Research and Development License and Options for Commercial License - PanGenetics BV, Panorama Research Inc., Mark de Boer and Chiron Corp.
CHIRON-PANGENETICS RESEARCH AND DEVELOPMENT
LICENSE AND OPTIONS FOR COMMERCIAL LICENSE
THIS AGREEMENT, by and between PanGenetics B.V. ("PanGenetics B.V.") a company
organized and existing under the laws of the Netherlands and having its
principal place of business at E. van Calcarstraat 30, 1963 DG Heemskerk, the
Netherlands, and Panorama Research Inc. ("Panorama"), a company organized and
existing under the laws of California, and having its principal place of
business at 2462 Wyandotte Street, Mountain View, California 94043 (collectively
PanGenetics B.V. and Panorama shall be deemed "PanGenetics"), Mark de Boer
("de Boer"), and Chiron Corporation ("Chiron"), a Delaware corporation
having its principal place of business at 4560 Horton Street, Emeryville,
California 94608, is effective upon the last signature date (the "Effective
Date").
BACKGROUND
WHEREAS, certain inventions relating to marine monoclonal antibodies against the
human antigen known as CD40 ("Anti CD40 Mabs") have been made by Chiron, and
by de Boer, subject to the provisions of a material transfer agreement between
Chiron's predecessor Cetus and de Boer dated December 16, 1991, (the "1991
MTA"), a consulting agreement between Chiron and de Boer dated January 1, 1993,
(the "1993 Consulting Agreement"), a consulting agreement between Chiron and
de Boer dated January 1, 1994 (the "1994 Consulting Agreement"), a material
transfer agreement between Chiron and Panorama dated November 9, 1994 (the
"1994 MTA") and their subsequent amendments.
WHEREAS, PanGenetics, Chiron and de Boer (the "Parties") now wish to provide
for the licensing of rights relating to such inventions and the further
development of anti-CD40 antibodies for human therapeutic uses;
AGREEMENT
NOW, THEREFORE, PanGenetics, Chiron and de Boer agree as follows:
1 DEFINITIONS
As used in this Agreement:
1.1 "AFFILIATE" with respect to any person, means any company, entity,
joint venture or similar business arrangement which is controlled by,
controlling or under common control with such person, and shall include without
limitation any company fifty percent or more of whose voting stock or
participating profit interest is owned or controlled, directly or indirectly, by
such person, and any company which owns or controls, directly or indirectly,
fifty percent or more of such person. Without limiting the generality of the
foregoing, the Affiliates of Chiron expressly exclude Ciba-Geigy Limited, a
Switzerland corporation, or any wholly owned subsidiaries of Ciba-Geigy Limited
("Ciba"), unless and until such time as Ciba-Geigy and Chiron may mutually
agree upon the terms and conditions upon which Ciba may be deemed an Affiliate
of Chiron for the purposes of this Agreement.
1.2 "ANTI-CD40 MABS" means monoclonal antibodies against human CD40
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produced by the hybridomas 5D12, 3A8 and 3C6, or any monoclonal antibody derived
therefrom, including humanized anti-CD40 Mabs, and/or human anti-CD40 Mabs, and
fragments thereof capable of binding the Human CD40 Molecule.
1.3 "CHIRON TECHNOLOGY" means all information, developments,
discoveries, inventions, know-how, products, substances, processes and
methodologies, and other proprietary information or technology developed or
otherwise acquired by Chiron relating to the Field as of the Effective Date,
including, but not limited to, the hybridoma cell lines described in Section
1.2, the Anti-CD40 Mabs produced therefrom, and the use of said Anti-CD-40 Mabs.
1.4 "CHIRON PATENTS" means any U.S. patents or patent applications,
including any continuations, renewals, extensions or re-issues or divisions
thereof, relating to, or incorporating the Chiron Technology, together with any
foreign counterpart thereof and any divisional, continuation,
continuation-in-part and any reissue or extension thereof, to the extent they
claim or incorporate the Chiron Technology, including, but not limited to, U.S.
patent application USSN 08/070,158, and those patent applications filed in the
countries designated by PCT filing WO 94/01547 and are listed on the PCT Patent
Application Schedule attached as Exhibit 1, and any patentable improvements
invented by Chiron or relating to the lumanization of Anti-CD40 Mabs and
fragments thereof capable of binding the Human CD40 Molecule.
1.5 "CHIRON TERRITORIES" shall mean all countries of the world, except
Europe and Japan.
1.6 "DE BOER RIGHTS" shall mean de Boer's interest in inventions within
the Field (i) which are governed by the 1991 MTA, attached as Exhibit 3 to this
Agreement, and its subsequent amendments; and (ii) without limiting the
foregoing, inventions within the Field created by de Boer during the course of
this agreement. With respect to all de Boer inventions within the Field which
are governed by the terms and conditions of the 1993 Consulting Agreement, the
1994 Consulting Agreement, (collectively the "Consulting Agreements") and
their subsequent amendments, de Boer has assigned or will assign all right title
and interest in such inventions to Chiron in accordance with the terms of said
Consulting Agreements. de Boer rights arising from inventions within the Field
made by de Boer after the conclusion of the Consulting Agreements shall be
governed by the terms and conditions of this Agreement, including, without
limitation, the provisions of Article 3, relating to de Boer's assignment of de
Boer rights to PanGenetics, and Pan Genetics' obligations to assign to Chiron
patentable improvements relating to the humanization of Anti-CD40 Mabs and
fragments thereof capable of binding the Human CD40 Molecule for inclusion
within the Chiron Patents.
1.7 "FIELD" means the use of Anti-CD40 Mabs or products based on or
derived from the use of Anti-CD40 Mabs in human therapeutic applications wherein
the Mab mediates a therapeutic effect by binding to the Human CD40 Molecule. The
Field shall not include the use of gene therapy, except to the extent
PanGenetics is permitted under the terms and conditions of this Agreement,
including, without limitation, the terms and conditions set forth in Article 7
to undertake activities relating to Second Generation Products which use gene
therapy solely for the endogenous local delivery and synthesis of Anti-CD40
Mabs. The following commercial applications are specifically excluded from the
Field: (i)
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vaccines; (ii) diagnostics; (iii) gene therapy, anti-gene therapy, including,
without limitation, the use of antisense or ribozyme molecules, except as
provided in Article 7 and (iv) peptidomimetic or other synthetic,
small-molecular weight, non-peptide molecules. Without limiting the foregoing,
PanGenetics may use Anti-CD40 screening assays, provided that such assays are
used solely for non-commercial, internal research purposes.
1.8 "HUMAN CD40 MOLECULE" means the type I transmembrane protein encoded
by the CD40 gene and known to be expressed on a number of cells including,
without limitation, B cells, dendritic cells, monocytes and macrophages.
1.9 "JOINT TECHNOLOGY" shall mean Technology and inventions within the
Field which are invented jointly by employees of Panenetics (including persons
obligated to assign inventions to PanGenetics) and employees of Chiron
(including persons obligated to assign inventions to Chiron), whether or not
such inventions are also owned in conjunction with third parties pursuant to
this Agreement.
1.10 "JOINT TECHNOLOGY PATENTS" shall mean U.S. patents or patent
applications claiming or incorporating Joint Technology, together with any
foreign counterpart thereof and any divisional, continuation,
continuation-in-part and any reissue or extension thereof, to the extent they
claim or incorporate Joint Technology.
1.11 "LICENSED PRODUCT(S)" means any product, the manufacture, use or
sale of which, but for the license granted hereunder, would infringe any valid
and enforceable claim of any Chiron Patents or PanGenetics Patents in the
country of such manufacture, use or sale, or product, which relates to or
requires the use of Chiron Technology or Panorama Technology. Licensed Products
include, but are not limited to, any human therapeutic product(s), or one under
development, which is based directly or indirectly on an Anti CD40 Mab or
products based on or derived from the use of Anti-CD40 Mabs. The following
commercial applications are specifically excluded from the Field: (i) vaccines;
(ii) diagnostics; (iii) gene therapy, anti-gene therapy, including, without
limitation, the use of antisense or ribozyme molecules, except as provided with
respect to Second Generation Products as provided in Article 7 and (iv)
peptidomimetic or other synthetic, small-molecular weight, non-peptide
molecules.
1.12 "NET SALES" shall mean the amount billed or invoices for each unit
of Licensed Products sold less:
(i) Customary trade, quantity or cash discounts;
(ii) Amounts repaid or credited by reason of rejection or return; and/or
(iii) To the extent separately stated on purchase orders, invoices or
other documents of sale, taxes levied on and/or other governmental
charges made as to production, or transportation or insurance
charges.
(iv) sales and value-added taxes separately stated on invoices. Licensed
Products shall be considered sold when shipped.
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In the event that Licensed Products are sold in combination with another
product or active component, (a "Combination Product") for a single price, Net
Sales from sales of Combination Products for purposes of calculating royalties
due or allocating profits under this Agreement shall be calculated by
multiplying the Net Sales of that Combination Product by the fraction A/(A+B),
where A is the gross selling price of the Licensed Product sold separately in
the country of sale and B is the gross selling price of the other product(s) or
components sold separately in the country of sale. In the event that no such
separate sales are made, Net Sales, for purposes of determining royalty payments
on such Combination Products, shall be a reasonable apportionment of the gross
amount invoiced therefor based upon the relative contribution of the Licensed
Products to the price of the Combination Product. Such apportionment shall be
negotiated in good faith between the parties and such apportionment shall be
established prior to the time that a party hereto shall have the right to sell
such Combination Products.
1.13 "PANGENETICS TECHNOLOGY" shall mean all information, developments,
discoveries, inventions, know-how, products, substances, processes and
methodologies, and other proprietary information or technology developed or
otherwise acquired by PanGenetics relating to the development of Licensed
Products within the Field, including, but not limited to, methods for preparing
or using such materials as well as methodologies for testing their interaction
in biological systems, clinical and pre-clinical data and submissions,
discoveries and trade secrets, whether patentable or unpatentable, and other
proprietary information or technology developed by PanGenetics, or licensed to
PanGenetics with a right to sublicense, or otherwise acquired by PanGenetics
within the Field, prior to or after the Effective Date of this Agreement.
1.14 PANGENETICS PATENTS" shall mean U.S. patents or patents issuing from
patent applications claiming or incorporating PanGenetics Technology, together
with any foreign counterpart thereof and any divisional, continuation,
continuation-in-part and any reissue or extension thereof, to the extent they
claim or incorporate PanGenetics Technology, as set forth in the PanGenetics'
Patent Schedule, attached as Exhibit 2 to this Agreement, and as may be amended
from time to time. In the event that PanGenetics Patents include any patentable
improvements relating to the humanization of Anti-CD40 Mabs and fragments
thereof capable of binding the Human CD40 Molecule, or any other improvements to
Chiron Patents, the provisions of Article 1.4 and Section 3.9 shall apply.
1.15 "PANGENETICS TERRITORIES" shall mean Europe and Japan.
1.16 "SECOND GENERATION PRODUCTS" shall mean products which involve the
use of gene therapy solely for the endogenous local delivery and synthesis of
Anti-CD40 Mabs. Second Generation Products shall be governed by the provisions
of Article 7 of this Agreement, and shall not be governed by the provisions of
the Commercial License contemplated in Article 6. This Agreement grants
PanGenetics no license, express or implied, to create Second Generation
Products.
2. OWNERSHIP
PanGenetics hereby acknowledges and confirms that Chiron is the owner of
the Chiron Technology and the Chiron Patents. PanGenetics hereby agrees to
assign to Chiron all right, title and interest PanGenetics might acquire,
invent, develop or claim in Chiron
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improvements which fell within Claims Technology or Chiron Patents, or
improvements thereto, subject to the license rights granted to PanGenetics under
this Agreement. PanGenetics shall, without additional consideration from Chiron,
execute (or, if necessary, PanGenetics shall cause any of its employees to
execute) any assignment or other documentation reasonably required to record or
confirm such ownership by Chiron.
3. RESEARCH AND DEVELOPMENT LICENSE
The Parties commit to the following:
3.1 RESEARCH AND DEVELOPMENT LICENSE. Subject to the terms hereof, Chiron
hereby grants PanGenetics an exclusive, (except as to Chiron) research and
development license (the "Research and Development License") under the Chiron
Patents and Chiron Technology, solely to carry on research and development
activities worldwide with respect to the Licensed Products. This Research and
Development License grants PanGenetics no rights to make, use or sell Licensed
Products for commercial purposes. The Research & Development License is subject
to the provisions of Section 3.6 relating to due diligence. As provided in
Section 3.6, upon the failure of PanGenetics to fulfill its due diligence
obligations, Chiron shall have the right, but not the obligation, to terminate
the Research and Development License granted pursuant to this Section 3.1. In
the Event of such termination, Chiron shall retain all rights under the Chiron
Technology and Chiron Patients, and shall be granted rights under PanGenetics'
Patents and Technology pursuant to Section 5.2 of this Agreement.
3.2 EVALUATION OF PATENT RIGHTS. Chiron shall undertake commercially
reasonable efforts to prosecute and maintain all United States and foreign
patent applications and patents defining Chiron's rights in the Chiron
Technology and Chiron Patents. A report from an outside patent counsel assessing
the Parties' freedom of operation to develop, use, manufacture or sell Licensed
Products has been prepared and received by PanGenetics.
3.3 DE BOER PANGENETICS COUNSELING AGREEMENT. Subject to the rights and
obligations of Chiron and de Boer under the Consulting Agreements and their
subsequent amendments, PanGenetics and de Boer shall enter into a separate
agreement, (the "de Boer PanGenetics Consulting Agreement") to be effective on
the Effective Date, pursuant to which de Boer shall consult and collaborate with
PanGenetics, at no expense to Chiron, on research related to the Chiron
Technology, and the development of Licensed Product. The de Boer PanGenetics
Consulting Agreement may make provisions for coordinating the Anti CD40 Mab
related research activities of de Boer and PanGenetics with the anti CD40 Mab
related research activities of Professor Lucien Aarden at the Central Laboratory
of the Netherlands Red Cross Blood Transfusion Services ("CLB") in Amsterdam.
Any inventions made by de Boer within the Field which relate to or result from
collaborative activities, including, without limitation, collaborative
activities with the CLB, shall be subject to terms and conditions of this
Agreement, and if applicable, the terms and conditions of the 1991 MTA and
Consulting Agreements. PanGenetics and de Boer represent and warrant that any
and all collaborative activities undertaken by PanGenetics and de Boer shall
comply in all respects with the terms and conditions of this Agreement,
including, without limitation, the provisions of Section 3.4.
3.4 EMPLOYEE OBLIGATIONS. PanGenetics and de Boer represent and warrant
that all
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employees, representatives, agents or consultants who will be involved in
activities relating to this Agreement shall be bound by an obligation to assign
all inventions to PanGenetics and to cooperate with Chiron and/or PanGenetics in
connection with the patenting of any such inventions. Neither de Boer nor Pan
Genetics shall permit persons not bound by such obligations to work on the
Research.
3.5 RESEARCH & DEVELOPMENT PLAN. PanGenetics will product and submit to
Chiron for Chiron's review and approval a product development and business plan
(the "Research and Development Plan") which outlines the research and
development activities necessary to bring a Licensed Product to market. At a
minimum, PanGenetics' Research and Development Plan shall provide milestones
from early research activities though Phase III Clinical trials and evaluation,
which will permit Chiron to measure PanGenetics' diligence in complying with its
research and development obligations. The Research and Development Plan shall be
incorporated into this Agreement, and are attached as Exhibit 6.
3.6 DUE DILIGENCE. PanGenetics shall exercise its best efforts and due
diligence in developing and bringing to market a Licensed Product. Within four
(4) years after the Effective Date of this Agreement, PanGenetics shall enter
into clinical trials directed toward evaluating candidates for a Licensed
Product for commercial use. PanGenetics shall be solely responsible for
acquiring, and, if applicable, maintaining, any third party patents relating to
humanized Mabs and/or human Mabs and processes for making humanized Mabs and/or
human Mabs required by PanGenetics for the development and commercialization of
a Licensed Product. If, on the date occurring at the end of five (5) years from
the Effective Date, PanGenetics has not filed an IND or equivalent submission
related to Licensed Products with either the Japanese Koseisho, or a
corresponding regulatory agency in the United Kingdom, Germany, France or other
major market country in the European Community, Chiron shall have the right to
determine whether PanGenetics has made diligent efforts to produce Licensed
Products. In the event that Chiron reasonably determines that PanGenetics has
not satisfied the criteria set forth above, and has not exercised the requisite
diligence in developing Licensed Products, PanGenetics's license grant shall
continue, but PanGenetics shall pay to Chiron an annual maintenance fee of * to
preserve its rights under this Agreement. If, on the date occurring at the end
of eight (8) years from the Effective Date, PanGenetics has not released a
Licensed Product in any major market, and PanGenetics cannot demonstrate
commercially reasonable diligence in developing Licensed Products, Chiron shall
have the right to terminate this Agreement, and all license grants made to
PanGenetics hereunder shall revert back to Chiron. Once initiated, PanGenetics'
obligation to pay the * annual maintenance fee shall continue until PanGenetics
pays to Chiron the registration payment referenced in Section 6.6 of this
Agreement. PanGenetics' rights to undertake research and development activities
shall be subject to Chiron's First Refusal Rights as referenced in the
provisions of Section 6.12 of this Agreement.
3.7 PANGENETICS IMPROVEMENTS. Upon Chiron's request, as promptly as
reasonably practicable, PanGenetics shall supply Chiron with reasonable
quantities of improvements to Chiron Technology, including Anti-CD40 Mabs,
developed by PanGenetics, for Chiron's use. Further, in the event PanGenetics
develops any improvements relating to the humanization of Anti-CD40 Mabs and
fragments thereof capable of binding the Human CD40 Molecule, or any other
improvements to Chiron Patents, (the "PanGenetics Improvements") PanGenetics
shall assign to Chiron all right title and interest in such
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PanGenetics Improvements, including, without limitation, the right to file,
prosecute and maintain patients related to the PanGenetics Improvements. Chiron
shall grant back to PanGenetics licenses to such Pangenetics Improvements (the
"PanGenetics Improvement Grant-Back License"). During the term of the Research
and Development License, the PanGenetics Improvement Grant Back License(s) shall
be worldwide, co-exclusive and royalty free. Once the parties have concluded the
terms of the Commercialization License, the PanGenetics Improvement Grant-Back
Licenses shall be worldwide, co-exclusive and royalty free.
3.8 ASSIGNMENT OF DE BOER RIGHTS TO CHIRON. de Boer grants Chiron all
right, title and interest in the de Boer Rights existing as of the Effective
date. Further, de Boer and PanGenetics agree to undertake all measures necessary
to perfect Chiron's interest in all present and future de Boer Rights,
including, without limitation, the execution of assignments to convey all de
Boer Rights existing as of the Effective Date of this Agreement.
3.9 ASSIGNMENT OF DE BOER RIGHTS TO PANGENETICS AND CHIRON. deBoer Rights
arising from inventions within the Field made by de Boer after the conclusion of
the Consulting Agreements shall be governed by the terms and conditions of this
Agreement. de Boer and PanGenetics agree that de Boer shall assign all such de
Boer Rights to PanGenetics. de Boer and PanGenetics shall assign to Chiron all
patentable improvements relating to the humanization of Anti-CD40 Mabs and
fragments thereof capable of binding the Human CD40 Molecule for inclusion
within the Chiron Patent. PanGenetics and de Boer agree, represent and warrant
that the CD40 License & Collaboration Agreement between de Boer and Panorama,
dated October 1, 1994, and attached as Exhibit 7, is null, void, and of no
further effect. PanGenetics and de Boer further agree, represent and warrant
that they have undertaken or will undertake all measures necessary to render
such agreement null, void and of no legal effect.
3.10 PROGRESS MEETINGS During the term of the Research and Development
License, Chiron and PanGenetics shall meet at least annually to discuss research
and development progress and potential clinical indications and applications for
Licensed Products.
3.11 Except as set forth herein, PanGenetics shall have the sole
responsibility for, and shall bear the cost of, the research and development of
each Licensed Product. Chiron's sole responsibility shall be the prosecution and
maintenance of Chiron Patents, as provided herein. Prior to PanGenetics exercise
of its option rights as set forth in Article 4. Chiron shall pay for the
prosecution and maintenance of Chiron Patents in the United States all countries
listed in the PCT Patent Applications Schedule attached as Exhibit 1, to this
Agreement. After PanGenetics' exercise of its option rights as set forth in
Article 4, Chiron will pay for the prosecution and maintenance of Chiron Patents
in the Chiron Territories, and PanGenetics will reimburse Chiron for the cost of
filing, prosecution and maintenance of Chiron patents in the PanGenetics
Territories.
4. OPTION TO OBTAIN COMMERCIAL LICENSE
4.1 OPTION TO COMMERCIAL LICENSE. Subject to completion of the
obligations of Chiron, PanGenetics and deBoer set forth in Article 3 of this
Agreement, Chiron hereby grants PanGenetics, and Pangenetics hereby grants
Chiron, an option to obtain a commercial
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license (the "Commercial License"), subject to the provisions of Article 6. The
Commercial License shall grant Chiron and Pan Genetics all rights and licenses
necessary to make, use, have made and sell, market and otherwise commercialize
Licensed Product as provided in Article 6, including, without limitation,
licenses under the Chiron Technology, Chiron Patents, PanGenetics Technology,
PanGenetics Patents, any regulatory submissions and licenses. The Commercial
License shall be upon terms and conditions substantially similar to those set
forth below in Article 5 of this Agreement, and any additional terms of
conditions mutually acceptable to both parties and negotiated in good faith by
the parties. Such option shall be exercisable within six (6) months after the
injection of at least three patients with Licensed Product in a Phase I/II
clinical trial as referenced in the PanGenetics' Research and Development Plan
set forth in Exhibit 6.
5. TERM AND TERMINATION OF RESEARCH AND DEVELOPMENT LICENSE AND OPTION RIGHTS
5.1 TERM. This Research and Development License and Option Agreement
shall survive until:
5.1.1 the expiration of the options granted in Article 4 of this
Agreement;
5.1.2 the parties conclude the terms of the Commercial License in
accordance with Article 6 of this Agreement;
5.1.3 termination as provided below in Section 5.2.
5.2 TERMINATION. All licenses granted hereunder from one party to the
other may be terminated by written notice to the licensee party in the event
that the licensee breaches a provision of this Agreement and has failed to cure
or demonstrate the nonexistence of the breach within ninety (90) days of receipt
of a written notice and demand to cure such breach. Without limiting the
foregoing, if PanGenetics fails to perform its due diligence obligations
pursuant to Section 3.6, Chiron shall have the right, but not the obligation, to
terminate the Research and Development License or Option Right granted to
PanGenetics pursuant to this Agreement. In the event of such termination, the
following shall occur:
5.2.1 Chiron shall retain all rights under the Chiron Patents;
5.2.2 PanGenetics shall grant Chiron all licenses necessary to permit
Chiron to commercialize Licensed product, including, without limitation,
licenses to Pan Genetics Patents, PanGenetics Technology, regulatory
submissions and regulatory submissions and regulatory licenses. Such
licenses shall be worldwide and royalty free. Without limiting the
foregoing, in the event that PanGenetics obtains third party patents,
including, without limitation, any third party patents relating to
humanized Mabs and/or human Mabs and processes for making humanized Mabs
and/or human Mabs, PanGenetics shall (i) undertake commercially reasonable
efforts to secure the right to sublicense such patents, and (ii) shall
sublicense to Chiron Pangenetics' rights in such third party patents. With
respect to such licenses to third party patents, in the event that Chiron
wishes to exercise its right to obtain such sublicense, Chiron shall assume
PanGenetics' obligations with respect to earned royalties, but shall not
pay any milestone or other upfront fees.
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6. COMMERCIAL LICENSE AGREEMENT
6.1 TERMS. Upon the exercise of the option provided in Article 4 of this
Agreement, the Parties hereto shall enter into a commercial license agreement
(the "Commercial License") upon the terms and conditions set forth in this
Article 6.
6.2 CHIRON LICENSE GRANTS TO PANGENETICS. Chiron shall grant to
PanGenetics an exclusive Commercial License, with the right to sublicense
marketing rights only, to all rights and licenses necessary to make, have made,
use, sell market and otherwise commercialized Licensed Product(s) in the
PanGenetics' Territories, including, without limitation, licenses under the
Chiron Patents, Chiron Technology, and any regulatory submissions and approvals.
6.3 PANGENETICS LICENSE GRANTS TO CHIRON/EXCLUSIVITY AND
TERRITORIES. PanGenetics shall grant to Chiron an exclusive Commercial License,
to all rights and licenses necessary to make, have made, use, sell market and
otherwise commercialize Licensed Product(s) in the Chiron Territories, including
with the right to sublicense marketing rights, including, without limitation,
licenses under PanGenetics' Technology, PanGenetics Patents, and all regulatory
submissions and approvals.
6.4 MANUFACTURING RIGHTS. Chiron will have the right of negotiation to
manufacture the product for commercial sale world-wide. If the parties cannot
agree upon mutually acceptable terms for such manufacturing rights, each party
shall have the right to manufacture licensing products for commercial sale
within their respective territories.
6.5 MARKETING ARRANGEMENTS. Prior to the marketing of Licensed Product,
the parties shall agree on terms for the promotion and sale of Licensed Product.
The marketing provisions shall include appropriate termination and diligence
terms. In territories where the parties agree to co-promote or co-market
Licensed Product, the parties shall negotiate in good faith appropriate
compensation provisions that reflect the parties' relative contributions with
regard to the commercial sale of the Licensed Product. These negotiations shall
be subject to a time limit and the objective of the arrangements shall be to
maximize the economic return to both parties.
6.6 REGISTRATION PAYMENT. Within ninety (90) days after successful
registration of a Licensed Product by PanGenetics in either Japan, the United
Kingdom, France, or Germany, PanGenetics shall pay to Chiron One Million Dollars
($1,000,000) (the "Registration Payment").
6.7 ROYALTIES. Following the first Commercial Sale of a Licensed Product by
PanGenetics or Chiron pursuant to the Commercialization Agreement and licenses
granted therein, the party making such sale (the "Paying Party") shall submit to
the other party (the "Payee") within sixty (60) days of the end of every
calendar quarter a quarterly report setting out Net Sales of each Licensed
Product by country, royalty credits accumulated or taken, and sublicense
receipts, if any. The Paying Party shall, at the same time such report is
submitted, pay the Payee an earned royalty (the "Earned Royalty") in the amount
of * of Net Sales by the Paying Party or its affiliates of sublicensees, and *
of any up-front or milestone fees or other similar value received from
sublicensees.
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6.8 MANNER OF PAYMENT. All payments hereunder shall be made by bank
transfer to the bank account designated by the party to receive such payments.
Where required to do so by applicable law or treaty, the Paying Party shall
withhold taxes required to be paid to a taxing authority on account of such
income to the Payee, and the Paying Party shall furnish the Payee with
satisfactory evidence of such withholding and payment in order to permit the
Payee to obtain a tax credit or other relief as may be available under the
applicable law or treaty. If any sum due hereunder is not paid in full on the
due date, interest at the average prime rate for the month preceding payment of
the unpaid balance (as published from time to time by the THE WALL STREET
JOURNAL shall accrue and be payable on any unpaid balance from the date such
payment became due until the date paid.
6.9 RECORDS OF ROYALTY OBLIGATIONS. The Paying Party will keep and
maintain proper books and records as are required accurately to determine
royalties payable to the Payee for three (3) years following the date on which
such royalties were paid or reported. The Payee shall have the right, at its own
expense, to have such books and records examined by independent certified public
accountants acceptable to the Paying Party at reasonable times solely for the
purpose of verifying the accuracy of royalties paid or reported by the Paying
Party. The Payee shall bear the cost of any such inspection; provided, that in
the event the inspection discloses that any payments made to the Payee hereunder
for any accounting period were deficient by more than ten percent, the Paying
Party shall promptly reimburse the Payee for the cost of such independent audit
and shall pay to Payee the amount of such deficiency together with interest
thereon at the rate specified in Section 6.8 above.
6.10 TERM AND TERMINATION OF COMMERCIAL LICENSE AGREEMENT. Upon the later
of the expiration of the last to expire of the patent rights included in the
Chiron Parents, PanGenetics Patents, or Joint Technology Patents (if any), or
ten (10) years after the first commercial sale of Licensed Product, the
provisions of the Commercial License shall be of no further force and effect,
except for provisions of the Commercial License which impose obligations that
continue beyond the expiration of the agreement, including, without limitation,
provisions relating to confidentiality and indemnity. Prior to the expiration of
the last to expire of the Chiron Patents, PanGenetics Patents, or Joint
Technology Patents, neither party shall have the right to terminate the
Commercial License, except as follows:
6.10.1 Upon mutual written agreement of the parties; or
6.10.2 If a party materially breaches a material provision of the
Commercial License and has failed to cure or demonstrate the nonexistence
of the breach within ninety (90) days of receipt of a written notice and
demand to cure such breach; or
6.10.3 In the event that one of the parties becomes insolvent or
files for bankruptcy protection or fails generally to pay its debts as they
become due, makes an assignment of substantially all of its assets for the
benefit of creditors or applies for or consents to the appointment of a
custodian, trustee or receiver for such party or the majority of its
property, or if any other proceeding for relief under any bankruptcy law or
similar law for the relief of debtors is instituted by or against such
party and, if instituted against such party, is consented to or not
dismissed within ninety (90) days after such institution.
6.11 LIMITATION OF LICENSE. This license does not extend to any rights or
products other than those referred to herein.
10
<PAGE>
6.12 CHIRON'S FIRST REFUSAL RIGHTS.
6.12.1 GRANT OF RIGHT OF FIRST REFUSAL. PanGenetics grants Chiron a
right-of-first-refusal to obtain rights related to PanGenetics inventions;
provide funding for research or development activities; provide research or
development services; manufacture licensed product for commercial sale; and
market licensed product, within the Field of this Agreement in any country
(the "First Refusal Rights.")
6.12.2 NOTIFICATION TO CHIRON. PanGenetics shall promptly send to
Chiron, at the address specified herein, a reasonably detailed written
notification of any event which would give rise to the Chiron First Refusal
Rights referenced above. Chiron shall respond to PanGenetics within sixty
(60) days of its receipt of such notification of its interest in exercising
its First Refusal Rights.
6.12.3 NEGOTIATION OF TERMS. For a period of up to ninety (90) days
after PanGenetics receives notice of Chiron's intention to exercise its
First Refusal Rights, the parties shall negotiate in good faith a
reasonable agreement mutually acceptable to both parties.
6.12.4 COMMERCIALIZATION BY PANGENETICS. In the event that Chiron
fails to respond within sixty (60) days, or affirmatively indicates that it
is not interested in exercising its First Refusal Rights with respect to
the opportunity presented by PanGenetics, or the parties fail to reach a
definitive terms of agreement pursuant to Section 6.12.3, PanGenetics shall
be free to pursue other arrangements regarding the opportunity, either
independently or with one or more third parties, provided that PanGenetics
shall not offer to extend rights related to the opportunity to a third
party on terms more favorable than those previously offered to Chiron with
respect to such opportunity without first offering such more favorable
terms to Chiron.
7. SECOND GENERATION PRODUCTS
With respect to the development of any Second Generation Product, Chiron
and PanGenetics agree as follows:
7.1 NO LICENSE GRANTED FOR SECOND GENERATION PRODUCT. Nothing in this
Agreement shall be construed to grant to PanGenetics an express or implied
license under the Chiron Patents or Chiron Technology to undertake activities
related to the research, development, or marketing of a Second Generation
Product.
7.2 NOTICE. Each party agrees to keep the other party reasonably informed
of its activities which relate to the development of a Second Generation
Product. In the event that either party undertakes activities relating to the
research or development a Second Generation Product, each party shall notify the
other of such activities. Such notification and disclosure shall be subject to
the confidentiality obligations set forth in Article 9.
7.3 PANGENETICS' DEVELOPMENT OF SECOND GENERATION PRODUCT. With respect
to activities related to the development of a Second Generation Product that may
be undertaken by PanGenetics, the following shall apply:
11
<PAGE>
7.3.1 PanGenetics shall not undertake the internal commercial
development of any Second Generation Product without first obtained
Chiron's prior written approval;
7.3.2 PanGenetics shall not undertake any activities related to the
research or development of a Second Generation Product with any third party
without having obtained Chiron's prior written consent.
7.4 CHIRON'S DEVELOPMENT OF SECOND GENERATION PRODUCT. In the event that
Chiron undertakes activities related to the development of a Second Generation
Product, the following shall apply:
7.4.1 Chiron shall notify PanGenetics of its activities which relate
to Second Generation Product, as provided in Section 7.2.
7.4.2 PanGenetics may, at its discretion, present Chiron with
proposals regarding PanGenetics' participation in the Second Generation
Product research and development being undertaken by Chiron.
7.4.3 Chiron may, at its discretion, evaluate the PanGenetics
proposals referenced in Section 7.4.2, and may, at its discretion, invite
PanGenetics to enter into negotiations regarding the collaboration of
Chiron and PanGenetics in Second Generation Product related activities.
Neither party shall be obligated to collaborate with the other with respect
to such activities except upon terms and conditions mutually acceptable to
both parties.
7.4.4 In the event that (i) Chiron brings a Second Generation Product
to market in Europe or Japan, and (ii) Chiron and PanGenetics have not
entered into a definitive collaboration arrangement pursuant to Section
7.4.3 which provides additional compensation to PanGenetics in exchange for
value contributed by PanGenetics to the development of said Second
Generation Product, Chiron shall pay PanGenetics an earned royalty of * of
net sales of such Chiron Second Generation Product.
8. PATENT PROSECUTION, MAINTENANCE AND ENFORCEMENT
8.1 Chiron shall have the right and obligation to prepare, file and
maintain the Chiron Patents in the United States and the countries listed in the
PCT Patent Applications Schedule, and, if applicable, in such other countries as
Chiron may elect. Chiron shall use reasonable efforts to prosecute and maintain
the Chiron Patents. PanGenetics shall, at its cost and expense, cooperate fully
in such effort, including providing documentary support from de Boer if
necessary. Chiron shall keep PanGenetics informed as to the status of such
patent applications and provide to PanGenetics, upon PanGenetics' written
request, all relevant information relating to such applications.
8.2 PanGenetics shall, at its cost and expense, prepare, file and maintain
patent application(s) claiming the PanGenetics Technology in the United States
and all of the countries listed in the PCT Patent Application Schedule attached
as Exhibit 2, and such other countries as the parties mutually agree.
PanGenetics shall use diligent efforts toward the prosecution and maintenance of
the PanGenetics Patents. Chiron shall undertake reasonable cooperation in such
effort. In the event that PanGenetics files, prepares or otherwise
12
<PAGE>
prosecute patents relating to any patentable improvements relating to the
humanization of Anti-CD40 Mabs and fragments thereof capable of binding the
Human CD40 Molecule, or files, prepares or otherwise prosecutes any other
improvements related to subject matter claimed by the Chiron Patents,
PanGenetics shall grant to Chiron an option to obtain a license to the de Boer
Rights, which license shall be of such scope and upon such terms and conditions
as the parties may mutually agree.
8.3 Each party shall promptly notify the other if any legal proceedings
are commenced or threatened against either party or any purchaser of the
Licensed Products sold by either party on the ground that the manufacture,
possession, use, or sale of the Licensed Products is an infringement of a third
party's patent or other intellectual property rights. Each party shall, at its
own expense, conduct all suits brought against it as a result of the exercise of
the rights granted hereunder, and the other party shall, at the request and
expense of the party conducting such suit, give all reasonable assistance in any
such proceedings.
8.4 The preparation, filing and prosecution of patent application(s)
relating to any Joint Technology, if any, and the maintenance and prosecution of
any patent(s) resulting therefrom, shall be performed by counsel mutually
acceptable to the parties (which may be inside counsel for either party) and
costs for such preparation, filing, prosecution and maintenance shall be borne
equally by the parties. Decisions to abandon patents or patent applications
shall be taken jointly. The party conducting such activities shall keep the
other party reasonably informed and provide the other party with copies of
substantive actions from the US, European and Japanese Patent Offices, and (to
the extent feasible) provide the other party with copies of draft responses
thereto sufficiently in advance of filing to allow reasonable period for review
and comment. Filing of priority patent applications is to be undertaken without
delay introduced through consultation with the other party; nonetheless the
other party should be informed thereof as quickly as possible so that comments
from the other party can be considered in time for subsequent updated priority
applications. Each party agrees that it will not bring a claim for any act,
omission, fault or neglect against either the other party or its inside patent
attorney relating to that party's handling of the preparation, filing and
prosecution of any Joint Technology patent application or the maintenance and
prosecution of any patent(s) resulting therefrom.
9. CONFIDENTIALITY
9.1 CONFIDENTIALITY. Chiron and PanGenetics agree that, during the term
of this Agreement and for a period of five (5) years following the expiration or
termination of this Agreement, each of them shall maintain in confidence and not
disclose by any means any Confidential Information (as hereinafter defined)
received from the other party and to use such Confidential Information only in
furtherance of this Agreement. "Confidential Information" means any
confidential and proprietary information which is provided by one party to the
other party in writing or, if initially disclosed in non-tangible form,
summarized in writing within thirty (30) days after disclosure in non-tangible
form. The confidentiality and nondisclosure obligations shall not apply to the
extent that such disclosure is necessary for the prosecution and enforcement of
patents pursuant to this Agreement, or to comply with judicial decrees or
government actions or regulations; provided that the disclosing party shall use
all reasonable efforts to obtain confidential treatment of such disclosure to
the maximum extent permitted by law. In addition, such obligation of
confidentiality and limitation of use shall not apply to Confidential
Information that the receiving party can demonstrate:
13
<PAGE>
9.1.1 is known to the receiving party or is independently
developed, discovered or arrived at by the receiving party,
in each case to the extent evidenced by written records; or
9.1.2 was disclosed not subject to a confidentiality or similar
agreement to the receiving party by a third party that has
the right to make such disclosure; or
9.1.3 becomes patented, published or otherwise part of the public
domain through no fault of the receiving party; or
9.1.4 is required to be disclosed subject to a confidentiality
agreement or similar arrangement by order or regulation of
the FDA or similar authority in other countries of other
governmental or non-governmental authorities to facilitate
the issuance of marketing or safety approvals for products
licensed to either party or by order of a court of competent
jurisdiction; or
9.1.5 to the extent that it is provided to third parties under
appropriate terms and conditions, including confidentiality
and use provisions equivalent to those in this Agreement,
for subcontracting or consulting activities necessary for
conducting research and development.
Each party agrees to take all reasonable steps to protect the Confidential
Information of the other party in the same manner it ensures protection of its
own confidential or proprietary information.
10. MISCELLANEOUS
10.1 PROVISIONS CONTRARY TO LAW. In performing this Agreement, the
parties shall comply with all applicable laws. Nothing in this Agreement shall
be construed so as to require the violation of any applicable law, and wherever
there is any conflict between any provision of this Agreement and any applicable
law the law shall prevail, but in such event the affected provision of this
Agreement shall be affected only to the extent necessary to bring it within the
applicable law, provided that the resulting provisions are consistent with the
spirit and intent of the Agreement as originally entered into.
14
<PAGE>
10.2 NOTICES. Any notices required or permitted to be given by this
Agreement shall be given by postpaid, first class, registered or certified mail
addressed as set forth below unless changed by notice so given:
For Chiron: For PanGenetics: For Panorama:
Rajen Dalal James W. Larrick James W. Larrick
Vice President President President
Business Development PanGenetics B.V. Panorama Research Inc.
and Corporate Planning E. van Calcarstraat 30 2462 Wyandotte Street
Chiron Corporation 1963 DG Heeniskerk Mountain View,
4560 Horton Street The Netherlands California 94043
Emeryville, California 94608
U.S.A.
With a copy to:
General Counsel
Chiron Corporation
4560 Horton Street
Emeryville, California 94608
U.S.A.
10.3 USE OF NAMES. Neither party shall use the name of the other in any
promotional materials or advertising without the prior written consent of the
other.
10.4 ASSIGNMENTS. No license granted under this Agreement may be assigned
by the licensee except with the prior written consent of the licensor. The
licensor may assign its rights and obligations under such license upon
reasonable notice to the licensee.
10.5 WAIVERS AND MODIFICATIONS. The failure of any party to insist on the
performance of any obligation hereunder shall not act as a waiver of such
obligation. No waiver, modification, release or amendment of any obligation
under this Agreement shall be valid or effective unless in writing and signed by
both parties hereto.
10.6 SUCCESSORS IN INTEREST. This Agreement shall inure to the benefit of
and be binding on the parties' permitted assigns, successors in interest, and
subsidiaries.
10.7 NO WARRANTY. The licenses granted hereunder are provided WITHOUT
WARRANTY OF MERCHANTABILITY OF FITNESS FOR A PARTICULAR PURPOSE OF ANY OTHER
WARRANTY, EXPRESS OR IMPLIED. THE LICENSOR AS TO EACH LICENSE MAKES NO WARRANTY
THAT THE LICENSEE'S ACTIVITIES UNDER SAID LICENSES NOT NOT INFRINGE ANY PATENT
OR OTHER PROPRIETARY RIGHT OF A THIRD PARTY. The licensor will not be liable for
such infringement, or an allegation thereof, nor shall same be an excuse for
nonperformance of the licensee's obligations hereunder.
15
<PAGE>
10.8 MUTUAL INDEMNITIES. PanGenetics (and its Affiliates) shall
indemnify, defend, and hold harmless Chiron and its affiliates and their
officers and directors for any claim, demand, or injury arising out of the
actions of PanGenetics or its affiliates or sublicensees arising from or
relating to this Agreement; provided however that such indemnity shall not
extend to damages arising directly from any breach or willful or negligent act
of Chiron. Chiron shall indemnify, defend, and hold harmless PanGenetics and its
affiliates and their officers and directors for any claim, demand, or injury
arising out of the actions of Chiron or its affiliates or sublicensees arising
from or related to this Agreement; provided however that such indemnity shall
not extend to damages arising directly from any breach or willful or negligent
act of PanGenetics. The provisions of this Section shall survive expiration or
termination of this Agreement.
10.9 INSURANCE. PanGenetics shall at all times comply, through insurance or
self-insurance, with all statutory workers' compensation and employers'
liability requirements covering any and all employees with respect to activities
performed under this Agreement. In addition to the foregoing, PanGenetics shall
obtain and maintain, immediately prior to the first human clinical trial of a
Licensed Product, Comprehensive General Liability Insurance, including Products
Liability Insurance, with reputable and financially secure insurance carrier(s)
to cover the activities of PanGenetics and its sublicensee(s). Such insurance
shall provide minimum limits of liability of $2,000,000 per incident and shall
name Chiron as an additional insured party. Such insurance shall be written to
cover claims incurred, discovered, manifested, or made during or within five (5)
years after (a) the expiration of this Agreement, or (b) complete cessation of
sales of all Licensed Products, whichever is longer.
10.10 CHOICE OF LAW AND JURISDICTION. This Agreement is subject to and
shall be construed and enforced in accordance with the laws of the U.S.A. and
California. Chiron and PanGenetics shall attempt to settle any dispute or
controversy arising out of, or in connection with this Agreement without
resorting to litigation. If such attempts should fail, then the parties hereby
submit to arbitration in accordance with the rules then prevailing of the
American Arbitration Association ("AAA"), by one more arbitrator(s) appointed
in accordance with said rules as applicable at such time. The arbitration shall
be conducted in English and so shall be final, binding and enforceable.
10.11 ENTIRE AGREEMENT. Except as otherwise provided herein, this
Agreement constitutes the entire agreement between the parties hereto with
respect to the subject matter hereof, and all prior or contemporaneous
agreements, whether written or oral, or proposals or understandings concerning
the subject matter hereof are superseded hereby. This Agreement may be amended
only in a writing executed by both parties.
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<PAGE>
IN WITNESS WHEREOF, the parties have caused this agreement to be executed
as of the date first-above written.
CHIRON CORPORATION PAGENETICS, B.V.
By: /s/ LEWIS T. WILLIAMS By: /s/ JAMES W. LARRICK
Name: Lewis T. Williams Name: James W. Larrick
Title: Senior Vice President Title: Director
Date: September 25, 1995 Date: September 12, 1995
PANGENETICS B.V. PANORAMA RESEARCH INC.
By: /s/ MARK DE BOER By: /s/ JAMES W. LARRICK
Name: Mark de Boer Name: James W. Larrick
Title: Managing Director Title President
Date: September 17, 1995 Date: September 12, 1995
MARK DE BOER
By: /s/ MARK DE BOER
Name: Mark de Boer
Date: September 7, 1995
17
<PAGE>
EXHIBIT 1
WORLD INTELLECTUAL PROPERTY ORGANIZATION
PCT INTERNATIONAL BUREAU
INTERNATIONAL APPLICATION PUBLISHED UNDER
THE PATENT COOPERATION TREATY (PCT)
(51)INTERNATIONAL PATENT (11) INTERNATIONAL PUBLICATION NUMBER:
CLASSIFICATION(5): WO 94/01547
C12N 15/06, C12P 21/08 A2
C07K 15/00, C12N 15/86 (43) INTERNATIONAL PUBLICATION DATE:
A61K 39/395 20 JANUARY 1994 (20.01.94)
(21) INTERNATIONAL APPLICATION (81) DESIGNATED STATES: CA, JP, European patent (AT,
NUMBER: PCT/US93/06432 BE, CH, DE, DK, ES, FR, GB, GR, IE, IT, LU, MC,
NL, PT, SE).
(22) INTERNATIONAL FILING DATE:
8 July 1993 908.07.93)
(30) PRIORITY DATA: PUBLISHED
07/910,222 9 July 1992 WITHOUT INTERNATIONAL SEARCH REPORT AND TO BE
(09.07.92) US REPUBLISHED UPON RECEIPT OF THAT REPORT.
(71) APPLICANT: CETUS ONCOLOGY
CORPORATION [US / US]; 4560
Horton Street, Emeryville, CA
94608-2916 (US).
(72) INVENTORS: DE BOER, Mark; James
Stewartstraat 50, NL-132 JG
Almere (NL). CONROY, Leah, B.;
515 Beaumont Boulevard,
Pacifica, CA 94044 (US).
(74) AGENTS: McGARRIGLE, Philip, L.,
Jr. et al.; Chiron Corpora-
tion, 4560 Horton Street -
R440, Emeryville, CA 94608-2916
(US)
(54) TITLE: A METHOD FOR GENERATION OF ANTIBODIES TO CELL SURFACE MOLECULES
(57) ABSTRACT
The present invention relates to a method of generating antibodies directed
against cell surface antigens and its uses recombinant insect cells as
immunogens. The insect cells have been transfected with coding regions for a
molecule containing a cell surface antigen and these antigens are expressed on
the surface of the insect cells. Host animals are immunized with these
transfected insect cells to generate antibodies directed against the cell
surface antigen. Antibody-producing cells from the host animal are used to
generate monoclonal antibody-producing hybridoma cells. Sera and hybridoma
supernatants can be tested for the presence of antibodies against the surface
antigen, using the transfected cells in a screening assay. Specific antibodies
that have been generated by the present method are anti-B7 and anti-CD40
antibodies and they can be used to prevent or treat an antibody-mediated or
immune system disease in a patient. The anti-B7 antibodies can be used to cause
T cell anerty, treat allograft transplant rejection, treat graft versus host
disease, and prevent or treat rheumatoid arthritis. An immunosuppressive agent
may be co-administered with the antibody. The anti-CD40 antibodies which bind to
the CD40 antigen can be used to prevent the growth or differentiation of the B
cell. Monoclonal antibodies useful in these methods, and epitopes immunoreactive
with such monoclonal antibodies are also presented.
<PAGE>
FOR THE PURPOSES OF INFORMATION ONLY
Codes used to identify States party to the PCT on the front pages of
pamphlets publishing international applications under the PCT.
AT Austria FR France MR Mauritania
AU Australia GA Gabon MW Malawi
BB Barbados GB United Kingdom NE Niger
BE Belgium GN Guinea NL Netherlands
BF Burkina Faso GR Greece NO Norway
BG Bulgaria HU Hungary NZ New Zealand
BJ Benin IE Ireland PL Poland
BR Brazil IT Italy PT Portugal
BY Belarus JP Japan RO Romania
CA Canada KP Democratic People's RU Russian Federation
CF Central African Republic Republic SD Sudan
CG Congo of Korea SE Sweden
CH Switzerland KR Republic of Korea SI Slovenia
CI Cote d'Ivoire KZ Kazakhstan SK Slovak Republic
CM Cameroon LI Liechtenstein SN Senegal
CN China LK Sri Lanka TD Chad
CS Czechoslovakia LU Luxembourg TG Togo
CZ Czech Republic LV Latvia UA Ukraine
DE Germany MC Monaco US United States of America
DK Denmark MG Madagascar UZ Uzbekistan
ES Spain ML Mali VN Viet Nam
FI Finland MN Mongolia
<PAGE>
EXHIBIT 2
PanGenetics' Patent Schedule
<PAGE>
EXHIBIT 3
MATERIALS TRANSFER AGREEMENT
THIS AGREEMENT is made as of December 16, 1991, by and among Mark de Boer, Ph.D.
("Dr. de Boer") and Cetus Corporation ("Cetus").
A. During the course of his relationship with Cetus, Dr. de Boer has been
engaged in research in the area of T cell activation (the "Research").
B. Dr. de Boer wishes to continue certain aspects of the Research, and
Cetus desires to receive the benefits of the Research as set forth herein.
C. Therefore, Cetus is willing to provide Dr. de Boer with mouse
monoclonal antibody B7-24H4G12 and the related reagents/derivatives listed on
Attachment 1 hereto (which, together with any cell line, genetic material,
chemical or other substance derived by Dr. de Boer therefrom, constitute the
"Cetus Substances"); and confidential information, know-how, and data related
to the Cetus Substances (the "Cetus Confidential Information" which, together
with the Cetus Substances constitute the "Cetus Properties"). Cetus is willing
to allow Dr. de Boer to take the Cetus Properties with him under the terms of
this Agreement.
NOW, THEREFORE, the parties agree as follows:
1. SCOPE OF USE The Cetus Properties are provided to Dr. Boer only for his use
in the Research. Dr. de Boer agrees to maintain in confidence and not to
distribute, disclose, or release the Cetus Properties to any person other than
laboratory personnel directly under Dr. de Boer's supervision and will ensure
that no one may copy, send, or take the Cetus Properties to any other location,
or use the Cetus Properties in research which is subject to a licensing or
consulting obligation to a third party (other than the U.S. Government), unless
written permission is obtained from an authorized representative of Cetus. Dr.
de Boer promises that the Cetus Properties will be used only in laboratory
animals or in IN VITRO experiments and will not be used in human beings.
2. FREEDOM TO PUBLISH Dr. de Boer is free to present or publish the fundings of
the Research in a scientific publication, or public noncommercial conference, or
similar forum, provided that: (a) no Cetus Confidential Information is revealed
thereby; and (b) at lease 30 days prior to submission thereof to a publisher or
any third party, Dr. de Boer shall have delivered copies of the proposed
presentation or publication to Cetus for review. Cetus may, within 30 days of
such delivery, object to the publication or presentation because there would be
a disclosure of Cetus Confidential Information or because there is patentable
subject matter, in which Cetus has an interest under paragraph 4, which needs
protection. Upon Cetus' request, Dr. de Boer shall, for up to 60 days from
initial delivery to Cetus, delay disclosing such patentable subject matter in
order to permit the filing of patent applications thereon. The parties shall, in
any publication, acknowledge the contributions and publication of the other as
scientifically appropriate.
3. DISCLOSURES Dr. de Boer will promptly provide a full written "Disclosure"
to Cetus of any invention, improvement, or discovery made in the Research using
the Cetus Properties (an "Invention"). Cetus shall be free to use such
findings for any purpose. Except as expressly set
LMTA (5/91) PAGE 1 AGT 7655
<PAGE>
forth in this Agreement, neither party shall obtain rights in or a license to
any patent, copyright, trademark or other intellectual property right of the
other.
4. TITLE AND INVENTIONS All right, title, and interest in the Cetus Properties
shall belong to Cetus. Cetus shall be free, in its sole discretion, to
distribute the Cetus Properties to others and to use them for its own purposes.
In consideration of access to the Cetus Properties, Dr. de Boer hereby grants
Cetus and its affiliates an option to a non-exclusive royalty-free worldwide
license, and grants a further option to an exclusive license bearing a
reasonable royalty for such territories as Cetus may request, in any patent
issuing on an Invention. Cetus may exercise its option within one year of its
receipt of the written Disclosure described herein. A "reasonable royalty"
shall take into account the relative contributions of the parties to the
pertinent product and industry standards and shall be arbitrated by the American
Arbitration Association if the parties cannot in good faith agree on it.
5. CONTACT WITH COLLABORATORS Dr. de Boer may communicate and cooperate
regarding the Research with Cetus' collaborators who are rightfully possessing
and using the Cetus Properties, set forth in Attachment 2. To the extent, if
any, that an Invention arises from such collaboration, the rights in it shall be
governed by the respective agreements with Cetus. Dr. de Boer shall not initiate
new collaborations except through Cetus.
6. NO WARRANTY The Cetus Properties are investigational and experimental in
nature and are provided WITHOUT WARRANTY OF MERCHANTABILITY OR FITNESS FOR A
PARTICULAR PURPOSE OR ANY OTHER WARRANTY, EXPRESS OR IMPLIED. CETUS MAKES NO
REPRESENTATION OR WARRANTY THAT THE USE OF THE CETUS PROPERTIES WILL NOT
INFRINGE ANY PATENT OR OTHER PROPRIETARY RIGHT. To the extent permitted by law,
Dr. de Boer will hold Cetus harmless from any claims or liability arising from
the use, handling or storage of the Cetus Substances.
7. COMPLIANCE WITH LAW Dr. de Boer shall use the Cetus Properties in
compliance with all applicable laws and regulations including, where applicable,
those relating to the treatment of laboratory animals and current NIH
guidelines.
8. TERMS This Agreement is the entire agreement between Cetus and Dr. de Boer
relating to the Cetus Properties, and may not be modified, assigned or
transferred without the written consent of an authorized representative of
Cetus. This Agreement shall be governed by the law of California.
IN WITNESS WHEREOF, the Cetus and Dr. de Boer have executed this Agreement
as of the day and year first above written.
CETUS CORPORATION MARK DE BOER, PH.D.
By: /s/ JAMES H. MEADE /s/ MARK DE BOER, PH.D.
James H. Meade, Ph.D. Signature
Senior Director
Scientific Administration
LMTA (5/91) PAGE 2 AGT 7655
<PAGE>
EXHIBIT 3
ATTACHMENT 1
cDNA for soluble B
cDNA for full length B7
cDNA for ICAM-1
cDNA for ICAM-2
cDNA for LFA-3
cDNA for CD5G
cDNA for ELAM
cDNA for VCAM
recombinant baculovirus for soluble B7
recombinant baculovirus for full length B7
hybridoma cell line B7-24
3T6 cells expressing B7
3T6 cells expressing ICAM-1
Four PUC vectors with cloned VH and VL of B7-24
LMTA (5/91) PAGE 3 AGT 7655
<PAGE>
EXHIBIT 3
ATTACHMENT 2
Agt. No. Collaborator Name Institution
---------- ----------------- ----------------------------------
* * *
LMTA (5/91) PAGE 4 AGT 7655
<PAGE>
EXHIBIT 3
C H I R O N
July 24, 1992
Mark de Boer, Ph.D
Innogenetics
Industriepark 7-box 4
B-9052 Zwijnaarde
BELGIUM
RE: Letter Amendment #1 to Materials Transfer Agreement #7655
Dear Dr. de Boer:
Incorporating the terms and conditions of the Materials Transfer Agreement dated
December 16, 1991 by and among Cetus Corporation and you, we would like to add
murine B7 PCR primers GM546 through GM549 and murine library ML1019B to the
materials provided to you by Cetus. Accordingly, murine B7 PCR primers GM546
through GM549 and murine library ML1019B have been added to Attachment 1 of the
Agreement. The revised Attachment 1 is attached hereto.
If you agree to this amendment, please sign both originals of this letter and
return one original to Ms. Gaye Engler, Contracts Administrator, Legal
Department. The second original is provided for you records.
This Amendment #1, together with the Materials Transfer Agreement dated December
16, 1991, constitutes the entire agreement between the parties hereto regarding
the subject matter thereof and supersedes any prior or contemporaneous
agreement, understanding or negotiations.
If you have any questions, please feel free to contact Ms. Engler at
(510)601-2916.
Sincerely, Agreed to and Accepted by:
CHIRON CORPORATION MARK DE BOER, PH.D.
By: /s/ PABLO D. T. VALENZUELA /s/ MARK DE BOER
Pablo D. T. Valenzuela, Ph.D. Signature
Senior Vice President
Biological Research &
Development
La-Amd. (Rev. 9/90) Agt. 7655, Amd. 1
Chriron Corporation o 4560 Horton Street o Emeryville, CA o 94608-2916
o 510-655-8730
Law Department o General Fax: 510-654-5360 o Intellectual Property Fax:
510-655-3542
<PAGE>
EXHIBIT 3
ATTACHMENT 1
cDNA for soluble B7
cDNA for full length B7
cDNA for ICAM-1
cDNA for ICAM-2
cDNA for LFA-3
cDNA for CD5G
cDNA for ELAM
cDNA for VCAM
ML1019B murine library
Murine B7 PCR primers GM 546 through GM 549
recombinant baculovirus for soluble B7
recombinant baculovirus for full length B7
hybridoma cell line B7-24
3T6 cells expressing B7
3T6 cells expressing ICAM-1
Four PUC vectors with cloned VH and VL of B7-24
LMTA (5/91) PAGE 3 AGT 7655
<PAGE>
EXHIBIT 3
AMENDMENT #2 TO
MATERIALS TRANSFER AGREEMENT
BETWEEN
CHIRON CORPORATION AND DR. MARK DE BOER
Incorporating the terms and conditions of the Materials Transfer Agreement dated
December 16, 1991 and the Letter Amendment #1 dated July 24, 1992 by and between
Chiron Corporation and Dr. Mark de Boer, the Agreement is herein amended,
effective December 17, 1991, by adding anti-CD40 to Attachment 1 of the
Agreement. The revised Attachment 1 is attached hereto.
This Amendment #2, together with the Materials Transfer Agreement dated December
16, 1991 and the Letter Amendment #1 dated July 24, 1992, constitutes the entire
agreement between the parties hereto regarding the subject matter thereof and
supersedes any prior or contemporaneous agreement, understanding or
negotiations.
Agreed to and Accepted by:
CHIRON CORPORATION MARK DE BOER, PH.D.
By: /s/ NIEK J. ROOSDORP /s/ MARK DE BOER
Niek J. Roosdorp, Ph.D. Signature
Vice President
Business Development
<PAGE>
EXHIBIT 3
ATTACHMENT 1
cDNA for soluble B7
cDNA for full length B7
cDNA for ICAM-1
cDNA for ICAM-2
cDNA for LFA-3
cDNA for CD5G
cDNA for ELAM
cDNA for VCAM
ML1019B murine library
Murine B7 PCR primers GM546 through GM549
recombinant baculovirus for soluble B7
recombinant baculovirus for full length B7
hybridoma cell line B7-24
3T6 cells expressing B7
3T6 cells expressing ICAM-1
four PUC vectors with cloned VH and VL of B7-24
anti-CD40
<PAGE>
EXHIBIT 4
CONSULTING AGREEMENT
THIS AGREEMENT is effective as of January 1, 1993 by and between Chiron
Corporation ("Chiron"), and Dr. Mark de Boer ("Consultant").
1. CONSULTANCY. Chiron hereby retains Consultant, and Consultant hereby
accepts such retention, commencing as of the date of this Agreement and
continuing for one (1) year thereafter.
2. SERVICES. Consultant shall serve as a consultant to Chiron and its
subsidiaries and affiliates in the area to anti-CD40 (the "Field").
3. COMPENSATION. In consideration of Consultant's provision of consulting
services to Chiron, Chiron will pay Consultant a quarterly fee of *. In
addition, Chiron will reimburse Consultant for reasonable expenses approved in
advance by Chiron.
4. OUTSIDE EMPLOYMENT. (a) During the term of this Agreement Consultant
may be engaged by one or more other "Institutions(s)." Consultant represents
that he is not and shall not become a party to any agreement which conflicts
with the duties hereunder. Consultant shall use best effects to segregate work
done under this Agreement from work at an Institution, or done with Government
funding, so as to minimize any questions of disclosure or ownership of rights
under any Inventions or Confidential Information. Chiron may terminate this
Agreement if in its sole opinion the performance of such work will conflict with
its interests.
(b) Consultant shall not disclose to Chiron any inventions, trade secrets,
or other information of third parties that Consultant does not have the right to
disclose and that Chiron is not free to use without liability.
5. INVENTIONS. (a) "Invention" shall mean and refer to any composition
of matter, device, process, treatment, or improvement thereof discovered,
created, made, conceived, or reduced to practice ("Invented") by Consultant,
whether patentable or not, during the term of this Agreement and which: (i) was
Invented with the equipment, supplies, facilities, or Confidential Information
of Chiron or those acting on its behalf, or (ii) was Invented by Consultant
while performing services for Chiron, or (iii) resulted from any work performed
by Consultant for Chiron under this Agreement.
(b) Chiron shall own all right, title and interest in any Invention.
Consultant shall promptly, and without royalty but at Chiron's expense: (i)
disclose to Chiron all information with respect to any Inventions, (ii) execute
all applications, assignments, and other instruments and do such other acts that
Chiron may deem necessary to obtain and maintain patents, copyrights, and
similar rights anywhere in the world, and (iii) provide Chiron evidence needed
in any legal proceedings regarding the Invention.
6. CONFIDENTIALITY. (a) During the term of this Agreement and any
subsequent extensions, and for a period of one (1) year thereafter, Consultant
will not disclose without prior written consent of Chiron, any Chiron
Confidential Information. As used in this Agreement, "Confidential
Information" shall mean all data, technical information, commercial and
research strategies, trade secrets, and know-how disclosed by Chiron to
Consultant, directly or indirectly, whether in writing or orally except for such
information and know-how that (i) can be shown by contemporaneous documentation
to have been in Consultant's possession prior to disclosure by Chiron; (ii) at
the time of disclosure hereunder is, or thereafter becomes, through no fault of
Consultant, part of the public domain; or (iii) is furnished to Consultant by a
third party after the time of disclosure hereunder without the breach of any
duty to Chiron.
(b) Consultant shall not use any Confidential Information except for the
purposes of this Agreement unless Chiron shall otherwise agree in writing.
Consultant may disclose Confidential Information only to employees or agents who
have a need to know the Confidential Information for the purposes of this
Agreement and who are bound in writing to maintain the secrecy of the
Confidential Information and assign to Chiron any Inventions which they may
make.
(c) Consultant shall keep separate and segregated from other work all
documents, records, notebooks, correspondence, deposits of microorganisms, cells
or parts thereof, cell lines, part and progeny thereof, and
Page 1 f:\wpgen\done\agt 11092
<PAGE>
all products made thereby, arising from the work under this Agreement. All
right, title, and interest therein shall belong to Chiron, and upon expiration
or termination of this Agreement, all such documents and material, including
copies thereof, whether prepared by Consultant or others, will be delivered to
Chiron.
(d) Consultant may lecture upon, disseminate, and publish under
Consultant's own name scientific papers arising from the work done in the course
of performance of services for Chiron hereunder, but only upon the prior written
approval of Chiron. Chiron will not unreasonably withhold its approval provided
Confidential Information will not be disclosed thereby. Appropriate credit will
be given to Chiron in any publication.
7. NOTICE. ANY NOTICE TO CHIRON SHALL BE ADDRESSED AS FOLLOWS OR AS SHALL
BE SPECIFIED BY A PARTY IN WRITING:
If to Chiron: If Consultant:
Chiron Corporation Mark de Boer, Ph.D.
4560 Horton Street Meersenier Straat 13B
Emeryville, California 94608 Ghent B9000
Attention: Contracts Administrator BELGIUM
Legal Department
8. SURVIVAL AND TERMINATION. The terms and obligations of paragraph 5 and
6 shall survive termination of this Agreement for any reason whatsoever. If
Consultant breaches any of term of this Agreement Chiron may, in addition to any
other remedy, terminate Consultant's services by notice to Consultant by letter,
facsimile, telephone call, in person, or other reasonable means by any officer
or agent of Chiron.
9. ENTIRE AGREEMENT. This Agreement is the entire agreement of the
parties relating to the subject matter hereof, and supersedes all prior and
contemporaneous negotiations, correspondence, understandings, and agreements of
the parties relating to the subject matter hereof. It may be amended only by an
agreement in writing, signed by both parties.
10. NOT AN EMPLOYEE. Consultant is an independent contractor and is not
an employee or agent of Chiron. Consultant shall be entitled to no benefits or
compensation from Chiron except as set forth in this Agreement and shall in no
event be entitled to any fringe benefits payable to employees of Chiron.
IN WITNESS WHEREOF, the parties have executed this Agreement as of the date
first written above.
Agreed to and Accepted by:
CHIRON CORPORATION MARK DE BOER, PH.D.
By: /s/ NIEK J. ROOSDORP /s/ MARK DE BOER
Niek J. Roosdorp Signature
Vice President
Business Development
Page 2 f:\wpgen\done\agt 11092
<PAGE>
EXHIBIT 4
AMENDMENT #1 TO THE CONSULTING AGREEMENT
MADE BETWEEN
CHIRON CORPORATION
AND
DR. MARK DE BOER
Incorporating the terms and conditions of the Consulting Agreement dated January
1, 1993 made by and between Chiron Corporation and Dr. Mark de Boer, Section 1
and 2 of the Agreement is herein amended, effective January 1, 1994, to read as
follows:
"1. CONSULTANCY. Chiron hereby retains Consultant, and Consultant hereby
accepts such retention, commencing as of the date of this Agreement and
continuing for two (2) years thereafter."
"2. SERVICES. Consultant shall serve as a consultant to Chiron and its
subsidiaries and affiliates in the area of anti-CD40 and *.
This Amendment #1, together with the Consulting Agreement dated January 1, 1993,
constitutes the entire agreement between the parties hereto regarding the
subject matter thereof and supersedes any prior or contemporaneous agreement,
understanding or negotiations.
CHIRON CORPORATION MARK DE BOER, PH.D.
By: /s/ PATRICIA A. OLSON, PH.D. /s/ MARK DE BOER
Patricia A. Olson, Ph.D. Signature
Director, Research Operations
f:\wpgen\done\footer.amd\agt 11092.1
<PAGE>
EXHIBIT 5
MATERIALS TRANSFER AGREEMENT
Chiron Corporation ("Chiron") and Panorama Research, Inc. ("Institution"),
agree effective as of November 9, 1994 as follows:
1. RESEARCH.
a. Chiron is furnishing the following Chiron properties (the "Chiron
Properties"): (i) baculovirus strains AcCD40B and AcCD40C, containing gene
sequences for the extracellular domain (ECD) of human CD40 with, respectively,
the "KT3" or "gluglu" peptide tag expressed at the C terminus of the ECD;
(ii) SF9 insect cells; and (iii) KT3 and E5 monoclonal antibodies, which
respectively bind the KT3 or gluglu peptides tags.
b. These Chiron Properties are provided only for use in the following
non-commercial research activities (the "Research"): (i) AcCD40B and AcCD40C
may be used to produce soluble human CD40 ECD for use in screening and
characterizing humanized versions of anti-CD40 monoclonal antibodies; (ii) the
SF9 insect cell may be used to produce CD40 ECD; and (iii) KT3 or E5 monoclonal
anti-tag antibodies may be used for affinity purification.
2. PROPERTIES. The "Chiron Properties" are:
a. "Chiron Substances," including the materials provided by Chiron and
any part or portion of them, even if combined with other substances; if Chiron's
contributed materials have genetic material (such as a cell line, probe or
plasmid) then the Chiron Substances also include any progency, mutant, hybrid,
nucleic acid, or other material containing any portion of genetic material from
the Chiron Substances and any copy, complement, or transcription or expression
product of them; and
b. "Chiron Information," which includes Chiron's confidential
information, know-how, and data related to the Chiron Substances. Chiron
Information does not include information which: is shown by written records to
have been in Institution's possession before receipt from Chiron; is or becomes,
through no fault of Institution, part of the public domain; or is received from
a third party without breach of a duty to Chiron.
3. CONFIDENTIALITY. Institution shall maintain in confidence and not disclose
the Chiron Information to any third party without the written permission of an
authorized representative of Chiron.
4. USE. The Chiron Properties shall belong solely to Chiron and may only be
used by personnel of Institution under the terms hereof. The Chiron Properties
may not be taken to another location or used in research which is subject to a
licensing or consulting obligation to a third party (other than the U.S.
Government) unless Chiron has first consented in writing. The Chiron Properties
shall not be used in human beings, and shall be used in compliance with all
applicable laws and regulations including, where applicable, those relating to
the treatment of laboratory animals and current NIH guidelines. Upon Chiron's
request, Institutions shall stop using the Chiron Properties and shall, at
Chiron's election promptly return or destroy the Chiron Properties in their
possession, including all copies.
Chiron LMTA (6/94)
Page 1 of 2 f:\wpgen\done\footer.mta\panorama.mta
<PAGE>
5. PUBLICATION. The Institution shall periodically report to Chiron the
results of the Research involving the Chiron Properties for Chiron's internal
use. Institution may also present or publish the findings of the Research in a
scientific publication, conference or similar not-for-profit forum, provided
that: (a) no Chiron Information is revealed thereby; and (b) at least 45 days
prior to submission to a publisher or presentation to any third party,
Institution delivers copies of the proposed presentation or publication to
Chiron for review. At Chiron's request, Institution will, for a reasonable
period up to 90 days from initial delivery to Chiron, delay revealing any
patentable subject matter in the disclosure in order to permit the filing of
patent applications. In any publication, the parties will consider joint
authorship and acknowledge the contributions and publications of the other as
scientifically appropriate.
6. INVENTIONS. If an invention results from the use of the Chiron Properties,
Chiron shall have a non-exclusive royalty-free license to use such invention for
internal research purposes. Chiron shall also have an option to a license
bearing a reasonable royalty for such territories and scope of exclusivity as
Chiron may request in any patents or patent applications relating to such
inventions, the terms of which license will be negotiated in good faith and will
be arbitrated if the parties cannot agree. The option will be exercisable no
later than six months after Chiron's receipt of Institution's written request
that Chiron exercise or waive its rights with respect to a particular patent
application. Chiron may, at its election and expense, pursue and obtain patent
protection in consultation with Institution for any invention as to which Chiron
is a joint assignee or as to which Chiron has a right to an exclusive license
hereunder.
7. RISKS. The Chiron Properties are experimental in nature and are provided
WITHOUT WARRANTY OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE, OR ANY
OTHER WARRANTY OF NONINFRINGEMENT OR TITLE, EXPRESS OR IMPLIED. To the extent
permitted by law, Institution will indemnify and hold Chiron harmless from any
claims or liability arising from the use, handling or storage of the Chiron
Properties by Institution. Chiron will indemnify and hold Institution harmless
arising from any claim arising from Chiron's use of the findings of the
Research.
8. TERMS. Except as expressly set forth, nothing in this Agreement grants
either party rights or a license to any patent, copyright, trademark or other
intellectual property rights of the other. This Agreement is governed by the
laws of the State of California, is the entire agreement of the parties relating
to the Chiron Properties, and may not be modified, assigned or transferred
without the written consent of an authorized representative of Chiron.
CHIRON CORPORATION PANORAMA RESEARCH, INC.
By: /s/ LEWIS T. WILLIAMS By: /s/ J.W. WARRICK
Lewis T. Williams, M.D., Signature of Authorized Representative
Ph.D. Name: James W. Warrick
Senior Vice President Title: President
Research & Development
President, Chiron
Technologies
Chiron LMTA (6/94)
Page 2 of 2 f:\wpgen\done\footer.mta\panorama.mta
<PAGE>
EXHIBIT 6
PANGENETICS B.V. ***CONFIDENTIAL*** JULY 1995
PANGENETICS RESEARCH AND DEVELOPMENT PLAN
TITLE: HUMANIZED MONOCLONAL ANTIBODIES TO CD40 FOR THE TREATMENT OF AUTOIMMUNE
DISEASES
PROJECT CODE: A1-01
1. RATIONALE AND BACKGROUND
Most responses of our immune system, whether beneficial or deleterious
consists of an interplay of more than one lymphocyte subtype. The cellular
communication needed is mediated by soluble signaling molecules (cytokines) or
by direct cell-cell contact. The current believe is that cytokines predominately
act as modulators, whereas the specificity in cellular communications is
mediated by direct cell-cell contract. During cell-cell contact, key
ligand-receptor interactions transmit signals that determine the fate of the
receiving cell, with possible outcomes such as proliferation, differentiation or
cell death. At least two signals are required for immune cell activation. One of
these is highly specific for the antigen, the T cell receptor on T cells and
surface immunoglobulin on B cells. The other accessory signal is required to
consolidate and amplify the specific signal.
Two ligand-receptor systems that play a crucial role in the outcome of
cognate interactions between lymphocytes have recently been identified. First,
ligation of the B7 molecules on antigen-presenting cells such as
monocytes/macrophages and B lymphocytes with CD28/CTLA-4 on T lymphocytes.
Second, the ligation of CD40 ligand (CD40L) on activated T cells with CD40 on B
cells, dendritic cells and monocytes/macrophages. Recent experimental data from
others and ourselves clearly indicate that these cellular interactions may play
a role the pathophsiology of various autoimmune diseases.
2. CD40 AND ITS LIGAND
The CD40 molecule belongs to the TNF receptor family of type 1
transmembrane proteins. The members of this gene family, which include: the two
receptors for TNF the low-affinity nerve growth factor receptor; the T cell
activation antigens CD27, OX40 and 4-1BB; CD30 and; the FAS antigen, are
characterized by sequence homology in their cysteine-rich extracellular domains.
Cross-linking of the CD40 molecule with monoclonal antibody mediates a variety
of effects on B cells. Anti-CD40 monoclonal antibodies can induce homotypic and
heterotypic adhesion; mediate B-cell proliferation; promote the production of
IL-6 by B cells; and enhance soluble CD23 release from B cells. In addition, it
has been demonstrated that anti-CD40 monoclonal antibodies presented on
FcyRll-bearing mouse fibroblasts can support the outgrowth of long-term B-cell
lines and, in combination with certain cytokines, induce maturation to antibody
secreting cells. Furthermore, anti-CD40 monoclonal antibodies can prevent
programmed cell dead of B cells isolated from lymph node germinal centers.
Interestingly, the known ligands for the members of the TNF receptor
family are very homologous as
1
<PAGE>
well, forming an other gene family named the TNF/CD40L gene family. Although
TNF-(alpha) is a soluble cytokine, it is initially synthesized as a membrane
associated molecule. Most of the members of the TNF/CD40L receptor family are
type II transmembrane proteins. CD40L has had a lot of attention over the last
few years. The expression of the CD40L seems to be restricted to activated CD4+
T cells. It has recently been demonstrated by others and ourselves, that
activation of T cells through the TcR/CD3 complex and the CD80-CD28 interaction
is most likely the physiological trigger for CD40L expression. Not only is the
appearance of the CD40L on the cell surface tightly regulated, once engaged with
CD40, the molecule rapidly disappears again. The tight regulation of cell
surface ex2pressison of the CD40L seems logical given its potent biological
activities. The CD40L can stimulate the proliferation of purified B cells and,
in combination with cytokines mediate immunoglobulin production. Stimulation of
human B cells with CD40L in combination with IL-2 or IL-10 specifically enhances
the production of IgM, IgG and IgA, whereas addition of IL-4 or IL-13 enhances
the production of IgG4 and IgE. Furthermore, recombinant CD40L is able to
prevent apoptosis in normal and neoplastic B lymphocytes. It has recently been
demonstrated that in addition to the potent activities of CD40L on B cells, the
molecule can induce cytokine production and tumoroidal activity from monocytes.
This stimulatory activity of the CD40L on human monocytes correlates well with
the expression of the CD40 molecule on these cells. Finally, it was very
recently demonstrated that activation of dendritic cells through CD40
cross-linking strongly enhances their T-cell stimulatory capacity and induces
the secretion of pro-inflammatory cytokines.
3. THE IN VIVO IMPORTANCE OF THE CD40L-CD40 INTERACTION.
All the above described IN VITRO observations correlate well with the
recent finding that abnormalities in the gene for the CD40L, resulting in the
absence of a functional molecule on activated T cells, is responsible for the
occurrence of X-linked hyper-IgM syndrome (HIGM1). HIGM1 is one of at least
several inherited immunodeficiencies mapped to the X-chromosome and is
characterized by very low serum levels of IgG, IgA and IgE but normal or
elevated IgM, with a resultant susceptibility to opportunistic bacterial
infections. Interestingly, affected individuals are also prone to infections
more typical of T-cell deficiencies such as PNEUMOCYSTIC CARINII pneumonia and
cryptosporidial diarrhoea. More recently, the HIGM1 phenotype was also found in
genetically altered mice deficient for either CD40 or the CD40L. These data
clearly demonstrate the importance of this cellular interaction for competent
immune responses.
4. THE ROLE OF CD40L-CD40 IN AUTOIMMUNE DISEASES
There is an increasing number of scientific studies that clearly indicate
the involvement of the CD40L-CD40 interaction in the pathophysiology of various
autoimmune diseases. In these studies using mice suffering from spontaneous or
experimental autoimmune disease, blocking the CD40L-CD40 interaction had clear
beneficial effects. Also a number of IN VITRO observations using mouse and human
lymphocytes, as well as immunohistochemical analysis of pathological specimen
supports this hypothesis.
A. RHEUMATOID ARTHRITIS (RA)
Using a blocking mAb to the murine CD40L, it has been shown that it
possible to prevent
2
<PAGE>
PANGENETICS B.V. ***CONFIDENTIAL*** JULY 1995
collagen-induced arthritis in mice. The antibody treatment blocked the
development of joint inflammation, serum antibody titers to collagen, the
infiltration of inflammatory cells into the subsynovial tissue, and the
erosion of cartilage and bone. More recently, it was found that recombinant
CD40L strongly stimulates the production of pro-inflammatory cytokines such
as TNF-(alpha) by synovial cells obtained from inflamed joints of RA
patients.
C. MULTIPLE SCLEROSIS (MS)
Experimental allergic encephalomyelitis is an animal model for MS. It has
recently been found that injection of mice with antibody to CD40L at the
time of disease induction, completely prevents disease. More interestingly,
it has also been found that treatment with anti-CD40L after disease onset,
even shortly before maximum disability score is reached, leads to a dramatic
disease reduction. In MS, demyelination is thought to be the result of the
release of toxic mediators such as TNF-(alpha) and nitric oxide, released by
macrophages and or microglia. It is known some time that activated T cells
can induce the production of large amounts of nitric oxide. This was thought
to be mediated by the secretion of pro-inflammatory cytokines such as IFN-y
and TNF-(alpha). However, it was very recently demonstrated that a direct T
cell-macrophage contact is needed for optimal induction of nitric oxide,
which could largely be inhibited by anti-CD40L mAb. When we combine these
data with our recent findings that in MS lesions activated T cells
expressing CD40L co-localize with CD40-positive B cells (producing
antibodies to myelin basic protein) and CD-40-positive macrophages (capable
of producing toxic mediators such as TNF-(alpha) and nitric oxide), strongly
suggest that the CD40L-CD40 interaction plays a role in the pathophysiology
of MS.
C. SYSTEMIC LUPUS ERYTHEMASTOSUS (SLE)
In (SWR x NZB)F1 mice (lupus mice), pathogenic autoantibodies cause fatal
lupus nephritis. The generation of these autoantibodies is a T-cell
dependent process. It has very recently been demonstrated that lupus mice
have much higher percentages of CD40L-positive cells in their spleen than
normal mice, even at pre-autoimmune age. Furthermore, it has been shown that
the pathogenic autoantibody-inducing ability of T cells from lupus mice
could be blocked IN VITRO by anti-CD40L mAb. Finally, it has been
demonstrated that a brief treatment of lupus mice with anti-CD40L mAb had a
sustained beneficial effect on the spontaneous disease, long after the
antibody had cleared from their circulation.
5. SPECIFIC AIM
The aim of the project is to humanize anti-CD40L mAbs. After humanization,
the best antibody will be tested in relevant animal models and subjected to
pharmacokinetic and toxicology studies, before initiation of phase I/II clinical
trials in autoimmune disease patients. The outline of this project is
schematically represented in Figure 1 (at the end of Section 6), the numbers in
the various project blocks refer to well defined development tasks described in
detail below. The timing of the major project milestones is given in Table 1 at
the end of Section 6.
3
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PANGENETICS B.V. ***CONFIDENTIAL*** JULY 1995
6. DESCRIPTION OF THE DEVELOPMENT PLAN
6.1. GENERATION OF HUMANIZED MONOCLONAL ANTIBODIES TO CD40
Cell fusion techniques have made the generation of rodent monoclonal
antibodies (mAbs) a routine endeavor. As early as 1975 the first investigators
of this technology recognized the therapeutic and industrial potential of mAbs,
particularly human monoclonal antibodies (hu-mAbs), yet fifteen years later only
OKT3, an anti-T lymphocyte antigen [CD3] murine mAb is a licensed drug. There
are two reasons for this apparent lack of progress, target selection and
technical difficulties. Despite this modest beginning a large number of mAbs
generated primarily by cell fusion are in clinical development. Recent advances
using recombinant DNA technology will alleviate many of the technical problems
with cell fusion and will accelerate the availability of therapeutic hu-mAbs.
Recombinant mAbs have several attractive advantages over conventional
pharmaceuticals. These proteins can be generated with exquisite selectivity and
specificity in a short period of time. Recombinant antibodies can be designed to
have multiple effector functions in addition to their antigen-combining
abilities. This permits the design of molecules capable of performing complex
tasks involving host cells as well as other host mediator functions. Native
antibodies have a long serum half-life, fragments of antibodies can be designed
to penetrate tissues with a rapid plasma clearance. This facilitates
prophylactic treatment of at-risk patients. Finally, specific mAbs can be
generated more rapidly and with far less effort than that required for synthesis
of conventional low molecular weight organic molecules. This means that methods
devised to select antigen and receptor binding molecules have significant
pharmaceutical potential. Thus it is often possible to test whether neutralizing
a given mediator or removing a cell type with an antibody or antibody fragment
benefits the host with much less effort than is required to generate organic
receptor antagonists. Recombinant mAbs permit rapid testing of a THERAPEUTIC
CONCEPT. Finally and most importantly is the limited toxicity of mAbs.
As therapeutic agents, antibodies are not without their problems.
Antibodies are composed of protein; they are potentially immunogenic; they must
be given parenterally; and they are relatively expensive to produce. Many
therapeutic antibodies are aimed at the treatment of acute life-threatening
disease. In this case cost may be of minor importance. The construction of mAbs
will overcome some of these problems. Production costs of recombinant mAbs in
some systems are substantially below those of hybridomas.
Several laboratories have pioneered methods for construction of human
antibodies from rodent mAbs by splicing the rodent hypervariable complementarity
determining regions (CDRs) onto human variable framework region sequences. This
technique is called CDR-grafting. CDR-grafting is feasible because the antibody
combining site is constructed from several hypervariable regions held together
to form the antigen binding cleft by a beta-sheet comprised of framework
sequences and because the three dimensional conformation of antibodies is highly
conserved among different species. It has been shown that humanization can also
be achieved by "Selected Residue Replacement". In this process the exposed amino
acid residues in the mouse framework regions, which do not match between mouse
and human, are changed to human. We have recently used this approach
successfully for the humanization of a therapeutic antihuman B7 mAb.
4
<PAGE>
PANGENETICS B.V. ***CONFIDENTIAL*** JULY 1995
Very recently, a novel technology terms "Epitope Imprinted Selection", has
been developed for humanization of rodent mAbs. Sequences comprising the antigen
binding site of the rodent mAb are combined with a diverse, random repertoire of
sequences of human antibodies. Successful combinations of heavy-light chain
pairing will create compete rodent/human binding sites, which can be displayed
on the surface of filamentous phage, allowing selection of antigen-binding
phage. Next, the remaining rodent sequences are replaced by a repertoire of
complementary human sequences, and successful combinations of heavy-light chain
pairing can again be selected using immobilized antigen.
It should be noted that often even fully humanized murine mAbs may be
immunogenic. Although limited studies have demonstrated that chimeric
mouse-human antibodies are less immunogenic in humans than the parent mouse mAb,
more studies will be required to determine how much a problem the human
anti-idiotype response will be. With a humanized version of an anti-CD40 mAb we
do not expect any HAMA response, because the therapeutic use of this mAb, if
successful, blocks both primary and secondary antibody responses. However, from
a regulatory standpoint and for marketing reasons it is preferred to work with a
humanized mAb.
The humanization of the lead anti-CD40 mAb, 5D12, is well underway. The
cDNAs encoding the antibody heavy and light chain variable regions of the mouse
mAbs have been cloned and sequenced. The predicted protein sequences of the
mouse VH and VL regions were used to search different data bases for human
antibody sequences with the best homology to the mouse mAbs. The ten best
matching human antibody sequences were used to determine which of the mouse
amino acids had to be changed to what human amino acid in order to obtain a
humanized version of the mAbs using a method named resurfacing. Since
immunogenicity of a protein is dependent on the nature of its surface, replacing
only the exposed residues of a rodent antibody with those usually found in human
antibodies, will severely decrease or even abolish an immune response. The
judicious replacement of exterior residues only should have little or no effect
on the interior of the domains, or on the interdomain contacts. This method has
indeed successfully been used for the humanization of the anti-B7 mAb B7-24 (de
Boer et al, manuscript in preparation).
The next step in the humanization process of the mAb will be to change the
key residues identified by the above method from mouse to human. Finally,
correct clones will be transferred from the sequencing vector to an expression
vectors, already containing the human heavy or light chain constant region.
These expression vectors are for transient expression in insect cells, and upon
cotransfection the insect cells will secrete the antibody as a human IgG1 Fab
fragment. We will also cloned the original mouse heavy and light chain variable
regions in this vector system, resulting in expression of a chimeric mouse/human
IgG1 Fab fragment.
6.2. CONFIRM BIOLOGICAL ACTIVITY AND BINDING AFFINITY OF HUMANIZED MABS
Expression of the Fab constructs (both humanized and chimeric) will be
anlyzed using an ELISA system. The recombinant Fab fragments will subsequently
be tested for biological activity. First it will be tested whether the
recombinant Fab fragments can bind to their respective target molecules using
both ELISA and FACS analysis. We will perform BIAcore experiments to determine
the binding affinity of the Fab fragments (including on/off rates). Next we will
test the inhibitory capacity of the antibodies in functional
5
<PAGE>
PANGENETICS B.V. ***CONFIDENTIAL*** JULY 1995
experiments using human lymphocytes. These experiments will learn us whether the
humanized mAbs are functionally active. If there are no major differences in
binding affinity between the humanized and the chimeric version of the antibody,
we can continue to the next step of the project, which is the generation of
full-length antibody versions with human constant regions of different isotypes.
If there is a significant decrease in binding affinity of the humanized Fab
fragments, we will make several modifications to restore the original binding
affinity.
At this point in the project it will also be possible to generate variants
of the original antibodies with even higher binding affinity. This can be done
using various phage display technologies available to PanGenetics.
6.3. CONFIRM ROLE OF CD40L-CD40 INTERACTION IN THE PATHOPHYSIOLOGY OF VARIOUS
AUTOIMMUNE DISEASES
The objective of this task is to use relevant patient-derived lymphocytes
for IN VITRO experiments to assess/confirm the role of the CD40L-CD40 mediated
activation of inflammatory cells in autoimmune diseases such as RA, SLE and MS.
Subsequently, we will test the inhibitory capacity of the lead antibodies in
these experiments. If these key experiments are positive, we will perform a
larger number of IN VITRO experiments using human lymphocytes, both from
controls and obtained from inflamed tissue of autoimmune patients.
In this task of the project we will also perform IN VITRO experiments
addressing the issue of which human isotype should be used for the production of
the complete humanized mAbs. Major concerns are the antibody effector functions
(FcR binding, complement activation, etc) and the antibody half-life. Finally,
we will investigate the mechanisms by which the antibodies exert their
inhibitory activity. At present we do not know whether the antibodies block just
by hinderance, whether they induce negative signalling or whether they induce
conformational changes in their target molecules leading to a loss of function.
6.4. LARGE SCALE PRODUCTION OF BEST HUMANIZED MABS
After confirmation of the biological activity of the humanized Fab
fragments in task 6.2, we will express selected antibodies as complete human
antibodies. This is most likely best done using a CHO cell expression system.
6.5. OBTAIN PRELIMINARY IN VIVO DATA ON BLOCKING CAPACITY OF LEAD MABS
Before using the humanized anti-CD40 mAbs in various non-human primate
diseases models, we want to confirm that the antibodies can functionally block
the CD40L-CD40 interaction IN VIVO. It has been confirmed by FACS analysis that
the mAb in question bind to the CD40 molecule on the lymphocytes of various
non-human primates. This preliminary study will provide us proof of concept that
the mAb can functionally block the CD40L-CD40 interaction IN VIVO. We will test
whether treatment of rhesus monkeys with the lead anti-CD40 mAb can inhibit the
generation of a secondary antibody response to a T-cell dependent
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PANGENETICS B.V. ***CONFIDENTIAL*** JULY 1995
antigen. These experiments are scheduled to be performed at the BPRC in
Rijswijk, The Netherlands in collaboration with Dr. Bert 't Hart. Nine rhesus
monkeys will be selected that have previously been immunized with a T-cell
dependent antigen. These monkeys will be divided in 3 test groups: (i) control
treatment (PBS, every day for 10 days); (ii) low mAb dose (0.05 mg/kg, every day
for 10 days) and; (iii) high mAb dose (0.5 mg/kg, every day for 10 days). At day
0 all the monkeys will receive a booster injection with the antigen.
Administration of the mAb or control by IV bolus will be done 2 hours before
immunization. Serum will be collected at days 2, 4, 6, 8, 10, 12, 14. (on days
2-10 just prior to study drug administration). The serum samples will be anlyzed
for:
o total antibody titers
o antigen-specific antobody titers
o serum levels of study drug
o presence of anti-human (Ig) antibodies (RAHU)
If these preliminary experiments are postive (i.e. treated animals show
decreased secondary antibody responses), we intend to perform IN VIVO
experiments to study the effects of anti-CD40 on disease severity in various
primate autoimmune disease models (see below).
These preliminary in vivo experiments will also be used to analyze the
pharmacokinetic characteristics of the lead humanized mAb. The PK data will be
used to extrapolate (using mathematical models) to a serum half-live
in humans. This will be the basis for determining the dose schedules in further
animal experiments and future patient studies.
6.6 IN VIVO EXPERIMENTS IN NON-HUMAN PRIMATE MODELS FOR AUTOIMMUNE DISEASES
Before initiating clinical trials with the lead anti-CD40 mAb, it would be
preferred to have data from relevant IN VIVO models. Two models are available to
us: (i) collagen-induced arthritis in rhesus monkeys and chronic EAE in
marmosets. Although the collagen-induced arthritis model in rhesus monkeys does
not represent rheumatoid arthritis in humans (in particular not with respect to
the cause of the disease), we consider it a good model to study local
inflammation (in joints). We plan to perform a number of IN VITRO experiments
and immunohistochemical analysis using rhesus monkey tissue to confirm the role
of CD40L-CD40 in the pathophysiology of RA. If these initial experiments are
positive, we will immunize 12 rhesus monkeys with a single intracutaneous
injection of 3 mg B-CII. Starting at day 8, four animals will be treated with
saline, four with an optimal dose of PG-CD40 and four animals with an
appropriate control, for 14 consecutive days. Thereafter the severity of the
disease will be analyzed.
We will also test the therapeutic value of the humanized anti-CD40 mAbs in a
chronic EAE model in marmosets. The relatively new model is considered to
represent chronic relapsing multiple sclerosis. We are presently evaluating this
model with respect to the involvement of CD40 in the pathophysiology.
6.7 PRODUCTION OF GMP BATCH OF THERAPEUTIC MAB
For use in humans, the lead antibodies will have to be produced under GMP
conditions. It has
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PANGENETICS B.V. ***CONFIDENTIAL*** JULY 1995
presently not been decided where the material will be produced, although it
seems most likely that it will be subcontracted to a licensed contract
manufacturer. The produced material will be subjected to an extensive QC
analysis to verify purity, biological activity, etc. The testing program has
been divided in a biochemical part and a biological part.
6.8 BIOSAFETY TESTING OF GMP MATERIAL
As part of the procedure to produce the material under GMP, the produced
material will extensively be tested for the presence of infectious agents. Tests
will be conducted on the master cell bank (MCB), the bulk unpurified product
(BUP) and, the final purified product (FP).
6.9 TOXICOLOGY TESTING OF GMP MATERIAL IN NON-HUMAN PRIMATES
The GMP produced material will be subjected to toxicology testing in
Rhesus monkeys, before the initiation of clinical studies. These experiments
will be subcontracted to a GLP laboratory. In addition, a GLP study to address
tissue cross-reactivity will be performed.
6.10 PHASE I/II CLINICAL STUDIES
With the GMP grade material clinical studies in autoimmune disease
patients will be initiated as soon as possible. The primary objective of these
studies will be to determine the safety and tolerability of different dose
levels of anti-CD40 mAbs. Secondary objectives are to determine the efficacy and
to determine the incidence of anti-idiotype response. The studies will be
designed as open label phase I/II inter-patient dose escalation studies to
investigate the safety and tolerability of immunotherapy using blocking mAbs.
The outcome of the non-human primate experiments will determine for which
autoimmune disease the first clinical study will be initiated.
6.11 PHASE II AND III CLINICAL STUDIES
After successful completion of the initial phase I/II clinical studies,
further clinical studies to provide us with statistical evidence of the drug
efficacy will be initiated.
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PANGENETICS B.V. ***CONFIDENTIAL*** JULY 1995
FIGURE 1. PANGENETICS CD40 RESEARCH AND DEVELOPMENT PLAN
[INSERT CHART HERE]
TABLE 1. KEY MILESTONE SCHEDULE
------------------------------------------------------
MILESTONE TASK MILESTONE DATA
------------------------------------------------------
MS 1: Complete humanization of lead
antibody; update patent application Q4-1995
------------------------------------------------------
MS 2: Complete key in vitro
experiments Q4-1995
------------------------------------------------------
MS 3: Complete key in vivo
experiments in non-human primates Q4-1996
------------------------------------------------------
MS 4: GMP production Q2-1997
------------------------------------------------------
MS 5: Biosafety and Toxicology
testing Q4-1997
------------------------------------------------------
MS 6: Approval for Phase I/II study Q1-1998
------------------------------------------------------
MS 7: Completion of Phase I/II study Q3-1999
------------------------------------------------------
9
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EXHIBIT 7
C40 LICENSE\COLLABORATION AGREEMENT
DATE: October 1, 1994
PARTIES: 1. Mark Deboer Phd, "Deboer";
E. van Calcarstraat 30; 1963 DG
Heemskark; The Netherlands; T: 31
2510 41356; F: 31 2510 50719.
2. Panorama Research Inc., "PRI";
2462 Wyandotte St.; Mountain View, CA
94043; T: 415-694-4996; F:
415-694-7717.
DEBOER AGREES:
1. To grant PRI a license to all of the rights of Dr. Mark Deboer in the Chiron
CD40 technology.
PRI AGREES:
1. To cooperate with Dr. Mark Deboer who will be responsible for the execution
of the project plan and oversee the work of Dr. Lucien Aarden.
2. To share ownership of the project with Dr. Mark Deboer on a 50:50 basis.
AGREED:
/s/ MARK DeBOER PhD 10-1-94
Mark DeBoer PhD DATE
/s/ JAMES W. LARRICK MD PhD 10-1-94
James W. Larrick MD PhD DATE
CEO and President
Panorama Research Inc.