CONFIDENTIAL TREATMENT REQUESTED
UNDER 17 C.F.R. Sections 200.80(b)4, AND 240.24b-2
CLINICAL SUPPLY AGREEMENT
This Clinical Supply Agreement ("Agreement") between ISIS PHARMACEUTICALS, INC.
of 0000 Xxxxxxx Xxxxxx, Xxxxxxxx, XX 00000, XXX ("ISIS") and ANTISENSE
THERAPEUTICS LTD., ACN 000 000 000 of Xxxxx 0, 00 Xxxxxxx Xxxxxx, Xxxxxx,
Xxxxxxxx 0000, XXXXXXXXX ("ATL") is entered into and made effective in
accordance with the provisions of the agreement entitled "Master Agreement"
between ATL and ISIS, dated October 30 2001. The effective date of this Clinical
Supply Agreement will be the date upon which all of the conditions in the Master
Agreement have been met (the "Effective Date"). If the Effective Date has not
occurred by March 28, 2002, this Agreement will be null and void and will not
become effective.
INTRODUCTION AND OVERVIEW
ISIS and ATL will collaborate in the discovery and development of Products
pursuant to the related Collaboration and License Agreement. When ATL submits an
order to ISIS for a Collaboration Compound which ATL is committed to use in
IND-enabling studies, ISIS will manufacture active pharmaceutical ingredient
("API") for each such Collaboration Compound ordered, using ISIS Standard
Chemistry, for use by ATL in IND-enabling toxicology studies and subsequent
clinical studies, during the term of this Agreement.
During the term of this Agreement, the parties will also work together to
facilitate the transfer of antisense drug manufacturing technology to ATL or its
Contractors. As of the Effective Date, ISIS will supply ATL with API, and ATL
will be responsible for the formulation, filling, finishing, labeling and
packaging of all Products, including stability studies. By the time the term of
this Agreement ends, however, it is the parties' intent that ATL will be solely
responsible for manufacturing its requirements of API and Product.
Therefore, in consideration of the foregoing premises and the mutual
covenants herein contained, the parties hereby agree as follows.
ARTICLE 1
DEFINITIONS
Capitalized terms used in this Agreement have the meanings set forth in
Exhibit 1 hereto.
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ARTICLE 2
MANUFACTURE AND SUPPLY OF API AND ISIS 107248 PRODUCT
2.1 RESPONSIBILITIES OF ATL AND ISIS
ISIS will provide API for Collaboration Compounds to ATL for use
consistent with this Agreement and the Collaboration and License
Agreement, and ISIS will also perform API stability studies on all API
provided by ISIS. Except as provided in Section 2.3, ATL will be
responsible for the formulation, filling, finishing, labeling and
packaging of all Products, including stability studies.
2.2 FORMULATION, FILL AND FINISH OF PRODUCT
The parties acknowledge that as of the Effective Date, a Third Party
manufacturer typically performs the formulation, filling and finishing of
Product. Following the Effective Date, ATL will be responsible for the
formulation, filling and finishing of Product and will use commercially
reasonable efforts to promptly establish, by itself or through a Third
Party manufacturer, the manufacturing process for formulating, filling,
and finishing Product. If requested by ATL, ISIS will cooperate with ATL,
as appropriate, to enable ATL to enter into an agreement with the Third
Party manufacturer used by ISIS to perform the formulation, filling and
finishing of Product.
2.3 PURCHASE, FORMULATION AND CERTIFICATION OF ISIS 107248 PRODUCT FOR
IND-ENABLING STUDIES
(a) Within 30 days of the Effective Date, ATL will purchase from ISIS the
[***] grams of ISIS 107248 API that ISIS has in its inventory and will pay
ISIS for that API in the amount of [***], consistent with the provisions
of Article 7. ISIS will hold such API for ATL's account in order to
formulate and certify such ISIS 107248 API in January 2002, as further
described herein.
(b) Pursuant to ATL's request, and at ATL's expense, ISIS will formulate and
certify the ISIS 107248 API referenced in (a) above. ATL and/or an ATL
Contractor other than ISIS will participate in the formulation and
certification process, at ATL's expense, to facilitate the Technology
Transfer, as further described in Section 6.2.
(c) As ISIS will be performing the formulation and certification of the ISIS
107248 API and the release of Clinical Product for ATL as a Contractor,
ATL is responsible for certain losses prior to Delivery, consistent with
the provisions of Section 5.2.
2.4 FORMULATION AND RELEASE OF ISIS 107248 CLINICAL PRODUCT FOR HUMAN
STUDIES
ATL will bear sole responsibility for the formulation, fill, finish and
release of ISIS 107248 Clinical Product for use in human studies pursuant
to the Collaboration and License Agreement. ATL will use commercially
reasonable efforts to promptly establish,
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by itself or through a Third Party manufacturer, the manufacturing
process for formulating, filling, finishing, and releasing ISIS 107248
Clinical Product.
ARTICLE 3
ORDERS AND LIMITATION OF SUPPLY
3.1 PRODUCTION AND DELIVERY PLANS AND ORDERS
(a) With the exception of 2001, not later than July 1 of each year in
which this Agreement is in effect, up to and including July 1, 2005,
ATL will provide ISIS with a written API order estimate indicating
the amount of API ATL will require during the subsequent Calendar
Year, which estimate will indicate the quantity and identity of each
Collaboration Compound for which API is requested. ISIS has agreed,
pursuant to the Collaboration and License Agreement, to supply API
for up to [***] different Collaboration Compounds in active
development by ATL each year from 2002-2006. The total quantity of
such API to be supplied by ISIS in any Calendar Year during the term
of this Agreement will not exceed [***], and the minimum order of
API for each Collaboration Compound must be at least [***] kg. Each
estimate and order submitted by ATL will indicate which
Collaboration Compound API(s) is/are being ordered and the quantity
of each such API ordered.
(b) At the time ATL provides each API order estimate for Calendar Years
2003 through 2006, ATL representatives will meet with ISIS
representatives to discuss and agree upon a production and delivery
plan for the next Calendar Year (the "Production and Delivery
Plan"). Each year's agreed-upon Production and Delivery Plan will
specify the quantity and identity of each Collaboration Compound for
which ISIS will supply API to ATL during the subsequent Calendar
Year, taking into account all relevant factors including, without
limitation, ISIS' obligations to other parties. Each such
Production and Delivery Plan will be deemed a firm purchase order of
ATL for the quantity of API for each Collaboration Compound
specified therein, and a firm commitment of ISIS to Manufacture and
supply such quantities of API to ATL. Each lot of API Manufactured
and supplied to ATL by ISIS after the Effective Date and during the
term of this Agreement will be for use in IND-enabling studies and
human clinical studies.
(c) [***]
(d) The Production and Delivery Plan for Calendar Year 2002 is attached as
Exhibit 3.1 hereto and is considered ATL's firm purchase order of API for
Calendar Year 2002.
(e) The Production and Delivery Plan will further specify one or more
dates upon which Delivery of the API to be supplied by ISIS will
occur during the relevant Calendar Year. ISIS will use commercially
reasonable efforts to Deliver the API to ATL according to the
agreed-upon Delivery schedule set forth in the Production and
Delivery Plan. The Production and Delivery Plan will provide for
Delivery of API promptly after completion
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of Manufacture and release. The date on which the parties agree upon a
Production and Delivery Plan for the following Calendar Year will be
referred to herein as the "API Order Date."
(f) ISIS will perform a mutually agreed upon stability program for API
Manufactured by ISIS at ATL's expense. ISIS will invoice ATL for such
activities and for materials and expenses incurred in accordance
therewith, as further described in Article 7.
3.2 LIMITATIONS OF SUPPLY
(a) In the event that ISIS anticipates, at any time during the term of
this Agreement, that it will be unable to supply in whole or in part
the quantities of API set forth in an agreed-upon Production and
Delivery Plan for any reason, including without limitation force
majeure, ISIS will notify ATL in writing as soon as possible of such
shortfall. ISIS will also notify ATL of the underlying reason for
the shortfall, proposed remedial measures, the date such inability
to supply the full order of API is expected to end, and a proposed
amount of API to be Delivered to ATL. [***] The proposed amount of
API to be made available to ATL hereunder will be no less than [***]
of the amount of raw materials or other resources required for the
Manufacture of API, taking into consideration the amount of such
raw materials or other resources required by (i) ATL under this
Agreement and (ii) ISIS and its other programs.
(b) If ISIS cannot Manufacture as set forth in this Agreement, ISIS shall so
inform ATL immediately upon the prediction or occurrence such non-supply.
In such event, ATL shall have the right to Manufacture or have
Manufactured API for ATL's needs and ISIS shall provide all assistance and
relevant information, know-how and data necessary for ATL to establish and
begin the Manufacture of API.
ARTICLE 4
QUALITY STANDARDS
4.1 QUALITY STANDARDS
(a) With respect to API Manufactured by ISIS after the Effective Date,
ISIS will Manufacture such API in accordance with the API
Specification in effect at the start of Manufacture, US cGMP, and
other applicable rules and regulations of all Regulatory Authorities
and other regulatory agencies with jurisdiction over the
manufacture, use or sale of the API, as then in effect. If cGMP for
the U.S. and its foreign equivalent differ, ATL will specify in
writing which cGMP will apply to each batch of Collaboration
Compound API ordered from ISIS by ATL. ISIS will be responsible for
Manufacturing issues related to API safety and regulatory
compliance. Each party will promptly notify the other party of any
relevant new instructions or specifications required by a Regulatory
Authority, and of other applicable and regulations of which that
party becomes aware. The parties will confer with each other with
respect to the best means to comply with
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such requirement and will allocate any costs of implementing such
changes on an equitable basis.
(b) ISIS will perform quality control testing as is specified (i) in the API
Specification; and (ii) as required by a Regulatory Authority and by the
mutual written consent of the parties, on each lot of API supplied for use
in Product, prior to shipment of such API.
(c) As ATL develops Collaboration Compounds pursuant to the Collaboration and
License Agreement, modified or expanded API Specifications appropriate to
the stage of development may be required. Such API Specifications will be
consistent with the API Specifications of other ISIS antisense compounds
at a similar stage of development.
(d) New API Specifications will be prepared and processed as follows.
(i) Not later than [***] days prior to its submission of an API order
estimate for a new Collaboration Compound to ISIS, ATL will provide
ISIS with written notice of its intent to order API for which API
Specifications have not yet been prepared.
(ii) Upon receipt of such written notice, ISIS will initiate any required
development work and subsequently prepare an API Specification for
each new Collaboration Compound that ATL intends to order, which
will be consistent with the API Specifications of other ISIS
antisense compounds at a similar stage of development.
(iii) Once a new API Specification has been prepared by ISIS, it will be
added to this Agreement as an Exhibit thereto, and ATL will be
provided with a copy, in advance of Delivery of the API.
4.2 CERTIFICATE OF ANALYSIS
(a) ISIS will provide a Certificate of Analysis to ATL or its designated
Contractor with each lot of API supplied hereunder. Consistent with
Section 3.1(b), each lot of API supplied to ATL by ISIS after the
Effective Date and during the term of this Agreement will be for use
in IND-enabling studies and human clinical studies. The foregoing
provisions do not, however, apply to the ISIS 107248 Product for
IND-enabling studies, which Product ISIS will formulate and certify,
consistent with the provisions of Section 2.3. Each Certificate of
Analysis will contain the results of the analysis of API as required
in the API Specification, and will certify with respect to each
shipment and lot (identified by lot number): (i) the quantity of
the shipment, (ii) that the API delivered was Manufactured in
accordance with the API Specification and in conformance with the
applicable cGMP. The Certificate of Analysis will contain any
information in addition to that required herein as may be required
by the Regulatory Authority of the country of destination of API or
Product; provided, however, that ATL provides to ISIS, in a timely
manner, sufficient documentation and information necessary or useful
to enable ISIS to conform with such requirements. ISIS will provide
the results of such analysis to ATL, along with any supporting data.
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(b) ATL will be under no obligation to accept any Delivered lot of API without
an accompanying Certificate of Analysis that conforms to subsection (a)
above. ISIS will also make available for ATL's review ISIS' Manufacturing
records for the API, including its master and production batch records,
for the purposes of assuring product quality and compliance with
agreed-upon Manufacturing procedures.
4.3 CHANGES TO MANUFACTURING PROCESS
(a) If ISIS proposes a material change to the Manufacturing Process, ISIS will
notify ATL in writing and will provide information to ATL regarding the
change at a level sufficient to allow ATL to understand any impact of such
change on the Manufacturing Process.
(b) The parties will obtain the prior Regulatory Approval(s), and any other
approvals required to be obtained, before any changes are implemented.
4.4 COMPLIANCE WITH LAWS
In performing their obligations under this Agreement, the parties will
comply with all applicable present and future orders, regulations,
requirements and laws ("Legal Requirements") of any and all U.S.
authorities and agencies, including without limitation laws and
regulations applicable to the transportation, storage, use, handling and
disposal of hazardous materials (the "U.S. Legal Requirements"), and any
Legal Requirements of other countries ("Foreign Legal Requirements"). ATL
will inform ISIS of any such Foreign Legal Requirements. If the U.S. Legal
Requirements conflict with the Foreign Legal Requirements, the parties
will discuss and agree on how to resolve such conflict.
ARTICLE 5
SUPPLY PRICE; DELIVERY; PAYMENT TERMS
5.1 SUPPLY PRICE
(a) The API Supply Price will apply to all quantities of API supplied to ATL
hereunder.
(b) Within [***] days of each API Order Date, ISIS will invoice ATL for [***]
of the projected API Supply Price of API to be Manufactured during the
relevant Calendar Year pursuant to the Production and Delivery Plan. ATL
will pay each invoice within [***] days after receipt. Payment terms are
set forth in Section 5.5 below.
(c) For each Calendar Quarter, ISIS will invoice ATL for the actual API
Supply Price of API Delivered to ATL during such Calendar Quarter,
minus the amount already paid by ATL pursuant to subsection (b)
above. Such invoice will reflect an adjustment equal to the amount
by which the actual API Supply Price is greater than or less than
the projected API Supply Price for API Delivered to ATL during such
Calendar Quarter. ATL will pay each invoice within [***] days after
receipt. Payment terms are set forth in Section 5.5 below.
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5.2 DELIVERY
(a) ISIS will deliver API and ISIS 107248 Product for IND-enabling studies to
a carrier designated by ATL FCA ISIS' Facility (Incoterms 2000). The
shipping and packaging specifications will be agreed upon by the parties.
(b) In the event of a loss of work in process or API prior to the transfer of
title pursuant to the Delivery of API as provided in subsection (a) above,
any uninsured portion of the loss will be shared by ATL and ISIS as
follows: [***]. Any deductible will be applied ratably against all items
damaged or lost.
5.3 ACCEPTANCE AND CLAIMS; MATERIALS REVIEW BOARD
(a) If ATL claims that any sample of API did not meet the warranty specified
in Section 10.1, ATL will notify ISIS in writing within 30 days of such
Delivery, and a joint Materials Review Board formed under subsection (b)
below will review the test data generated by ATL and ISIS under QA
approved procedures mutually agreed upon by the parties within 30 days
after ATL's notice to ISIS.
(b) Promptly after the Effective Date, ISIS and ATL will each select 2 members
of their in-house materials review boards (or other senior personnel or
Contractors with appropriate qualifications) to participate in a joint
Materials Review Board ("MRB") that will review and consider any test data
generated by ATL and ISIS with respect to the Delivered lot of API.
(c) If the members of the MRB are thereafter unable to agree as to
whether the API met the warranty specified in Section 10.1, the
parties will cooperate and have the test data reviewed by an
independent third party selected by ATL and approved by ISIS, which
approval will not be unreasonably withheld. If the independent
third party reviewer cannot determine whether the Delivered API in
dispute met the warranty of Section 10.1, a sample of the batch of
the Delivered API in dispute retained by ISIS will be analyzed in
accordance with the API Specifications, under QA approved
procedures, by an independent testing laboratory of recognized
repute selected by ATL and approved by ISIS, which approval will not
be unreasonably withheld. Unless provided otherwise herein, the
results of such laboratory testing will be final and binding on the
parties on the issue of compliance of the API with such warranty.
(d) If the API is determined to meet the warranty set forth in Section
10.1, ATL will bear the cost of any third party review and/or
independent laboratory testing performed pursuant to subsection (c)
above and will pay for the API in accordance with the terms of this
Agreement. If the API is determined not to meet the warranty set
forth in Section 10.1, ISIS will bear the cost of any third party
review and/or independent laboratory testing performed pursuant to
subsection (c) above.
(e) If ISIS agrees, or if it is determined pursuant to subsection (c)
above, that API did not conform to the warranty set forth in Section
10.1, ISIS will use commercially reasonable efforts to Manufacture
and Deliver a replacement batch of API to ATL for the batch of
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API that did not conform to such warranty, and ATL will pay ISIS for any
such replacement batch of API, including without limitation, all
costs and expenses associated with such Manufacture, consistent with
the provisions of Section 5.1 herein. The API Supply Cost for the
Manufacture of the batch of API that did not conform to such
warranty will be shared by ATL and ISIS as follows: ISIS will be
responsible for the [***] for such batch of API; and ATL will be
responsible for the [***] for such batch of API. Replacement of API
will be ATL's sole and exclusive remedy for breach of the warranty
set forth in Section 10.1.
(f) Any Delivered API which ISIS agrees did not meet, or which was determined
not to have met, the Section 10.1 warranty that is in ATL's control will,
at ISIS' option, either be returned to ISIS or will be destroyed pursuant
to ISIS' instructions and with ATL's approval, which approval will not be
unreasonably withheld, at ISIS' expense.
(g) Failure by ATL to notify ISIS within [***] after Delivery of API which
does not meet the warranty under Section 10.1 will be a waiver of the
remedies available to ATL under this Section 5.3.
(h) Should either party identify any possible latent defect of API that is not
revealed by the procedures set forth above within [***] of receipt of any
shipment by ATL, it will so notify the other party immediately upon
discovery. ATL and ISIS will discuss in good faith and agree upon the
appropriate measures to be taken by the parties related to such latent
defect.
5.4 TERMS OF SALE
The terms and conditions of this Agreement will be controlling over any
inconsistent terms or conditions included in any agreed-upon order for API
or any other sales acknowledgment or document. No provision of any ATL
forms purporting to be orders for API that may impose different conditions
than those herein referenced upon ISIS, ATL or their respective
Contractors will be of any force or effect unless expressly agreed to in
writing by both parties.
5.5 PAYMENT TERMS
(a) PAYMENTS. All payments to ISIS under this Agreement will be made in United
States Dollars by bank wire transfer in next day available funds to such
bank account in the United States designated in writing by ISIS from time
to time. All amounts payable to ISIS hereunder are noncreditable and
nonrefundable, unless specifically provided otherwise herein.
(b) LATE PAYMENTS; COLLECTIONS. In the event that any payment,
including royalty, milestone or research payments, due hereunder is
not made when due, the payment will bear interest from the date due
at the lesser of (i) [***] per month, compounded monthly, or (ii)
the highest rate permitted by law; provided, however, that in no
event will such rate exceed the maximum legal annual interest rate.
The payment of such interest will not
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limit a party from exercising any other rights it may have as a
consequence of the lateness of any payment. [***]
ARTICLE 6
TECHNOLOGY TRANSFER
6.1 TECHNOLOGY TRANSFER COMMITTEE
(a) The Release Technology Transfer (as defined in Section 6.2) and the
API Technology Transfer (as defined in Section 6.3) will be
coordinated and implemented under the supervision of a joint
committee (the "Technology Transfer Committee" or "TTC") comprised
of 2 employees appointed by each of the parties. ATL may appoint a
Contractor instead of an employee, provided that any Contractor
appointed by ATL is approved by ISIS, which approval will not
unreasonably be withheld. ATL warrants that any Contractor
appointed by ATL will be bound by all applicable terms of this
Agreement and by the confidentiality provisions of the Collaboration
and License Agreement, which are incorporated herein and made part
of this Agreement by reference. Members of the Technology Transfer
Committee will each have appropriate technical credentials,
experience and knowledge; the TTC will be co-chaired by an ATL
representative and an ISIS representative. The advice of additional
employees of either party (or Contractors, in the case of ATL) may
by mutual consent of the parties be obtained.
(b) Decisions of the TTC will be made by unanimous decision of the
two-co-chairs; provided however, in the event that the co-chairs do not,
after good faith efforts, reach agreement on an issue, the resolution
and/or course of conduct in issue will be determined in good faith by the
Oversight Committee, as provided in Section 16.6.
(c) Throughout the entire Technology Transfer Term, the TTC will meet as
needed, but no less often than every 2 months, either in person or by
teleconference, videoconference or by other mutually acceptable means, as
necessary to implement effectively and efficiently the Release Technology
Transfer Plan and the API Technology Transfer Plan.
6.2 TECHNOLOGY TRANSFER FOR CLINICAL PRODUCT RELEASE
(a) Promptly after the Effective Date, the Technology Transfer Committee
will establish a plan (the "Release Technology Transfer Plan") for
the transfer to ATL or a Contractor designated by ATL of the Release
Technology for ISIS 107248 and the Release Technology for other
Collaboration Compounds, as specified in the Release Technology
Transfer Plan (the "Release Technology Transfer"). Before any
Release Technology is transferred to any Contractor of ATL, such
Contractor must be approved by ISIS, which approval will not
unreasonably be withheld. The goal of the Release Technology
Transfer Plan is to effect the Release Technology Transfer within
the first year that this
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Agreement is in effect to enable ATL to carry out its obligation to
conduct release testing for all Products, including without limitation
Clinical Products.
(b) The Release Technology Transfer applicable to ISIS 107248 will begin
promptly after the Effective Date, in conjunction with the
formulation and certification of ISIS 107248 Product for
IND-enabling studies scheduled for [***]. ATL will appoint
employees or ISIS-approved Contractors to participate with ISIS in
the formulation and certification of ISIS 107248 Product for
IND-enabling studies at the site at which the formulation and
certification activities will take place. It is anticipated by the
parties that the Release Technology Transfer applicable to ISIS
107248 Clinical Product will take place during the [***] this
Agreement is in effect, in order to enable ATL to carry out its
obligations hereunder.
(c) The Release Technology Transfer Plan will include INTER ALIA (i)
procedures designed to effect the prompt and efficient Release Technology
Transfer; (ii) a list of events necessary to accomplish the Release
Technology Transfer; (iii) a description of the training and support to be
provided by ISIS to ATL during the Release Technology Transfer; and (iv)
the time period during which ISIS will perform the Release Technology
Transfer.
(d) During the Technology Transfer Term with respect to the Release Technology
Transfer, ISIS will (i) disclose and transfer to ATL all of the Release
Technology as specified in the Release Technology Transfer Plan and (ii)
provide to ATL the training and support described in the Release
Technology Transfer Plan and in this Agreement.
(e) ISIS will perform the Release Technology Transfer in accordance with the
Release Technology Transfer Plan and the terms of this Agreement. The
parties will cooperate so that the Release Technology Transfer may be
completed as expeditiously as possible.
(f) ATL and its Contractors will use commercially reasonable efforts, pursuant
to the Technology Transfer Plan described above, to implement the Release
Technology to be transferred by ISIS pursuant to this Section 6.2 and to
make available all necessary personnel and other resources to enable such
transfer without delay.
6.3 TECHNOLOGY TRANSFER PLAN FOR MANUFACTURE OF API
(a) Within [***] of the Effective Date, the Technology Transfer
Committee will establish a plan (the "API Technology Transfer Plan")
for the transfer of the Manufacturing Process and the Manufacturing
Technology for the Manufacture of API from ISIS to ATL and/or its
Contractors (the "API Technology Transfer"). The goal of the API
Technology Transfer Plan is to enable ATL to apply the Manufacturing
Technology, implement the Manufacturing Process and Manufacture API
as soon as practicable thereafter and in no event later than
December 31, 2006.
(b) The API Technology Transfer Plan will include, INTER ALIA, (i) procedures
designed to effect the prompt and efficient API Technology Transfer; (ii)
a list of events necessary to
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accomplish the API Technology Transfer; (iii) a description of the
training and support to be provided by ISIS to ATL during the API
Technology Transfer; (iv) a budget and resource plan; and (v) the time
period during which ISIS will perform the API Technology Transfer.
(c) During the Technology Transfer Term with respect to the API Technology
Transfer, ISIS will (i) disclose and transfer to ATL all of the
Manufacturing Process and the Manufacturing Technology as specified in the
API Technology Transfer Plan and (ii) provide to ATL the training and
support described in the API Technology Transfer Plan and in this
Agreement.
(d) ISIS will perform the API Technology Transfer in accordance with the API
Technology Transfer Plan and the terms of this Agreement. The parties will
cooperate so that the API Technology Transfer may be completed as
expeditiously as possible.
(e) ATL and/or its Contractor will use commercially reasonable efforts to
establish the Manufacturing Process for the Manufacture of API to be
transferred by ISIS pursuant to this Section 6.3, and to make available
all necessary personnel and other resources to enable such transfer
without delay.
6.4 TRAINING AND SUPPORT
The training and support to be provided by ISIS to ATL and its
ISIS-approved Contractors in connection with the Release Technology
Transfer and the API Technology Transfer (the "Technology Transfer") will
include without limitation training and support in a mutually acceptable
facility in all of the methods necessary to practice the Release
Technology and the Manufacturing Technology, as detailed in the Release
Technology Transfer Plan and the API Technology Transfer Plan. In
addition, a reasonable number of employees or ISIS-approved Contractors of
ATL will be entitled to visit ISIS facilities including, without
limitation, pilot and commercial scale facilities and testing laboratories
to observe relevant processes in operation.
ARTICLE 7
FUNDING PROVISIONS
7.1 FUNDING FOR VARIOUS ACTIVITIES AND MATERIALS HEREUNDER
(a) ATL will compensate ISIS for the following:
(i) ATL's purchase of the ISIS 107248 API referenced in Section 2.3(a);
(ii) the formulation and certification of ISIS 107248 Product for
IND-enabling studies;
(iii) ISIS' performance of a mutually agreed upon stability program for
API Manufactured by ISIS, as set forth in Section 3.1(f);
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(iv) all future API supplied to ATL by ISIS, consistent with
Section 5.1 herein;
(v) all ISIS' activities relating to the Release Technology
Transfer and/or the API Technology Transfer pursuant to
Article 6, [***];
(vi) preparation of CMC Reports and regulatory filings pursuant to
Section 9.1; and
(vii) analytical method development and stability program activities
pursuant to Section 9.2.
(b) ATL will submit payment to ISIS for the materials and activities
referenced in subsections (a)(i) and (iv) above at the times
indicated in the Sections specifically referenced therein. Unless
otherwise indicated herein, ISIS will invoice ATL on a quarterly
basis for all activities performed and for materials and expenses
incurred in accordance with the activities enumerated herein,
including those listed in subsections (a)(ii), (iii), and (v) -
(vii) above. [***]. ATL will pay each invoice within [***] days
after receipt. The terms set forth in Section 5.5 will apply to all
payments made hereunder and include, without limitation, the payment
of interest on late payments.
ARTICLE 8
RECORDS AND AUDITS
8.1 QUALITY STANDARDS
ISIS will keep complete, accurate and authentic accounts, notes, data and
records of all of ISIS' work performed under this Agreement, including,
but not limited to, complete and adequate records pertaining to the
methods and facilities used for the Manufacture in accordance with master
production records, batch production records, product history documents
(e.g., master formulae, validation packages, specifications,
batch-specific deviation reports, COAs) Standard Operating Procedures
("SOPs"), as well as the applicable regulations, including in the United
States, so that API may be used in the production of a substance to be
used in humans. ISIS will maintain these records for 2 years after
expiration of the Product that incorporates the particular API. ATL will
notify ISIS in writing of the expiration of Products that incorporate
specific API and if ATL changes the expiration date on any Product. SOPs
will be maintained for 5 years after the document is superseded or
deleted. Upon expiration of the retaining periods for the respective
records as provided in this Section and in case ISIS wishes to cease
retention of such records, ISIS will notify ATL so that ATL may, at its
cost, retain such records.
8.2 API SUPPLY PRICE; RECORD KEEPING AND AUDIT
(a) ISIS will keep accurate records in sufficient detail to enable the
API Supply Price to be verified. Upon written request of ATL and not
more than once in each Calendar Year, ISIS will permit ATL's
independent certified public accountant (or equivalent) to have
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access during normal business hours to such records of ISIS as may
be reasonably necessary to verify the accuracy of the invoices for
API Supply Price submitted to ATL hereunder for the preceding
Calendar Year. Once specific records have been audited under this
Section 8.2, no further audit of such records may be made. The
accounting firm will disclose to ATL only whether the invoiced
amounts are correct or incorrect, the specific details concerning
the basis for the invoiced amounts, and the corrected amount, if
applicable. No other information will be provided to ATL.
(b) If such accounting firm concludes that any amounts invoiced were in
error during such period and ATL is entitled to a refund of such
amounts, ISIS will refund to ATL the amounts overcharged within
[***] days of the date ATL delivers to ISIS such accounting firm's
written report. The fees charged by such accounting firm will be
paid by ATL unless the additional refunded amounts owed by ISIS
exceed [***] of the total amount for which ATL was invoiced during
the time period subject to the audit, in which case ISIS will pay
the reasonable fees and expenses charged by the accounting firm.
(c) ATL and its accounting firm will treat all financial information
subject to review under this Section 8.2 in accordance with the
confidentiality provisions of Article 9 of the Collaboration and
License Agreement, which provisions are incorporated herein and made
part of this Agreement by reference, and will cause its accounting
firm to enter into an acceptable confidentiality agreement with ISIS
obligating such firm to retain all such financial information in
confidence pursuant to such confidentiality agreement.
8.3 TECHNOLOGY TRANSFER RECORDS
ISIS will maintain records, in sufficient detail and in good scientific
manner appropriate for patent, regulatory and manufacturing purposes,
which will fully and properly reflect all of the work done and the
progress achieved in the performance of the Release Technology Transfer
and the API Technology Transfer (the "Records"). The Records at all times
will be available to the Technology Transfer Committee and ATL will have
the right, during normal business hours and upon reasonable notice, to
inspect and copy all such Records. ATL also will have the right to arrange
for its employees and/or Contractors to visit ISIS at its offices and
laboratories and other facilities during normal business hours on
reasonable notice concerning or in furtherance of the Release Technology
Transfer or the API Technology Transfer and/or to discuss the progress of
the Release Technology Transfer or the API Technology Transfer and its
results in detail with the technical personnel and consultants of ISIS.
13
ARTICLE 9
OTHER SUPPORTING ACTIVITIES
9.1 CMC ACTIVITIES
As of the Effective Date and during the first [***] years this Agreement
is in effect, ISIS will support ATL's efforts to timely file an IND
application for each Collaboration Compound with respect to the CMC
activities described in Exhibit 9.1 for Collaboration Compounds for which
ISIS supplied API.
9.2 ANALYTICAL METHOD DEVELOPMENT AND STABILITY PROGRAM ACTIVITIES
As of the Effective Date, ISIS will undertake various development efforts,
such as analytical methods development for raw materials, API, API
stability programs, and process development in connection with MOE gapmers
and other second generation oligonucleotides made using ISIS Standard
Chemistry, which additional activities support the activities of ISIS and
ATL with regard to ISIS 107248 and other Collaboration Compounds under the
Collaboration and License Agreement.
ARTICLE 10
PRODUCT WARRANTY
10.1 API SPECIFICATIONS; CGMPS; APPLICABLE LAWS
Subject to Section 10.2 below, ISIS warrants that the API will, at the
time of Delivery, be Manufactured in accordance with and meet (a) the API
Specification; (b) cGMP; and (c) the Legal Requirements.
10.2 FOREIGN MANUFACTURING REQUIREMENTS
If the cGMP or the Legal Requirements applicable to the Manufacture of API
for use in the U.S. (the "U.S. Manufacturing Requirements") are different
from those applicable outside to the Manufacture of API for use in
countries other than the U.S. (the "Foreign Manufacturing Requirements"),
the warranty of Section 10.1 will include such Foreign Manufacturing
Requirements only if ATL has informed ISIS thereof in writing as provided
in Sections 4.1 and 4.4 and if the parties have adapted the Manufacturing
Process, if necessary, as provided in Section 4.3.
14
ARTICLE 11
QUALITY SYSTEMS
11.1 MATTERS RELATING TO THE FACILITY
(a) ISIS will Manufacture API supplied by ISIS hereunder at the Facility,
which ISIS represents and warrants has been and will be approved by
Agencies which have inspected or will inspect the Facility for the
manufacture of API. ISIS will perform release testing of API at the
Facility and/or the facility of subcontractors approved by ISIS.
(b) ISIS will arrange for one or more qualified technical specialists
from ATL or one or more qualified Contractors of ATL approved by
ISIS (which approval will not unreasonably be withheld), upon
reasonable prior notice and during normal business hours, to conduct
inspections of the Facility. Observations and conclusions of ATL's
audits or inspections will be issued to and promptly discussed with
ISIS and such corrective action as ATL determines to be reasonably
required will be promptly implemented by ISIS. ISIS will maintain
complete and accurate records of all reasonably relevant information
relating to the performance by ISIS of its obligations hereunder.
ISIS will permit ATL or its ISIS-approved Contractors to review,
during the inspection at the Facility, relevant cGMP documentation.
The total number of inspections under this Section per CalendarYear
will not exceed two.
11.2 TESTING
(a) ISIS will perform, at its laboratories, such tests as are indicated
in the API Specification. Such tests and methods will be qualified
by ISIS and accepted by ATL prior to use and certain of such tests
will be stability indicating. No production lot of API will be
released for Delivery unless such tests show the API to meet the API
Specification. Should any production lot fail to meet the API
Specification, such lot will not be released, unless the failure is
identified following release, in which case the identifying party
will immediately notify the other party and they will cooperate on
the actions to be taken.
(b) ISIS is responsible for obtaining and retaining, at ATL's expense, the
amount of API required for quality control release testing as indicated in
the API Specification. Such amounts will be retained for a period of not
less than one (1) year from the last retest date prescribed by ISIS, and
thereafter shipped at ATL's request for longer term storage at a
designated ATL facility.
(c) After Technology Transfer with respect to analytical testing is
complete in accordance with the terms contained herein and in the
Collaboration and License Agreement, ATL may perform, at a
designated quality control laboratory of recognized repute selected
by ATL and approved by ISIS, which approval will not be unreasonably
withheld, such quality control tests of API as specified in the API
Specification and advise ISIS of any failure of such API to meet the
API Specification.
15
11.3 INFORMATION RELATING TO MANUFACTURING CONDITIONS
(a) Each party will notify the other immediately of any health hazards with
respect to API of which it becomes aware which may impact employees
involved in the Manufacture or handling of API or Product.
(b) Each party will promptly advise the other of any safety or toxicity
problem that is not part of the knowledge base readily available in
chemical manufacturing facilities of which either party becomes aware
regarding the API or Product.
11.4 AGENCY INSPECTIONS
ISIS hereby agrees to advise ATL of any visit or inspection by an Agency
of the Facility relating to the Manufacture of API, provide copies of all
communications relating thereto and will permit one or more qualified
representative(s) of ATL to be present, when possible. If ATL is not
present during such a visit or inspection for any reason, ISIS will
promptly provide a copy of the actual report of the results of the
inspection to ATL. ISIS will furnish ATL copies of all reports, documents
or correspondence with respect to any such Agency inspections of the
Facility.
11.5 STORAGE AND DELIVERY
ISIS will store and Deliver API in accordance with the applicable API
Specification and cGMP.
ARTICLE 12
REGULATORY MATTERS
12.1 ISIS will prepare and promptly provide necessary and useful information,
including without limitation Manufacturing information, as is needed to
support filings of Registrations by ATL, its Contractors, sublicensees or
distributors of Product. In addition, ISIS will participate as required in
resolving regulatory concerns. ISIS will be responsible for maintaining
current technical information needed to support such submissions of
Registrations, and accordingly will promptly provide ATL with advance
notification of all changes in such technical information required to be
filed as amendment(s) to CMC. All such activities will be at ATL's
expense, which will be agreed to in advance by the parties.
12.2 The mutual goal of ISIS and ATL will be to maintain an integrated approach
to the content and timing of all submissions of Registrations made by ATL
in an effort to obtain and maintain regulatory approvals of a Product. To
ensure this mutual goal is met, with respect to issues pertaining to API
or to a Product, ISIS will provide to ATL the right to review and
reference all authorizations, certificates, methodologies and
specifications in the possession or under the control of ISIS relating to
the pharmaceutical/technical
16
development and Manufacture or any component thereof to the extent needed
for ATL's filings of Registrations.
ARTICLE 13
INDEMNIFICATION AND INSURANCE
13.1 INDEMNIFICATION
(a) ISIS will defend, indemnify and hold harmless ATL, its Affiliates
and their respective directors, officers, employees and agents, and
their respective successors and permitted assigns, from any and all
claims, actions, causes of action, liabilities, losses, damages,
costs or expenses, including reasonable attorney's fees, which arise
out of or relate to claims that may be brought or instituted against
them by Third Parties to the extent based upon or arising out of (i)
the failure by ISIS to meet the warranties set forth in Article 10;
(ii) a material breach by ISIS of its obligations set forth in this
Agreement; or (iii) gross negligence or willful misconduct of ISIS,
its officers, employees and agents in the performance of its
obligations hereunder.
(b) ATL will defend, indemnify and hold harmless ISIS, its Affiliates
and their respective directors, officers, employees and agents, and
their respective successors and permitted assigns, from any and all
claims, actions, causes of action, liabilities, losses, damages,
costs or expenses, including reasonable attorney's fees, which arise
out of or relate to claims that may be brought or instituted against
them by Third Parties to the extent based upon or arising out of (i)
a material breach by ATL of its obligations set forth in this
Agreement; or (ii) gross negligence or willful misconduct of ATL,
its officers, employees and agents in the performance of its
obligations hereunder.
13.2 CLAIMS
If a claim is made against a party entitled to indemnification under this
Article 13, and if that party intends to seek indemnification with respect
thereto under this Article 13, the party seeking indemnification (the
"Indemnitee") will promptly notify the indemnifying party (the
"Indemnifying Party") of such claim. The Indemnifying Party will defend,
negotiate and settle such claim, and the Indemnitee will cooperate with
the Indemnifying Party in connection therewith. The Indemnitee may
participate in the defense of any claim with counsel of its own choice and
at its own expense. Neither party will settle or compromise any such claim
without the other party's prior written consent, which consent will not be
unreasonably withheld. The indemnity agreement in this Article 13 will not
apply to amounts paid in settlement of any claim if such settlement is
effected without the consent of the Indemnifying Party, which consent will
not be unreasonably withheld. Failure of the Indemnitee to deliver notice
to the Indemnifying Party within a reasonable time after becoming aware of
a claim will not relieve the Indemnifying Party
17
of any liability to the Indemnitee pursuant to this Article 13, except to
the extent such delay prejudices the Indemnifying Party's ability to
defend such claim.
13.3 INSURANCE
Each party will maintain during the term of this Agreement and for [***]
thereafter, at its own expense, (i) commercial general liability
insurance, including contractual liability coverage, with a minimum limit
of [***] per occurrence and [***] annual aggregate; (ii) property
insurance with a minimum limit of [***]; and (iii) statutory workers'
compensation coverage as required by law.
ARTICLE 14
TERM AND TERMINATION
14.1 TERM
This Agreement will be effective as of the Effective Date, and unless
sooner terminated as provided herein, will continue in effect until
December 31, 2006, unless extended by mutual agreement of the parties.
14.2 TERMINATION BY EITHER PARTY
This Agreement may be terminated with written notice by either party at any time
during the term of this Agreement:
(a) if the other party is in breach of its material obligations hereunder and
has not cured such breach within 90 days after written notice requesting
cure of the breach has been given; provided, however, in the event of a
good faith dispute with respect to the existence of a material breach, the
90-day cure period will be tolled until such time as the dispute is
resolved pursuant to Section 16.6; or
(b) upon the filing or institution of bankruptcy, reorganization,
liquidation or receivership proceedings by the other party or upon
an assignment of a substantial portion of the assets for the benefit
of creditors by the other party; provided, however, in the case of
any involuntary bankruptcy proceeding such right to terminate will
only become effective if the party consents to the involuntary
bankruptcy or such proceeding is not dismissed within 90 days of the
filing thereof.
14.3 TERMINATION OF COLLABORATION AND LICENSE AGREEMENT
This Agreement will automatically terminate in the event the Collaboration
and License Agreement is terminated for any reason.
18
14.4 PAYMENT OF OUTSTANDING DEBTS
Upon expiration or termination of this Agreement for whatever reason, ATL
and ISIS will settle all outstanding invoices or monies owed to the other
party in accordance with the terms of this Agreement.
14.5 EFFECT OF TERMINATION OR EXPIRATION
(a) If this Agreement is terminated by ATL pursuant to Section 14.2(a),
all orders will be automatically cancelled and ISIS will terminate
the Manufacture of API as soon as practicable. ATL will have the
option but not the obligation to (i) purchase all quantities of API
stored at ISIS by paying the price of API, as applicable, as
provided in Section 5.1, and (ii) undertake the Manufacture of API
or seek a Third Party to do such Manufacture. If ATL undertakes to
Manufacture or have Manufactured API, then ISIS will continue the
transfer of technology pursuant to Article 6 on an expedited basis,
at ATL's expense.
(b) If this Agreement is terminated by ATL pursuant to Section 14.2(b), ATL
(i) will purchase all quantities of API stored at ISIS by paying the price
of API, as applicable, as provided in Section 5.1, and (ii) will have the
right to undertake the Manufacture of API or seek a Third Party to do such
Manufacture.
(c) If this Agreement is terminated by ISIS pursuant to Section 14.2(a), ISIS
will have the option but not the obligation to supply under all
outstanding quantities set forth in the Production and Delivery Plan at
the API Supply Price. If ISIS elects to so supply, ATL's payment
obligations relating thereto including, without limitation, those set
forth in Section 5.1 will continue to apply until all outstanding
obligations of ATL to ISIS are fulfilled.
(d) If this Agreement is terminated pursuant to Section 14.3, all
outstanding quantities of API set forth in the Production and
Delivery Plan will be automatically cancelled and ISIS will
terminate the Manufacture of API as soon as practicable. In
addition, ATL will be responsible for all other Manufacturing costs
associated with API pursuant to Section 5.1 at the time of
termination. Notwithstanding the foregoing, ISIS will use its best
efforts to mitigate any costs payable by ATL under this Section
14.5(d).
(e) If this Agreement expires pursuant to Section 14.1, ATL will purchase all
API ordered by ATL during the term of this Agreement. ISIS will Deliver
such API in accordance with Section 5.2.
ARTICLE 15
DAMAGE LIMITATIONS
NOTWITHSTANDING ANYTHING TO THE CONTRARY CONTAINED HEREIN, IN NO EVENT WILL
EITHER PARTY HERETO, OR ITS DIRECTORS, OFFICERS,
19
EMPLOYEES, AGENTS OR AFFILIATES BE LIABLE TO THE OTHER PARTY OR SUCH OTHER
PARTY'S DIRECTORS, OFFICERS, EMPLOYEES, AGENTS, AFFILIATES OR SUBLICENSEES
FOR ANY INDIRECT, CONSEQUENTIAL, INCIDENTAL OR SPECIAL DAMAGES, COSTS OR
EXPENSES (INCLUDING, BUT NOT LIMITED TO, LOST PROFITS, LOST REVENUES AND/OR
LOST SAVINGS) SUFFERED OR INCURRED BY THE OTHER PARTY, WHETHER BASED UPON A
CLAIM OR ACTION OF CONTRACT, WARRANTY, NEGLIGENCE, STRICT LIABILITY OR
OTHERWISE, ARISING FROM THIS AGREEMENT.
ARTICLE 16
MISCELLANEOUS
16.1 FORCE MAJEURE
Neither party will be held liable or responsible to the other party nor be
deemed to have defaulted under or breached the Agreement for failure or
delay in fulfilling or performing any term of the Agreement when such
failure or delay is caused by or results from causes beyond the reasonable
control of the affected party including without limitation embargoes, war,
acts of war (whether war be declared or not), insurrections, riots, civil
commotions, strikes, lockouts or other labor disturbances, or acts of God.
The affected party will notify the other party of such force majeure
circumstances as soon as reasonably practical and will make every
reasonable effort to mitigate the effects of such force majeure
circumstances.
16.2 ASSIGNMENT
This Agreement will inure to the benefit of and be binding upon each
party, its successors and assigns. The Agreement may not be assigned or
otherwise transferred, nor, except as expressly provided hereunder, may
any right or obligations hereunder be assigned or transferred by either
party without the prior written consent of the other party; provided,
however, that either party may, without such consent, assign the Agreement
and its rights and obligations hereunder to an Affiliate or in connection
with the transfer or sale of all or substantially all of its assets, or in
the event of its merger or consolidation or change in control or similar
transaction. Any permitted assignee will assume all obligations of its
assignor under the Agreement. Any attempted assignment not in accordance
with this Section 16.2 will be void.
16.3 SEVERABILITY
In the event any one or more of the provisions contained in this Agreement
should be held invalid, illegal or unenforceable in any respect, the
validity, legality and enforceability of the remaining provisions
contained herein will not in any way be affected or impaired thereby,
unless the absence of the invalidated provision(s) adversely affect the
substantive rights of the parties. The parties will in such an instance
use their
20
best efforts to replace the invalid, illegal or unenforceable
provision(s) with valid, legal and enforceable provision(s) which, insofar
as practical, implement the purposes of this Agreement.
16.4 NOTICES
All notices which are required or permitted hereunder will be in writing
and sufficient if delivered personally, sent by facsimile or electronic
mail (and promptly confirmed), sent by nationally-recognized overnight
courier or sent by registered or certified mail, postage prepaid, return
receipt requested, addressed as follows:
if to ISIS, to: ISIS PHARMACEUTICALS, INC.
Carlsbad Research Center
0000 Xxxxxxx Xxxxxx
Xxxxxxxx, XX 00000
Attention: Executive Vice President
Fax No.: (000) 000-0000
E-Mail: xxxxxxxxx@xxxxxx.xxx
with a copy to: Attention: General Counsel
Fax No.: (000) 000-0000
E-Mail: xxxxxx@xxxxxx.xxx
if to ATL, to: ANTISENSE THERAPEUTICS, LTD.
ACN 000 000 000 of Xxxxx 0
00 Xxxxxxx Xxxxxx
Xxxxxx, Xxxxxxxx 0000
XXXXXXXXX
Attention: CEO
Fax No.: x00 0 0000 0000
E-Mail:____________________
with a copy to: Attention: Research Director
Fax No.: x00 0 0000 0000
E-Mail:____________________
or to such other address as the party to whom notice is to be given may
have furnished to the other party in writing in accordance herewith. Any
such notice will be deemed to have been given when delivered if personally
delivered or sent by facsimile or electronic mail on a business day, on
the business day after dispatch if sent by nationally-recognized overnight
courier and on the third business day following the date of mailing if
sent by mail.
21
16.5 GOVERNING LAW
This Agreement will be governed by and construed in accordance with the
laws of the State of Delaware without reference to any rules of conflict
of laws.
16.6 DISPUTE RESOLUTION; OVERSIGHT COMMITTEE
The parties recognize that disputes may from time to time arise between
the parties during the term of this Agreement. In the event of such a
dispute, either party, by written notice to the other party, may have such
dispute referred to the Oversight Committee, the function of which is to
attempt resolution of any disputes arising under this Agreement by good
faith negotiations. The Oversight Committee will endeavor to resolve such
disputes within 30 days after such notice is received. The Oversight
Committee will be comprised of two designated executive officers (or their
successors), one from each party. Said designated officers are as follows:
For ISIS: Executive Vice President
For ATL: CEO
16.7 REMEDIES
In the event the parties are unable to resolve any disputes hereunder
pursuant to the dispute resolution measures provided herein, each party
may pursue its rights and remedies in law or equity in any court of
competent jurisdiction.
16.8 ENTIRE AGREEMENT
This Agreement and the Collaboration and License Agreement contain the
entire understanding of the parties with respect to the license,
development and commercialization of Products containing API and the
Manufacture and supply of API. All express or implied agreements and
understandings, either oral or written, heretofore made by the parties on
the same subject matter are expressly superseded by this Agreement and the
Collaboration and License Agreement. This Agreement may be amended, or any
term hereof modified, only by a written instrument duly executed by both
parties hereto.
16.9 HEADINGS
The captions to the several Articles and Sections hereof are not a part of
the Agreement, but are merely a convenience to assist in locating and
reading the several Articles and Sections hereof.
16.10 INDEPENDENT CONTRACTORS
It is expressly agreed that ISIS and ATL will be independent contractors
and that the relationship between the two parties will not constitute a
partnership, joint venture or
22
agency. Neither ISIS nor ATL will have the authority to make any
statements, representations or commitments of any kind, or to take any
action, which will be binding on the other, without the prior consent of
the other party.
16.11 WAIVER
The waiver by either party hereto of any right hereunder, or the failure
to perform, or a breach by the other party will not be deemed a waiver of
any other right hereunder or of any other breach or failure by said other
party whether of a similar nature or otherwise.
16.12 COUNTERPARTS
The Agreement may be executed in two or more counterparts, each of which
will be deemed an original, but all of which together will constitute one
and the same instrument.
16.13 WAIVER OF RULE OF CONSTRUCTION
Each party has had the opportunity to consult with counsel in connection
with the review, drafting and negotiation of this Agreement. Accordingly,
the rule of construction that any ambiguity in this Agreement will be
construed against the drafting party will not apply.
IN WITNESS WHEREOF, the parties have executed this Agreement as of the Effective
Date.
ANTISENSE THERAPEUTICS, LIMITED ISIS PHARMACEUTICALS, INC.
By: /s/ X. Xxxxxx By: /s/ B. Xxxxx Xxxxxxxx
---------------------------- ----------------------------------------
Name: X. Xxxxxx Name: B. Xxxxx Xxxxxxxx
-------------------------- --------------------------------------
Title: CEO Title: Executive Vice President and CFO
------------------------- -------------------------------------
23
EXHIBIT 1
DEFINITIONS
1.1 "AFFILIATE" with respect to either party means any person, organization,
corporation or other business entity (collectively, "Person") controlling,
controlled by, or under common control with such party. For purposes of
this definition, "control" refers to (a) the possession, directly or
indirectly, of the power to direct the management or policies of a Person,
whether through the ownership of voting securities, by contract or
otherwise, and (b) the ownership, directly or indirectly, of at least 50%
of the voting securities or other ownership interest of a Person.
1.2 "AGENCY" means the U.S. Food and Drug Administration. In the event ATL
provides written notice to ISIS that ATL intends to conduct Development
Program activities outside of the United States, the term "Agency" will
mean with respect to such activities outside the United States the
Regulatory Authority (as defined below) of the country specified in such
notice involved in granting any approvals relating to such Development
Program activities.
1.3 "API" means a drug substance made using ISIS Standard Chemistry, before
formulation, filling and finishing and containing a Collaboration Compound
developed pursuant to the Collaboration and License Agreement.
1.4 "API ORDER DATE" means the date on which the parties agree upon a
Production and Delivery Plan for the following Calendar Year, as set forth
in Section 3.1(d).
1.5 "API SPECIFICATION" means the specification applicable to each API, which
may variously comprise a product description, methods, tests and
acceptance criteria, or test limits on API, as appropriate to the stage of
development. API Specifications may be amended from time to time by ISIS.
API Specifications will change from time to time as compounds advance
through development and as analytical methods evolve. Thus, the API
Specification for an early stage compound may consist only of a product
description. The API Specification for each API Manufactured hereunder
will be attached as an exhibit hereto; such exhibits will be amended from
time to time as appropriate.
1.6 "API SUPPLY COST" means the cost of Manufacture of API described in
Exhibit 5.2.
1.7 "API SUPPLY PRICE" means [***] of the API Supply Cost.
1.8 "API TECHNOLOGY TRANSFER" has the meaning set forth in Section 6.3
herein.
1.9 "CALENDAR QUARTER" means the respective periods of 3 consecutive calendar
months ending on March 31, June 30, September 30 and December 31.
1.10 "CALENDAR YEAR" means each successive period of 12 months commencing on
January 1 and ending on December 31.
24
1.11 "CGMP" means the current good manufacturing practices described in Q7A ICH
Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients
and 21 CFR Parts 210 ET SEQ. as applicable to the Manufacture of API in
the U.S., as are in effect on the Effective Date or as may subsequently be
modified or supplemented. In the event ATL provides written notice to ISIS
that ATL intends to conduct the Development Program activities in
countries outside of the United States, the term "cGMP" will also include
corresponding good manufacturing practices in such countries, provided
that to the extent any conflict exists between cGMP applicable in the U.S.
and in such countries, the cGMP of the U.S. will apply, unless the parties
agree otherwise as provided in Sections 4.1, 4.4 and 10.2.
1.12 "CLINICAL PRODUCT" means a formulated and finished pharmaceutical product
containing API for use in conducting clinical trials prior to Regulatory
Approval.
1.13 "CMC ACTIVITIES" means the activities listed Exhibit 9.1 hereto.
1.14 "COLLABORATION COMPOUND" has the meaning set forth in Exhibit 1 of the
Collaboration and License Agreement.
1.15 "COLLABORATION AND LICENSE AGREEMENT" means the agreement for the
collaborative research, development and commercialization of ISIS 107248
and other antisense drugs entered into by ISIS and ATL on even date
herewith.
1.16 "CONTRACTOR" means ISIS or a Third Party to whom ATL or any of its
Affiliates grants any right or obligation to manufacture, fill, finish,
and/or release a Product, or to carry out any other obligations of ATL
under this Agreement. Except as provided otherwise herein, each such
Contractor must be approved by ISIS, which approval will not unreasonably
be withheld.
1.17 "DELIVER" OR "DELIVERY" means the delivery of API by ISIS to the carrier
pursuant to Section 5.2.
1.18 "FACILITY" means the Manufacturing facility of ISIS located in 0000
Xxxxxxx Xxxxxx, Xxxxxxxx, Xxxxxxxxxx.
1.19 "ISIS 107248" means the oligonucleotide that targets human CD49d
disclosed and claimed (as SEQ ID NO 81) in U.S. Patent No. 6,258,790.
1.20 "ISIS FTE RATE" means the compensatory rate to be paid per FTE at
ISIS for all activities under this Agreement. As used herein, "FTE"
means [***].
1.21 "ISIS STANDARD CHEMISTRY" has the meaning set forth in Exhibit 1 of the
Collaboration and License Agreement.
1.22 "LEGAL REQUIREMENTS" has the meaning set forth in Section 4.4 herein.
1.23 "MANUFACTURE" or "MANUFACTURED" or "MANUFACTURING" means all operations
involved in the manufacturing, quality control testing (including
in-process, certification,
25
release and stability testing, if applicable), releasing, packaging and
shipping of API under this Agreement.
1.24 "MANUFACTURING PROCESS" means the process steps set forth in master batch
records for any API Manufactured for ATL hereunder during the term of this
Agreement, including reasonable minor variants and extensions of process
steps thereof.
1.25 "OVERSIGHT COMMITTEE" has the meaning set forth in Section 16.6
herein.
1.26 "PRODUCT" means a formulated and finished pharmaceutical product
containing API, including a Clinical Product and including formulated and
finished product for use in toxicology studies.
1.27 "PRODUCTION AND DELIVERY PLAN" has the meaning set forth in Section
3.1(b) herein.
1.28 "RAW MATERIALS" means any raw materials intended for use in the
Manufacture of the Product, including those that may not appear in the
Product.
1.29 "REGISTRATIONS" means the technical, medical and scientific licenses,
registrations, authorizations and/or approvals of API or Product
(including, without limitation, IND, DMF, NDA or other prerequisite
manufacturing approvals or authorizations, and marketing authorization
based upon such approvals or authorizations) that are required by any
national, supranational (e.g., the European Commission or the Council of
the European Union), regional, state or local regulatory agency,
department, bureau or other governmental entity, as amended or
supplemented from time to time.
1.30 "REGULATORY AUTHORITY" means any applicable government regulatory
authority involved in granting approvals for the marketing, and/or pricing
of a Product worldwide, including without limitation, in the United
States, the Food and Drug Administration ("FDA"), and any successor
government authority having substantially the same function, and foreign
equivalents thereof.
1.31 "REGULATORY APPROVAL" means the act of a Regulatory Authority necessary
for the Manufacture of Product in a country or regulatory jurisdiction.
1.32 "RELEASE TECHNOLOGY" means any and all scientific and technical data and
information including without limitation formulas, methods, techniques,
protocols, and processes controlled by ISIS as of the Effective Date
regarding API release and Clinical Product release and any improvements
therein during the term of this Agreement.
1.33 "RELEASE TECHNOLOGY TRANSFER" has the meaning set forth in Section
6.2 herein.
1.34 "TECHNOLOGY TRANSFER COMMITTEE" has the meaning set forth in Section
6.1 herein.
1.35 "TECHNOLOGY TRANSFER TERM" means the time period following the Effective
Date, as determined by the Technology Transfer Committee, during which the
Technology Transfer will take place.
26
1.36 "THIRD PARTY" means any party other than ISIS or ATL and their respective
Affiliates.
27
EXHIBIT 3.1
PRODUCTION AND DELIVERY PLAN FOR CALENDAR YEAR 2002
[***]
28
EXHIBIT 5.2
CALCULATION OF API SUPPLY COST
1) [***]
29
EXHIBIT 9.1
CMC ACTIVITIES
[***]
30
