Development and License Agreement - Protein Design Labs Inc. and Yamanouchi Pharmaceutical Co. Ltd.
DEVELOPMENT AND LICENSE AGREEMENT
FOR HUMANIZED MONOCLONAL ANTIBODIES AGAINST gpllb/llla
between
PROTEIN DESIGN LABS, INC.
and
YAMANOUCHI PHARMACEUTICAL COMPANY, LTD.
DEVELOPMENT AND LICENSE AGREEMENT
Effective 12 February 1991 ("Effective Date"), PROTEIN DESIGN LABS,
INC., a Delaware corporation having offices at 2375 Garcia Avenue, Mountain
View, CA 94043 USA ("PDL") and YAMANOUCHI PHARMACEUTICAL CO., LTD., a Japanese
corporation having offices at No. 1-8 Azusawa 1 -chome, Itabashi-ku, Tokyo 174
Japan ("YAMANOUCHI") agree as follows:
1. BACKGROUND
1.1 YAMANOUCHI owns rights to make, have made, use or sell a
proprietary murine monoclonal antibody against gpllb/llla ("Murine Anti-
gpllb/llla Antibody").
1.2 YAMANOUCHI wishes to have developed humanized derivatives of
a Murine Anti-gpllb/llla Antibody, including F(ab')2 and Fab fragments
thereof (collectively "Humanized Anti-gpllb/llla Antibody").
1.3 PDL is willing to undertake such development effort and to
grant to YAMANOUCHI an exclusive worldwide license under PDL's patent
applications and other proprietary rights to such Humanized Anti-
gpllb/llla Antibody.
2. DEFINITIONS
2.1 "Background Patents" means all patent applications and
issued patents in the United States or any foreign jurisdictions,
including any addition, continuation, continuation-in-part or division
thereof or any substitute application based on U.S. Patent Application
S.N. 310,252 filed February 13, 1989 entitled "Designing Improved
Humanized Immunoglobulins."
2.2 "Exclusive Period" means the term beginning as of the
Effective Date and either:
(a) ending on the later of January 1, 1995 or one year
after the last payment pursuant to Paragraph 5.6.1 (a), (b), (c)
and (d); or
(b) becoming perpetual upon the payment specified in
Paragraph 5.6.1 (e).
The Exclusive Period defines the period during which PDL agrees not to
humanize any other murine antibody against the target antigen gpllb/llla as
provided in Paragraph 4.6 hereof.
2.3 "gpllb/llla" means the antigens gpllb and gpllla, together
including their complex, or separately.
2.4 "Hybridoma Cell Line" means a hybridoma cell line producing
Murine Anti-gpllb/llla Antibody in sufficient quantity to enable PDL to
undertake its duties and obligations under this Agreement.
2.5 "Licensed Patents" means all patent applications and issued
patents in the United States or any foreign jurisdictions, including any
addition, continuation, continuation-in-part or division thereof or any
substitute application claiming the Humanized Anti-gpllb/llla Antibody.
2.6 "Licensed Products" means products, for any use,
incorporating any Humanized Anti-gpllb/llla Antibody, including all or
any part thereof, whether or not developed by PDL under this Agreement.
2.7 "Net Sales" means the gross invoice price charged by
YAMANOUCHI for any Licensed Product sold to third parties in bona fide
arm's length transactions less the following deductions as incurred by
YAMANOUCHI:
(a) discounts and rebates;
(b) returns;
(c) charges of transportations, insurance and packing; and
(d) duties and taxes assessed on sales.
2.8 "Non-Exclusive Period" means the term, if any, beginning the
later of January 1, 1995 or one year after the last payment pursuant to
Paragraphs 5.6.1(a), (b), (c) and (d) and ending on the termination or
expiration of the Agreement. Once the payment of Paragraph 5.6.1(e) is
paid, there is no Non-Exclusive Period under this Agreement.
2.9 "Technical Information" means confidential proprietary
technical information, know-how and materials owned by YAMANOUCHI or PDL
as of the Effective date, or hereinafter developed by YAMANOUCHI or PDL
in connection with this Agreement and relating to the Hybridoma Cell
Line or Humanized Anti-gpllb/llla Antibody or their manufacture or use
for any purpose. In particular, the producer cell line(s) developed by
PDL under this Agreement is PDL Technical Information.
2.10 "YAMANOUCHI" is understood to include all of its Affiliates.
An "Affiliate" means any corporation or other business entity controlled
by, controlling or under common control with YAMANOUCHI; "control" means
direct or indirect beneficial ownership of at least 50% of the voting
shares of a corporation or any corporation in which the maximum amount
of stock permitted by law is beneficially owned by YAMANOUCHI.
3. DEVELOPMENT
3.1 Delivery of Hybridoma Cell Line.
Immediately upon execution of this Agreement, YAMANOUCHI shall.
provide to PDL a sufficient quantity of a Hybridoma Cell Line together
with any Technical Information which in the judgment of YAMANOUCHI and
PDL would be useful in assisting PDL to accomplish the objectives of
this Agreement. Upon completion of the development work contemplated
under this Agreement or termination of this Agreement, which ever is
earlier, any and all quantities of the Hybridoma Cell Line in the
possession of PDL shall immediately be returned to YAMANOUCHI or
destroyed, in accordance with YAMANOUCHI'S instruction.
3.2 Development of Humanized Antibody.
3.2.1 Upon receipt of the Hybridoma Cell Line, PDL shall
immediately commence and diligently pursue commercially reasonable
efforts to apply its proprietary humanization technology to the
Murine Anti-gpllb/llla Antibody with the objective of producing:
(a) a humanized anti-gpllb/llla intact antibody;
(b) a humanized F(ab')2 fragment of such antibody;
and
(c) a humanized Fab fragment of such antibody.
3.2.2 PDL agrees to provide YAMANOUCHI with reports upon
determination of DNA sequence of Murine Anti-gpllb/llla Antibody,
upon completion of a chimeric anti-gpllb/llla antibody and upon
completion of the humanization of anti-gpllb/llla intact antibody.
3.3 Manufacturing Agreements.
Upon request by YAMANOUCHI, PDL agrees to consider manufacturing
Humanized Anti-gpllb/llla Antibody for and on behalf of YAMANOUCHI on
terms to be reasonably negotiated.
4. OWNERSHIP AND EXPLOITATION OF RESULTS
4.1 YAMANOUCHI Rights.
The Humanized Anti-gpllb/llla Antibody developed by PDL under.
this Agreement, as well as all results of pharmacological, toxicology
and other tests and evaluations relating thereto, shall be exclusively
used for commercial purposes by YAMANOUCHI, subject to any rights of
third parties and YAMANOUCHI's obligations of confidentiality hereunder.
4.2 Patent Applications/Patents.
4.2.1 During the Exclusive Period: PDL shall file and
prosecute all U.S. patent applications on Humanized Anti-
gpllb/llla Antibody, which will be jointly assigned to PDL and
YAMANOUCHI. PDL shall use its best efforts to have such
applications granted. YAMANOUCHI, at its option, shall have the
right to file and prosecute all non-U.S. patent applications on
Humanized Anti-gpllb/llla Antibody which will be jointly assigned
to PDL and YAMANOUCHI. Each party shall keep the other informed
as to the patent filing and prosecution status and will provide
the other with copies of the patent application(s) and subsequent
correspondence with the various patent examining offices. Within
thirty days of YAMANOUCHI's receipt of a statement from PDL,
YAMANOUCHI agrees to reimburse PDL for all direct costs including
fees, out-of-pocket legal expenses, etc. charged to PDL by non-PDL
entities with respect to the filing, prosecution and maintenance
of Licensed Patents.
4.2.2 During the Non-Exclusive Period or upon. termination
of the Agreement: PDL and YAMANOUCHI shall mutually agree as to
the filing and prosecution of all Licensed Patents. Neither party
shall be obligated to account to the other for its use or
exploitation or sublicensing of jointly owned Licensed Patents;
provided however, rights to the Humanized Anti-gpllb/llla Antibody
developed by PDL are vested exclusively in YAMANOUCHI as provided
in Paragraph 4.1 of this Agreement.
4.3 Infringement by Others/Infringement Claims.
4.3.1 During the Exclusive Period and the Non-Exclusive
Period: YAMANOUCHI shall be responsible for prosecuting patent
infringements of Licensed Patents by third parties and/or
defending patent infringements claimed by third parties. PDL
shall cooperate with YAMANOUCHI in providing information
reasonably necessary to such actions.
4.3.2 Upon termination of the Agreement: PDL and YAMANOUCHI
each have the right to prosecute patent infringements of Licensed
Patents by third parties.
4.4 PDL Rights.
The producer cell line and all other Technical Information
developed or used by PDL under this Agreement shall remain the property
of PDL. Upon receipt of the Second Benchmark Payment provided for in
Paragraph 5.2.3, PDL will disclose the sequence information about
Humanized Anti-gpllb/llla Antibody and PDL shall provide Technical
Information to YAMANOUCHI to the extent necessary to enable YAMANOUCHI
to effectively develop, seek marketing approval for, manufacture and
market any Humanized Anti-gpllb/llla Antibody developed by PDL under
this Agreement, subject however to the confidentiality obligations set
forth herein.
4.5 Grant of Licenses.
Conditioned upon and effective on the date of receipt by PDL of
the Second Benchmark Payment of Paragraph 5.2.3, PDL shall grant to
YAMANOUCHI the following licenses, to the extent necessary for
YAMANOUCHI to make, have made, use or sell any Humanized Anti-gpllb/llla
Antibody developed by PDL:
(a) a worldwide nonexclusive license under
Background Patents or other proprietary rights owned by PDL
for the sole purpose of enabling YAMANOUCHI to make, have
made, use or sell any Humanized Anti-gpllb/llla Antibody
developed by PDL.
(b) a worldwide nonexclusive sublicense under the
Medical Research Council (MRC) of England's so-called Winter
(Application Number UK PA 8607679 27.03.86) and Boss
(European Patent Application 0 120 694 (84301996.9)) patent
applications for the sole purpose of enabling YAMANOUCHI to
make, have made, use or sell any Humanized Anti-gpllb/llla
Antibody developed by PDL;
(c) to the extent PDL is legally able to do so and
upon request by YAMANOUCHI, nonexclusive sublicense(s) to
any other third party patents licensed to PDL for the sole
purpose of enabling YAMANOUCHI to make, have made, use or
sell any Humanized Anti-gpllb/llla Antibody developed by
PDL; and
(d) a worldwide exclusive license to PDL's rights in
those specific claims, if any, in Licensed Patents which
claim Humanized Anti-gpllb/llla Antibody developed by PDL.
4.6 Exclusivity Agreement.
PDL agrees not to humanize any other murine antibody, or part
thereof, against the target antigen gpllb/llla for any other party
during the Exclusive Period.
4.7 License to Third Parties.
Upon written request by YAMANOUCHI, PDL shall grant the rights
granted to YAMANOUCHI under Paragraph 4.5 to other company(ies) to
enable said other company(ies) to manufacture and market Humanized Anti-
gpllb/llla Antibody developed by PDL; provided, however, that YAMANOUCHI
and said other company agree with PDL in writing that:
(a) said other company(ies) is bound by the terms of
this Agreement;
(b) sales by said other company(ies) shall be deemed
sales by YAMANOUCHI; and
(c) YAMANOUCHI is responsible for compliance with
this Agreement by said other company(ies).
5. PAYMENTS
5.1 Payment on Execution.
Within ten (10) days of the execution of this Agreement,
YAMANOUCHI shall pay to PDL a nonrefundable Development and License
issue fee of One Million Dollars (US $1,000,000). PDL shall use
commercially reasonable efforts to deliver samples of:
(i) a humanized anti-gpilb/llla intact
antibody;
(ii) a humanized F(ab')2 fragment thereof; and
(iii) a humanized Fab fragment thereof;
("Delivered Samples") within one year of the receipt
by PDL of Hybridoma Cell Line from YAMANOUCHI;
however, pursuant to Paragraph 5.2.8 below, PDL may
deliver Delivered Samples to YAMANOUCHI within fifteen
(15) months without penalty.
5.2 Benchmark Payments.
5.2.1 YAMANOUCHI shall make the determination whether or not
each of Delivered Samples has a binding affinity not less than 25%
of the corresponding original Murine Anti-gpllb/llla Antibody or
fragments thereof ("Binding Affinity Requirement") within sixty
(60) days after receipt of such Delivered Samples. YAMANOUCHI and
PDL agree that binding affinity will be measured by the method of
competitive binding set forth in Queen, et al., Proceedings of the
National Academy of Sciences, USA, 86, 1030 (1989). YAMANOUCHI
agrees to provide PDL with samples of Murine Anti-gpllb/llla
Antibody, F(ab')2 and Fab fragments thereof in order for PDL to
perform the competitive binding assay. In addition, PDL agrees to
perform Scatchard plot analyses of Delivered Samples. If such
Delivered Samples meet the Binding Affinity Requirement,
YAMANOUGHI shall pay PDL [ ] ("First Benchmark Payment") within
thirty (30) days after such determination. If YAMANOUCHI has not
determined the binding affinity within sixty (60) days after
receipt of last Delivered Sample, then First Benchmark Payment is
due ninety (90) days after receipt of last Delivered Sample.
5.2.2 YAMANOUCHI and PDL shall promptly commence inhibition
of platelet aggregation and other in vitro assays as described in
Exhibit A to determine the biological activity of Delivered
Samples. Within one (1) month of receipt by YAMANOUCHI of the
last of Delivered Samples, YAMANOUCHI shall inform PDL in writing
if the platelet aggregation inhibition activity of each
CONFIDENTIAL TREATMENT REQUESTED
Delivered Sample does or does not meet YAMANOUCHI's criteria
for further development.
5.2.3 If YAMANOUCHI informs PDL that one or more of
Delivered Samples meets YAMANOUCHI's criteria for further
development, PDL shall commence production of sample quantities
sufficient for further testing. YAMANOUCHI shall pay PDL [ ]
("Second Benchmark Payment") within four (4) months of receipt by
YAMANOUCHI of:
[ ] mg of humanized anti-gpllb/llla intact antibody;
[ ] mg of humanized F(ab')2 fragment thereof; and
[ ] mg of humanized Fab fragment thereof.
Concurrent with such payment, YAMANOUCHI shall inform PDL in writing as to
which cell line YAMANOUCHI wishes PDL to deliver pursuant to Paragraph 5.2.4.
5.2.4 YAMANOUCHI shall pay PDL [ ] ("Third Benchmark
Payment") upon receipt of the producer cell line requested by
YAMANOUCHI pursuant to Paragraph 5.2.3, said producer cell line
having an expression level, as measured under standard tissue
culture conditions, of at least:
[ ] mg/106cells/ml/24 hours, if producing humanized anti-
gpllb/llla intact antibody;
the molar equivalent of [ ]mg/106cells/ml/24 hours intact
antibody, if producing F(ab')2;
the molar equivalent of [ ]mg/106cells/ml/24 hours intact
antibody, if producing Fab.
5.2.5 If Delivered Samples do not meet the Binding Affinity
Requirement and YAMANOUCHI requests in writing that PDL develop
another Humanized Anti-gpllb/llla Antibody, PDL will have the
option at no additional cost to YAMANOUCHI to develop another
Humanized Anti-gpllb/llla Antibody. If PDL delivers to YAMANOUCHI
another Humanized Anti-gpllb/llla Antibody which meets the Binding
Affinity Requirement, YAMANOUCHI shall pay PDL the Benchmark
Payment in accordance with Paragraph 5.2.1.
5.2.6 If PDL has received written notice pursuant to
Paragraph 5.2.2 that the platelet aggregation activity of
Delivered Samples do not meet YAMANOUCHI's requirement for further
development and YAMANOUCHI requests in writing that PDL develop
another Humanized Anti-gpllb/llla Antibody, PDL will have the
option at no additional cost to YAMANOUCHI to develop another
Humanized Anti-gpllb/llla Antibody. If PDL delivers to YAMANOUCHI
another Humanized Anti-gpllb/llla Antibody which meets
CONFIDENTIAL TREATMENT REQUESTED
YAMANOUCHI's platelet aggregation activity requirement for
further development, YAMANOUCHI shall so inform PDL and PDL will
produce testing samples as provided in Paragraph 5.2.3.
5.2.7 Notwithstanding the failure to meet the Binding
Affinity Requirement, if YAMANOUCHI decides to proceed to conduct
animal studies with Humanized Anti-gpllb/llla Antibody or any
other Licensed Product, YAMANOUCHI agrees to pay PDL the First
Benchmark Payment prior to so proceeding.
5.2.8 If PDL has not delivered Delivered Samples within
fifteen (15) months of the receipt of the Hybridoma Cell Line from
YAMANOUCHI, the First Benchmark Payment will be reduced by 5% for
each month thereafter until PDL delivers Delivered Samples. If
PDL delivers Delivered Samples prior to the one year period,
YAMANOUCHI agrees to pay PDL an additional 5% of the First
Benchmark Payment for each month by which PDL's delivery precedes
the end of such period. For example, if PDL delivers Delivered
Samples within 10 months of the receipt of the Hybridoma Cell
Line, YAMANOUCHI shall pay PDL [ ]; if PDL delivers Delivered
Samples no later than fifteen months from the receipt of the
Hybridoma Cell Line, YAMANOUCHI shall pay PDL $880,000; if PDL
delivers Delivered Samples within 18 months of the receipt of the
Hybridama Cell Line, YAMANOUCHI shall pay PDL $680,000. Neither
bonuses nor penalties will be applied if PDL develops another
Humanized Anti-gpllb/llla Antibody(s) pursuant to Paragraphs 5.2.5
or 5.2.6. For purposes of this Paragraph 5.2.8, a "month" means
the time period from the actual date in one month to the same date
in the next month, i.e., November 10 to December 10 constitutes
one month.
5.3 Royalties to PDL.
YAMANOUCHI agrees to pay PDL earned royalties of [ ] on the
Net Sales of all Licensed Products sold by YAMANOUCHI for a period of [
] years from the date of first commercial sale of any Licensed Product
in each country. YAMANOUCHI agrees to promptly inform PDL in writing of
the date of first commercial sale in each country. In the event of
significant material improvements made by YAMANOUCHI on the Licensed
Products, PDL and YAMANOUCHI shall discuss and agree upon lower
royalties than [ ].
5.4 Royalties to Third-Parties.
5.4.1 YAMANOUCHI shall pay MRC earned royalties of [ ] on
the Net Sales of all Licensed Products sold by YAMANOUCHI in each
country where the Winter and Boss patents are valid under the
sublicense of Paragraph 4.5(b).
5.4.2 PDL shall discuss with YAMANOUCHI the necessity of any
sublicenses of Paragraph 4.5(c). [ ]. If YAMANOUCHI wishes to
obtain such nonexclusive sublicense(s) to any other third party
patents nonexclusively licensed to PDL and which PDL is legally
able to sublicense to YAMANOUCHI, royalties under such
sublicense(s) shall be borne by YAMANOUCHI.
5.4.3 Third party royalties, including those payable to the
MRC, borne by YAMANOUCHI shall be paid by YAMANOUCHI through PDL
who shall remit payment to such third party licensor(s). At PDL's
option, YAMANOUCHI shall make direct payment to such third parties
of the third party royalties borne by YAMANOUCHI.
5.5 Combination Products.
If a Licensed Product is sold in a combination containing
another or other biologically active therapeutic ingredient(s) which are
not Licensed Products, then Net Sales for purposes of determining
royalty payments on the combination shall be calculated by multiplying
the Net Sales of the combination by a fraction, the numerator of which
shall be the established market price for the Licensed Product contained
in the combination and the denominator of which shall be the sum of the
established market prices for the Licensed Product and each other
biologically active therapeutic ingredient in the combination. When
separate market prices for such ingredients are not established, then
the parties shall negotiate in good faith to determine a fair and
equitable method of calculating Net Sales for the combination.
5.6 Exclusive Period Maintenance Fees.
5.6.1 YAMANOUCHI, at its option, may elect to maintain the
Exclusive Period beyond January 1, 1995 on a year to year basis by
paying the following Exclusive Period maintenance fees:
(a) [ ] beginning January 1, 1995 and each January
thereafter until January 1, [ ];
(b) [ ] on January 1, [ ];
(c) [ ] on January 1, [ ];
(d) beginning January 1, [ ] and each January 1
thereafter:
(i) prior to the first commercial sale for
therapeutic purposes, [ ]; or
(ii) after the first commercial sale for
therapeutic purposes, [ ].
(e) Upon payment by YAMANOUCHI of cumulative earned
royalties of [ ] to PDL, the maintenance fees otherwise
required above will no longer be payable.
5.6.2 The maintenance fees of Paragraph 5.6.1 are
nonrefundable but shall be credited to YAMANOUCHI against up to
fifty percent (50%) of each earned royalty payment which
YAMANOUCHI would be required to pay pursuant to Paragraph 5.3
until the entire credit is exhausted.
6. REPORTS, PAYMENTS, ACCOUNTING
6.1 Reports and Payment.
After the first commercial sale, YAMANOUCHI shall make written
reports and earned royalty payments to PDL within ninety (90) days after
the end of each calendar quarter. This report shall state the number,
description, and aggregate Net Sales of Licensed Products during such
completed calendar quarter, and resulting calculation pursuant to
Paragraphs 5.3 and 5.4 of earned royalty payment for such completed
calendar quarter. Concurrent with the making of each such report,
YAMANOUCHI shall include payment of royalties for the calendar quarter
covered by such report. All payments to PDL shall be in U.S. Dollars
and net of all non-U.S. taxes.
6.2 Accounting.
YAMANOUCHI agrees to keep records for a period of three (3)
years showing the manufacturing, sales, use, and other disposition of
Licensed Products sold or otherwise disposed of under this Agreement in
sufficient detail to enable the royalties payable hereunder by
YAMANOUCHI to be determined, and further agrees to permit its books and
records to be examined from time to time to the extent necessary to
verify reports provided for in Paragraph 6.1. Such examination is to be
made by PDL, or at PDL's option an independent auditing firm selected by
PDL, at the expense of PDL, except in the event that the results of the
audit reveal a discrepancy in YAMANOUCHI's favor of five percent (5%) or
more, then all expenses of the examination shall be paid by YAMANOUCHI.
Any discrepancies will be promptly corrected by payment by either party.
6.3 Currency Conversion.
The royalty on sales made in currencies other than U.S. Dollars
shall be calculated using the average of the daily exchange rates for
such currency quoted by Citibank N.A.'s foreign exchange desk, for each
of the last thirty (30) banking days of each calendar quarter. All
payments to PDL shall be in U.S. Dollars and net of all non-U.S. taxes.
6.4 Progress Report.
On or before September 1 of each year until YAMANOUCHI markets a
Licensed Product(s), YAMANOUCHI shall make a written annual report to
PDL covering the year ending an the preceding June 30, regarding the
progress of YAMANOUCHI toward commercialization of Licensed Products.
Such report shall include, as a minimum, information sufficient to
enable PDL to ascertain progress by YAMANOUCHI toward developing and
marketing Licensed Products.
7. WARRANTIES; NO WARRANTIES, INDEMNIFICATION
7.1 Warranties.
The parties warrant that they know of no legal reason to prevent
them from entering into this Agreement.
7.2 No Warranties.
PDL makes no representations or warranties, express or implied,
with respect to any producer cell line or Humanized Anti-gpllb/llla
Antibody delivered to YAMANOUCHI under this Agreement. In particular,
PDL makes no representations or warranties as to the merchantability or
fitness for any particular purpose of any such antibody or that its
manufacture, use or sale will not infringe any patent or other
proprietary rights other than those licensed or sublicensed hereunder.
7.3 Indemnification.
YAMANOUCHI will indemnify and hold PDL harmless against any and
all liability, loss, damage, claim or expense (including reasonable
attorney's fees) resulting from any use, testing, manufacture,
packaging, labeling, or sale by YAMANOUCHI of any producer cell line,
antibody, antibody fragment thereof or any Licensed Products.
8. CONFIDENTIALITY AND PUBLICATIONS.
8.1 Confidentiality.
Each party shall keep confidential, and shall not use for any
purpose other than the development and commercial exploitation of any
Humanized Anti-gpllb/llla Antibody developed by PDL hereunder, during
the term of this Agreement and for five years after termination hereof,
all Technical Information supplied by the other, provided however, that
the foregoing obligation of confidentiality shall not apply to the
extent that any Technical Information:
(a) is already known to the recipient at the time of
disclosure or is developed by recipient thereafter in the
course of work entirely independent of any disclosure by the
other party;
(b) is publicly known prior to or becomes publicly
known after disclosure other than through acts or omissions
of the recipient; or
(c) is lawfully disclosed in good faith to recipient
by a third party.
In addition, disclosure may be made by YAMANOUCHI (i) to governmental
agencies to the extent required or desirable to secure governmental approval
for the development or marketing of any Humanized Anti-gpllb/llla Antibody
developed by PDL provided that all reasonably possible steps are taken by
YAMANOUCHI to assure the confidentiality of the information in the hands of
such agencies, or (ii) to preclinical and clinical investigators under a
secrecy agreement with essentially the same confidentiality provisions
contained herein and then only where necessary for YAMANOUCHI to exercise its
rights hereunder. YAMANOUCHI shall be responsible for any breach of these
confidentiality obligations by the parties above.
YAMANOUCHI and PDL agree that a breach or threatened breach of any of
the confidentiality obligations contained herein will result in irreparable
and continuing damage to the other party for which there will be no adequate
remedy at law and that, in the event of such breach or threatened breach, the
damaged party shall be entitled to injunctive relief, an order for specific
performance and/or other provisional or equitable relief, and such other and
further relief as may be proper (including money damages).
8.2 Publications.
Each party agrees to give the other party reasonable opportunity
to review and comment on any proposed publication arising from the
development of a Humanized Anti-gpllb/llla Antibody under this
Agreement. Determination of authorship for any paper shall be in
accordance with accepted scientific practice.
9. TERM AND TERMINATION
9.1 Term.
This Agreement is effective on the date first set forth above
and shall, unless terminated earlier in accordance with this Article 9,
continue until expiration of the obligation to pay royalties to PDL, or
to MRC or other third parties through PDL, in accordance with
Paragraphs 5.3 and 5.4 above, whichever is later; provided, however,
this Agreement shall be continued on a country-by-country basis so long
as YAMANOUCHI elects to maintain this Agreement by paying revised
royalties after the expiration of YAMANOUCHI's obligation to pay
royalties in accordance with Paragraph 5.3. In such case, PDL and
YAMANOUCHI shall discuss and agree upon revised royalties which shall be
lower than the earned royalties defined in Paragraph 5.3.
9.2 Termination.
9.2.1 YAMANOUCHI may terminate this Agreement immediately on
written notice by YAMANOUCHI to PDL if:
(a) the Humanized Anti-gpllb/llla Antibody(ies) does
not meet the Binding Affinity Requirement or come
sufficiently close thereto for YAMANOUCHI to wish to further
pursue this Agreement; or
(b) the platelet aggregation inhibition activity of
each Delivered Sample does not meet YAMANOUCHI's criteria
for further development; or
(c) the producer cell line delivered to YAMANOUCHI
in accordance with Paragraph 5.2.3 does not have an
expression level defined in Paragraph 5.2.4.
9.2.2 PDL may terminate this Agreement if YAMANOUCHI:
(a) Is in default in payment of any payment or
providing of reports; or
(b) Is in breach of any provision hereof; or
(c) Provides any materially false report; and
YAMANOUCHI fails to remedy any such default, breach, or
false report within thirty (30) days after written notice
thereof by PDL.
9.2.3 Either party may terminate this Agreement, and the
licenses granted herein if: (a) the other party becomes insolvent
or enters in any arrangement or composition with creditors, or
makes an assignment for the benefit of creditors; (b) there is a
dissolution, liquidation or winding-up of the other party's
business; or (c) a trustee in bankruptcy of the assets of the
other party is appointed and such trustee does not, within thirty
(30) days after receipt of written notice from the other party,
confirm this Agreement and provide adequate assurance that the
terms and conditions hereof shall faithfully be fulfilled.
9.2.4 The right of either party to terminate this Agreement
as provided above shall not be affected in any way by its waiver
of, or failure to take action with respect to, any previous
failure to perform hereunder.
9.2.5 Surviving any termination or expiration of this
Agreement are:
(a) YAMANOUCHI's obligation to pay royalties or
other fees accrued or accruable;
(b) the confidentiality obligations under Article 8;
(c) the indemnity provisions of Paragraph 7.3.
9.2.6 Upon termination other than expiration of this
Agreement in accordance with Paragraph 9.1, PDL will return to
YAMANOUCHI all biological material owned by YAMANOUCHI, YAMANOUCHI
will return to PDL all biological material owned by PDL and all
licenses and sublicenses will terminate.
10. MISCELLANEOUS
10.1 Force Majeure.
Neither party shall be responsible to the other for any failure
or delay in performing any of its obligations under this Agreement or
for other non-performance hereof provided that such delay or non-
performance is occasioned by a cause beyond the reasonable control and
without fault or negligence of such party, including, but not limited to
fire, flood, explosion, discontinuity in the supply of power, court
order or governmental interference, act of God, strike or other labor
trouble and provided that such party will immediately inform the other
party and that it will entirely perform its obligations immediately
after the relevant cause has ceased its effect.
10.2 Arbitration.
Any controversy or claim arising out of or relating to this
Agreement, or the breach thereof, which cannot be satisfactorily
resolved by the parties by correspondence or mutual conference shall be
determined by arbitration in Santa Clara, California, or such other
venue as may be mutually agreed upon, under the then prevailing rules of
the American Arbitration Association; provided however, that if any
issue in dispute involves scientific or technical matters, the
arbitrator(s) chosen shall have educational training and/or experience
sufficient to demonstrate a reasonable level of knowledge in the field
of biotechnology. The decision of the arbitrators shall be final and
binding and any party may apply for judgment upon the award rendered by
the arbitrator(s) in a court having jurisdiction thereover.
10.3 Notices.
All notices, documents, statements, reports and other writings
required or permitted to be given by the terms of this Agreement shall
be sent either by pre-paid, registered or certified mail, telegram,
telecopier or telex, addressed as follows:
To PDL: Protein Design Labs, Inc.
2375 Garcia Avenue
Mountain View, CA 94043
USA
Attention: President
with a copy to: Marta L. Morando
Ware & Freidenrich
400 Hamilton Avenue
Palo Alto, CA 94301
USA
TO YAMANOUCHI: Yamanouchi Pharmaceutical Company
No. 1-8 Azusawa 1-chome
Itabashi-ku, Tokyo 174
Japan
Attention:
Hiroshi Gushima, Ph.D.
Director of Molecular Biology Dept.,
Biomedical Research Labs 11,
Central Research Labs
Each party may change its address upon written notice to the other party
and each notice shall be deemed to be given upon receipt.
10.4 Governing Law.
This Agreement shall be subject to the laws of California,
United States of America.
10.5 Entire Agreement.
This Agreement embodies the entire understanding of the parties
relating to the subject matter hereof and supersedes all prior
understandings and agreements except that certain Confidentiality
Agreement dated November 1, 1990 which shall continue to govern any
Confidential Information shared other than pursuant to this Agreement.
No modification or amendment of this Agreement shall be valid or binding
except by a writing signed by each of the parties.
10.6 Assignment.
This Agreement may not be assigned except (a) with the advance
written consent of the other party, which consent shall not be
unreasonably withheld, or (b) as part of a sale or transfer of
substantially the entire business relating to operations pursuant to
this Agreement.
10.7 Counterparts.
This Agreement may be executed in any number of counterparts,
each of which shall be deemed to be an original, and such counterparts together
shall constitute one agreement.
IN WITNESS WHEREOF, the parties hereto have duly executed this
Development and License Agreement in duplicate originals by their duly-
authorized officers or representatives.
PROTEIN DESIGN LABS, INC.
YAMANOUCHI PHARMACEUTICAL CO., LTD.
By: /s/ Laurence Jay Korn
By: /s/Moriyoshi Inubai
Title: President
Title: Director of Central Research Laboratories
EXHIBIT A
Methods for the binding assay of anti-GPllb/llla antibodies
Iodination of antibodies
Antibodies (lgG whole molecule, F(ab')2 and Fab fragment) were iodinated
using chrolamine T. One hundred m Ci of 125I were incubated with the
antibodies (15m g of 1gG. 10m g of F(ab')2, 5m g of Fab') for 4 min. in the
presence of 1 m g of chrolamine T. Free 125I was separated from the antibody
on a Sephadex G-25 column. 3-15 m Ci of 125I were incorporated into 1 m g of
protein corresponding to 1000 - 2000 cpm/fmole protein.
Platelet preparation
Platelete-rich plasma (PRP) was prepared by differential centriguation
of anti-coagulated blood from a normal donor. Platelets were washed three
times with modified Tyrode's buffer (0.13M NaC1, 2.6mM KC1, 0.4mM NaH2P04,
12mM NaHCO3, 5.5mM glucose, 2% bovine serum albumin, pH 7.4) containing lmM
EDTA. Washed platelets (WP) were used for the binding experiment of
antibodies.
For the antibody binding assay of stimulated platelets, ADP (final
concentration: 10 m M) or thrombin (final concentration: 0.3U/ml) was added
together with CaC12 (1mM final) just before or after the addition of the
radio-labelled antibody.
Antibody binding assay
Washed platelets (3 x 106 platelets/tube for antibody B, 1-3 x 107
platelets/tube for antibody C) were incubated with constant amount (100pM) of
125I-labelled antibody in the presence or absence of various amounts of
unlabelled antibody, for 1hr at room temperature. Platelets and antibodies
were diluted with modified Tyrode's buffer without EDTA and total volume of
the assay mixture was adjusted to 500 ml. Incubation was stopped by adding 2
ml of ice-cold buffer and free antibody was separated from bound antibody by
the centrifugation for 10 min. at 3000rpm. Tubes were then counted in a gamma
counter.
Nonspecific binding was determined by adding 1300 fold-excess (10 m g)
cold antibody before adding the labelled antibody.
Dessociation constants(Xd) and No. of binding sites (Bmax) were
determined by Scatchard plot analysis.
Fibrinogen binding assay
Human fibrinogen (Sigma, F4883) was iodinated as described above except
that 300 m g of fibrinogen were used, resulting in specific radioactivityi at
0.02 m Ci/m g. ADP-stimulated platelets (3 x 107/tube) were incubated with
125I-fibrinogen (1 m g) in the presence or absence of increasing amounts of
cold [illegible].
Platelet Preparation
Platelet-rich plasma (PRP) was obtained by centrifugation of the
citrated blood at 110 X g for 10 minutes at room temperature. After removal
of PRP, the remaining sample was centrifuged at 1500 X g for 15 minutes to
obtain platelet poor plasma (PPP). Platelet counts in PRP were determined by
hemocytometery and adjusted to a final concentration of 3X103/ml with
autologous PPP.
Platelet Aggregometry
A 200 ul aliquot of PRP was warmed to 37 C in a silanized cuvette and
stirred continuously at 1200 rpm in an aggregometer HEMA TRACER (Niko
Bioscience Co., Ltd.). After equilibration for 1 min. ADP (Sigma Chemical
Co.) at a final concentration of 20 uM or 2 uM or bovine tendon collagen
(Sigma Chemical Co.) at a final concentration of 20 ug/ml was added and
aggregation was recorded as an increase in light transmission, with that of
PRP and PPP representing 0% and 100% transmission, respectively. For
deaggregation experiments, 1gG or its fragments, or an equivalent volume of
Tris-Buffered Saline (TBS) was added as light transmission approached a
maximum and at selected later time intervals. Deaggregation (inhibition of
aggregation) was assessed as the decrease in light transmission measured 5
minutes after addition of sample or saline as expressed as a percentage of the
maximal light transmission.
Platelet studies were completed within 3 hours after blood collection.
CONFIDENTIAL TREATMENT REQUESTED
Amendment No. 1
to the
February 12, 1991
Development and License Agreement
between
Protein Design Labs, Inc.
and
Yamanouchi Pharmaceutical Co., Ltd.
Effective March 27, 1991 ("Effective Date"), PROTEIN DESIGN LABS, INC.,
a Delaware corporation having offices at 2375 Garcia Avenue, Mountain View, CA
94043 USA ("PDL") and YAMANOUCHI PHARMACEUTICAL CO., LTD., a Japanese
corporation having offices at No. 1-8 Azusawa 1-chome, Itabashi-ku, Tokyo 174
Japan ("YAMANOUCHI") agree as follows:
1. BACKROUND
1.1 PDL and YAMANOUCHI are parties to a February 12, 1991
Development and License Agreement covering humanized monoclonal
antibodies against gpllb/llla ("Original Agreement").
1.2 PDL and YAMANOUCHI wish to amend Original Agreement to
clarify each party's obligations with respect to non-U.S. withholding
taxes.
1.3 In addition, PDL and YAMANOUCHI wish to correct certain
typographical errors.
2. AMENDMENT
2.1 The last sentence of Paragraph 6.1 of Original Agreement is
deleted and the following sentence added to Paragraph 6.1:
All payments to PDL shall be in U.S. Dollars.
2.2 Paragraphs 6.1.1, 6.1.2 and 6.1.3 are added as follows:
6.1.1 The Development and License issue fee, all Benchmark
Payments and all Exclusive Period maintenance fees shall be
remitted to PDL in full without deducting any Japanese
withholding taxes and PDL agrees to return to YAMANOUCHI
amounts, if any, that represent an actual reduction in PDL
U.S. taxes permanently realized as a result of taxes paid in
Japan by YAMANOUCHI on behalf of PDL. YAMANOUCHI shall
provide copies to PDL of all tax receipts for taxes paid in
Japan by YAMANOUCHI or other company(ies) defined in
Paragraph 4.7 on behalf of PDL.
6.1.2 Earned royalty payments remitted to PDL under
Paragraph 5.3 shall be reduced by the amount of all non-U.S.
withholding taxes paid by YAMANOUCHI or other company(ies)
defined in Paragraph 4.7 on behalf of PDL. PDL is not
required to return recovered U.S. taxes realized as a result
of taxes paid in other countries than the U.S.A., if any.
Notwithstanding the foregoing:
a) in the case of sales made into Japan, earned
royalty payments remitted to PDL shall not be below [
];
b) in the case of sales made into the United
States, earned royalty payments remitted to PDL shall
not be below [ ] and
c) in the case of sales made into countries other
than Japan or the United States, earned royalty
payments remitted to PDL shall not be below [ ].
YAMANOUCHI shall provide copies to PDL of all tax receipts
for taxes paid, if any, by YAMANOUCHI or other company(ies)
defined in Paragraph 4.7 on behalf of PDL.
6.1.3 earned royalties remitted to third parties under
Paragraph 5.4 shall be paid in full without deducting any
withholding taxes unless otherwise agreed upon with such
third parties. In no event shall PDL's earned royalty
payments remitted to PDL after deductions permitted by
Paragraph 5.4 be less than [ ].
2.3 The last sentence of Paragraph 6.3 is deleted and the
following sentence substituted in its place:
All payments to PDL shall be in U.S. Dollars.
2.4 Paragraph 5.2.4 is amended to change "mg" to "ug":
CONFIDENTIAL TREATMENT REQUESTED
[ ] mg/106cells/ml/24 hours, if producing humanized anti-
gpllb/llla intact antibody;
the molar eqivalent of [ ]mg/106 cells/ml/24 hours intact
antibody, if producing F(ab')2;
the molar equivalent of [ ]mg/106 cells/ml/24 hours intact
antibody, of producing Fab.
2.5 All other provisions of Original Agreement remain in full
force and effect.
IN WITNESS WHEREOF, the parties hereto have executed this Amendment in
duplicate originals.
PROTEIN DESIGN LABS, INC.
YAMANOUCHI PHARMACEUTICAL CO., LTD.
By: /s/ Laurence Jay Korn
By: /s/ Moriyoshi Inubai
Title: President
Title: Director of Central Research Laboratories