterative enrichment of inhibitory peptides and their
characterization will be carried out by Rigel as shown in Figure 2.
(b) (12 MONTHS) As noted in Figure 2, Rigel will endeavor
to confirm that individual peptide inhibitors confer the IL-4 resistant
phenotype in a Fas-mediated apoptosis cell survival assay. The capacity of
this assay would allow 100+ peptide inhibitors to be taken forward
through this assay for confirmation.
2.1.2 RESEARCH ACTIVITIES, 12-18 MONTHS:
DELIVERABLE 2 (D2)--IgE SYNTHESIS INHIBITION AND SPECIFICITY
OF INDIVIDUAL PEPTIDE HITS:
Rigel will endeavor to demonstrate that recovered single peptide hits
inhibit IgE synthesis SELECTIVELY over IgG synthesis as follows:
(a) Measure IgE versus IgG secretion/switching
inhibition in a cytokine stimulated BL16 B-cell line. The goal is that the
inhibitory peptide will inhibit IgE levels in the media produced by the IgM+
BL16 cell line stimulated with IL-4 by 20 fold over an irrelevant peptide
control. If the peptide also inhibits IL-10 driven IgG levels from the IgM+
BL16 cell line, the goal will be that the peptide will inhibit IgE levels by
20 fold more than IgG. Secreted antibody levels will be measured in the media
by ELISA. Because of the higher throughput of the BL16 assay (capacity = 100+
peptides) versus the primary PBL assay (capacity = 10 peptides), it is
expected that the BL16 assay will be used to rapidly select peptides that
will serve as baits in YTH screening, while the PBL assay will only be
performed on those peptides whose ligands are not known components of the
IL-4 signaling pathway.
(b) Confirm that the peptide inhibitor meets the same
criteria as in D2a in primary cells by performing similar experiments to
those in D2a in cytokine stimulated IgM+ enriched human peripheral blood
lymphocytes or IgM+ enriched human tonsillar B-cells. Because of the low
throughput and variability of this assay, those peptides that are the binding
partners of known members of the IL-4 signaling pathway will not be tested in
this assay.
D2 CRITERIA: Section 2.1.2(a) shall be known as D2a criteria, and Section
2.1.2(b) above shall be known as D2b criteria.
DELIVERABLE 3 (D3)--CLONING OF FULL LENGTH CDNAS OF PROTEINS BINDING OF
INHIBITORY PEPTIDES:
<PAGE>
Rigel will deliver full length sequences of protein binding partners of
inhibitory peptides. Up to 20 functionally active single peptide hits will
be used as bait in a YTH system (YTH level 1) to identify cDNAs encoding the
target protein partners of the active peptides. Rigel will perform
bioinformatic analysis to identify the isolated clones. Pfizer will also
contribute bioinformatic analysis in order to attempt to identify some of
these clones based on homology to sequences in public databases and private
databases available to Pfizer. Bioinformatics, RACE (Rapid Amplification of
CDNA Ends), or cDNA cloning will be used by Rigel to obtain full length cDNA
sequences encoding up to 12 independent target proteins from the cDNA
sequences isolated using YTH.
D3 MILESTONE CRITERIA: D3 criteria comprise meeting each of the
following: (1) The cDNA is the ligand of an inhibitory peptide that met the
criteria in D2a and D2b. (2) The cDNA contains the full length coding region,
and is either the only ligand for a given peptide inhibitor or can be
conclusively shown to be the ligand responsible for the IL-4 inhibition. (3)
At the time of its discovery, the cDNA did not encode a protein already known
in the literature or to Pfizer to be a component of the IL-4 signaling
pathway whose inhibition would be expected to have a specific effect on the
germline epsilon promoter. These proteins must include the following: IL-4R
alpha chain, IL-4R gamma chain, Jak kinases, STAT6, as well as two other
proteins (a transcription factor and an enzyme) whose role is unpublished and
identity is known to Pfizer through confidential sources. The identity of
these proteins are as follows: The transcription factor Bc16, and the Pim
family of Ser/Thr Kinases, particularly Pim-2.
[to be added at the time of the execution of the Agreement.] (4) The cDNA is
not identical or overlapping with another cDNA for which a D3 milestone has
already been triggered.
At Pfizer's sole, unfettered discretion, a D3 milestone may be paid to
Rigel by Pfizer in the absence of one or more of the first three criteria being
met.
2.1.3 RESEARCH ACTIVITIES, 18-24 MONTHS
DELIVERABLE 4 (D4)--VALIDATION OF CDNAS IDENTIFIED IN
DELIVERABLE 3 (D3):
(a) Rigel will endeavor to complete mutagenesis target
validation data for two proteins identified in Deliverable 3. Greater than
one hundred mutants will be generated for each target by error prone PCR and
delivered via retrovirus constructs to the Fas-mediated apoptosis survival
assay to select for dominant negative mutants that confer the IL-4 resistant
phenotype. If dominant negatives are found, selective inhibition of IgE
synthesis over IgG synthesis will be measured as in Deliverable 2a and 2b
above, with the same throughput for the BL16 and PBL assays.
(b) Rigel will endeavor to deliver additional protein
targets and pathway mapping in the IL-4/germline epsilon pathway. Up to five
full length cloned protein targets identified in Deliverable 3 will be used
as bait in YTH experiments (YTH level 2) to identify further protein binding
partners which interact with each clone in order to map the IL-4 signaling
pathway and validate the role of these proteins in IL-4 signaling. If the
protein binding partner of an inhibitory peptide were to be found to bind to
a known member of the IL-4 signaling pathway, this would represent partial
validation of this D3 protein in the IL-4 signaling pathway. Full length
clones for up to 8 of the binding partners will be sought in preparation for
possible future YTH level 3 screening during an optional 3rd year of the
Pfizer-Rigel collaboration.
D4 MILESTONE CRITERIA: D4 criteria comprise meeting either one of the
following two criteria for a D3 cDNA clone or its encoded protein. (a)
Successful selection of one or more dominant negative mutants of a cDNA whose
effect after intracellular retroviral expression satisfies the criteria
applied to inhibitory peptides in D2a and D2b. (b) Demonstration in YTH
level 2 that the protein encoded by a given cDNA binds to a known member of
the IL-4 signal transduction pathway. Specific qualifying components would be
all those noted in the D3 Milestone Criteria.
At Pfizer's sole, unfettered discretion, a D4 milestone may be paid to
Rigel by Pfizer in the absence of one or more of the criteria being met.
2.2 PROGRAM TECHNOLOGIES
Certain reagents will be enabling to Pfizer's efforts to validate Molecular
Targets, to progress Molecular Targets to the HTS phase, and to engage in
research in the IgE synthesis inhibition area. Since they are not explicitly
stated elsewhere, the following reagents will be considered Program
Technologies: the IL-4 driven Fas reporter cell line, an IL-4 driven GFP
reporter cell line, the BL16 cell line derivative used in this collaboration,
any useful derivatives of these that may be used in the course of the
collaboration, other enabling cell lines specifically made for this
collaboration, and the PBL assay.
2.3 PROGRESSION OF MOLECULAR TARGETS AT PFIZER
Once potential Molecular Targets are available, Pfizer will have the
sole unfettered discretion of which to select for progression to HTS and
beyond. Pfizer will perform target validation experiments and will adapt the
Molecular Target for HTS. From this point, a Pfizer project team will follow
a standard drug discovery progression from lead discovery, candidate
optimization, and candidate validation using IN VITRO and IN VIVO models.
Compounds satisfying candidate criteria will follow the usual Pfizer
preclinical development program (i.e. General Pharmacology, Genetic
Toxicology, and Exploratory Toxicology studies) to the recommendation for
development (RFD) stage.
After a Candidate Alert Notice ("CAN") is issued, General Pharmacology
and Exploratory Toxicology studies in two species will be conducted. A RFD
(or CANTOX) document will issue by approval of Pfizer's Early Development
Management Team after a satisfactory completion of General Pharmacology and
the 14-day rat and dog (or monkey) Exploratory Toxicology, including
histopathology, evaluations. For studies in man, Pfizer policy is that a
clinical candidate should have a safety margin of 10x between a predicted
human efficacious dose (plasma concentration and/or exposure taken into
account) and a non-observable-adverse-effect-level (NOAEL).
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Rigel-Pfizer Collaboration
FIGURE 1
[DIAGRAM]
33
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FIGURE 2
RIGEL: SELECTION OF PEPTIDE INHIBITORS OF IL-4 SIGNALING (0-12 months)
[CHART]
34