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EXHIBIT 10.23
CONFIDENTIAL TREATEMENT REQUESTED
UNDER 17 C.F.R. SECTIONS 200.80(b)(4), 200.83
AND 240.24b-2. * INDICATES OMITTED
MATERIAL THAT IS THE SUBJECT OF A
CONFIDENTIAL TREATMENT REQUEST THAT IS
FILED SEPARATELY WITH THE COMMISSION.
RESEARCH AND DEVELOPMENT
AGREEMENT
BETWEEN
ISIS PHARMACEUTICALS, INC.
AND
ZENECA LIMITED
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TABLE OF CONTENTS
BACKGROUND........................................................................... 1
DEFINITIONS.......................................................................... 1
RESEARCH PROGRAM; ANNUAL RESEARCH SUPPORT............................................ 1
2.1 GOAL OF RESEARCH COLLABORATION............................................... 1
2.2 MANAGEMENT OF THE RESEARCH PROGRAM........................................... 2
2.3 INFORMATION AND REPORTS...................................................... 3
2.4 TECHNOLOGY ACCESS FEE; RESEARCH PAYMENTS..................................... 3
2.5 THE RESEARCH TERM............................................................ 4
2.6 PROPOSAL OF COMPOUNDS FOR DEVELOPMENT........................................ 5
2.7 REJECTED COMPOUNDS........................................................... 5
2.8 EXPANSION OF THE RESEARCH COLLABORATION; SUBSTITUTION OR ADDITION OF TARGETS. 6
2.9 TERMINATION OF RESEARCH PROGRAM FOR A TARGET................................. 8
ZENECA DEVELOPMENT AND COMMERCIALIZATION............................................. 8
3.1 ZENECA DILIGENCE OBLIGATION.................................................. 8
3.2 ISIS DILIGENCE OBLIGATION.................................................... 9
3.3 DISCONTINUATION BY ZENECA OF DEVELOPMENT OR COMMERCIALIZATION................ 9
3.4 ISIS RIGHT TO DEVELOP AND COMMERCIALIZE ABANDONED COMPOUNDS.................. 10
3.5 ZENECA RIGHT TO RECONSIDER ABANDONED COMPOUNDS............................... 11
3.6 SHARED COMPOUNDS............................................................. 11
3.7 PROGRESS REPORTS............................................................. 11
3.8 COMPULSORY LICENSING......................................................... 11
PAYMENTS FOR DEVELOPMENT CANDIDATES.................................................. 12
4.1 MILESTONE PAYMENTS........................................................... 12
4.2 ROYALTY...................................................................... 13
4.3 TERM OF ROYALTY OBLIGATIONS.................................................. 13
4.4 PAYMENTS BY ZENECA........................................................... 14
4.5 CURRENCY CONVERSION.......................................................... 14
4.6 TAXATION OF PAYMENTS......................................................... 14
4.7 INTEREST..................................................................... 14
MANUFACTURING AND SUPPLY............................................................. 15
5.1 RESEARCH SUPPLY.............................................................. 15
5.2 CLINICAL SUPPLY.............................................................. 15
5.3 COMMERCIAL SUPPLY............................................................ 15
5.4 MANUFACTURING INFORMATION.................................................... 16
BOOKS AND RECORDS.................................................................... 16
6.1 RECORDKEEPING; AUDIT......................................................... 16
LICENSE GRANTS....................................................................... 17
7.1 LICENSE FOR COLLABORATION PRODUCTS........................................... 17
TERM AND TERMINATION................................................................. 18
8.1 TERM......................................................................... 18
8.2 TERMINATION BY EITHER PARTY.................................................. 18
8.3 TERMINATION FOR BANKRUPTCY................................................... 19
8.4 TERMINATION BY ZENECA WITHOUT CAUSE.......................................... 19
8.5 EFFECTS OF TERMINATION....................................................... 19
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INVENTIONS AND PATENTS............................................................... 19
9.1 INVENTIONS................................................................... 19
9.2 PATENTS...................................................................... 20
9.3 PATENT MARKING............................................................... 20
9.4 DEFENSE OF PATENT INFRINGEMENT SUITS......................................... 20
9.5 SUITS FOR THIRD-PARTY INFRINGEMENT........................................... 21
WARRANTIES AND DISCLAIMERS........................................................... 22
10.1 REPRESENTATIONS AND WARRANTIES............................................. 22
10.2 DISCLAIMER................................................................. 23
INDEMNITY AND INSURANCE.............................................................. 23
11.1 INDEMNITY.................................................................. 23
11.2 INSURANCE.................................................................. 24
TRADENAMES, TRADEMARKS, CONFIDENTIALITY AND PUBLICATIONS............................. 24
12.1 TRADENAMES AND TRADEMARKS.................................................. 24
12.2 CONFIDENTIALITY............................................................ 24
12.3 SHARED CONFIDENTIAL INFORMATION............................................ 24
12.4 PUBLICATIONS............................................................... 25
MISCELLANEOUS........................................................................ 25
13.1 BANKRUPTCY................................................................. 25
13.2 WAIVER..................................................................... 26
13.3 ASSIGNMENT................................................................. 26
13.4 NOTICES.................................................................... 26
13.5 GOVERNING LAW.............................................................. 27
13.6 AMENDMENT.................................................................. 27
13.7 FORCE MAJEURE AND HARDSHIP................................................. 27
13.8 INDEPENDENT CONTRACTORS.................................................... 28
13.9 SEVERABILITY............................................................... 28
13.10 ENTIRE AGREEMENT........................................................... 28
13.11 DISPUTE RESOLUTION......................................................... 28
13.12 GOVERNMENT APPROVALS....................................................... 29
LIST OF EXHIBITS
A. DEFINITIONS
B. RESEARCH PLAN
C. JOINT MANAGEMENT COMMITTEE COMPOSITION
D. RESEARCH TARGET PROFILE FOR THE INITIAL TARGETS
E. TECHNOLOGY MILESTONE CRITERIA
F. MANUFACTURING SPECIFICATIONS
G. ISIS LICENSES
H. GMO TERM SHEET
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RESEARCH AND DEVELOPMENT AGREEMENT
THIS RESEARCH AND DEVELOPMENT AGREEMENT (the "Agreement") is made as of
the 18th day of December, 1998 by and between Isis Pharmaceuticals, Inc.
("ISIS"), a Delaware Corporation having a principal place of business at 0000
Xxxxxxx Xxxxxx, Xxxxxxxx, Xxxxxxxxxx 00000, and Zeneca Limited., 00 Xxxxxxxx
Xxxx, Xxxxxx X0X0XX, Xxxxxx Xxxxxxx ("ZENECA").
BACKGROUND
ISIS is engaged in the research and development of therapeutic
pharmaceutical products known as antisense oligonucleotides, and ISIS has
accumulated considerable knowledge in the field of molecular biology, including
processes and techniques relating to the design, investigation and research
(including the synthesis) of oligonucleotides and oligonucleotide analogues.
ZENECA has expertise in the research, development, distribution and
exploitation of prophylactic and therapeutic treatments for human use.
ZENECA and ISIS wish to establish a collaborative relationship to work
jointly with one another with the aim to identify antisense compounds which
inhibit the in vivo synthesis of certain biological molecules primarily involved
in various disease processes, initially focusing on cancer in humans for ZENECA
development and commercialization of products containing such antisense
compounds initially focusing on specific targets.
THE PARTIES AGREE AS FOLLOWS:
ARTICLE 1
DEFINITIONS
Capitalized terms used in this Agreement but not otherwise defined will
have the meaning set forth in Exhibit A.
ARTICLE 2
RESEARCH PROGRAM; ANNUAL RESEARCH SUPPORT
2.1 Goal of Research Collaboration.
(a) The goal of the Research Collaboration is, through the combined
efforts of ISIS and ZENECA scientists and using ISIS and ZENECA
technology, to discover Compounds having the potential to be
commercialized as drugs for human therapeutic use. The Research
Collaboration will be conducted by ISIS and ZENECA and will be
managed by the Joint Research Committee.
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(b) Research relating to a Target includes the elaboration of necessary
cellular, biochemical and molecular-biological approaches (i.e., the
development of the knowledge not already available to the two
parties, the development and setting up of relevant assays) towards
the inhibition of the expression of the protein target molecules by
Antisense Technology as well as the conception, design, synthesis
and development of therapeutic entities, including the
characterization of their biophysical and pharmacokinetic
properties. Subject to Section 3.1 the research relating to a Target
will explore all reasonable therapeutic applications of a Compound.
(c) The Research Collaboration will include access to all ISIS
Technology for purposes of developing Compounds within the terms of
article 7 except as described below. The Research Collaboration does
not include research relating to or access by ZENECA to ISIS
technology or Know-How relating to [ * ] of oligonucleotides. When
and if the Parties decide to include such technology and research in
the Research Collaboration, they will negotiate in good faith
additional technology access fees to reflect ISIS investment in the
technology and an appropriate increase in the Research Payments to
fund additional research relating thereto.
(d) ZENECA and ISIS will work together exclusively on the use of
Antisense Technology to discover, develop or commercialize antisense
inhibitors for any Target for which ZENECA has an Active Target
Program. ISIS will not license or assign to a Third Party any ISIS
Target Patents relating to a particular target for so long as ZENECA
has an Active Target Program for that Target.
2.2 Management of the Research Program.
(a) The Research Collaboration will be managed by a Joint Research
Committee composed of 4 members: 2 members to be designated by each
party. The initial composition of the Joint Research Committee is
set forth in Exhibit C. Each party will be entitled to designate
from time-to-time a successor to the member previously designated by
it unless the other party has a reasonable objection to such
successor.
(b) The Joint Research Committee will hold meetings as necessary but at
least twice per year, at times and locations to be mutually agreed
upon. The minutes of the meetings will be recorded and marked
"confidential" and will be subject to the secrecy obligations and
restrictions on use contained in Paragraphs 12.2 and 12.3.
(c) The Joint Research Committee will review and evaluate the work on
the Research Collaboration. Its functions will be to decide:
(i) on Targets to be included within the Research Collaboration;
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(ii) on Research Target Profiles for any Target (including
any subsequent modifications of such Research Target
Profile);
(iii) on therapeutic indications to be pursued for Compounds
inhibiting a Target;
(iv) the territorial patenting strategy for Compounds and the
"freedom to operate" position by patent due diligence on
new Targets or Compounds;
(v) assignment of financial resources and personnel to
specific Targets; and/or emphasis among Targets;
(vi) approval of Target-specific Research Plans;
(vii) determination of whether a Compound fulfills the
Research Target Profile;
(viii) approval of Excess Research Costs;
(ix) when necessary, on taking appropriate action to adopt
alternative approaches or to make recommendations on
redirecting or restructuring the Research Plan set out
in Exhibit B; and
(x) determine the detailed manufacturing specifications for
research Compounds.
(d) The Joint Research Committee will act by unanimous decision.
Disputes will be resolved pursuant to Paragraph 13.11 hereof.
2.3 Information and Reports.
ISIS will promptly make available and disclose to ZENECA all information
regarding the design, synthesis and screening of lead antisense
oligonucleotides for the Targets generated by ISIS in carrying out the
Research Collaboration. All discoveries or inventions made by ISIS in
undertaking the Research Collaboration will be promptly disclosed to
ZENECA. ISIS will keep ZENECA promptly informed of all patenting
activities undertaken by ISIS, including without limitation, the
opportunity to comment on the specifications filed after any first
provisional or priority patent filing on any invention and patent
prosecution in PCT, USA, Europe and Japan. ISIS and ZENECA will exchange
at a minimum, monthly verbal or written reports, presenting a meaningful
summary of the work done under this Agreement. In addition, at ZENECA's
request, ISIS will provide written reports of any studies performed by
ISIS required to support regulatory submissions to be made by ZENECA,
its Affiliates or Sublicensee and will allow ZENECA, its Affiliates or
Sublicensees to use the data included in such reports to support such
submissions.
2.4 Technology Access Fee; Research Payments.
(a) ZENECA will pay to ISIS [ * ] million in technology access fees
payable as follows:
(i) $2,000,000 payable upon the later of (x) execution of
this Agreement or (y) 15 days after execution of the GMO
License Agreement;
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(ii) [ * ] on June 30, 1999;
(iii) [ * ] payable within 45 days after ISIS first achieves
the Technology Milestone.
(b) As payment for the research to be conducted by ISIS in the
Research Collaboration, ZENECA will pay to ISIS [ * ] during the
Research Term, in four equal quarterly installments of [ * ]
beginning on the Effective Date and every 3 months thereafter
(the "Research Payments"). [ * ]
(c) Within 12 months of the Effective Date, Zeneca may either add or
substitute [ * ] as an Initial Target in the Research
Collaboration pursuant to Paragraph 2.7 hereof. If [ * ] is
added as a Target, [ * ] . The Joint Research Committee will
determine the length of the [ * ] project and related research
payments.
(d) The Research Payments will be applied exclusively to cover only
work of the [ * ] employed in carrying out work under this
Research Collaboration [ * ]. Any studies or work agreed by
ZENECA to be conducted outside ISIS, or within ISIS but outside
the scope of the Research Plan described in Exhibit B
(including, without limitation any ISIS Development Expenses),
and any compound to be supplied [ * ], as described above in any
calendar year will be paid for by ZENECA separately, with such
costs called "Excess Research Costs." Excess Research Costs will
be invoiced by ISIS to ZENECA with payment due within [ * ] of
receipt of invoice. Excess Research Costs for [ * ] will be
billed at [ * ] (including an appropriate allocation of the
costs of process development, analytical development and scale
up for such manufacture). [ * ]
2.5 The Research Term.
(a) The Research Term will be three years beginning with the
Effective Date and will be cancelable by ZENECA for any reason
at the end of the second year with 6 months prior written notice
(i.e., by notice given on or before the 18-month anniversary of
the Effective Date). Failure to cancel at the end of the second
year will automatically extend the agreement to the full 3-year
term; however, the scope of Research Payments for the third year
will be mutually agreed to by the Joint Research Committee in
light of the agreed Research Collaboration program needs.
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(b) The Research Term may be extended by mutual consent at any time
prior to the end of the [ * ] year for [ * ] additional
extensions of [ * ] as specified by ZENECA at the time of the
extension, based on the program of work agreed to by the Joint
Research Committee on the terms contained herein, [ * ]. The
scope of the Research Payments for each subsequent year will be
mutually agreed to by the Joint Research Committee in the light
of the agreed Research Collaboration program needs.
Notwithstanding the foregoing, if the program of work is earlier
completed or if the program appears unlikely to be successful,
the Parties can, upon mutual agreement, terminate any extension
of the Research Term sooner.
2.6 Proposal of Compounds for Development.
(a) During the course of the Research Collaboration, the Joint
Research Committee will propose to ZENECA Compounds, which the
Joint Research Committee determines meet the Research Target
Profile for selection as Development Candidates. ZENECA will
have [ * ] days after receiving the Joint Research Committee's
proposal to accept or reject any such Compound.
(b) Within [ * ] days of [ * ], ZENECA will pay to ISIS an [ * ] and
ZENECA will have the exclusive right to develop and
commercialize such Development Candidate and subsequent
Development Candidates inhibiting the same Target as provided
herein.
2.7 Rejected Compounds.
(a) Compounds which the Joint Research Committee determines meet
Research Target Profile but which are not accepted by ZENECA for
development as Development Candidates will continue to be owned
in their entirety by ISIS. However, ISIS will not have the right
to develop, commercialize or sublicense any such Compounds for
so long as ZENECA has an Active Target Program for the Target
for such Compound.
(b) [ * ]
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(c) At the time ZENECA ceases to have an Active Target Program, such
Target will be considered an Abandoned Target and ISIS will be
free to develop and commercialize any Compound inhibiting such
Target fully with, subject to Paragraph 3.4 no further
obligation to ZENECA. Notwithstanding the foregoing, ZENECA will
retain the right to use any such Compound for internal research
purposes.
2.8 Expansion of the Research Collaboration; Substitution or Addition of
Targets.
(a) ZENECA may, upon mutual agreement with ISIS, at any time during
the first [ * ] months of the Research Collaboration Term,
substitute or add [ * ] as a Target. [ * ] may be (i)
substituted for one of the other Initial Targets or for any
subsequently added Cancer-Related Target for no additional
technology access fee and, assuming that the mutually agreed
research plan for [ * ] is similar to that for the Target being
substituted, for no additional Research Payments or (ii) added
as a Target by initiation of a research program and an increase
in the Research Payments which will be agreed by the Joint
Research Committee, subject to the Inflation Rate beginning on
the second anniversary of the Effective Date. The substitution
or addition may occur (i) with [ * ] months prior notice for a
substitution or [ * ] months prior notice for an addition; and
(ii) upon agreement by ZENECA, if required, that the Research
Collaboration Term will extend for a period to be determined by
the Joint Research Committee to include the term of the Survivin
research program following such substitution or addition.
(b) ZENECA may, upon mutual agreement with ISIS at any time during
the Research Collaboration Term add additional Cancer-Related
Target(s) and subsequently substitute or add such Cancer-Related
Target(s) to the Research Collaboration. The substitution or
addition to the Research Collaboration may occur (i) with at
least [ * ] months notice for a substitution or addition; (ii)
upon agreement by ZENECA that the Research Collaboration Term
will continue for at least [ * ] months following the
substitution or addition. If a substitution is made, assuming
that the mutually agreed upon research plan for the new Target
is similar to that for the Target being substituted, there will
be no increase in Research Payments when such substitution is
made. Addition of Cancer-Related Targets will require the
payment of additional technology access fees [ * ]. In addition,
if the Target is [ * ], the Parties will agree on additional
upfront funding [ * ]; [ * ], [ * ]. If ZENECA designates a
desire to add [ * ]
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[ * ]
(c) ZENECA may, upon mutual agreement with ISIS at any time during the
Research Collaboration Term add additional Non-Cancer-Related
Target(s), and subsequently substitute or add such
Non-Cancer-Related Target(s) to the Research Collaboration. The
substitution or addition to the Research Collaboration may occur (i)
with at least [ * ] months notice for a substitution or [ * ] months
notice for an addition; (ii) upon agreement by ZENECA that the
Research Collaboration Term will continue for at least [ * ] months
following the substitution or addition. If a substitution is made,
assuming that the mutually agreed upon research plan for the new
Target is similar to that for the Target being substituted, there
will be no increase in Research Payments when such substitution is
made. Addition of non-cancer-related Targets will require the
payment of additional technology access fees [ * ]. If ZENECA
designates a desire to add [ * ].
(d) ISIS and ZENECA will negotiate in good faith any additional terms
for the substitution or addition of Targets beyond the Initial
Targets. ISIS will have no obligation to substitute or add a Target
for one that is subject to active discussions, negotiations or an
agreement with a Third Party. ISIS will notify ZENECA of the
initiation of discussions with a Third Party regarding Apoptosis
Targets unless it is precluded from doing so by confidentiality
restrictions.
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(e) For purposes of this paragraph 2.7 "substitution" will mean the
termination of a research program relating to one Target and the
initiation of a similar research program for the substituted Target.
The Target for which the research program is terminated will
thereafter be deemed to be an Abandoned Target and the new Target
will become a Target for purposes of this Agreement.
2.9 Termination of Research Program for a Target.
(a) ZENECA may at any time after [ * ] discontinue research relating to
any specific Target [ * ]. The Joint Research Committee will
determine the reallocation of the funding for a discontinued Target
among the other Targets. For each Abandoned Target, ISIS will be
free to continue research on Compounds to inhibit such Target and to
use, make, have made and sell the resulting products for such
Abandoned Target in accordance with Paragraph 2.7.
(b) Discontinuation of research in a particular Target will not affect
the continuation of the Research Collaboration in accordance with
its terms.
ARTICLE 3
ZENECA DEVELOPMENT AND COMMERCIALIZATION
3.1 ZENECA Diligence Obligation.
(a) ZENECA will use commercially reasonable efforts to develop a
Development Candidate as expeditiously as possible consistent with
ZENECA's own practices for drugs of similar commercial potential and
for all indications for which ZENECA reasonably determines the
Development Candidate is likely to be commercially attractive. If
ZENECA determines that it will not develop a Development Candidate
for such commercially attractive indication outside of the initial
therapeutic focus of the Target as determined by the Joint Research
Committee, taking into account ZENECA's overall development plan for
the Development Candidate for all indications, ZENECA will
reasonably consider development and commercialization of the
Development Candidate by ISIS or a Third Party in any indication
ZENECA is not pursuing. Such consideration by ZENECA will be
intended to maximize the commercial value of the Development
Candidate to ZENECA and ISIS without jeopardizing the development or
commercialization of the Development Candidate by ZENECA in the
indication ZENECA is pursuing. Determination by ZENECA not to permit
such commercialization on the grounds that such development could
jeopardize the development or commercialization of the Development
Candidate shall be deemed to be reasonable.
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(b) ZENECA will use commercially reasonable efforts to commercialize and
sell Collaboration Product in each of the Major Countries for all
commercially attractive indications as determined by ZENECA in
Article 3.1(a) as expeditiously as is reasonable consistent with
sound scientific and business judgment and ZENECA's practices with
drugs of similar commercial potential. ISIS will provide ZENECA with
assistance reasonably requested by ZENECA which will be billed to
ZENECA as ISIS Development Cost [ * ].
(c) If ZENECA fails in its obligations to develop or commercialize a
Development Candidate or Collaboration Product under subparagraph
(a) or (b) above, at the option of ISIS and after written notice
from ISIS and a reasonable opportunity to cure such failure but
ZENECA having failed to do this within a reasonable period ZENECA
will be deemed to have abandoned such Development Candidate or
Collaboration Product and such Compound will become an Abandoned
Compound. If such failure relates solely to the failure to
commercialize a Collaboration Product in a particular Major Country
or if, after written notice from ISIS, ZENECA fails to commercialize
a Collaboration Product in a country that is not a Major Country in
a manner consistent with ZENECA's typical product launch strategy,
the Collaboration Product will become an Abandoned Compound only for
that country and ISIS will have the right to commercialize such
Collaboration Product in such country whether or not ZENECA has an
Active Target Program relating to such Collaboration Product.
Failure by ZENECA to adequately develop a Development Candidate or
to commercialize a Collaboration Product pursuant to this Paragraph
3.1(c) will not constitute a material breach of this Agreement
pursuant to Paragraph 8.2.
3.2 ISIS Diligence Obligation.
ISIS agrees to commit the resources set forth in Paragraph 2.4(c) to
exert the efforts necessary and reasonable and consistent with its
normal business practices to execute and substantially perform its
obligations under the Research Plan, to maintain and utilize the
scientific staff, laboratories, offices and other facilities consistent
with such undertaking and to reasonably cooperate with ZENECA in the
conduct of the Research Collaboration.
3.3 Discontinuation by ZENECA of Development or Commercialization.
ZENECA may discontinue development of any Development Candidate or
commercialization of any Collaboration Product by giving written notice
to ISIS. Upon such discontinuation, all rights to such Development
Candidate will revert to ISIS and be considered an Abandoned Compound.
Failure of ZENECA to develop a Development Candidate or commercialize a
Collaborative Product pursuant to Paragraph 3.1 will be deemed to
constitute discontinuation of
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development or commercialization and the Development Candidate or
Collaboration Product will become an Abandoned Compound with or without
notice to ISIS hereunder. [ * ].
3.4 ISIS Right to Develop and Commercialize Abandoned Compounds.
(a) If, and when, ZENECA does not have an Active Target Program relating
to an Abandoned Compound or if ISIS has the right to commercialize
the Abandoned Compound in a particular country or countries pursuant
to Paragraph 3.1 (c), ISIS will be free to develop and/or
commercialize such Abandoned Compound.
(b) Following the occurrence of any event described in 3.4(a) above and
at ISIS' request, ZENECA will provide in so far it is legally able
to do so, and on a non-exclusive basis to ISIS all rights, licenses
or other permissions obtained including, without limitation all
clinical and preclinical data, regulatory submissions obtained by
ZENECA together with, access to ZENECA technology utilized by ZENECA
in the development of such Development Candidate both of which exist
at the date a Development Candidate becomes an Abandoned Compound
and are necessary or useful to continue the development and/or
commercialization of such Abandoned Compound, [ * ]:
STAGE OF COMPOUND ABANDONMENT ROYALTY
----------------------------- -------
[ * ] [ * ]
[ * ] [ * ]
[ * ] [ * ]
[ * ] [ * ]
Royalties will be paid to ZENECA hereunder on the same basis and
terms as royalties are paid to ISIS by ZENECA hereunder.
If ZENECA has incorporated into the Abandoned Compound significant
proprietary ZENECA technology or Third Party technology which it may
sublicense to ISIS (including, but not limited to, specialized
formulation or delivery technology) the Parties will negotiate in
good faith an additional royalty for access to such technology, if
required.
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3.5 ZENECA Right to Reconsider Abandoned Compounds.
(a) If ISIS pursues the development and/or commercialization of an
Abandoned Compound, ZENECA will have a right of first negotiation to
reacquire such Abandoned Compound on the earlier of: (i) if ISIS
determines that it desires to license such Abandoned Compound to a
Third Party (a commercial distribution arrangement will explicitly
not be considered a license for these purposes) or (ii) prior to
initiation of Pivotal Quality Clinical Study for such Abandoned
Compound if ISIS has not licensed rights to a Third Party at that
time. If ZENECA desires to be considered a commercial distributor
for an Abandoned Product, ISIS will reasonably consider such
request.
(b) At the time ZENECA has the right to reacquire an Abandoned Compound,
ISIS will provide ZENECA with access to all material data relating
to such Abandoned Compound. ZENECA will have [ * ] following receipt
of such information to initiate good faith negotiations with ISIS.
Should the Parties fail to reach a mutually agreeable set of terms,
ISIS will be free to license the Abandoned Compound to a Third Party
on terms no more favorable to such Third Party than those last
offered by ZENECA, or to continue on its own to develop and
commercialize the Abandoned Compound.
3.6 Shared Compounds.
ZENECA may, at its option, offer to ISIS the opportunity to participate
in the joint development and commercialization of a Development
Candidate, on a [ * ].
3.7 Progress Reports.
Beginning on January 30 in the calendar year in which, in the case of
ZENECA the first Development Candidate is accepted by ZENECA and in the
case of ISIS, an Abandoned Compound is taken into development by ISIS
or, if the period following such acceptance to January 30 is less than 6
months, then on the following January 30, each party will submit to the
other on each January 30 an annual written progress report summarizing
its activities related to product development and clinical evaluation of
Development Candidates and Abandoned Compounds as appropriate and the
efforts to secure governmental approval to market the Collaboration
Products.
3.8 Compulsory Licensing.
If a Third Party seeks a compulsory license for a Collaboration Product
in accordance with appropriate provisions of the laws of any country and
ISIS and ZENECA agree that the Third Party is legally entitled to such
license or the Third
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Party is awarded such license by a decision of the appropriate
governmental authority to make such decisions, the granting of such
license will not constitute a breach of ISIS' obligations ZENECA will
have right to reduce the royalty on sales in such country to an amount
no greater than the amount payable by the said Third Party as
consideration for the compulsory license.
ARTICLE 4
PAYMENTS FOR DEVELOPMENT CANDIDATES
4.1 Milestone Payments.
(a) Subject to Subparagraph (b) and (d) below, in addition to the other
payments required to be made by ZENECA hereunder, ZENECA will pay to
ISIS the following amounts with respect to each Development
Candidate to reach each milestone:
[ * ] [ * ]
[ * ] [ * ]
[ * ] [ * ]
[ * ] [ * ]
(b) Milestone Payments made for a Development Candidate, which inhibits
a specific Target, [ * ]. Milestone payments [ * ] for a Development
Candidate for which a milestone has already been paid. Milestones [
* ] in clinical trials [ * ] for such subsequent Development
Candidate at which time, [ * ] , the previously unpaid milestone
payment for the subsequent Development Candidate will be paid.
(c) All milestone payments will be due within 45 days of the milestone
being met.
(d) If ZENECA sublicenses development or commercial rights to a
Collaboration Product to a Third Party, ZENECA will pay to ISIS the
amount ISIS would have received under this Agreement had ZENECA
conducted the development or commercialization. If this cannot be
achieved within the terms of the proposed sublicense, ZENECA and
ISIS will negotiate in good faith payment terms for ISIS which are
acceptable to both parties.
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4.2 Royalty.
(a) In consideration of the license rights set forth in Article 7
hereof, ZENECA will pay a royalty to ISIS on each Collaboration
Product equal to:
[ * ] of Net Sales Revenue for the Collaboration Product [ * ] for
such Collaboration Product paid pursuant to Paragraph 4.1(a) [ * ],
and (ii) any royalty [ * ]; provided, however, that the royalty
payment on Net Sales Revenue will not be [ * ]. Because ISIS will be
paying directly to Genzyme Molecular Oncology the royalties owed
under the GMO License Agreement, the royalty payable to ISIS
hereunder for a Collaboration Product [ * ] will not be [ * ] for so
long as, and in such territories for which, royalties are owed by
ISIS to Genzyme Molecular Oncology under the GMO License Agreement
for such Collaboration Product.
(b) The royalties payable hereunder [ * ].
4.3 Term of Royalty Obligations.
The royalty obligations specified in Paragraph 4.2 will be due and
payable and continue as to each Collaboration Product on a country by
country basis from the date of First Commercial Sale for the longer of:
(i) the term of the last to expire of the ISIS Patents which prevents a
Third Party from discovering, developing, making, using or selling such
Collaboration Product in that country; [ * ]. ZENECA will notify ISIS
promptly upon introduction of each Collaboration Product in each
country. Upon termination of the royalty payment obligation, ZENECA will
have, in perpetuity, a fully paid license under the ISIS Technology to
discover, develop, make, have made, use, sell, have sold Collaboration
Product without further accounting to ISIS.
* CONFIDENTIAL TREATMENT REQUESTED
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4.4 Payments by ZENECA.
Royalties owed by ZENECA to ISIS pursuant to this Article 4 will be paid
no later than 45 days after the end of the calendar quarter during which
such royalties accrued.
4.5 Currency Conversion.
Royalties will be calculated and paid in United States dollars. For the
purpose of computing the Net Sales Revenue made in a currency other than
United States dollars, ZENECA will convert such currency from local
currency to pounds sterling on a consistent monthly basis using a 5 day
average of exchange rates published by Reuters and then convert such
pounds sterling to United States dollars monthly using the average of
the exchange rate from pounds sterling to United States dollars
published by Reuters for the same 5 days provided, however, that with
respect to Net Sales Revenue from sales made in a currency other than
United States dollars by ZENECA's Affiliates a quarterly exchange rate
shall be used for both the conversion from local currency to pound
sterling and from pound sterling to United States dollars that is the
average of the foregoing exchange rates for each of the three months in
the quarter. The foregoing conversion method is in accordance with
ZENECA's current accounting policies. In the event ZENECA's policies for
currency conversion change in the future, the parties will meet and
mutually agree upon a new conversion method.
4.6 Taxation of Payments.
ZENECA will withhold taxes from the royalty or other payments as
required by the internal tax law of the U.K. In the case of such
withholding being applicable, ISIS may apply for the reduction of rate
of withholding tax under the U.K./U.S. Income Tax Treaty with the
assistance of ZENECA and, provided the claim is accepted and ZENECA is
duly authorized by the Inland Revenue, ZENECA will apply the reduced
rate accordingly. If applicable laws required that taxes be withheld,
ZENECA will deduct those taxes from the remittable payments, make timely
payment of the taxes to the proper taxing authority, and send a
confirmation of such payment in a form approved by the UK Inland Revenue
to ISIS within 60 days following that payment.
4.7 Interest.
All payments due hereunder from ZENECA that are not paid to ISIS when
due and payable as specified in the Agreement will bear interest at an
annual rate [ * ], or at such lower rate of interest as will then be the
maximum rate permitted by applicable law.
* CONFIDENTIAL TREATMENT REQUESTED
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ARTICLE 5
MANUFACTURING AND SUPPLY
5.1 Research Supply.
ISIS agrees to supply all of ZENECA's requirements of Development
Candidates for its research program under the Research Collaboration in
the amounts and in accordance with the specifications set out in Exhibit
F.
5.2 Clinical Supply.
ISIS will, if ZENECA requests, supply all of ZENECA's requirements of
Development Candidates required for clinical trials [ * ]. ISIS will
supply clinical material on the same basis as research material billed
as Excess Research Costs pursuant to mutually agreed upon
specifications. ZENECA will provide ISIS with 18-month rolling forecast
and a final purchase order [ * ]. Timing of deliveries will be scheduled
consistent with ISIS' other facility requirements and ZENECA's
reasonable needs for clinical supply stocking. The Parties will
negotiate in good faith the terms of a clinical supply agreement
containing these and other customary terms. If ISIS is not able to
supply Development Candidates or if ZENECA determines to obtain supply
from a Third Party, then ISIS will, at ZENECA's request, promptly
transfer all necessary technology and technical assistance [ * ].
5.3 Commercial Supply.
(a) ZENECA will be free to obtain commercial supply of Collaboration
Products from the manufacturer of its choice. If ZENECA desires ISIS
to provide commercial supply of Collaboration Products and if ISIS
has the capacity and desire to do so, the parties will negotiate in
good faith the terms of a commercial supply agreement to be
concluded before the initiation of the first Pivotal Quality
Clinical Trial.
(b) If ISIS is not able to provide commercial supply or ZENECA
determines to manufacture Collaboration Products itself or through
an Affiliate or have Collaboration Products manufactured by a Third
Party then ISIS will, at ZENECA's request, promptly transfer all
necessary technology and technical assistance and grant a [ * ]
* CONFIDENTIAL TREATMENT REQUESTED
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[ * ].
5.4 Manufacturing Information.
As reasonably requested by ZENECA, ISIS will provide ZENECA all
information in ISIS control relating to Development Candidates and
Collaboration Products being developed by ZENECA including without
limitation information regarding process, in process control methods,
final product characterization/analysis methods, scale, cost and
alternative manufacturing sites.
ARTICLE 6
BOOKS AND RECORDS
6.1 Recordkeeping; Audit.
(a) Each party will keep accurate accounts and records in sufficient
detail to properly determine the royalties payable to the other
under this Agreement for at least 3 years following the end of the
calendar quarter to which they pertain.
(b) Each party will make available such accounts and records for
inspection during such 3 year period by a certified public
accountant retained by the other for such purpose, solely for the
purpose of verifying the royalty payments hereunder. Such
inspections may be made no more than once in each calendar year, at
reasonable times mutually agreed upon by the parties after at least
15 days written notice to the other.
(c) If an audit concludes that additional royalties were owed during the
period audited, the party in default will pay the additional
royalties within 45 days of the date the other party delivers to it
the accounting firm's written report. The fees charged by such
accounting firm will be paid by the party initiating the inspection
unless the additional royalties owed by the party in default exceed
5% of the royalties paid for the period subject to the audit, in
which case that party will pay the fees of the accounting firm.
(d) Each party will include in each sublicense granted by it pursuant to
this Agreement a provision requiring the Sublicensee to make reports
to the other party, to keep and maintain records of sales made
pursuant to such sublicense and to grant access to such records by
the other's independent accountant to the same extent required of
the Licensor under this agreement.
(e) Each party will treat all financial information subject to review
under this Paragraph 6.1 or under any sublicense agreement in
accordance with the confidentiality provisions of this Agreement.
* CONFIDENTIAL TREATMENT REQUESTED
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(f) ISIS will maintain complete and accurate records which are relevant
to its expenditure of research manpower provided under this
Agreement pursuant to the Research Plan. With reasonable notice,
said records will be open during reasonable business hours for a
period of from [ * ] for examination at ZENECA's expense by an
independent certified public accountant appointed by ZENECA and
reasonably acceptable to ISIS. Such examination will be for the sole
purpose of verifying for ZENECA the cost of the research conducted
and whether or not funds received by ISIS from ZENECA were used for
conducting the research.
ARTICLE 7
LICENSE GRANTS
7.1 License for Collaboration Products.
In consideration of the payments made under Paragraphs 2.6, 4.1 and 4.2:
(a) ISIS hereby grants to ZENECA and its Affiliates during the term of
the Collaboration a co-exclusive (with ISIS), worldwide,
non-transferable royalty free license under the GMO License
Agreement subject to the terms of this Agreement, solely to the
extent necessary or appropriate to carry out ZENECA's
responsibilities under this Agreement.
(b) Upon payment by ZENECA of the milestone payment due on [ * ] for a
Collaboration Product, ISIS will grant to ZENECA (i) a worldwide
exclusive, sublicensable license under the portions of the ISIS
Technology necessary to make, have made, use and sell such
Collaboration Product and the right to xxx any Third Party for any
act of infringement of any such portion of the ISIS Technology in
the event that the Third Party infringes an ISIS Target Patent under
this 7.1(b), (ii) a worldwide, exclusive, sublicensable license to
the ISIS Target Patents relating to the Target of the Collaboration
Product to make, have made, use and sell such Collaboration Product
and to xxx any Third Party for any act of infringement within the
scope of the claims of such ISIS Target Patent. If ZENECA reasonably
determines that it is necessary for it to obtain the licenses
granted hereunder [ * ] in order to allow sublicensing in a
territory in which ZENECA cannot reasonably develop or commercialize
on its own, ISIS will grant such licenses upon notice from ZENECA of
its requirement and an agreement from ZENECA to pay ISIS any
additional expenses incurred by it for example, fees required to
convert patents and/or patent applications to Large Entity status.
(c) Nothing contained herein will be deemed to grant a license to any
technology not owned or controlled by ISIS or to any technology of
which ISIS is a licensee but for which ISIS is prohibited from
granting sublicenses all which technology existing at the date of
this Agreement is identified in Exhibit G.
* CONFIDENTIAL TREATMENT REQUESTED
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(d) For any technology acquired by ISIS from a Third Party before the
Effective Date (which is described in Exhibit G) or after the
Effective Date which is necessary or useful to make, use or sell a
Collaboration Product, before such technology is included in any
license granted pursuant to Paragraph 7.1(a), ZENECA and ISIS will
negotiate a mutually agreeable set of terms for the inclusion of
such technology, which terms will consider the cost to ISIS to
acquire and develop such technology as well as any milestone or
royalty payments ISIS may owe to the licensor with respect to such
technology. The Parties acknowledge and agree that the Patents
licensed to ISIS pursuant to the GMO License Agreement are included
herein under the terms contained herein with no additional
negotiation.
(e) ISIS will not take any action after the Effective Date that would
encumber its technology in any way that would impair its ability to
grant the licenses contemplated hereunder.
(f) ZENECA agrees that the rights and licenses granted hereunder do not
provide to ZENECA the right to use ISIS Technology for any purpose
except as expressly provided in this Paragraph 7.1.
ARTICLE 8
TERM AND TERMINATION
8.1 Term.
This Agreement will be in effect beginning the Effective Date and,
unless otherwise terminated by operation of law or by acts of the
Parties in accordance with the terms of this Agreement, will remain in
effect until the last to expire of any royalty obligation under
Paragraph 4.2. Provided, however, that if the GMO License Agreement is
not executed by January 31, 1999, in accordance with Exhibit H, in so
far as is necessary to protect ZENECA's freedom-to-operate hereunder
with respect to the patents covered thereby, ZENECA will have the right
to terminate the Agreement or, at its option, to initiate renegotiation
of the Agreement.
8.2 Termination by Either Party.
(a) Termination for Breach.
In the event of either Party being in default of any material
obligation contained in this Agreement and failing to cure or
obtain the cure of such breach within 60 days after receipt of
written notice thereof from the non-defaulting party (45 days in
the case of any payment required to be made hereunder); provided,
however, that if the defaulting party is unable to cure a breach
for causes beyond its reasonable control, then such sixty-
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day period will be extended for a period of time reasonable under
the circumstances as long as the defaulting party is continuing
to pursue such a cure in good faith; provided, further that in
the event of a good faith dispute about payment amounts, the
party allegedly owing the money may deposit any contested amount
(but not the uncontested portion, which must be paid) in an
interest bearing escrow account pending resolution of such
contest, with the prevailing party receiving both principal and
interest upon resolution.
(b) Notwithstanding the foregoing, in the event of an uncured
material breach by one party the non-breaching party may choose
not to terminate this Agreement and to continue it in full force
with all of the rights and obligations of the Parties continuing
in place and may rely in stead on a damage remedy to compensate
for the effects of the breach.
8.3 Termination for Bankruptcy.
The institution by or against either party of proceedings to be
adjudicated as bankrupt or insolvent or to be reorganized or
released under any bankruptcy or equivalent statute applicable to
that party, the appointment of a receiver, liquidator or trustee,
or the making of an assignment for the benefit of creditors;
provided, however, that if any such proceeding is instituted
without the consent or acquiescence of that party against whom
such order is made, this Agreement may not be terminated if such
party causes such proceedings to be dismissed within 60 days from
the date the proceeding was instituted.
8.4 Termination By ZENECA Without Cause.
After the Research Collaboration Term as defined in Paragraph 2.5,
ZENECA may terminate this Agreement by written notice to ISIS.
8.5 Effects of Termination.
Upon termination of this Agreement by ISIS or ZENECA pursuant to
Paragraph 8.2 or 8.3, all rights and licenses granted by ISIS to ZENECA
will terminate and the right to develop Development Candidates and to
commercialize Collaboration Products will revert to ISIS.
ARTICLE 9
INVENTIONS AND PATENTS
9.1 Inventions.
ISIS will retain title to inventions, whether or not patentable, made
solely by employees of or consultants to ISIS, and to patents thereon.
ZENECA will retain
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title to inventions, whether or not patentable, made solely by employees
of or consultants to ZENECA and to patents thereon. ISIS will hold title
to all inventions, whether or not patentable, made jointly by employees
of or consultants to ISIS and ZENECA and to patents thereon.
9.2 Patents.
ISIS will be responsible to diligently file, prosecute and maintain in
force and defend in those countries in the world determined by the JRC
all patent applications and patents for ISIS Target Patents. [ * ]. If
ISIS declines to apply for or decides to abandon any ISIS Target Patent
and relinquish its rights thereunder in any particular country, it will
promptly notify ZENECA in writing and ZENECA will have the right to
assume responsibility for maintaining such patent application or patent,
at its own expense and in its own name. ISIS agrees to cooperate with
ZENECA so as to enable ZENECA to undertake such maintenance without loss
of patent rights. ZENECA will have complete responsibility for such
continued maintenance and may, in its sole discretion, allow any such
patent application or patent to lapse at any time.
9.3 Patent Marking.
ZENECA, its Affiliates and Sublicensees will xxxx all Collaboration
Products made, used or sold under the terms of this Agreement, or their
containers, in accordance with the applicable patent marking laws, as
required.
9.4 Defense of Patent Infringement Suits.
(a) Notwithstanding the foregoing, [ * ]. The Parties acknowledge that
any royalty owed to Genzyme Molecular Oncology under the GMO License
Agreement will be paid by ISIS to Genzyme Molecular Oncology [ * ].
(b) In the event that (i) ZENECA's use, as set forth in this Agreement,
of any ISIS Technology licensed under this Agreement infringes or is
likely to infringe any patent or other intellectual property rights
of any Third Party, (ii) such infringement is likely to prevent
ZENECA from selling Commercial Products, and (iii) at the time a
Compound is proposed by the Join Research Committee as a Development
Candidate, ISIS has not informed ZENECA in writing of the existence
of such potential patent infringement then, and only to the extent
that ZENECA is required to pay royalties or other payments to a
Third Party, [ * ], but in no event will ISIS' royalty be reduced to
less than [ * ] in any calendar year.
* CONFIDENTIAL TREATMENT REQUESTED
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(c) In the event that (i) the discovery, development, manufacture, use
or sale of a Collaboration Product is determined by ZENECA in its
reasonable estimation to have infringed or to be likely to infringe
any patent of any Third Party, and (ii) such infringement is not
covered by Paragraph 9.4(b), then, and only to the extent that
ZENECA is required to pay royalties or other payments to a Third
Party. ISIS and ZENECA will discuss in good faith reducing the
royalty payable by ZENECA to ISIS under this Agreement.
(d) If a Third Party asserts that the manufacture, use or sale of any
Collaboration Product infringes a patent owned or controlled by a
Third Party, ZENECA will be solely responsible for defending and
settling in its sole discretion against any such assertions. ISIS
will provide all reasonable assistance requested by ZENECA to defend
or settle such action. ISIS will have the right at its own expense
to participate in such suit at its own expense.
(e) The Parties acknowledge that, under certain licenses listed on
Exhibits G-1 and G-3 and other licenses that Isis may acquire in the
future and which ISIS shall notify ZENECA of in writing, royalties
might owe to parties from whom ISIS has acquired nonsublicensable
licenses if ISIS is not the manufacturer of a Collaboration Product
and no royalty reduction will be made by reason of these royalties.
9.5 Suits for Third-Party Infringement.
(a) Each party will advise the other promptly upon its becoming aware of
any third party infringement of an ISIS Target Patent. ISIS agrees,
within reasonable business judgement and at its own discretion, to
promptly take such action as is required to restrain such
infringement at its own cost. ZENECA will cooperate fully with ISIS
at ISIS' expense in ISIS' attempt to restrain such infringers.
ZENECA may be represented by counsel of its own selection at its own
expense at any suit or proceeding brought by ISIS to restrain such
infringement. ISIS will bear the expense of any suit or suits and
will obtain all benefits of the recoveries from such suit or suits,
whether by judgment, award, decree or settlement up to an amount
equal to [ * ]
* CONFIDENTIAL TREATMENT REQUESTED
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[ * ] and the remainder will be allocated among ISIS and ZENECA in a
manner reasonably calculated to correspond to the relative
distribution of profits on the Collaboration Product(s) to which
such recovery pertains between ISIS and ZENECA.
(b) If, within 14 days of becoming aware of a third party infringement
under 9.5(a), ISIS fails to institute an infringement suit that
ZENECA feels is reasonably required, ZENECA will have the right, at
its own discretion, to institute an action for infringement. ZENECA
will bear the expense of any such suit or suits and will obtain all
of the benefits of the recoveries from such suit or suits, whether
by judgement, award, decree or settlement up to an amount equal to
[ * ] and the remainder will be allocated among ISIS and ZENECA in
a manner reasonably calculated to correspond to the relative
distribution of profits on the Collaboration Product(s) to which
such recovery pertains between ISIS and ZENECA. Should ZENECA bring
any such suit, ISIS will cooperate in all reasonable ways with
ZENECA in any such suit or suits at ISIS' expense. ISIS may be
represented by counsel of its own selection at its own expense
(c) If the parties agree to mutually share expenses and to pursue an
infringement suit together, they will (i) share in any and all
benefits in the recovery from such suit, whether by judgment, award,
decree or settlement in the manner mutually agreed among them, and
(ii) agree on the lead plaintiff, selection of counsel and other
litigation strategy matters.
ARTICLE 10
WARRANTIES AND DISCLAIMERS
10.1 Representations and Warranties.
(a) Each party warrants to the other party that it is free to enter into
this Agreement and carry out its obligations hereunder, and that its
execution and delivery of this Agreement and performance of its
obligations hereunder will not violate, be in conflict with, or
constitute a default (or an event which, with notice or lapse of
time or both, would constitute a default) under any agreement to
which it is party or by which it is bound.
(b) Each party warrants to the other that, to the best of its knowledge,
its use (or use by the other party under this Agreement) of its
existing technology does not infringe any issued patent of any Third
Party of which it is aware, and it has not received any
communication alleging that it has infringed or acted in conflict
with, or by conducting its business as proposed, would infringe or
act in conflict with the right of any Third Party.
* CONFIDENTIAL TREATMENT REQUESTED
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(c) Neither Party has granted, nor during the term of the Agreement will
grant, any right to any Third Party relating to its respective
technology which would conflict with the rights granted to the other
Party in this Agreement.
(d) Notwithstanding the foregoing, both parties acknowledge that Genzyme
Molecular Oncology has certain issued patents and patent
applications that ISIS is in the process of licensing under the
terms of the GMO License Agreement. Nothing contained in either
Party's representations will be deemed to be made without
recognition of the existence of these patents.
10.2 Disclaimer.
ALL ITEMS, INFORMATION AND MATERIALS PROVIDED TO ZENECA BY ISIS
HEREUNDER ARE TO BE USED BY ZENECA FOR INVESTIGATIONAL PURPOSES ONLY.
NEITHER PARTY MAKES ANY WARRANTIES, EXPRESS, IMPLIED, STATUTORY OR
OTHERWISE, OF ANY KIND, INCLUDING ANY WARRANTY OF MERCHANTABILITY OR
FITNESS FOR A PARTICULAR PURPOSE.
ARTICLE 11
INDEMNITY AND INSURANCE
11.1 Indemnity.
(a) Each Party (the "Indemnifying Party") will indemnify, defend and
hold the other Party (the "Indemnified Party") harmless from and
against any and all liabilities, claims, damages, costs, expenses or
money judgments incurred by or rendered against the Indemnified
Party and its Affiliates and sublicensees arising out of any
injuries to person and/or damage to property resulting from (a)
negligent acts of the Indemnifying Party performed in carrying out
its obligations hereunder, including failure by the Indemnifying
Party to provide the Indemnified Party with any information of the
Indemnifying Party's which, if timely received would have avoided
injury, death or damage, provided such failure to provide such
information is due to negligence on the part of the Indemnifying
Party, and (b) personal injury to the Indemnified Party's employees
or agents or damage to the Indemnified Party's property resulting
from acts performed by, under the direction of, or at the request of
the Indemnifying Party in carrying out activities contemplated by
this Agreement.
(b) In addition to its obligations in Paragraph 11.1(a) hereof, ZENECA
will indemnify and hold ISIS harmless from and against any and all
liabilities, claims, damages, costs, expenses or money judgments
which result from the manufacture (other than manufacture by ISIS),
use, promotion and sale of Development Candidates or Collaboration
Products under this Agreement.
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(c) The Indemnifying Party's obligations hereunder as to any claim are
subject to (i) its being given prompt notice thereof; (ii) the sole
right to control the defense and settlement; and (iii) the lack of
negligence or willful misconduct leading to the claim by the
Indemnified Party.
11.2 Insurance.
Each Party will obtain and maintain, in all places in which
Collaboration Products are developed, used or sold, product liability
insurance in the amounts and with the deductibles customarily maintained
by that party and which are consistent with its obligations with respect
to the products sold. Each Party will provide to the other information
concerning the existence of such insurance upon request from time to
time.
ARTICLE 12
TRADENAMES, TRADEMARKS, CONFIDENTIALITY AND PUBLICATIONS
12.1 Tradenames and Trademarks.
Nothing contained in this Agreement will be construed as conferring any
right of one Party to use in any manner any tradename or trademark of
the other Party or any of its Affiliates without such other party's
prior written consent and approval as to form.
12.2 Confidentiality.
ZENECA and ISIS agree for themselves, and for their Affiliates and
Sublicensees, and on behalf of their respective officers, employees and
agents, that for the greater of five years following the expiration or
termination of this Agreement or fifteen years from the Effective Date,
each will treat as confidential, using the maximum degree of care that
it uses for its own proprietary information, and that it will not use
(except as permitted under this Agreement) for its own benefit or the
benefit of any third party, any of the Confidential Information
furnished to it by the other party unless the furnishing party otherwise
agrees in writing or unless the party receiving the Confidential
Information is required to disclose such Confidential Information to a
court of law or to appropriate governmental agencies to enable the
recipient to secure governmental approval of a Collaboration Product. In
each such case, the recipient will notify the disclosing party of the
requirement and work together with the disclosing party to obtain the
maximum amount of confidentiality provided by such court of law or
governmental agency.
12.3 Shared Confidential Information.
In the course of performance of this Agreement, the Parties may jointly
develop, invent or discover information, which will be considered to be
the "Shared
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Confidential Information" of both Parties. Each Party agrees that it
will take the same steps to protect the confidentiality of the Shared
Confidential Information as it takes to protect its own proprietary and
confidential information.
Each Party will protect and keep confidential and will not publish or
otherwise disclose to any Third party, except as contemplated by this
agreement or with the other Party's written consent, the Shared
Confidential Information for the same period which covers the
Confidential Information. Each Party may, however, use any Shared
Information for any purpose provided that such use will not be deemed a
license or grant of any additional right or license other than or in
addition to the rights and licenses granted in this Agreement.
This Paragraph 12.2 and 12.3 supersedes any confidential disclosure
agreement between the Parties as to the subject matter hereof. Any
confidential information under such agreement will be treated as
Confidential Information hereunder.
12.4 Publications.
ISIS and ZENECA agree to discuss the timely publication in respected
scientific journals of articles prepared by their respective researchers
relating to such researchers' work on Development Candidates or
Collaboration Products with a view toward resolving the competing
interests of confidentiality and desired scientific credit through
publication. The manuscript of each proposed publication will first be
submitted to both parties and if either Party advises within 30 days of
receipt of the manuscript that publication of particular information
would materially diminish the commercial value of a Development
Candidates or Collaboration Products, publication of such information
will be delayed for such time as the parties agree, in order to permit
the preparation of patent applications or other documents to protect the
commercial interests of the parties. The Parties acknowledge that
publication delay may be beneficial to ensure that patent filings
contain appropriate support and, as a result, the Party whose invention
is involved will inform the other of the time reasonably required to
ensure an optimal patent coverage strategy and both parties agree to
abide by that decision. Notwithstanding the foregoing, there will be no
publication of any Confidential Information or Shared Confidential
Information reasonably valuable to ISIS or ZENECA without the agreement
of both ISIS or ZENECA.
ARTICLE 13
MISCELLANEOUS
13.1 Bankruptcy.
All rights and licenses granted under or pursuant to this Agreement by
ISIS to ZENECA are, and will otherwise be deemed to be, for purposes of
Section 365(n) of Title 11, U.S. Code (the "Bankruptcy Code"), licenses
of rights to "intellectual property" as defined under section 101(60) of
the Bankruptcy Code. The Parties
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agree that ZENECA, as a licensee of such rights under this Agreement,
will retain and may fully exercise all of its rights and elections under
the Bankruptcy Code. ISIS agrees during the term of this Agreement to
create and maintain current copies or, if not amenable to copying,
detailed descriptions or other appropriate embodiments, of all such
intellectual property. The Parties further agree that, in the event of
the commencement of a bankruptcy proceeding by or against ISIS under the
Bankruptcy Code, ZENECA will be entitled to a complete duplicate of (or
complete access to, as appropriate) any such intellectual property and
all embodiments of such intellectual property, and same, if not already
in its possession will be promptly delivered to ZENECA (a) upon any such
commencement of a bankruptcy proceeding upon written request therefore
by ZENECA, unless ISIS elects to continue to perform all of its
obligations under this Agreement or (b) if not delivered under (a)
above, upon the rejection of this Agreement by or on behalf of ISIS upon
written request therefore by ZENECA.
13.2 Waiver.
No waiver by either party hereof of any breach or default of any of the
covenants or agreements herein set forth will be deemed a waiver as to
any subsequent or similar breach or default.
13.3 Assignment.
This Agreement will be binding upon and inure to the benefit of the
parties hereto and their successors and assigns; provided, however, that
neither party will assign any of its rights and obligations hereunder to
a non-Affiliate without the consent of the other party which consent
will not be withheld unreasonably except as incident to the merger,
consolidation, reorganization, or acquisition of stock or assets
affecting substantially all of the assets or actual voting control of
the assigning party with regard to the business unit to which this
Agreement relates.
13.4 Notices.
Any notice or other communication required or permitted to be given to
either party hereto will be in writing and will be deemed to have been
properly given and to be effective on the date of delivery if delivered
in person or by telex or facsimile or 2 business days after mailing by
expedited delivery or 5 days after mailing by registered or certified
mail, postage paid, to the other party at the following address:
In the case of ISIS: Isis Pharmaceuticals, Inc.
0000 Xxxxxxx Xxxxxx
Xxxxxxxx, XX 00000
Attention: CEO (Fax: 000-000-0000)
With copy to: B. Xxxxx Xxxxxxxx
(Fax: 000-000-0000)
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In the case of ZENECA Zeneca Pharmaceuticals
Attention: The Legal Director
Xxxxxxxx Xxxxx, Xxxxxxxx Xxxx,
Xxxxxxxxxxxx Xxxxxxxx XX00 0XX.
Attention: Legal Director
(Fax: [ * ])
Either party may change its address or fax number for communications by
a notice to the other party in accordance with this Paragraph 13.4.
13.5 Governing Law.
This Agreement will be interpreted and construed in accordance with the
substantive laws of the State of Delaware. ZENECA and ISIS hereby submit
to the jurisdiction and venue and procedural rules of the United States
District Courts for the State of Delaware for any action hereunder that
is permitted consistent with Paragraph 13.11. ZENECA and ISIS agree that
service of process may be effected against each of them by certified or
registered mail with respect to legal actions commenced in any such
jurisdiction by the other, its successors or assigns.
13.6 Amendment.
No amendment or modification hereof will be valid or binding upon the
parties unless made in writing and signed by both parties.
13.7 Force Majeure and Hardship.
(a) Any delays in performance by any party under this Agreement will not
be considered a breach of this Agreement if and to the extent caused
by occurrences beyond the reasonable control of the party affected,
including but not limited to acts of God, embargoes, governmental
restrictions, strikes or other concerted acts of workers, fire,
flood, explosion, riots, wars, civil disorder, rebellion or
sabotage. The party suffering such occurrence will immediately
notify the other party and the time for performance of any
obligation hereunder, except the due diligence obligations set forth
in Paragraph 3.1, will be extended by the actual time of delay
caused by the occurrence.
(b) If for reasons unforeseen at the Effective Date the performance of
this Agreement becomes an undue burden for either party the parties
will in good faith negotiate for an appropriate amendment hereof
with a view to alleviating or eliminating said burden.
* CONFIDENTIAL TREATMENT REQUESTED
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13.8 Independent Contractors.
Nothing contained in this Agreement will be construed to create an
agency, partnership or employer and employee relationship between ISIS
and ZENECA. At no time will one party make commitments or incur any
charges or expenses for or in the name of the other party except as
specifically provided herein.
13.9 Severability.
If any term, condition or provision of this Agreement is held to be
unenforceable for any reason, it will, if possible, be interpreted
rather than voided, in order to achieve the intent of the parties to
this Agreement to the extent possible. In any event, all other terms,
conditions and provisions of this Agreement will remain valid and
enforceable to the full extent.
13.10 Entire Agreement.
This Agreement when they are executed embody the entire understanding
of the parties with respect to the subject matter of this Agreement and
will supersede all previous communications, representations or
understandings, either oral or written, between the parties relating to
the subject matter hereof.
13.11 Dispute Resolution.
Any dispute or claim arising out of or in connection with the Agreement
will be resolved as follows: (i) for a period of 30 days after a dispute
arises the CEO of ISIS and the Research and Development Director of
ZENECA Pharmaceuticals business will negotiate in good faith in an
effort to resolve the dispute and (ii) if the dispute has not been
resolved at the close of such 30 day period, the matter will be finally
settled by binding arbitration under the Rules of Arbitration of the
American Arbitration Association, by their arbitrators appointed in
accordance with said rules; provided that if the parties cannot agree on
who is to serve as the arbitrator, each party will appoint one nominee
and those nominees will in turn jointly appoint the third arbitrator.
Arbitration will take place in Delaware. The costs of the arbitration,
including administrative and arbitrators' fees, will be shared equally
by the parties; provided, that each party will bear the costs of its own
attorneys' fees and expert witness fees. Judgment on an award rendered
by an arbitrator or arbitrators may be entered in any court having
jurisdiction thereof. Notwithstanding the foregoing, the parties may
apply to any court of competent jurisdiction for preliminary or interim
equitable relief without breach of this arbitration provision.
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13.12 Government Approvals.
The Parties agree to make all filings with governmental agencies as
shall be required by law in connection with this Agreement and the
activities contemplated hereunder.
IN WITNESS WHEREOF, the Parties have executed this Agreement, in duplicate
originals, by their respective officers hereunto duly authorized, as of the day
and year hereinabove written.
Isis Pharmaceuticals, Inc.
BY ________________________________
B. Xxxxx Xxxxxxxx
Title: Executive Vice President
Zeneca Limited
By _________________________________
C.R.W. Xxxxx
Title: Legal Director, Authorized Signatory
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EXHIBIT A
DEFINITIONS
1.1 "ABANDONED COMPOUND" means a Development Candidate which ZENECA
subsequently ceases to develop or commercialize pursuant to Paragraph
3.1(b) or 3.3.
1.2 "ABANDONED TARGET" means (i) any Target for which another Target is
substituted pursuant to Paragraph 2.8; (ii) any Target following
termination of the research program for such Target; and (iii) all
Targets upon termination of the Research Collaboration.
1.3 "ACTIVE TARGET PROGRAM" means (i) an ongoing research program as part of
the Research Collaboration on the Target; (ii) an active clinical
development program for a Development Candidate inhibiting such Target;
or (iii) a marketing and commercialization program for a Collaboration
Product inhibiting such Target.
1.4 "AFFILIATE" means, as to ISIS, any corporation, company, partnership,
joint venture or firm which controls, is controlled by, or is under
common control with, ISIS; and, as to ZENECA, any enterprise which,
directly or indirectly, is controlled by ZENECA alone or together with
partners of ZENECA or partners of ZENECA alone, as long as such control
exists. For the purpose of the preceding sentence, the word "control"
means the ownership of at least 50% of the outstanding voting stock of
such enterprise or, a comparable equity interest in any other type of
entity.
1.5 "ANTISENSE TECHNOLOGY" means the selective inhibition of protein
synthesis at the nucleic acid level. This inhibition is caused by the
binding of an oligonucleotide or an analog thereof (termed
"oligonucleotide") to the complementary sequence. In particular, an
oligonucleotide will specifically bind to the sequence of the selected
messenger or viral RNA by base-pairing and will hence bring about a
selective inhibition of gene expression.
1.6 "[ * ] " means those molecular targets which play a direct role in
regulation of [ * ] and for which inhibitors are anticipated to provide
a positive therapeutic benefit in the treatment of [ * ]. Targets
covered are: [ * ].
1.7 "CANCER-RELATED TARGETS" means Targets added to the Research
Collaboration pursuant to Paragraph 2.8 whose primary therapeutic use is
the treatment of cancer.
1.8 "COLLABORATION PRODUCT(S)" means a Development Candidate which ZENECA
commercialize itself or through its Affiliate or Sublicensees.
* CONFIDENTIAL TREATMENT REQUESTED
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1.9 "COMPOUNDS" means any oligonucleotide or analogs designed using
Antisense Technology for use as a human therapeutic to inhibit a Target
as part of the Research Collaboration.
1.10 "CONFIDENTIAL INFORMATION" means any confidential information including,
without limitation, information which is disclosed by one party to the
other relating to any technology research project, development project
or plan, manufacturing process, technology or plan, marketing or
commercial plan, financial or personnel matter relating to either Party,
its present or future products whether within or outside the
Collaboration, whether in oral, written, graphic or electronic form.
Confidential Information will not include information which:
(a) is or will have been known to the receiving party prior to the
disclosure by the other party as evidenced by written record or
other proof; or
(b) is or will have been public knowledge through no fault of the
receiving party; or
(c) has been received from a Third Party who did not acquire it directly
or indirectly from the disclosing party; or
(d) is independently developed by the receiving party without the use of
or reference to information disclosed by the other party.
The material financial terms of this Agreement constitute Confidential
Information.
1.11 "DEVELOPMENT CANDIDATE" means a Compound and formulation which meets the
Research Target Profile and is accepted for development by ZENECA.
Chemical modifications to a Development Candidate or materially
different formulations that have a significant effect on the commercial
desirability of the Development Candidate will be considered separate
Development Candidates.
1.12 "EFFECTIVE DATE" means December 18, 1998.
1.13 "EXCESS RESEARCH COSTS" means the costs of the Research Collaboration in
addition to Research Payments described in subparagraph 2.4(b). Excess
Research Costs for compound supply in excess of [ * ] per compound per
calendar year or [*] of all compounds per calendar year will be billed
at [ * ] of the sum of ISIS' actual cost of raw materials for such
compound plus ISIS' Personnel Fully Burdened Rate for such manufacture
(including an appropriate allocation of costs of process development,
analytical development and scale up for such manufacture). Excess
Research Costs for outside expenditures will be billed at [ * ]. Excess
Research Costs for ISIS performance outside the tasks outlined in the
Research Plan will be billed at ISIS' Personnel Fully Burdened Rate.
1.14 "FDA" means the United Stated Food and Drug Administration or an
equivalent agency in a Major Country.
* CONFIDENTIAL TREATMENT REQUESTED
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1.15 "FIRST COMMERCIAL SALE" means the first transfer for value of title to a
Collaboration Product by ZENECA, its Affiliates or Sublicensees to a
non-Affiliate for consideration in any arm's length transaction or the
first use (excluding the supply of clinical trial materials) of a
Collaboration Product by ZENECA, its Affiliates or Sublicensees in a
country following Governmental Approval in such country, whichever
occurs first. For the purpose of this definition all transfer of title
to reasonable quantities of any free samples of Collaboration Product or
to clinical trial material shall not constitute a First Commercial Sale.
1.16 "GMO LICENSE AGREEMENT" means a non-exclusive license agreement with
Genzyme Molecular Oncology to license certain [ * ] patents having the
terms attached hereto as Exhibit H.
1.17 "IND" means the regulatory filing required to initiate Phase I Clinical
Trials in the US or any other country. If Phase I Clinical Trials are
initiated without a requirement for regulatory filing or approval an IND
will be deemed to have been filed on initiation of Phase I Clinical
Trials.
1.18 "INFLATION FACTOR" will mean an annual adjustment based upon changes in
the Consumer Price Index for Urban Wage Earnings and Clerical Worker -
U.S. City Average, for the prior 12 months, rounded up to the nearest
$5,000 per FTE.
1.19 [ * ].
1.20 "ISIS DEVELOPMENT EXPENSES" means costs incurred by ISIS to conduct, at
ZENECA's request, additional work on a Compound after it has been
designated a Development Candidate and will include ISIS labor, billed
at the ISIS Personnel Fully-Burdened Rate (which will include overhead
items such as operating leases, rents, equipment, supplies and related
departmental and company overhead) plus outside expenses including the
cost of raw materials for compound supply, clinical grants, laboratory
work, CRO, outside data management charges, charges for outside
pharmacokinetic, toxicological and other testing, and an appropriate
allocation of all manufacturing functions which directly benefit a
Development Candidate including process development and analytical
research and development.
1.21 "ISIS KNOW-HOW" means all proprietary inventions, technology, trade
secrets, clinical and preclinical results (collectively, "inventions")
discovered or developed by ISIS prior to the Effective Date which are
necessary or useful to make, use or sell Collaboration Products and
which are not covered by ISIS Patents. ISIS Know-How will also include
any inventions which are not covered by ISIS Patents which are necessary
or useful to make, use or sell Collaboration Products, discovered or
developed by ISIS after the Effective Date or acquired by ISIS from
* CONFIDENTIAL TREATMENT REQUESTED
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Third Parties before or after the Effective Date provided that ISIS is
free to license such inventions to ZENECA, and, provided further, that
if ISIS developed or acquired such inventions for or from a Third Party,
ISIS and ZENECA have mutually agreed on the terms upon which ISIS will
provide such inventions to ZENECA, as provided for in Paragraph 7.1(c).
1.22 "ISIS PATENTS" means any and all patents, both foreign and domestic,
which relate to inventions made by ISIS on or prior to the Effective
Date which are necessary or useful to make, use or sell Collaboration
Products including without limitation ISIS Target Patents. ISIS Patents
will also include any patents relating to inventions made by ISIS after
the Effective Date or licensed to ISIS before or after the Effective
Date which are necessary or useful to make, use or sell Collaboration
Products, provided that ISIS is free to license such patents to ZENECA
and, provided further, that if ISIS developed or acquired such
inventions for or from a Third Party, ISIS and ZENECA have mutually
agreed on the terms upon which ISIS will provide such patents to ZENECA
as provided in Paragraph 7.1(c). Notwithstanding the foregoing, ISIS
Patents will include any Patents licensed to ISIS under the GMO License
Agreement with no further payments required except as expressly provided
in this Agreement. "Patents" as used herein will include, without
limitation, all substitutions, extensions, reissues, renewals,
divisions, continuations, continuations-in-part, inventors' certificates
and all foreign counterparts of the aforementioned. Attached hereto as
Exhibit G is a list of all ISIS' licenses as of the Effective Date that
may be relevant to the Research Collaboration including the technology
covered and the royalty rate.
1.23 "ISIS PERSONNEL FULLY-BURDENED RATE" means [ * ].
1.24 "ISIS TARGET PATENTS" means claims of ISIS Patents arising out of
inventions made by ISIS during the Research Collaboration which cover
specific antisense compounds directly inhibiting a particular Target.
1.25 "ISIS TECHNOLOGY" means ISIS Patents, ISIS Target Patents and ISIS
Know-How.
1.26 "JOINT RESEARCH COMMITTEE" means the Committee defined in Paragraph 2.2.
1.27 "MAJOR COUNTRY" means the United States, Japan, the Federal Republic of
Germany, France, the United Kingdom or other European Community country
if chosen by ZENECA to be rapporteur country for the Hi-Tech product
registration procedure within the European Community.
1.28 "NDA" means a New Drug Application filed with FDA after completion of
clinical trials to obtain marketing approval for a commercial product in
the United States or equivalent application for regulatory approval in
other countries.
* CONFIDENTIAL TREATMENT REQUESTED
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1.29 "NET SALES REVENUE" means the total invoiced amount of all sales of
Collaboration Product by ZENECA its Affiliates or Sublicensees less:
i) Prompt payment or other trade or other quantity discounts,
rebates or retroactive price reductions actually allowed and
taken in such amounts as are customary in the trade;
ii) Commissions paid or allowed to distributors and agents who are
independent Third Parties other than such parties who are
performing detailing functions;
iii) Amounts repaid or credited by reason of timely failure or
rejection or recalls (whether voluntary or mandatory);
iv) Customs, duties and taxes (other than franchise or income taxes
on the income of ZENECA) actually paid or withheld;
v) Allowances [ * ] in any period including any allowances for bad
debt, provided that upon the extinguishment of any such
allowance, the extinguishment will be determined to be a
receipt; and
vi) Transportation and delivery charges [ * ] in any period,
including insurance premiums.
Net Sales Revenue shall exclude:
i. The transfer of reasonable and customary quantities of free
samples of Collaboration Product, clinical trial materials and
sales to an Affiliate or a Sublicensee, other than for
subsequent resale.
ii. Sales or transfers of Collaboration Product among ZENECA and its
Affiliate unless the receiving party is the consumer or user of
the Collaboration Product.
iii. Use by ZENECA, its Affiliates or Sublicensees of Collaboration
Product for any use connected with the securing of regulatory
approval or validating of a manufacturing process or the
obtaining of other necessary marketing approvals for
Collaboration Product.
If ZENECA, its Affiliates or Sublicensees intend to use a Collaboration
Product rather than resell it, the sales price for such Product will be
calculated based on the average of the sales of Collaboration Product to
Third Parties during the period in which such Collaboration Product is
transferred to such Affiliate or Sublicensee and included in Net Sales
Revenue as if sold to a Third Party at such price during such period.
Net Sales Revenue will be calculated in U.S. dollars in accordance with
Paragraph 4.5.
* CONFIDENTIAL TREATMENT REQUESTED
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1.30 "NON-CANCER-RELATED TARGETS" means Targets added to the Research
Collaboration pursuant to Paragraph 2.8(c) whose primary therapeutic use
is the treatment of a disease or diseases other than cancer.
1.31 "PARTY" means ISIS or ZENECA, or ISIS and ZENECA.
1.32 "PHASE II CLINICAL TRIALS" means the initial clinical testing of a
Compound in humans who are patients with a disease for which the
Compound is being tested with the intention of gaining a preliminary
assessment of the safety, efficacy and dosing regimen of a Compound in
treating such disease.
1.33 "PIVOTAL QUALITY CLINICAL TRIAL" will mean a human clinical trial of a
Compound designed to be of a size and statistical power to support an
NDA Filing alone or in combination with other studies. If it is unclear
whether or not a study design will be sufficient to support an NDA
Filing (other than by virtue of the uncertainty of efficacy data from
that trial) the study will be deemed to be a Pivotal Quality Trial on
the initiation of activities to support an NDA Filing. Initiation of a
Phase III clinical study will be deemed to be initiation of a Pivotal
Quality Study.
1.34 "RESEARCH COLLABORATION" means the collaboration between ISIS and ZENECA
to discover antisense drugs as defined in this Agreement.
1.35 "RESEARCH PAYMENTS" mean the regular payments described in Paragraph
2.4(b) as increased and pursuant to Paragraph 2.4(c) and 2.8, but will
not include the Excess Research Costs.
1.36 "RESEARCH TARGET PROFILE" means the scientific criteria specified by the
Joint Research Committee to be fulfilled for a Compound to be met prior
to designation of the Compound as a Development Candidate and prior to
the initiation of IND-enabling toxicology, pharmacology and
pharmacokinetic studies, including the methods for testing Compounds to
determine whether the Profile is met. The Research Target Profile for
the [ * ] are attached as Exhibit D.
1.37 "SHARED COMPOUND" means a Development Candidate which ZENECA proposes
and ISIS accepts to develop and commercialize on a shared basis pursuant
to Paragraph 3.5.
1.38 "SUBLICENSEE" means any Third Party (including a distributor) who is
given the right to market and sell a Collaboration Product. A Third
Party who is given only the right to sell a Collaboration Product (such
as a wholesaler) will not be considered a Sublicensee. It is recognized
and agreed that distributors appointed by ZENECA whose sole function is
to purchase and resell Collaboration Product are not sublicensees for
the purpose of this definition.
* CONFIDENTIAL TREATMENT REQUESTED
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1.39 "TARGETS" means specific individual molecular targets either initially
or from time-to-time, collectively the Initial Targets, Cancer-Related
Targets, and Non-Cancer-Related Targets. When an Active Target Program
for a Target terminates, that Target will cease to be a Target and will
thereafter become an Abandoned Target. Targets will include the Initial
Targets plus any other Targets added or substituted pursuant to
Paragraph 2.8 hereof, with any Abandoned Target when abandoned. Research
relating to the Targets includes the elaboration of necessary cellular,
biochemical and molecular-biological approaches (i.e., the development
of the knowledge not already available to the two partners, the
development and setting up of relevant assays) towards the inhibition of
the expression of the proteinic target molecules by Antisense Technology
as well as the conception, design, synthesis and development of
therapeutic entities, including the characterization of their
biophysical and pharmacokinetic properties.
1.40 [ * ].
1.41 "THIRD PARTY" means any party other than ISIS and its Affiliates or
ZENECA and its Affiliates and Sublicensees.
1.42 "THIRD PARTY SUPPLIER" means any person or entity other than a party to
this Agreement, its Affiliates, and/or its respective employees from
whom ZENECA purchases commercial quantities of Bulk Drug Substance.
1.43 "ZENECA FIELD OF USE" means [ * ].
* CONFIDENTIAL TREATMENT REQUESTED
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EXHIBIT B
COLLABORATION RESEARCH PLAN
[ * ]
ENTIRE EXHIBIT REDACTED.
* CONFIDENTIAL TREATMENT REQUESTED
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EXHIBIT C
JOINT RESEARCH COMMITTEE COMPOSITION
[ * ]
ENTIRE EXHIBIT REDACTED.
* CONFIDENTIAL TREATMENT REQUESTED
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EXHIBIT D
RESEARCH TARGET PROFILE FOR THE INITIAL TARGETS
[ * ]
ENTIRE EXHIBIT REDACTED.
* CONFIDENTIAL TREATMENT REQUESTED
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EXHIBIT E
TECHNICAL MILESTONE CRITERIA
[ * ]
ENTIRE EXHIBIT REDACTED.
* CONFIDENTIAL TREATMENT REQUESTED
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EXHIBIT F
MANUFACTURING SPECIFICATIONS
Typical Specifications for a Uniform Phosphorothioate Active Pharmaceutical
Ingredient
IDENTITY:
ES-MS [ * ]
Sequencing by MALDI-TOF MS [ * ]
Functionality [ * ]
IMPURITY PROFILES: (AT LEAST TWO):
P-NMR [ * ]
Capillary Gel Electrophoresis [ * ]
Reversed-phase HPLC [ * ]
Anion Exchange HPLC [ * ]
ASSAY: (AT LEAST ONE)
Oligonucleotide Content by uV [ * ]
Full-length Oligonucleotide by [ * ]
uV X CGE Impurity Profile
IMPURITIES:
Organic Volatiles by Capillary GC [ * ]
ACS Heavy Metals by ICP-MS [ * ]
QUALITY:
Endotoxins, USP [ * ]
Bioburden, USP [ * ]
OTHER:
Sodium content [ * ]
pH of 1% solution [ * ]
Moisture Content (KF or GC) [ * ]
* CONFIDENTIAL TREATMENT REQUESTED
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EXHIBIT G-1
ISIS LICENSES
CONTRACT FIELD PATENTS PAYMENT OBLIGATIONS
-------------------- -------------------- ------------------ ------------------------------
CHEMISTRY
Cross License [ * ] [ * ] In consideration for the
Agreement (and reciprocal license, [ * ];
amendments) with however, a royalty of [ * ]
Novartis Pharma AG of sublicensee's net sales
of each product in countries
where the incorporation of
the modifications into such
product, or sale of such
product would infringe an
issued and valid Novartis
patent
GENES
Genzyme Molecular [ * ] [ * ] [ * ] of net sales of all
Oncology License licensed products
Agreement
* CONFIDENTIAL TREATMENT REQUESTED
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EXHIBIT G-2
ISIS LICENSES
CONTRACT FIELD PATENTS PAYMENT OBLIGATIONS
-------------------- -------------------- ------------------ ------------------------------
CHEMISTRY
Ajinomoto License [ * ] [ * ] [ * ] of net sales (gross
Agreement invoice price to any third
party, less only accepted
returns from Isis's or Isis'
sublicensee's customer,
breakage, etc). Any
transaction between Isis and
any Isis sublicense shall
not be included in net sales
PNA Group License [ * ] [ * ] [ * ] royalty payable to PNA
Agreement Group of net sales revenues
and a [ * ] royalty of
sublicensing revenue (not to
be less than [ * ] of the
sublicensee's net sales
revenues) on sale of products
covered by patents
Centre National De [ * ] [ * ] [ * ] of the billed sales
La Recherche price on products using
Scientifique patented technology
(CNRS) License
Agreement
The Research [ * ] [ * ] [ * ] royalty of the net
Foundation of sales revenue derived by
State University Isis or affiliates or
of New York sublicensees from the sale
License Agreement of products
Vical License [ * ] [ * ] [ * ] royalty on the net
Agreement sales revenues for patented
products sold by Isis and
[ * ] royalty of net
sales revenues for patented
products sold by Isis'
sublicensees
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CONTRACT FIELD PATENTS PAYMENT OBLIGATIONS
-------------------- -------------------- ------------------ ------------------------------
[ * ] [ * ] Total royalty payment of [ * ]
Gen-Probe Assets on net sales revenues ([ * ])
Purchase Agreement received by Isis from the
territories in which the
issued patents subsists
(i.e. United States and its
territories, Australia,
Canada, Israel and Japan) or
on net sales revenues
received by Isis from
product made in the
territories in which the
issued patents subsists
(i.e. United States and its
territories, Australia,
Canada, Israel and Japan)
XxXxxx University [ * ] [ * ] [ * ] royalty on Isis net
Research and sales revenue for any
License Agreement chirally pure
oligonucleotide therapeutic
or diagnostic product or
reagent developed,
manufactured or sold by Isis
and [ * ] of all
sublicensing revenues
received from unrelated
third parties
* CONFIDENTIAL TREATMENT REQUESTED
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EXHIBIT G-3
ISIS LICENSES
USE/PROCESS/MANUFACTURING
University [ * ] [ * ] [ * ] of adjusted gross revenue
Technologies on products sold as linker
International Inc. derivatized support matrices for
License Agreement oligonucleotide synthesis, [ * ]
of adjusted gross revenue on
products sold as nucleoside
reagents with Q-linker or
alternate linkers governed by
patents, [ * ] of adjusted gross
revenue on all other products
with the exception of the
therapeutic drug candidate
Applied [ * ] [ * ] [ * ] of ABI published list
Biosystems, Inc price for a gram of the same or
License Agreement equivalent licensed reagent then
being marketed by ABI
Perseptive [ * ] [ * ] Royalty free license to
Biosystems, Inc. manufacture, have manufactured
License Agreement and use for its own use in house
and for its own purposes and to
incorporate as a raw material
into its own products for its
own use, the use of others or
for sale, but not to sell
licensed products, and to use
licensed product
National Technical [ * ] [ * ] [ * ] royalty payable to NTIS on
Information net sales revenues received by
Service (NTIS) Isis from sales within the
License Agreement United States and its
territories.
* CONFIDENTIAL TREATMENT REQUESTED
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EXHIBIT H
GMO TERM SHEET
ISIS REVISED PROPOSAL FOR NON-EXCLUSIVE LICENSE
November 12, 1998
Licensee: Isis Pharmaceuticals, Inc. ("Isis")
Licensor: Genzyme Corporation ("Genzyme")
Field: Oligonucleotide Inhibition of [ * ] gene expression.
Patent rights: The patent rights include any issued patents or patent
applications owned by or assigned to Genzyme or licensed to
Genzyme that would cover the discovery, development or
commercialization of oligonucleotide inhibiting [ * ] gene
expression. The patent rights specifically include without
limitation patents or patent applications claiming priority to
[ * ] including patents that issue on such patent applications
and improvements, reissues, reexaminations, renewals,
extensions, divisions, continuations, and continuations-in-part
and foreign counterparts of such patents and patent
applications.
License Grant: Genzyme grants a non-exclusive, worldwide, royalty-bearing
sublicense under the Patent Rights to discover, develop, make,
have made, use, import and export, offer for sale, and sell
Licensed Products for use in the Field (including the right to
develop, make and use the Licensed Methods in the Field).
Genzyme will also grant to Isis the right to sublicense, but
only to the extent necessary to allow development and
commercialization of an [ * ] antisense inhibitor as a drug.
Any such sublicense will survive any termination of the Isis
License if the sublicensee agrees to be bound by its terms.
A Licensed Product shall mean a compound, the
discovery, development, manufacture, use or sale of
which would, but for the licenses granted hereunder,
infringe a valid claim of an issued patent, the Patent
Rights or a Licensed Method.
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A Licensed Method shall mean a method of use that is
covered by an issued valid and unexpired claim of the
patent rights.
Up-front Payment: $______ within 30 days of signing
Milestone Payments [ * ] $_______
for the first Licensed
Product : [ * ] $_______
[ * ] $_______
[ * ] $_______
[ * ] $_______
All milestone payments will be increased by ___% if
commercialization of the Licensed Product would, except
for the License Grant, otherwise infringe claims of
issued US patent(s).
Royalties: ___% on Net Sales of Licensed Products in territories where
commercialization of the Licensed Product would, except for the
License Grant, infringe a claim of a valid issued patent in the
territory of sale.
or:
___% on Net Sales of Licensed Products in territories
where a Licensed Method was used to derive the Licensed
Product, and where valid patent(s) with valid claim(s)
covering the Licensed Method are in force.
Credits/stacking The upfront payment and milestone payments will not be
creditable against royalties.
Favored Licensee Genzyme agrees that if additional non-exclusive sublicenses are
Status: granted to third parties in the Field that ISIS will have the
option to change the terms of the ISIS-Genzyme
agreement to match those of the sublicensing agreement
with the third party.
* CONFIDENTIAL TREATMENT REQUESTED
6