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                                               CONFIDENTIAL TREATMENT REQUESTED
                              UNDER 17 C.F.R. SECTIONS 200.80(b)4 AND 240.24B-2


                       COLLABORATION AND LICENSE AGREEMENT


This Collaboration and License Agreement (the "Agreement") between ISIS
PHARMACEUTICALS, INC. of 2292 Faraday Avenue, Carlsbad, CA 92008, USA ("ISIS")
and ANTISENSE THERAPEUTICS LTD., ACN 095 060 745 of Level 1, 10 Wallace Avenue,
Toorak, Victoria 3142, AUSTRALIA ("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
Collaboration and License 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 possesses proprietary technology and expertise related to antisense
drug discovery and the development of antisense including target validation and
gene functionalization.

       ATL is interested in using antisense for developing and discovering
antisense drugs.

      ATL and ISIS desire to collaborate to enable ATL to develop and
commercialize antisense drugs, on the terms and conditions set forth herein. In
essence, ISIS and ATL are jointly creating a new company focused on the
discovery and development of antisense therapeutic drugs.

      In support of the foregoing, ISIS will license ISIS 107248 to ATL, as the
first Collaboration Compound hereunder, for development and commercialization
and will work together with ATL to discover antisense drugs to additional gene
targets and grant ATL licenses to intellectual property related to ISIS'
antisense technology necessary to develop and commercialize such drugs. In
addition, ISIS will manufacture active pharmaceutical ingredient ("API") for use
in preclinical and clinical studies during the collaboration term. ATL will be
responsible for all of its other manufacturing needs, including the manufacture
of Product. ISIS will provide contract and consulting services for ATL for
preclinical studies and will provide various other services in support of
activities hereunder.

      In consideration for the licenses and other services provided by ISIS, ATL
will grant ISIS pre-IPO common shares in ATL pursuant to the related Stock
Purchase Agreement and will reimburse ISIS on a cash basis for contract service
work performed by ISIS during the term of the collaboration. ATL will be
responsible for developing, marketing, selling, and distributing all Products
that arise from the collaboration and will pay ISIS certain royalty payments on
sales of such Products.

      In connection with the collaborative and development activities described
herein, the parties will also enter into the related Clinical Supply Agreement
pursuant to which ISIS will supply ATL with API.

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      Therefore, in consideration of the foregoing premises and the mutual
covenants herein contained, the parties hereby agree as follows.

                                    AGREEMENT


                                    ARTICLE 1

                                   DEFINITIONS

      Capitalized terms used in this Agreement have the meanings set forth in
Exhibit 1.


                                    ARTICLE 2

                            DRUG DEVELOPMENT PROGRAM

2.1   GENERAL.

Under the Drug Development Program, ATL will develop and commercialize antisense
drugs arising out of the Collaborative Research Program conducted hereunder as
well as ISIS 107248, a Collaboration Compound discovered by ISIS. In general,
ATL will be responsible for all development and commercialization activities for
Collaboration Compounds. ISIS will initially perform preclinical activities
(IND-supporting toxicology) for ISIS 107248, but it is the intent of the parties
that ATL will assume responsibility for all preclinical and IND-enabling
activities with respect to subsequent Collaboration Compounds, as more
specifically provided in this Agreement. Other than certain consulting services
to be provided by ISIS to ATL hereunder at no charge, ATL will be responsible
for all costs of development and commercialization of Collaboration Compounds
including, without limitation, the reimbursement of ISIS' expenses as provided
herein. Because ISIS 107248 is a Collaboration Compound discovered by ISIS and
licensed to ATL hereunder, ISIS will be heavily involved in the development
plans for ISIS 107248. With regard to future Collaboration Compounds, it is the
parties' intent that, subject to meeting the Development Milestones, ATL will
proceed with considerably more autonomy.

2.2   ISIS 107248 DEVELOPMENT PLAN.

(a)   The plan for the development of ISIS 107248, including the roles and
      responsibilities of the parties, is contained in Exhibit 2.2 (the
      "ISIS 107248 Development Plan").  ATL will use commercially
      reasonable efforts to develop ISIS 107248 to maximize its commercial
      value. ISIS will use commercially reasonable efforts to assist ATL
      pursuant to the Development Plan. Each party will conduct its
      portion of the ISIS 107248 Development Plan in a good scientific
      manner and in compliance in all material respects with all
      requirements of applicable laws, rules and regulations to achieve
      the objectives efficiently and expeditiously. Each party will
      proceed diligently with its projects set out in the ISIS 107248
      Development

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      Plan using commercially reasonable efforts to provide sufficient time,
      effort, equipment, facilities and skilled personnel.

(b)   The target that is modulated by ISIS 107248 is CD49d, which is a Research
      Target hereunder and is listed in Exhibit 3.4.

(c)   ISIS 107248 DEVELOPMENT MILESTONES.  ATL commits to reach the
      following milestones in the development of ISIS 107248.

      (i)   MILESTONES:

            (A)   File IND (or analogous AU application) not later than
                  December 31, 2002;

            (B)   Initiate Phase I studies not later than the first
                  quarter of 2003;

            (C)   Initiate Phase IIa studies not later than December 31,
                  2004;

            (D)   Initiate Phase III studies not later than December 31,
                  2007;

            (E)   File an NDA not later than 18 months after the successful
                  completion of a pivotal trial; and

            (F)   Use commercially reasonable efforts to bring ISIS 107248
                  Product to market and maximize the commercial value of such
                  Product worldwide.

      (ii)  Pursuant to the provisions of this Agreement and the Joint
            Development Plan, ISIS will conduct certain IND-enabling studies and
            will use commercially reasonable efforts to complete such studies
            prior to [***]. In addition, ISIS will supply API ordered by ATL
            pursuant to the Clinical Supply Agreement.

      (iii) If ATL will not be able to meet the milestone set forth in (i)(A)
            above due to a delay on the part of ISIS in completing the studies
            referenced in (ii) or if ISIS is unable to meet its obligations to
            supply API ordered by ATL pursuant to the Clinical Supply Agreement,
            the [***].

      (iv)  Except as provided otherwise in (v) below, if ATL fails to meet any
            of the ISIS 107248 Development Milestones, the License to Research
            applicable to ISIS 107248 will immediately terminate.

      (v)   If a Development Milestone is not met, but ATL has proceeded in good
            faith and the Development Milestone was missed for circumstances
            beyond ATL's control, [***]. If the JDC cannot agree on this issue,
            the matter will be referred to the designated officers of ATL and
            ISIS for resolution, consistent with the provisions of Section
            16.6(a).

2.3   ADDITIONAL DEVELOPMENT ACTIVITIES.

(a)   GENERAL.

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      (i)   As provided herein, during the term of this Agreement, ATL
            will advance additional Collaboration Compounds through the
            various stages of an Active Program hereunder, i.e., from the
            research phase through preclinical and IND-enabling studies to
            human clinical studies and commercialization.  To maintain any
            Collaboration Compound in Active Development status, ATL must
            meet the Development Milestones for each such Collaboration
            Compound.

      (ii)  The terms under which ISIS and ATL will collaborate to develop such
            additional Collaboration Compounds will be in accordance with the
            terms set forth herein. Within [***] days of ATL's providing written
            notice to ISIS that ATL has initiated IND enabling studies on a
            Collaboration Compound, ATL will prepare a mutually-agreed-upon
            Development Plan for that Collaboration Compound, with ISIS'
            assistance, consistent with the terms of this Agreement.

(b)   IND-ENABLING STUDIES.  While it is the intent of the parties that
      ATL will assume responsibility for all preclinical and IND-enabling
      activities with respect to Collaboration Compounds other than ISIS
      107248, ISIS will be available to assist with the management of, or
      provide consulting support for, IND-enabling toxicology studies on
      up to [***] Collaboration Compounds following ISIS 107248, if
      requested to do so by ATL.  Should ATL request ISIS' assistance in
      this regard, the parties will agree on terms pertaining to ISIS'
      participation, which terms will be included in the Development Plan
      referenced in (a). With the possible exception of ISIS 107248 and an
      IGF-1R Collaboration Compound, ISIS will not be requested to
      participate in the conducting, management or support of IND-enabling
      toxicology studies for more than one Collaboration Compound at a
      time.

2.4   ANNUAL REPORTS.

ATL will provide ISIS with an annual written report describing all activities
performed by the parties and the results achieved during the relevant year with
respect to each Collaboration Compound in Active Development hereunder
including, without limitation, ISIS 107248. Each such report will include
details regarding the stage of development a Collaboration Compound has reached
within an Active Program including, without limitation, what Development
Milestones have been achieved. To the extent that it is feasible to do so, ATL
will also include the projected goals and Development Milestones it anticipates
achieving during the coming year with respect to such Collaboration Compound in
each such report.

2.5   COMMERCIALIZATION.

(a)   ATL will use commercially reasonable efforts to bring Products into
      commercial use as quickly as is reasonably possible, in a manner
      designed to maximize the commercial potential of such Products
      worldwide.  Prior to the launch of any Product, ATL will prepare a
      global integrated Product plan outlining the key aspects of market
      launch and commercialization (the "Integrated Product Plan" or
      "IPP"). Each IPP will be updated annually in accordance with ATL's
      internal planning and budgeting process.  ATL will provide ISIS a
      copy of the final draft of each IPP (original and updates) for each
      Major

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      Market.

(b)   Each IPP will also include appropriate milestones and the dates upon
      which such milestones must be met by ATL.  If ATL prepares and
      manages or carries out the IPP, ATL will use commercially reasonable
      efforts to Manufacture, market, promote, distribute, and sell the
      Product on a worldwide basis.  ATL will provide resources and expend
      funds in connection with such activities in a manner and to an
      extent comparable to the efforts of similar companies that
      manufacture, market, and sell pharmaceutical products of similar
      commercial potential at a similar stage of the product life cycle.

(c)   If a Sublicensee of ATL bears primary responsibility for preparing,
      managing and carrying out the IPP, the sublicense agreement will
      require that such Sublicensee will use commercially reasonable
      efforts to Manufacture, market, promote, distribute, and sell the
      Product on a worldwide basis and will require that the Sublicensee
      provide resources and expend funds in connection with such
      activities in a manner and to an extent comparable to the efforts of
      similar companies that manufacture, market, and sell pharmaceutical
      products of similar commercial potential at a similar stage of the
      product life cycle.  In addition, the IPP to be carried out by such
      Sublicensee will include appropriate milestones and the dates upon
      which such milestones must be met, as approved by ISIS in advance,
      which approval will not unreasonably be withheld.

(d)   Consistent with Section 4.3 below, if ATL elects to meet any of its
      responsibilities and obligations under this Section via sublicense
      agreements, ATL will ensure that such agreements are subject to and will
      be consistent with the terms and conditions of this Agreement including,
      without limitation, the provisions of this Section.

(e)   If ATL or a Sublicensee of ATL anticipates any difficulty in meeting its
      commercialization obligations under this Section including, without
      limitation, the milestones set forth in the IPP, ATL or its Sublicensee
      will provide ISIS with prompt notice thereof, in order that the parties
      may endeavor to work out an appropriate and acceptable resolution prior to
      pursuing other remedies hereunder.


                                    ARTICLE 3

                         COLLABORATIVE RESEARCH PROGRAM


3.1   GENERAL; COLLABORATION TERM.

(a)   ATL and ISIS will work together under the Collaborative Research
      Program described herein and as further detailed in the
      Collaborative Research Plan, as described in Section 3.2, to
      discover and develop antisense therapeutics.  The parties will
      collaborate to assess Research Targets that may be important in the
      prevention or treatment of a disease or condition, consistent with
      Sections 3.2 - 3.5.  ISIS will discover and design antisense
      oligonucleotides to modulate the Research Targets as provided in
      Section 3.7 and will

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      provide them to ATL; also, if contracted by ATL, will evaluate the
      antisense oligonucleotides in various functional assays.  ATL will
      perform IN VITRO and IN VIVO studies utilizing the antisense
      oligonucleotides provided by ISIS.  ISIS may perform additional studies,
      at ATL's request and expense, with the antisense oligonucleotides as
      part of a GeneTrove Investigation to better understand a particular
      Research Target's role in a specific biological pathway, as further
      described in Section 3.8.  It is the intent of the parties that
      Collaboration Compounds will be identified during the Collaboration Term
      and that pursuant to Active Programs hereunder, such Collaboration
      Compounds will progress through research and preclinical development,
      meeting the relevant Development Milestones (see Exhibit 1, Section 1.2)
      and will each become the focus of a Development Plan hereunder.

(b)   The Collaboration Term will begin on the Effective Date and will continue
      for 5 years unless earlier terminated due to termination of the Agreement
      under Sections 12.2 or 12.3, or unless terminated or extended upon mutual
      agreement of the parties.

3.2   JOINT RESEARCH COMMITTEE.

(a)   Within [***] days of the Effective Date, the parties will create a
      Joint Research Committee of 4 people to facilitate the research
      collaboration called for herein. The JRC will consist of 2
      representatives nominated by each party. Each party will designate a
      representative as a project leader to serve as the principal contact
      person for that party.  The parties may agree to add additional
      members to the JRC, as long as equal representation is maintained.
      [***].

(b)   During the Collaboration Term, the JRC will be the primary vehicle
      for interaction between the parties with respect to the
      collaborative research conducted hereunder. The JRC will be
      responsible for preparing an annual budget and plan for the
      collaborative research activities to be conducted during each year
      of the Collaborative Research Program (the "Collaborative Research
      Plan") and for managing that program.  The JRC will be responsible
      for updating the Collaborative Research Plan as needed and will also
      be responsible for determining the order in which Research Targets
      are prioritized for Gene Walks.

(c)   The JRC will meet as needed during the Collaboration Term. Meetings
      will be via teleconference or videoconference, or as the parties may
      otherwise agree. The JRC will review the progress of the activities
      carried out under the Collaborative Research Program and will
      consider and decide on proposed modifications to the strategy and
      goals of that program.  The frequency, dates and times of all
      meetings will be mutually agreed upon by the parties. At its first
      meeting the JRC will determine such procedures as it will reasonably
      require to conduct its business.

3.3   RESEARCH TARGETS:  GENERAL.

As noted above, ATL and ISIS will collaborate to assess Research Targets that
may be important in the prevention or treatment of a disease or condition.

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3.4   RESEARCH TARGETS:  DESIGNATION.

(a)   The collaborative research hereunder will be focused on specific gene
      targets thought to be attractive for the development of antisense drugs.
      ATL will choose targets in accordance with the provisions of this Section
      3.4 as the basis for its antisense drug discovery efforts. ATL commits to
      use commercially reasonable efforts to conduct research and drug discovery
      activities with respect to each Research Target to maximize its commercial
      value.

(b)   Exhibit 3.4 hereto contains a list of the initial targets that are
      the object of Licenses to Research (the "Research Targets"), as well
      as the nucleic acid sequences for the corresponding human genes and
      a brief record of any studies performed on those targets by ISIS.
      Research Targets listed on Exhibit 3.4 that are Dermatology Targets
      are listed in Section B, and all other Research Targets are listed
      in Section A of Exhibit 3.4.  During the Collaboration Term, targets
      may be added to and removed from Exhibit 3.4 in accordance with the
      terms of this Section and Section 3.5.

3.5   RESEARCH TARGETS:  SELECTION, REMOVAL, REPLACEMENT AND APPROVAL
      PROCESS.

(a)   As noted above, on the Effective Date, Exhibit 3.4 will list the
      initial Research Targets agreed upon by the parties.  ATL warrants
      and represents that if it has not provided ISIS with the nucleic
      acid sequences for the corresponding human genes for any of the
      Research Targets listed in Exhibit 3.4 by the Effective Date, it
      will do so promptly thereafter.  Consistent with the terms of this
      Agreement, ISIS will have no obligation to conduct any activities
      with respect to such Research Targets until the required materials,
      information and/or payments (if applicable) have been submitted to
      ISIS by ATL. The addition of new Research Targets to the list in
      Exhibit 3.4 is at ISIS' sole discretion.


(b)   If ATL wishes to designate a new Research Target, it will provide
      ISIS with written notice of the target it wishes to add to the list
      set forth in Exhibit 3.4.  Such written notice will include the gene
      name, the NCBI accession number or nucleic acid sequence, and one or
      more mammalian cell lines that express the Research Target.  ISIS
      will not, and is not required to, accept a proposed Research Target
      without such information.  In addition, ATL will inform ISIS of
      whether or not to the best of ATL's knowledge the proposed target is
      in the public domain or is proprietary to a Third Party.

      (i)   ATL will not propose a target for consideration as a possible
            Research Target if to its knowledge ATL is not able to provide ISIS
            with rights to use such target sufficient to enable ISIS to carry
            out its activities in support of the Collaborative Research Program
            as contemplated by the parties hereunder.

      (ii)  If ATL proposes a target that is encumbered by Third Party
            restrictions, [***].

      (iii) If a target proposed by ATL is subject to an ISIS drug discovery and
            development program or a contractual obligation of ISIS to a Third
            Party with respect to that target, then the proposed target will not
            be approved as a Research Target hereunder.

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(c)   Within [***] days after receipt of the ATL notice under subsection (b),
      ISIS will notify ATL, in writing, of its decision either to approve or to
      reject a proposed target.

      (i)   If a proposed target is not approved as a Research Target, the
            notice provided by ISIS will advise ATL of the reason(s) the target
            was not approved, and ATL will be invited to submit a different
            proposed target for consideration.

      (ii)  If a proposed target is approved as a Research Target, ISIS' notice
            to ATL will indicate this and will also indicate whether or not the
            new Research Target is a Dermatology Target. ISIS will add the
            Research Target to the list in Exhibit 3.4 (as well as the nucleic
            acid sequence of the gene) and will provide ATL with an amended copy
            of Exhibit 3.4. If ISIS has performed animal or other preclinical
            studies on any antisense molecule that modulates the newly-added
            Research Target, or has established efficacy, ISIS will add that
            information to Exhibit 3.4 and will provide ATL with a copy of the
            amended exhibit.

      (iii) Upon receipt of written notice from ISIS that a proposed target has
            been approved as a Research Target and added to Exhibit 3.4, ATL
            will begin Active Development of such Research Target, consistent
            with the terms of this Agreement.

(d)   After the Effective Date, Research Targets may be removed from the list in
      Exhibit 3.4 as follows.

      (i)   If ATL wishes to remove a Research Target from the approved list in
            Exhibit 3.4, it will provide ISIS with prompt written notice of its
            election to do so. Upon ISIS' receipt of such notice, it will remove
            the Research Target from the list.

      (ii)  Upon receipt of notice at any time during the term of this Agreement
            that a Research Target is no longer in Active Development, ISIS will
            remove the target from the list set forth in Exhibit 3.4 and will
            provide ATL with prompt written notice of same.

      (iii) The License to Research or License to Exploit applicable to any
            Research Target removed pursuant to (i) or (ii) herein (each an
            "Abandoned Research Target") will immediately terminate, consistent
            with the provisions of Sections 4.1 or 4.2, as applicable.
            Notwithstanding the foregoing, an Abandoned Research Target may
            still bear royalty or other payment obligations, as described in
            Sections 5.1 - 5.3 herein.

      (iv)  Once a target has been removed from the list of Research Targets,
            Exhibit 3.4 will be amended to delete such target and a copy of
            amended Exhibit 3.4 will be sent to ATL by ISIS.

      (v)   Upon termination of a License to Research or a License to Exploit
            for any reason, a Research Target will be automatically removed from
            Exhibit 3.4 and will thereafter be considered an Abandoned Research
            Target.

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(e)   At no time during the term of this Agreement or the Collaboration Term
      will there be any more than [***] designated Research Targets. As of the
      Effective Date, ATL may nominate up to [***] Research Targets; after the
      Effective Date, ATL may not substitute more than [***] Research Targets in
      any year during the Collaboration Term.

3.6   GENEWALKS; GENETROVE INVESTIGATIONS.

(a)   GENERAL OVERVIEW.  ISIS will perform Gene Walks on all of the
      Research Targets designated in Exhibit 3.4, with the exception of
      CD49d, as a Collaboration Compound for that Research Target has
      already been identified by ISIS (i.e., ISIS 107248).  The Gene Walks
      are expected to provide ATL with at least one optimized antisense
      oligonucleotide designed to modulate the respective Research Target
      together with control oligonucleotides.  Upon ATL's request, ISIS
      will then evaluate those antisense oligonucleotides selected for
      further study by ATL in functional assays.  ATL will utilize the
      antisense oligonucleotides further in IN VITRO and IN VIVO studies.
      A GeneTrove Investigation, which ATL may request after a Gene Walk
      for the relevant Research Target has been performed, includes the
      use of the antisense oligonucleotides that are obtained as a direct
      result of the Gene Walk in primary cellular phenotypic assays
      currently conducted by ISIS, as further described below and in
      Exhibit 3.8.  The ownership and use of all materials, including
      Antisense Inhibitors, and of all data and information generated as a
      result of a Gene Walk, a GeneTrove Investigation, or otherwise
      provided to ATL by ISIS pursuant to this Agreement, is governed by
      the provisions of Article 6.

(b)   PROJECT COORDINATORS.  ATL and ISIS will each select one employee to
      serve as the Project Coordinator for that party, with respect to
      Gene Walks and GeneTrove Investigations.   The Project Coordinators
      will facilitate the selection, prioritization, removal and
      replacement of Research Targets.  The Project Coordinators will each
      have appropriate technical credentials, knowledge and ongoing
      familiarity with the foregoing activities. The Project Coordinators
      will meet on an as-needed basis via teleconference or
      videoconference, at times mutually agreed upon by the parties.
      Decisions of the Project Coordinators will be unanimous.  If the
      Project Coordinators cannot agree on an issue, the issue will be
      submitted to the JRC for resolution.

3.7   GENE WALKS.

(a)   ISIS agrees to perform up to [***] Gene Walks on Research Targets
      for ATL during the Collaboration Term [***].  Gene Walks performed
      on genes of different species are considered separate Gene Walks;
      for example, a Gene Walk performed on a mouse gene and one performed
      on its human equivalent counts as two Gene Walks.  ATL may request
      that ISIS perform an additional [***] Gene Walks on Research Targets
      during the Collaboration Term, at a cost to ATL of [***] each.  If
      ISIS agrees to perform additional Gene Walks, ATL will compensate
      ISIS for the cost of each such additional Gene Walk [***].

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(b)   Irrespective of the timing of ATL's requests for Gene Walks - that
      is, whether or not ATL uses its allocation of [***] Gene Walks
      within the first [***] years of the Collaboration Term, and
      regardless of when ATL elects to use its allocation of [***] Gene
      Walks at [***] apiece - ISIS will not be required to perform more
      than [***] Gene Walks per year for ATL during the first [***] years
      of the Collaboration Term and will not be required to perform more
      than [***] Gene Walks per year for ATL during the remaining [***]
      years of the Collaboration Term.  Gene Walks, a sample Gene Walk
      schedule for the Collaboration Term, and the related activities of
      the parties are further described in Exhibit 3.7.

(c)   A Gene Walk is automatically requested when a Research Target is
      added to the list in Exhibit 3.4.  Therefore, as of the Effective
      Date, ATL will be deemed to have requested a Gene Walk for each
      Research Target listed in Exhibit 3.4, except for CD49d.  Within
      [***] days of the Effective Date, ATL will provide ISIS with written
      notice of the order in which it wishes the Research Targets to be
      scheduled for Gene Walks.  As new Research Targets are added to
      Exhibit 3.4, they will be added to the end of the list of targets on
      which Gene Walks are to be performed.

(d)   After each successful Gene Walk, ISIS will provide up to [***] Antisense
      Inhibitors and a control oligonucleotide to ATL for use in confirming
      studies in quantities not to exceed 2 (mu)mole per Research Target. ATL
      may request quantities for use in preclinical pharmacology studies at the
      price of [***] per order for amounts up to [***] of the particular
      Antisense Inhibitor ordered. [***]


3.8   GENETROVE INVESTIGATIONS.

(a)   ATL may request that ISIS perform up to [***] GeneTrove Investigations per
      year during the Collaboration Term on Research Targets at a cost to ATL of
      [***] per GeneTrove Investigation. GeneTrove Investigations and the
      related activities of the parties are further set forth in Exhibit 3.8.

(b)   ATL may request that ISIS perform additional GeneTrove Investigations. If
      ISIS agrees, at its sole discretion, to perform additional GeneTrove
      Investigations, ATL will compensate ISIS for each such additional
      GeneTrove Investigation in accordance with comparable rates charged by
      ISIS' GeneTrove division to other GeneTrove customers.

(c)   To request a GeneTrove Investigation under subsection (a) or (b) herein,
      ATL will submit a written request to ISIS, which request will indicate the
      identity of the Research Target on which ATL requests that a GeneTrove
      Investigation be performed. ATL will provide ISIS with any additional
      information reasonably requested by ISIS to enable ISIS to conduct such
      GeneTrove Investigation.

(d)   Except as provided otherwise herein, the data and information generated by
      the GeneTrove Investigations pursuant to the collaboration hereunder will
      be considered confidential and will be subject to the provisions of
      Article 6.


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(e)   ATL agrees that ISIS may enter data and information from ISIS' conduct of
      each GeneTrove Investigation for ATL hereunder into its proprietary human
      gene function database(s), [***].


3.9   OTHER COLLABORATIVE RESEARCH PROGRAM-RELATED ACTIVITIES.

(a)   ACCESS TO CONSULTING SUPPORT AND TRAINING.


      (i)   During the Collaboration Term, ISIS will provide ATL with reasonable
            amounts of preclinical and research advice [***] (phone consultation
            or visit at ISIS only) in support of any Active Program hereunder
            that involves a Collaboration Compound made using ISIS Standard
            Chemistry for which a License to Research exists.

      (ii)  During the first [***] years of the Collaboration Term, upon ATL's
            request and at times mutually agreed upon by the parties, ISIS will
            allow [***] visiting scientists from ATL to work in the ISIS
            laboratories to be trained in [***], during normal business hours
            and upon reasonable prior notice, subject to any restrictions
            imposed by ISIS in order to protect the confidentiality of programs,
            activities and information unrelated to any ongoing Active Program
            hereunder. The visiting scientists may visit and receive training at
            ISIS for up to [***]. ATL will pay all expenses (e.g. salary,
            travel, lodging, meals, transportation, etc.) incurred by its
            visiting scientists while receiving training from ISIS personnel. No
            ISIS personnel will be required to visit ATL's facilities.

      (iii) ISIS acknowledges that ATL may desire to train its academic
            collaborators. If ATL wishes to substitute an academic collaborator
            for an ATL employee with respect to the training referenced in (a)
            above, ATL will provide ISIS with a specific written request to do
            so in advance, for ISIS' approval, which approval will not
            unreasonably be withheld. Any such academic collaborator, once
            approved by ISIS, must enter into a confidentiality agreement with
            ISIS before any training can be initiated.

      (iv)  If ATL requests additional amounts or types of consulting support or
            training and if ISIS agrees to provide such training, the parties
            will negotiate appropriate terms including, without limitation, the
            scope, timing, duration and cost of such training, in good faith.


                                    ARTICLE 4

                         LICENSE GRANTS AND OTHER RIGHTS

4.0   LICENSE TERM. As used herein, "License Term" means the term beginning on
      the Effective Date and ending on the date on which all obligations to pay
      royalties hereunder have expired.

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4.1   LICENSES TO RESEARCH. A License to Research is a license to perform
      research and development activities relating to a Research Target until
      the filing of an NDA or non-US equivalent on a Product that modulates such
      Research Target.

(a)   LICENSE GRANT.

      (i)   For each Research Target, ISIS will grant to ATL and its
            Affiliates when ATL takes a License to Research, an exclusive,
            worldwide license under the ISIS Core Technology Patent Rights, the
            ISIS Formulation Patent Rights, the Manufacturing Patent Rights, the
            Research Target Patent Rights and the Third Party Patent Rights
            solely to conduct research and clinical development for all
            therapeutic and cosmetic applications for Collaboration Compounds
            that modulate such Research Target. For Collaboration Compounds that
            modulate Dermatology Targets, the license is limited to topical
            dermatological indications only. These rights will only be
            sublicensable as explicitly provided in Section 4.3. The license
            grant described hereunder will commence automatically on grant of
            the License to Research and will terminate upon termination of the
            corresponding License to Research.

      (ii)  For each Research Target, ISIS will grant to ATL and its Affiliates
            when ATL takes a License to Research, a nonexclusive, worldwide
            license under the Research Target Patent Rights, the ISIS C5-Propyne
            Patent Rights, and the ISIS Formulation Patent Rights solely to
            conduct research and clinical development for all therapeutic and
            cosmetic applications for Research Target Compounds that modulate
            such Research Target. For Research Target Compounds that modulate
            Dermatology Targets, the license is limited to topical
            dermatological indications only. These rights will only be
            sublicensable as explicitly provided in Section 4.3. The license
            granted hereunder will commence automatically on grant of the
            License to Research and will not terminate upon termination of the
            corresponding License to Research.

(b)   As of the Effective Date, ISIS grants to ATL a License to Research with
      respect to each Research Target listed in Exhibit 3.4. ATL will receive
      additional Licenses to Research with respect to Research Targets when
      added to Exhibit 3.4. Licenses to Research may only be obtained during the
      Collaboration Term. No License to Research will be granted to ATL on any
      Research Target after the Collaboration Term ends.

(c)   [***]

(d)   ATL may terminate a License to Research with respect to a Research Target
      for any reason, at any time during the term of this Agreement, by
      providing ISIS with written notice that the Research Target is being
      removed from Exhibit 3.4.

(e)   With the exception of the License to Research applicable to ISIS 107248,
      which is governed by the provisions of subsections (f) and (g) below, if a
      Research Target is no longer part of an Active Program, ISIS may terminate
      the License to Research applicable to that Research Target at any time
      during the term of this Agreement upon written notice to ATL.

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(f)   As provided in Section 2.2(c), ISIS may terminate the License to Research
      applicable to ISIS 107248 at any time during the term of this Agreement
      upon written notice to ATL, if the milestones or other conditions set
      forth in Section 2.2(c) are not timely met.

(g)   Once ATL has elected and obtained 5 Licenses to Exploit pursuant to
      Section 4.2, all remaining Licenses to Research will immediately
      terminate, and all rights to the remaining Research Targets licensed to
      ATL will revert to ISIS; provided, however, that the licenses granted
      pursuant to Section 4.1(a)(ii) will remain in effect.

(h)   ISIS will provide ATL with a semiannual report summarizing the status of
      Research Target Patent Rights subject to a License to Research hereunder
      and will include updates to any Exhibits that are affected.



4.2   LICENSES TO EXPLOIT. A License to Exploit is a license to perform
      research, development and commercialization activities on Products that
      modulate a Research Target.

(a)   ISIS grants ATL the option to convert any active License to Research
      hereunder into a License to Exploit, as set out below.
      Notwithstanding the foregoing, ATL may convert not more than 5
      Licenses to Research into Licenses to Exploit, and each License to
      Exploit must be requested by ATL prior to the filing of an NDA (or
      non-US equivalent) for the relevant Research Target.   The option to
      convert Licenses to Research to Licenses to Exploit expires [***]
      after the end of the Collaboration Term.

(b)   If ATL elects to convert a License to Research into a License to
      Exploit, ATL will provide ISIS with written notice effecting the
      exercise of the option, which will identify the particular Research
      Target to which the License to Research applies and will include
      written verification that all applicable milestones and obligations
      of ATL with respect to that Research Target have been timely met.
      Upon ISIS' receipt of such written notice, ISIS will have [***] days
      to object if it believes that ATL has not timely met all applicable
      milestones and obligations with respect to that Research Target.  At
      the end of such [***]-day period, the License to Exploit will be
      granted with respect to the relevant Research Target if ISIS has not
      objected. [***].

(c)   LICENSE GRANT.

      (i)   For each Research Target for which a License to Exploit is
            granted ISIS will grant to ATL an exclusive, worldwide license under
            the ISIS Core Technology Patent Rights, the ISIS Formulation Patent
            Rights, the Manufacturing Patent Rights, the Research Target Patent
            Rights and the Third Party Patent Rights solely to make, have made,
            use, develop, offer for sale and sell Collaboration Compound
            Products that modulate such Research Target for all therapeutic and
            cosmetic applications. For Collaboration Compound Products that
            modulate Dermatology Targets, the license is limited to topical
            dermatological indications only. These rights will only be
            sublicensable as explicitly provided in Section 4.3. This license
            will commence automatically on grant of the corresponding License to
            Exploit and will terminate upon termination of the corresponding
            License to Exploit.

                                       13

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      (ii)  For each Research Target for which a License to Exploit is
            granted ISIS will grant to ATL a nonexclusive worldwide license
            under the Research Target Patent Rights, the ISIS C5-Propyne Patent
            Rights, and the ISIS Formulation Patent Rights solely to make, have
            made, use, develop, offer for sale and sell Research Target Compound
            Products for all therapeutic and cosmetic applications. For Research
            Target Compound Products that modulate Dermatology Targets, the
            license is limited to topical dermatological indications only. These
            rights will only be sublicensable as explicitly provided in Section
            4.3. This license will commence automatically on grant of the
            corresponding License to Exploit and will not terminate upon
            termination of the corresponding License to Exploit.

(d)   No substitutions may be made on Licenses to Exploit. Once a License to
      Exploit has been taken with respect to a Research Target, a different
      Research Target may not be substituted thereunder.

(e)   ATL may terminate a License to Exploit with respect to a Research Target,
      for any reason, at any time during the term of this Agreement, by
      providing ISIS with written notice.

(f)   The party bearing primary responsibility for the prosecution,
      maintenance and defense of any Research Target Patent Rights
      pursuant to Article 8 herein will provide the other party hereto
      with a semiannual report summarizing the status of Research Target
      Patent Rights subject to a License to Exploit hereunder for which
      such party is responsible and will include updates to any Exhibits
      listing rights in any Patents licensed hereunder that are affected,
      if appropriate.

4.3   SUBLICENSES UNDER ISIS PATENT RIGHTS AND THIRD PARTY PATENT RIGHTS.

(a)   Any sublicense granted by ATL and its Affiliates under this
      Agreement is subject to and will be consistent with the terms and
      conditions of this Agreement and with the terms of the agreements
      pursuant to which ISIS obtained its rights in Third Party Patent
      Rights.  The grant of any such sublicense hereunder will not relieve
      ATL or its Affiliates of its obligations under this Agreement. ATL
      will promptly provide ISIS with copies of all sublicenses granted by
      ATL or its Affiliates, as well as Sublicensee contact information.

(b)   Subject to the terms and conditions of this Agreement and during the
      License Term, ATL and its Affiliates will have the right to grant
      sublicenses (each an "ATL Sublicense") under the licenses from ISIS set
      forth in Sections 4.1 and 4.2 to Third Parties as follows.

      (i)   ATL and its Affiliates may grant an ATL Sublicense to a Third
            Party collaborator under the Research Target Patent Rights solely
            for the purpose of enabling such Third Party to collaborate with ATL
            on bona fide research, development and commercialization work on a
            Research Target Compound and, after such collaborative work, to
            make, have made, use, offer for sale and sell a Product containing
            such Research Target Compound.

      (ii)  ATL and its Affiliates may grant an ATL Sublicense to a Third Party
            collaborator

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<Page>

            under the ISIS Core Technology Patent Rights, the ISIS
            Formulation Patent Rights, the Manufacturing Patent Rights, the
            Research Target Patent Rights and the Third Party Patent Rights
            solely for the purpose of making, developing or using a
            Collaboration Compound or making, having made, using, developing,
            offering for sale or selling a Collaboration Compound Product.

      (iii) In the event of a material default by any Sublicensee under an ATL
            Sublicense, ATL will inform ISIS and take commercially reasonable
            efforts to cause the Sublicensee to cure the default or will
            terminate the ATL Sublicense. ATL will specifically state that ISIS
            is a third party beneficiary in any ATL Sublicense(s) hereunder.


4.4   MAXIMUM NUMBER OF LICENSES.

Not more than [***] Licenses to Research or Licenses to Exploit may be in
existence at any time during the term of this Agreement. Each such license is to
a discrete Research Target.

4.5   RIGHT OF FIRST REFUSAL.

(a)   During the term of this Agreement, if ATL is approached by a Third
      Party regarding, or elects to offer to a Third Party, the
      opportunity to collaborate on the development of a compound that
      modulates a Research Target other than IGF-1R, ATL will provide
      written notice of same to ISIS.  Such notice will include
      information identical to that presented by ATL to a Third Party
      including, at a minimum, (i) information possessed and disclosable
      by ATL that supports the development of such a compound and is
      reasonably necessary for ISIS to assess the commercial potential of
      such compound; and (ii) a proposal that ATL would be prepared to
      accept.  Within [***] days of receipt of such notice, ISIS will
      provide written notice to ATL indicating whether it is interested in
      negotiating with ATL to obtain the rights to develop and
      commercialize such compound with ATL.

(b)   If ISIS fails to respond to ATL's notification within [***] days or
      indicates that it is not interested in developing and commercializing such
      compound with ATL, ATL will thereafter be free to enter into discussions
      with one or more Third Parties regarding the development and
      commercialization of such compound.

(c)   If ISIS timely indicates its interest in obtaining such rights to
      develop and commercialize such compound with ATL, the parties will
      negotiate in good faith the terms of a separate development and
      commercialization agreement, which terms will be commercially
      reasonable, including without limitation license fees, milestone
      payments, and royalties, during the period up to [***] days
      following receipt of ISIS' notice.  If the parties are unable to
      execute such an agreement within such time period, despite good
      faith negotiations by each party, ATL will thereafter be free to
      develop and commercialize such compound with one or more Third
      Parties, provided that the terms offered to such Third Party include
      financial terms that are no more favorable than those offered to
      ISIS.

4.6   RIGHTS RETAINED BY ISIS.

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<Page>

ISIS will retain the right to practice under all patent rights licensed to ATL
hereunder as necessary to carry out ISIS' obligations under this Agreement and
the Clinical Supply Agreement, and for any purpose other than to make, have
made, use, import, offer for sale and sell Collaboration Compound Products,
except as provided otherwise herein. ATL will not practice any of the patent
rights licensed to ATL hereunder other than as expressly licensed in this
Article 4.

4.7   ACCESS TO ADDITIONAL TECHNOLOGY.

(a)   If, after the Effective Date and during the Collaboration Term, ISIS
      comes to own, or acquires a license with the right to grant
      sublicenses thereunder, any new or additional ISIS Core Technology
      Patent Rights or Manufacturing Patent Rights, and ATL desires access
      to such rights, any licenses or sublicenses from ISIS to ATL under
      such Patents pursuant to Sections 4.1 and 4.2 are conditioned on
      ATL's agreement (i) to pay, on a flow-through basis, any royalties,
      milestones or other financial obligations owed to ISIS' licensor
      arising from a license or sublicense grant to ATL and the practice
      under such license or sublicense by ATL, its Affiliates or
      Sublicensees; and (ii) to abide by all terms of the agreement under
      which a Third Party license is granted to ISIS.

(b)   If, after the Effective Date and during the Collaboration Term, a
      change in the manufacturing process as a result of a change in the
      master batch records for ISIS 107248 requires access of ATL to
      Manufacturing Patent Rights that were not practiced in the
      manufacture of the ISIS 107248 API prior to such change, and if ISIS
      has obtained ownership or control of such Manufacturing Patent
      Rights by way of a license from or via collaboration with a Third
      Party, then any license or sublicense granted to ATL under such
      Manufacturing Patent Rights is conditioned on the prior agreement to
      be negotiated in good faith by the parties regarding (i) the
      assumption by ATL of all financial obligations owed to such Third
      Party arising from the grant of a license or sublicense to ATL and
      the practice under such license or sublicense by ATL, its Affiliates
      or Sublicensees; (ii) the payment to ISIS of an equitable portion of
      acquisition costs incurred by ISIS; and (iii) an agreement by ATL to
      abide by all terms of the agreement under which such Manufacturing
      Patent Rights were acquired, if applicable.

4.8   EFFECT OF TERMINATION OF LICENSES TO RESEARCH AND LICENSES TO
      EXPLOIT.

(a)   Upon termination of any License to Research or License to Exploit
      hereunder, ATL will assign and transfer to ISIS, to the extent ATL is not
      prohibited from doing so, all rights it owns or controls and any data and
      information relating to any Collaboration Compound or Collaboration
      Compound Product relating to the relevant Research Target obtained or
      generated by ATL during the term of the Agreement. [***].

(b)   If a License to Research or License to Exploit pertaining to a
      Research Target other than ISIS 107248 is terminated for any reason,
      promptly upon any such termination, the parties will

                                       16

<Page>

      prepare a transition plan to ensure the seamless transition of any
      clinical studies and distribution and sales activities relating to any
      Antisense Inhibitor, Collaboration Compound, and/or Collaboration
      Compound Product from ATL to ISIS.  In addition, ATL will provide
      ISIS with any and all data relating to such Antisense Inhibitor,
      Collaboration Compound, Product using ISIS Standard Chemistry and/or
      to any ISIS Patent Rights relating to any Research Target that are
      in ATL's possession or control.

(c)   Upon termination of the License to Research or License to Exploit
      applicable to ISIS 107248, ATL will promptly return to ISIS all
      information and materials relating to ISIS 107248 provided to ATL by ISIS
      or independently generated by ATL, its Affiliates, Sublicensees or
      contractors and all quantities of ISIS 107248 API provided by ISIS under
      the Clinical Supply Agreement that have not been used.

(d)   Upon termination of any License to Research or License to Exploit
      applicable to a Collaboration Compound or Collaboration Compound
      Product, ATL will promptly return to ISIS all quantities of API
      provided by ISIS under the Clinical Supply Agreement that have not
      been used.  In addition, ATL will promptly provide to ISIS all
      information and materials relating to such Collaboration Compound or
      Collaboration Compound Product provided to ATL by ISIS.  ATL will
      also promptly provide to ISIS all information and materials relating
      to such Collaboration Compound or Collaboration Compound Product
      independently generated by ATL, its Affiliates, Sublicensees or
      contractors.  With respect to information and materials relating to
      such Collaboration Compound or Collaboration Compound Product that
      were independently generated by ATL, its Affiliates, Sublicensees or
      contractors, ISIS will compensate ATL as follows:

      (1)   [***].

      (2)   [***].

                                    ARTICLE 5

                             ROYALTIES AND PAYMENTS



5.1   MINIMUM ROYALTIES PAYABLE TO ISIS BY ATL ON SALES OF PRODUCTS BY ATL OR
      ITS AFFILIATES.

Subject to the terms and conditions of, and during the term of, this Agreement,
ATL will pay to ISIS royalties on sales of Products by ATL or its Affiliates,
according to the terms set forth below.

(a)   The minimum royalty payable to ISIS by ATL for sales of any Product by ATL
      or its Affiliates containing ISIS 107248 is [***] of Net Sales for as long
      as there are issued and unexpired claims within the patent rights
      applicable to such Product and [***] of Net Sales thereafter for the life
      of such Product.

                                       17

<Page>

(b)   [***].

(c)   Except as otherwise provided above, the minimum royalty payable to ISIS
      for sales of any Product by ATL or its Affiliates comprising a compound
      that modulates a Research Target or Abandoned Research Target for which
      ISIS has not established efficacy in an animal model or has not conducted
      preclinical toxicology studies is [***] of Net Sales. Such minimum royalty
      is due and payable for the life of the Product.

(d)   Except as otherwise provided above, the minimum royalty payable to ISIS by
      ATL for sales of any Product by ATL or its Affiliates for which ISIS has
      established efficacy in an animal model or has conducted preclinical
      toxicity studies will be negotiated in good faith by the parties on a
      case-by-case basis, but will not be less than [***] of Net Sales.

(e)   For Products under (a) or (c), in addition to any minimum royalties
      due under (a) or (c), the royalty payable to ISIS by ATL for sales
      of any Product by ATL or its Affiliates, the manufacture, use, sale,
      or importation of which would, but for the licenses granted
      hereunder, infringe an issued and unexpired claim under the ISIS
      Formulation Patent Rights is [***] of Net Sales for Products
      containing compounds that modulate a Research Target.  Such minimum
      royalty is due and payable for the term of issued and unexpired
      claims within the patent rights applicable to such Product.

(f)   The minimum royalties payable as described in Sections 5.1 (a)-(e) are in
      addition to any royalties payable to ISIS for Third Party Patent Rights as
      set forth in Section 5.3 below.

5.2   SUBLICENSE INCOME PAYABLE TO ISIS BY ATL OR ITS AFFILIATES ON PRODUCTS
      SOLD BY SUBLICENSEE(S).

Subject to the terms and conditions of, and during the term of, this Agreement,
ATL or its Affiliates will pay to ISIS certain shares of Sublicense Income
received by ATL or its Affiliates, according to the terms set forth hereinbelow.

(a) The share of Sublicense Income payable to ISIS by ATL or its Affiliates on
Sublicensee sales of a Collaboration Compound Product containing ISIS 107248 is
[***] of all Sublicense Income for the term of issued and unexpired claims
within the patent rights applicable to such Product and [***] of all Sublicense
Income thereafter for the life of such Product.

(b) [***].

(c) Except for Products containing ISIS 107248 or a compound that modulates
IGF-1R, ATL will pay ISIS a [***] royalty on Net Sales of any Product by
Sublicensee and [***] of Sublicense Income exclusive of royalties. Such amounts
are due and payable for the life of the Product.

(d) In addition to amounts payable under (a) or (c), ATL will pay ISIS [***] of
Sublicense Income for sales of Products by Sublicensees containing compounds
that modulate a Research

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<Page>

Target other than IGF-1R and that that would, but for the licenses granted
hereunder, infringe the ISIS Formulation Patent Rights. Such amounts are due
and payable for the term of issued and unexpired claims within the ISIS
Formulation Patent Rights.

(e) Except as otherwise provided above, the share of Sublicense Income payable
to ISIS by ATL or its Affiliates for the license of rights to and/or sale of a
Product for which ISIS has established efficacy in an animal model or has
conducted preclinical studies will be negotiated in good faith by the parties,
but will not be less than [***] of the Sublicense Income.

5.3   ROYALTIES PAYABLE TO ISIS FOR THIRD PARTY PATENT RIGHTS.

(a)   In addition to the royalties and other payments set forth in
      Sections 5.1 and 5.2, the following royalties (percentages of Net
      Sales) are payable to ISIS by ATL for sales of Products including
      Products that modulate IGF-1R, whether sold by ATL, its Affiliates,
      or Sublicensees, the manufacture, use, sale, or import of which
      would, but for the licenses granted hereunder, infringe an issued
      and unexpired claim of the following patent rights on a Product by
      Product basis:

            [***]


(b)   [***].

(c)   [***]

5.4   ROYALTY CAP.

(a)   Should the royalty payable by ATL to ISIS pursuant to Sections 5.1 and 5.3
      with respect to sales of a Product comprising a CD49d-modulating compound,
      including ISIS 107248, exceed [***] of Net Sales, the total royalty ATL
      must pay ISIS for such Product will be [***] of Net Sales.

(b)   Should the royalty payable by ATL to ISIS pursuant to Sections 5.1 and 5.3
      with respect to sales of a Product other than a Product comprising a
      CD49d-modulating compound, exceed [***] of Net Sales, the total royalty
      ATL must pay ISIS for such Product will be [***] of Net Sales.

(c)   The foregoing royalty caps apply only to the royalty rates set forth in
      Sections 5.1 and 5.3 and thus do not apply to any new technology or patent
      rights acquired or accessed by ISIS after the Effective Date, as described
      in Sections 4.7 and 8.4 or to the royalties owed pursuant to Section 5.2.

5.5   EXAMPLES.

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<Page>

(a)   EXAMPLE OF CALCULATION OF ROYALTY RATE FOR SALES OF PRODUCTS COMPRISING
      ISIS 107248 BY ATL OR ITS AFFILIATES:

      The royalty payable to ISIS for sales of Product by ATL or its Affiliates
      (as a percentage of Net Sales) comprising non-topically-administered
      formulations of ISIS 107248 is calculated as follows (assuming all
      relevant patent rights are issued and unexpired):


[***]


(b)   EXAMPLE OF ROYALTIES AND SUBLICENSE INCOME PAYABLE TO ISIS BY ATL OR ITS
      AFFILIATES ON SALES OF PRODUCTS COMPRISING ISIS 107248 BY SUBLICENSEES:

      [***]

5.6   PAYMENT OF ROYALTIES AND INCOME; REPORTS.

ATL will make royalty payments to ISIS for each Product sold during a Calendar
Quarter within [***] days of the last day of that Calendar Quarter. Each royalty
payment will be accompanied by a written report for that Calendar Quarter
showing the calculation of Net Sales of the Product sold by ATL, its Affiliates
and its Sublicensees worldwide during the quarterly reporting period and the
calculation of the royalties and Sublicense Income payable under this Agreement,
all on a country-by-country and Product-by-Product basis.

5.7   PAYMENT MODALITIES; FOREIGN CURRENCY CONVERSION; LATE PAYMENT
      CHARGES.

(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.

(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.
      If ATL disputes the amount of an invoice presented by ISIS within
      [***] days of receipt of such invoice, the late fees will only apply
      to the correct amount as later determined or agreed. The payment of
      such interest will not limit a party from exercising any other
      rights it may have as a consequence of the lateness of any payment.
      In addition, ATL agrees to pay all costs of collection, including
      reasonable attorneys' fees, incurred by ISIS in enforcing the
      payment obligations of ATL after a due date has passed under this
      Agreement.


5.8   AUDITS REQUESTED BY ISIS.


                                       20



<Page>

(a)   Upon the written request of ISIS, and not more than once in each
      calendar year, ATL will permit ISIS' independent certified public
      accountant to have access during normal business hours to such of
      the records of ATL as may be reasonably necessary to verify the
      accuracy of the royalty reports hereunder for the current year and
      the preceding 2 years prior to the date of such request.  The
      accounting firm will disclose to ISIS only whether the royalty
      reports are correct or incorrect, the specific details concerning
      any discrepancies, and the corrected amount of Net Sales and
      Sublicense Income.  No other information will be provided to ISIS.

(b)   At the request of ISIS, ATL will direct its Affiliates to permit
      audits of the Affiliates' records in accordance with the provisions
      of subsection (a) above.  Further, ATL will include in each
      sublicense granted by it pursuant to this Agreement a provision
      requiring the Sublicensee to submit reports to ATL, to keep and
      maintain records of sales made pursuant to such sublicense and to
      grant access to such records by ISIS' independent accounting firm,
      to the same extent required of ATL hereunder. ISIS' independent
      accounting firm will also be granted access to such reports in ATL's
      possession as part of the audit referenced in subsection (a) above.

(c)   If such accounting firm concludes that additional royalties were
      owed during such period, ATL will pay the additional royalties
      within [***] days of the date ISIS delivers to ATL such accounting
      firm's written report.  The fees charged by such accounting firm
      will be paid by ISIS unless the additional royalties, milestones or
      other payments owed by ATL exceed [***] of the royalties, milestones
      or other payments paid for the time period subject to the audit, in
      which case ATL will pay the reasonable fees and expenses charged by
      the accounting firm.

(d)   ISIS will treat all financial information subject to review under this
      Section 5.8 or under any sublicense agreement in accordance with the
      confidentiality provisions of Article 9, and will cause its accounting
      firm to enter into an acceptable confidentiality agreement with ATL and
      its Sublicensees obligating such firm to retain all such financial
      information in confidence pursuant to such confidentiality agreement.

5.9   AUDITS REQUESTED BY ATL.

(a)   Upon the written request of ATL, and not more than once in each
      calendar year, ISIS will permit ATL's independent certified public
      accountant to have access during normal business hours to such of
      the records of ISIS as may be reasonably necessary to verify the
      accuracy of the invoices submitted to ATL hereunder for the 12
      months preceding the date of such request.  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.


                                      21
<Page>

(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 will treat all financial information subject to review under this
      Section 5.9 in accordance with the confidentiality provisions of Article 9
      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.


5.10  TAXES.

If laws, rules or regulations require withholding of income taxes or other
taxes imposed upon payments set forth in this Article 5, ATL will make such
withholding payments as required and subtract such withholding payments from
the payments set forth in this Article 5. ATL will submit appropriate proof
of payment of the withholding taxes to ISIS within a reasonable period of
time.

                                    ARTICLE 6

                   USE OF MATERIALS, DATA AND INFORMATION

6.1   Unless provided otherwise herein, all Antisense Inhibitors and any related
      research materials delivered to ATL under this Agreement will be used only
      in furtherance of a Development Program or Collaborative Research Program,
      will not be used or delivered to or for the benefit of any Third Party
      without the prior written consent of ISIS, and will not be used in
      research or testing involving human subjects. The Antisense Inhibitors and
      any related research materials supplied under this Agreement must be used
      with prudence and appropriate caution in any experimental work, since not
      all of their characteristics may be known. ATL agrees to comply with all
      applicable laws, rules and regulations in connection with its use of
      Antisense Inhibitors and related research materials provided hereunder.

6.2   All Antisense Inhibitors and related research materials provided to ATL
      hereunder are proprietary to ISIS. Any unused quantities of Antisense
      Inhibitors and research materials will be returned to ISIS by ATL, upon
      ISIS' request, at ISIS' expense.

6.3   ATL may use data and information generated pursuant to a Gene Walk or
      GeneTrove Investigation, or otherwise provided to ATL by ISIS hereunder,
      for internal drug discovery purposes only, consistent with the terms of
      this Agreement. Except as provided otherwise herein, all data and
      information provided to ATL by ISIS pursuant to this


                                      22
<Page>

      Agreement is confidential and proprietary to ISIS and will not be
      disclosed to Third Parties, consistent with the provisions of Article 9
      herein. ISIS acknowledges that ATL may wish to provide such data and/or
      information to a Third Party in connection with ATL's bona fide
      development, commercialization or partnering activities under this
      Agreement; ISIS will not unreasonably withhold its consent to such a
      transfer of data and information, provided that the receiving party is
      advised of the confidentiality provisions hereunder and agrees to be bound
      thereby. Notwithstanding the foregoing, ISIS reserves the absolute right
      to withhold consent if ATL wishes to transfer such data or information to
      an antisense company or other competitor of ISIS.

6.4   Consistent with the foregoing provisions, if ATL conducts studies
      comparing ISIS Standard Chemistry with the chemistry of a Third Party, all
      data and information incorporating or relating to ISIS Standard Chemistry
      that result from such studies is confidential and proprietary to ISIS and
      will not be disclosed to Third Parties, consistent with the provisions of
      Article 9 herein.

                                    ARTICLE 7

                               FUNDING PROVISIONS

7.1   FUNDING FOR DEVELOPMENT ACTIVITIES.

(a)   As of the Effective Date, ATL will pay for all activities described in the
      ISIS 107248 Development Plan or any other Development Plan hereunder, or
      as approved by the JDC and performed by ISIS in the course of any
      Development Program on a time and materials basis. Labor will be [***].
      Materials and out of pocket expenses incurred by ISIS will be [***].

(b)   ISIS will submit an invoice for such expenditures to ATL after each
      Calendar Quarter, and ATL will submit payment to ISIS within [***] days
      from the date of invoice, consistent with the provisions of Section 5.7.

7.2   FUNDING FOR COLLABORATIVE RESEARCH PROGRAM ACTIVITIES.

(a)   Except as specifically provided otherwise herein, as of the Effective
      Date, ATL will pay for all activities performed by ISIS in the course of
      the Collaborative Research Program hereunder on a time and materials
      basis. Labor will be [***]. Materials and out of pocket expenses incurred
      by ISIS will be [***].

(b)   ATL will pay for additional Gene Walks, for GeneTrove Investigations, and
      for additional quantities of Antisense Inhibitors as specified in Sections
      3.7 and 3.8 herein.

(c)   ISIS will submit an invoice for such expenditures to ATL after each
      Calendar Quarter, and ATL will submit payment to ISIS within [***] days
      from the date of invoice, consistent with the provisions of Section 5.7.


                                      23
<Page>

7.3   FUNDING FOR OTHER ATL ACTIVITIES.

ATL will also pay for any other activities ATL deems necessary to research,
develop or commercialize a Collaboration Compound or Product, or which are
otherwise required for ATL to fulfill its obligations hereunder, on a time and
materials basis. Labor will be [***]. Materials and out of pocket expenses
incurred by ISIS will be [***].

                                    ARTICLE 8

                              INTELLECTUAL PROPERTY

8.1   OWNERSHIP OF INVENTIONS.

(a)   Neither party hereto will be deemed by this Agreement to have been granted
      any license or other rights to the other party's rights in any inventions,
      technology, discoveries, or other proprietary property (collectively,
      "Inventions") existing as of the Effective Date of this Agreement, except
      as expressly provided herein.

(b)   Except as provided otherwise herein, each party will solely own all
      Inventions that are made (as determined by U.S. rules of
      inventorship) solely by employees of or Consultants to that party
      pursuant to the Collaborative Research Program or any Development
      Program under this Agreement.  Such an Invention will be an "ISIS
      Invention" or an "ATL Invention," as the case may be, and Patents
      claiming such Inventions will be "ISIS Patents" or "ATL Patents,"
      respectively.

(c)   ISIS agrees to assign to ATL its rights in any ISIS Inventions or
      Joint Inventions claiming Antisense Inhibitors that modulate IGF-1R
      and methods of using same, provided that a License to Research or
      License to Exploit for IGF-1R exists.  If ATL does not convert the
      License to Research for IGF-1R into a License to Exploit IGF-1R, or
      if the License to Research or License to Exploit applicable to
      IGF-1R is terminated for any reason, ATL will assign back to ISIS
      the latter's rights in any such ISIS Inventions and Joint
      Inventions, as well as ISIS' rights in any Patents filed on such
      Inventions.  Notwithstanding the foregoing, if such assignment of
      rights back to ISIS would interfere with ATL's ability to practice
      any ATL Inventions or ATL Patent Rights pertaining to IGF-1R, ISIS
      agrees to sublicense, in favor of ATL, only that portion of any such
      Invention or Patent, and only for that time period, as is required
      for ATL to practice an ATL Invention or ATL Patent that would
      otherwise infringe the ISIS Invention or ISIS Patent, on a
      nonexclusive, mutually agreeable basis that is consistent with the
      royalties set out in this Agreement, provided that ISIS is not
      otherwise precluded from doing so.

(d)   Except as provided otherwise herein, ISIS and ATL will jointly hold
      title to all Inventions, whether or not patentable, that are made
      (as determined by the U.S. rules of inventorship) jointly by
      employees of or Consultants to ISIS and ATL pursuant to the
      Collaborative


                                      24
<Page>

      Research Program or any Development Program under this Agreement,
      as well as to Patents filed thereon.  Such Inventions will be "Joint
      Inventions," and Patents claiming such Joint Inventions will be "Joint
      Patents."  ISIS and ATL will promptly provide each other with notice
      whenever a Joint Invention is made. The parties agree and acknowledge
      that, except insofar as this Agreement provides otherwise, the default
      rights conferred on joint owners under US patent law, including the right
      of each party to independently practice, license and use a Joint Patent,
      will apply in relation to the Joint Patents throughout the world as though
      US patent law applied worldwide.

(e)   The parties understand that if ATL or a Third Party collaborator of ATL
      provides a proprietary gene sequence or utility not known to ISIS, the
      discovery of inhibitors of that sequence may be a Joint Invention.
      Similarly, the parties understand that the discovery of a method of
      treating human disease by inhibiting a particular gene product, where
      ISIS' Antisense Inhibitor data is used to support the claims of the
      Patent, may be a Joint Invention.

(f)   The parties agree, upon reasonable request, to execute any documents
      reasonably necessary to effect and perfect each other's ownership of any
      Invention.

(g)   [***].


8.2   FILING, PROSECUTION, MAINTENANCE, ENFORCEMENT AND DEFENSE OF PATENTS
      OWNED OR CONTROLLED BY ISIS AND OF CERTAIN JOINT PATENTS.

(a)   Except as provided otherwise herein, ISIS will have the sole and
      exclusive right to file, prosecute, maintain, enforce and defend any
      Research Target Patent Rights and any ISIS Patents or Joint Patents
      filed on Inventions claiming an Antisense Inhibitor to a Research
      Target or a method of treatment using an antisense molecule that
      modulates a Research Target subject to a License to Research or
      License to Exploit hereunder, regardless of inventorship.  ISIS will
      consider ATL's input with respect to the prosecution, maintenance,
      enforcement and defense of any such Patents.  ISIS will also
      consider any supporting information provided by ATL that relates to
      the Research Target and its uses, as well as any supporting IN VIVO
      or IN VITRO efficacy data generated from experiments performed by
      ATL or its collaborators.  As used herein, Patent prosecution
      includes, without limitation, the handling of interference
      proceedings, oppositions, reexaminations and reissues.

(b)   In the event ATL proposes the filing of a Joint Patent pursuant to
      subsection (a) and ISIS does not wish to file and prosecute such Joint
      Patent, ATL will have the right to file, prosecute, maintain, enforce and
      defend such Joint Patent. ATL will consider ISIS' input with respect to
      the prosecution, maintenance, enforcement and defense of any such Joint
      Patents.

(c)   ISIS will also have the sole and exclusive right, in its sole discretion,
      to file, prosecute, maintain, enforce and defend any Patents within the
      ISIS Core Technology Patent Rights, the Manufacturing Patent Rights, and
      the ISIS Formulation Patent Rights.


                                      25
<Page>

(d)   ISIS will pay for its own labor costs incurred in the filing, prosecution,
      maintenance, enforcement and defense of any Patents for which ISIS is
      responsible hereunder.

(e)   ATL will reimburse ISIS for reasonable materials and out of pocket
      expenses incurred in connection with the activities recited in subsections
      (a), (c) and (d). As used herein, materials and out-of-pocket expenses
      means costs, other than ISIS' labor costs, [***]. ISIS will invoice ATL on
      a quarterly basis and ATL will submit payment to ISIS consistent with the
      provisions of Article 7 herein.

(f)   Should ATL elect not to pay expenses relating to Patent protection
      in a particular country, ATL will provide ISIS with written notice
      of same, and ATL's payment obligations with respect to that country
      will cease once ISIS has received such notice, provided that all
      noncancelable costs and expenses incurred by ISIS prior to such date
      will nevertheless be reimbursed by ATL.  Immediately upon ISIS'
      receipt of such written notice from ATL, the applicable License to
      Research or License to Exploit will be terminated with respect to
      such country.

(g)   With respect to any ISIS Patent Rights exclusively licensed to ATL under a
      License to Exploit, ISIS will promptly advise ATL if ISIS becomes aware of
      any suspected or actual infringement of such ISIS Patent Rights by any
      person. Similarly, ATL will promptly advise ISIS if ATL becomes aware of
      any suspected or actual infringement of such ISIS Patent Rights by any
      person.

(h)   If ISIS fails to initiate proceedings against any actual or suspected
      infringement of the ISIS Patent Rights exclusively licensed to ATL
      hereunder or to defend any claim of infringement against the parties
      pertaining to such rights within [***] days of receipt of a notice from
      ATL asking ISIS to do so, ATL will be entitled to initiate those
      proceedings at ATL's expense.

(i)   Except as provided otherwise herein, ISIS will endeavor to take all action
      necessary to ensure that the ISIS Patent Rights that are or become subject
      to a License to Research or License to Exploit are maintained and
      diligently prosecuted.

8.3   FILING, PROSECUTION, MAINTENANCE, ENFORCEMENT AND DEFENSE OF PATENTS
      OWNED OR CONTROLLED BY ATL.

(a)   Except as provided otherwise herein, ATL will have the sole and
      exclusive right and responsibility, in its sole discretion, to file,
      prosecute, maintain, enforce and defend any Patents filed on
      Inventions made solely by ATL (i.e., ATL Patents).  ATL will provide
      ISIS with a semiannual report summarizing the status of any such ATL
      Patents. ATL hereby grants ISIS a worldwide, royalty-free,
      sublicensable, perpetual, nonexclusive license to practice under
      ATL's rights to any such ATL Patent to carry out the activities
      contemplated by this Agreement and to make, have made, use, import,
      offer for sale and sell products other than a Product.


                                      26
<Page>

(b)   If a License to Exploit is granted to ATL with respect to a Research
      Target or Collaboration Compound hereunder, ISIS will promptly
      thereafter transfer to ATL the sole and exclusive right to
      prosecute, maintain, enforce and defend any Patents owned,
      controlled or to which ISIS has prosecution rights that are within
      the Research Target Patent Rights.  ATL will consider ISIS' input
      with respect to the prosecution, maintenance, enforcement and
      defense of any such Patents.  If ATL decides to discontinue the
      prosecution, maintenance, enforcement or defense of any such Patent
      entirely or in a particular country, it will inform ISIS thereof
      with sufficient time for ISIS to assume those responsibilities with
      respect to such Patent and will thereafter transfer the relevant
      Patent files to ISIS or its designee.

8.4   INFRINGEMENT OF THIRD PARTY PATENTS.

If either party receives notice that a Product infringes a Third Party Patent,
and the parties hereto agree to settle with and pay royalties to such Third
Party, the additional royalty burden will be allocated as follows.

(a)   If the alleged infringement is due to ATL's practice of ISIS Core
      Technology Patent Rights, Manufacturing Patent Rights, or ISIS 107248
      Patent Rights, [***].

(b)   If the alleged infringement is due to ATL's practice of any other
      Patent Rights licensed hereunder, [***].

8.5   PATENT COORDINATORS.

(a)   Within 30 days of the Effective Date, the parties will each select a
      Patent Coordinator ("PC") to facilitate and coordinate the preparation,
      filing, prosecution and maintenance of Patents pursuant to this Agreement.
      The parties may agree to name additional Patent Coordinators, as long as
      equal representation is maintained.

(b)   During the Collaboration Term, the PCs will be the primary contacts for
      interaction between the parties with respect to the activities referenced
      in (a).

(c)   The PCs will meet as needed during the Collaboration Term. Meetings will
      be via teleconference or videoconference, or as the parties may otherwise
      agree. The frequency, dates and times of all meetings will be mutually
      agreed upon by the parties. At their first meeting, the PCs will determine
      such procedures as they will reasonably require to conduct their
      activities.

(d)   The parties further agree that to facilitate the activities
      described in this Section, ATL's Patent Coordinator may, upon prior
      written notice to ISIS' Patent Coordinator and at such times as are
      mutually agreed upon by the Patent Coordinators, obtain access to
      and make copies of Patent file documents that are relevant to
      filing, prosecution, maintenance, enforcement and defense of Patents
      licensed to ATL hereunder.   Any and all such documents will be
      maintained by ATL in confidence, pursuant to the provisions of
      Article 9 below.


                                      27
<Page>

                                    ARTICLE 9

                                 CONFIDENTIALITY

9.1   NONDISCLOSURE OBLIGATION.

All Confidential Information disclosed by one party to the other party hereunder
will be maintained in confidence by the receiving party and will not be
disclosed to a Third Party or Affiliate or used for any purpose except as set
forth below.

9.2   PERMITTED DISCLOSURES.

Except as otherwise provided herein, a party may disclose Confidential
Information received from the other party:

(a)   to governmental or other regulatory agencies in order to obtain Patents or
      approval to conduct clinical trials, or to gain Marketing Approval;
      provided that such disclosure may be made only to the extent reasonably
      necessary to obtain such patents or approvals;

(b)   to Affiliates, Sublicensees, agents, consultants, and/or other Third
      Parties for the development, manufacturing and/or marketing of the
      Product (or for such parties to determine their interest in
      performing such activities) in accordance with this Agreement on the
      condition that such Affiliates and Third Parties agree to be bound
      by the confidentiality obligations contained in this Agreement,
      provided the term of confidentiality for such Affiliates and Third
      Parties will be no less than 7 years; or

(c)   if such disclosure is required by law or court order, provided that notice
      is promptly delivered to the other party in order to provide an
      opportunity to challenge or limit the disclosure obligations.

                                   ARTICLE 10

                            PUBLICATION AND PUBLICITY

10.1  PUBLICATION.

(a)   The parties agree that it is customary in the industry to publish results
      obtained from clinical trials and other studies of a Collaboration
      Compound or Product, and that each party may publish such information
      obtained by such party in the performance of the Development Program,
      subject to the provisions of this Section.

(b)   Except as provided otherwise herein, the parties will be entitled to
      publish or present on the results of any Development Program
      hereunder including, without limitation, the ISIS 107248 Development
      Program, and any Collaboration Compound or Product, provided that
      the party seeking to publish will deliver to the other party for its
      review a copy of any


                                      28
<Page>

      proposed publication or an abstract of any oral presentation of clinical
      results at scientific meetings involving ISIS 107248, any Collaboration
      Compound or Product hereunder, or the Proprietary Information of the
      other party, at least 30 days prior to submission of scientific
      publications or abstracts of oral presentations.  The reviewing party
      will have the absolute right to request that any of its Proprietary
      Information be deleted from such publication or presentation, and the
      disclosing party will comply with that request.  If the disclosing party
      does not receive any feedback from the reviewing party within that
      30-day period, the disclosing party will be free to proceed with the
      publication or presentation, with the following limitations:

      (i)   ISIS will be permitted to publish on matters relating to ISIS
            107248, a Collaboration Compound or Product containing ISIS 107248,
            or any other Collaboration Compound or Product developed by ATL
            hereunder during the term of this Agreement only upon the prior
            written approval of ATL, which may be reasonably withheld by ATL.

      (ii)  ATL will be permitted to publish on matters relating to any
            Manufacturing Technology or Manufacturing Technology Improvements
            relating to a specific Collaboration Compound or Product developed
            hereunder during the term of this Agreement only upon the prior
            written approval of ISIS, which may be given at ISIS' sole
            discretion.

10.2  PUBLICITY.

(a)   The parties will issue a joint press release regarding the execution of
      this Agreement.

(b)   Except as otherwise provided herein or required by law, neither
      party will originate any publication, news release or other public
      announcement, written or oral, whether in the public press, or
      stockholders' reports, or otherwise, relating to this Agreement, and
      neither party will use the name, trademark, trade name, logo or
      likeness of the other party or its employees in any publicity, news
      release or disclosure relating to this Agreement, or its subject
      matter, without the prior express written permission of the other
      party.

(c)   ATL will inform ISIS of any press releases relating to a Product permitted
      hereunder or required to be made by law in advance of general release to
      the public.

                                   ARTICLE 11

                                 INDEMNIFICATION

11.1    INDEMNIFICATION BY ATL.

ATL will indemnify, defend and hold ISIS and its agents, employees, officers and
directors (the "ISIS Indemnitees") harmless from and against any and all
liability, damage, loss, cost or


                                     29
<Page>


expense (including reasonable attorneys' fees) arising out of Third Party
claims or suits related to (a) ATL's performance of its obligations under
this Agreement; (b) breach by ATL of its representations and warranties set
forth in Article 13; (c) patent infringement allegations or claims asserted
by a Third Party against ISIS arising out of ISIS' performance of activities
for ATL pursuant to this Agreement; or (d) ATL's choice of Research Targets
pursuant to Section 3.4 or 3.5; PROVIDED, HOWEVER, that ATL's obligations
pursuant to this Section 11.1 will not apply to the extent such claims or
suits result from the gross negligence or willful misconduct of any of the
ISIS Indemnitees. Notwithstanding the foregoing, ATL will have no obligation
to indemnify the ISIS Indemnitees with respect to claims arising out of
breach by ISIS of its representations and warranties set forth in Section
13.1.

11.2    INDEMNIFICATION BY ISIS.

ISIS will indemnify, defend and hold ATL and its Affiliates and each of their
respective agents, employees, officers and directors (the "ATL Indemnitees")
harmless from and against any and all liability, damage, loss, cost or
expense (including reasonable attorney's fees) arising out of Third Party
claims or suits related to (a) ISIS' performance of its obligations under
this Agreement; or (b) breach by ISIS of its representations and warranties
set forth in Article 13; PROVIDED HOWEVER, that ISIS' obligations pursuant to
this Section 11.2 will not apply to the extent that such claims or suits
result from the gross negligence or willful misconduct of any of the ATL
Indemnitees. Notwithstanding the foregoing, ISIS will have no obligation to
indemnify the ATL Indemnitees with respect to claims arising out of a breach
by ATL of its representations and warranties set forth in Sections 3.5(b)(i)
and 13.1.

11.3    NOTIFICATION OF CLAIMS; CONDITIONS TO INDEMNIFICATION OBLIGATIONS.

As a condition to a party's right to receive indemnification under this
Article 11, it will (i) promptly notify the other party as soon as it becomes
aware of a claim or action for which indemnification may be sought pursuant
hereto, (ii) cooperate with the indemnifying party in the defense of such
claim or suit, and (iii) permit the indemnifying party to control the defense
of such claim or suit, including without limitation the right to select
defense counsel. In no event, however, may the indemnifying party compromise
or settle any claim or suit in a manner which admits fault or negligence on
the part of the indemnified party without the prior written consent of the
indemnified party. The indemnifying party will have no liability under this
Article 11 with respect to claims or suits settled or compromised without its
prior written consent.

                                   ARTICLE 12

                        TERM AND TERMINATION OF AGREEMENT


12.1  TERM AND TERMINATION OF AGREEMENT.

This Agreement will be effective as of the Effective Date and unless terminated
earlier pursuant to Sections 12.2 or 12.3 below, the term of this Agreement will
continue in effect until expiration of


                                      30
<Page>


the License Term.

12.2  TERMINATION UPON FUNDAMENTAL BREACH.

This Agreement may be terminated upon written notice by either party to the
other at any time during the term of this Agreement if the other party is in
fundamental breach of its obligations hereunder (i.e., a breach which goes to
the heart of the Agreement) and has not cured such breach within 90 days
after written notice requesting cure of the breach; providing, however, that
in the event of a good faith dispute with respect to the existence of such a
fundamental breach, the 90-day cure period will be stayed until such time as
the dispute is resolved pursuant to Section 16.6 hereof. Material breaches
that are not fundamental give rise solely to a right of damages but not a
right to terminate the Agreement.

12.3  TERMINATION UPON BANKRUPTCY; RIGHTS IN BANKRUPTCY.

All rights and licenses granted under or pursuant to this Agreement by ISIS
or ATL are, and will otherwise be deemed to be, for purposes of Section
365(n) of the U.S. Bankruptcy Code, licenses of right to "intellectual
property" as defined under Section 101 of the U.S. Bankruptcy Code. The
parties agree that the parties, as licensees of such rights under this
Agreement, will retain and may fully exercise all of their rights and
elections under the U.S. Bankruptcy Code. The parties further agree that, in
the event of the commencement of a bankruptcy proceeding-by or against either
party under the U.S. Bankruptcy Code, the party hereto which is not a party
to such proceeding 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 their possession,
will be promptly delivered to them (i) upon any such commencement of a
bankruptcy proceeding upon their written request therefor, unless the party
subject to such proceeding elects to continue to perform all of its
obligations under this Agreement, or (ii) if not delivered under (i) above,
following the rejection of this Agreement by or on behalf of the party
subject to such proceeding upon written request therefor by the non-subject
party.

12.4  ACCRUED RIGHTS AND SURVIVING OBLIGATIONS.

Expiration or termination of the Agreement will not relieve the parties of
any obligation accruing prior to such expiration or termination. Sections
4.8, 12.4 and 16.7, and Articles 5-9, 11 and 13-15 will survive expiration or
termination of the Agreement. Provisions concerning reporting requirements
will continue in effect in accordance with any applicable timetables set
forth herein. Any expiration or early termination of this Agreement will be
without prejudice to the rights of either party against the other accrued or
accruing under this Agreement prior to termination, including the obligation
to pay royalties for Product sold prior to such termination.


                                      31
<Page>

                                   ARTICLE 13

                 REPRESENTATIONS AND WARRANTIES; DISCLAIMER

13.1 REPRESENTATIONS AND WARRANTIES OF THE PARTIES.

Each party represents and warrants to the other party that, as of the date of
this Agreement:

(a)   Such party is duly organized and validly existing under the laws of the
      state of its incorporation and has full corporate power and authority to
      enter into this Agreement and to carry out the provisions hereof;

(b)   Such party has taken all corporate action necessary to authorize the
      execution and delivery of this Agreement and the performance its
      obligations under this Agreement;

(c)   This Agreement is a legal and valid obligation of such party,
      binding upon such party and enforceable against such party in
      accordance with the terms of this Agreement The execution, delivery
      and performance of this Agreement by such party does not conflict
      with any agreement, instrument or understanding, oral or written, to
      which such party is a party or by which such party may be bound, and
      does not violate any law or regulation of any court, governmental
      body or administrative or other agency having authority over such
      party. All consents, approvals and authorizations from all
      governmental authorities or other Third Parties required to be
      obtained by such party in connection with this Agreement have been
      obtained;

(d)   Such party has the full and exclusive right, power and authority to enter
      into this Agreement, to perform the Development Program, the Collaborative
      Research Program and to grant the licenses granted hereunder;

(e)   There are no agreements between such party and any Third Parties which
      would preclude or otherwise limit such party's ability to conduct its
      tasks and obligations under the Development Plan, the Collaborative
      Research Program or otherwise fulfill its obligations under this
      Agreement; and

(f)   All individuals who will perform any activities on such party's behalf in
      connection with the Development Program and/or the Collaborative Research
      Program have assigned to such party or its Affiliates the whole of their
      rights in any intellectual property conceived or reduced to practice by
      them as a result of either program.

13.2    REPRESENTATIONS AND WARRANTIES BY ATL.

ATL warrants and represents that to the best of its knowledge, none of the
Research Targets listed on Exhibit 3.4 as of the Effective Date are encumbered
by any Third Party rights including, without limitation, intellectual property
rights, that would interfere with ISIS' ability to carry out the activities
contemplated by the parties hereunder. ATL further warrants and represents that,
to the best of its knowledge as of the Effective Date, if ISIS makes an
Antisense Inhibitor to any of the Research Targets, it will not constitute an
infringement of any Third Party rights and that ATL will indemnify ISIS, as set
forth in Section 11.1 herein, should a subsequent determination be made that
Third Party rights were infringed.


                                      32
<Page>

13.3    REPRESENTATIONS AND WARRANTIES BY ISIS.

ISIS warrants and represents that to the best of its knowledge, the practice of
the technology claimed in the ISIS Core Technology Patent Rights and the
Manufacturing Patent Rights will not infringe any Third Party patents.

13.4    DISCLAIMERS.

THE ANTISENSE INHIBITORS BEING PROVIDED TO ATL HEREUNDER ARE PROVIDED "AS IS"
AND WITHOUT ANY REPRESENTATION OR WARRANTY, EXPRESS OR IMPLIED, INCLUDING
WITHOUT LIMITATION ANY IMPLIED WARRANTY OF MERCHANTABILITY OR OF FITNESS FOR ANY
PARTICULAR PURPOSE OR ANY WARRANTY THAT THE USE OF THE MATERIALS WILL NOT
INFRINGE OR VIOLATE ANY PATENT OR OTHER PROPRIETARY RIGHTS OF ANY THIRD PARTY.

THE PARTIES EXPRESSLY DISCLAIM ALL WARRANTIES, EXPRESS OR IMPLIED, INCLUDING
WITHOUT LIMITATION WARRANTIES OF MERCHANTABILITY, FITNESS FOR A PARTICULAR
PURPOSE, OR NON-INFRINGEMENT OF THIRD PARTY RIGHTS, UNLESS OTHERWISE EXPRESSLY
PROVIDED IN THIS AGREEMENT.

                                   ARTICLE 14

                                     NOTICE

14.1  NOTICE.

All notices which are required or permitted hereunder will be in writing and
sufficient if delivered personally, sent by facsimile (and promptly confirmed by
personal delivery, registered or certified mail or overnight courier), 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
                              2292 Faraday Avenue
                              Carlsbad, CA 92008
                              Attention:  Executive Vice President
                              Fax No.: +1 (760) 931-9639

            with a copy to:   Attention: General Counsel
                              Fax No.: +1 (760) 603-3820


                                      33
<Page>

            if to ATL, to:    Antisense Therapeutics, Limited
                              ACN 095 060 745 of Level 1
                              10 Wallace Avenue, Toorak
                              Victoria 3142, AUSTRALIA
                              Attention:  CEO
                              Fax No.: +61 (3) 9826 4399

            with a copy to:   Attention:  General Counsel
                              Fax No.: +61 (3) 9826 4399

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 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.




                                      34
<Page>

                                   ARTICLE 15

                                     RECORDS

15.1  RECORDS.

Each party will maintain records, in sufficient detail and in good scientific
manner, which will fully and properly reflect all work done and results achieved
in the performance of its responsibilities under each Development Plan hereunder
including, without limitation, the ISIS 107248 Development Plan. Each party will
have the right, during normal business hours and upon reasonable prior notice,
to inspect and copy those records of the other party referred to herein that are
necessary or useful to the inspecting party for the purposes of making any
required filings with Regulatory Authorities in order to obtain manufacturing
approvals and/or Marketing Approvals. Each party will maintain such records and
the information disclosed therein in confidence in accordance with Article 9.

                                   ARTICLE 16

                            MISCELLANEOUS PROVISIONS

16.1  RELATIONSHIP OF THE PARTIES.

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 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.

16.2  SUCCESSORS AND ASSIGNS.

Neither this Agreement nor any interest hereunder may 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, except that no intellectual
property of any Third Party acquirer of ATL or ISIS will be included in the
licenses granted hereunder. This Agreement will be binding upon the successors
and permitted assigns of the parties. Any attempted assignment not in accordance
with this Section 16.2 will be void.


                                      35
<Page>

16.3  ENTIRE AGREEMENT; AMENDMENTS.

This Agreement, the Stock Agreement and the Clinical Supply Agreement contain
the entire understanding of the parties with respect to the license, development
and commercialization of antisense APIs hereunder. 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.
The Agreement may be amended, or any term hereof modified, only by a written
instrument duly executed by both parties hereto.


16.4  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, 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.

16.5  APPLICABLE LAW

The 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

(a)   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 parties' respective executive officers designated
      below or their successors, for attempted resolution by good faith
      negotiations within 30 days after such notice is received. Said designated
      officers are as follows:

            For ISIS:         Executive Vice President
            For ATL:          CEO

(b)   In the event the designated executive officers are not able to resolve
      such dispute after such 30-day period, each party may pursue its rights
      and remedies in law or equity in any court of competent jurisdiction.


                                      36
<Page>

16.7  NO CONSEQUENTIAL DAMAGES

IN NO EVENT WILL EITHER PARTY OR ANY OF ITS RESPECTIVE AFFILIATES BE LIABLE TO
THE OTHER PARTY OR ANY OF ITS AFFILIATES FOR SPECIAL, INDIRECT, INCIDENTAL OR
CONSEQUENTIAL DAMAGES, WHETHER IN CONTRACT, WARRANTY, TORT, NEGLIGENCE, STRICT
LIABILITY OR OTHERWISE, INCLUDING, BUT NOT LIMITED TO, LOSS OF PROFITS OR
REVENUE, OR CLAIMS OF CUSTOMERS OF ANY OF THEM OR OTHER THIRD PARTIES FOR SUCH
OR OTHER DAMAGES.

16.8  CAPTIONS

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.

16.9  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.

16.10 COMPLIANCE WITH LAW

Nothing in this Agreement will be deemed to permit a party to export, re-export
or otherwise transfer any Licensed Product sold under this Agreement without
compliance with applicable laws.

16.11 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 best efforts to replace the
invalid, illegal or unenforceable provision(s) with valid, legal and enforceable
provision(s) which, insofar as practical, maintains the balance of the rights
and obligations of the parties under this Agreement.

16.12 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.

16.13 COUNTERPARTS.


                                      37
<Page>

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.


IN WITNESS WHEREOF, the parties have executed this Agreement as of the Effective
Date.


ANTISENSE THERAPEUTICS, LIMITED          ISIS PHARMACEUTICALS, INC.


By: /s/ C. Belyea                        By: /s/ B. Lynne Parshall
   ----------------------------             ------------------------------------
Name: C. Belyea                          Name:  B. Lynne Parshall
     --------------------------               ----------------------------------
Title: CEO                               Title: Executive Vice President and CFO
      -------------------------                ---------------------------------




                                      38
<Page>


                                    EXHIBIT 1

                                   DEFINITIONS

1.1     "ABANDONED RESEARCH TARGET" has the meaning set forth in Section
        3.5(d) herein.

1.2     "ACTIVE PROGRAM" in relation to a Collaboration Compound or Product
        means an ongoing program for optimizing, developing and commercializing
        such Collaboration Compound or Product, including preclinical studies,
        human clinical studies, development activities aimed at obtaining
        registration for marketing, and marketing and selling activities,
        wherein such program includes the following specific "DEVELOPMENT
        MILESTONES" that must be met in order for the Collaboration Compound or
        Product to achieve and maintain "ACTIVE DEVELOPMENT" status:

      (a)   initiation of phenotypic or functional assays by ATL within 12
            months of ATL's receipt of reasonably sufficient quantities of the
            Antisense Inhibitors directed to a Research Target and corresponding
            control oligonucleotides;

      (b)   initiation of IND-enabling toxicology studies by ATL within 18
            months of ATL's receipt of an Antisense Inhibitor directed to a
            Research Target;

      (c)   filing of an IND not later than 6 months after the completion
            of IND-enabling studies;

      (d)   initiation of Phase I studies not later than 6 months after
            the filing of the IND;

      (e)   initiation of Phase IIa studies not later than 24 months after
            the initiation of Phase I studies;

      (f)   initiation of Phase III studies not later than 3 years after
            the initiation of Phase IIa studies;

      (g)   filing of an NDA not later than 18 months after the successful
            completion of a pivotal trial; and

      (h)   the use of commercially reasonable efforts by ATL to bring each
            Product to market and to maximize the commercial value of each such
            Product worldwide.

      If ATL will not be able to meet a Development Milestone set forth above
      for circumstances beyond ATL's control but has proceeded in good faith in
      its development efforts, ATL will be granted a 12-month extension on any
      of the milestones identified in above, provided that ATL [***].

      A compound that is in "Active Development" is one that is in an Active
      Program, as defined above.

1.3     "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 the


                                      39
<Page>

        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, of a Person.

1.4     "ANTISENSE INHIBITOR" means an oligonucleotide or analog thereof that
        inhibits protein synthesis at the nucleic acid level by specifically
        binding to the sequence of a selected messenger or viral ribonucleic
        acid (RNA) by base-pairing, thus causing a selective inhibition of gene
        expression.

1.5     "ANTISENSE TECHNOLOGY" means the selective modulation of protein
        synthesis at the nucleic acid level caused by the binding of an
        oligonucleotide or an analog thereof to a complementary sequence.

1.6     "ATL INVENTION" has the meaning set forth in Section 8.1(b).

1.7     "ATL PATENT" has the meaning set forth in Section 8.1(b).

1.8     "ATL SUBLICENSE" has the meaning set forth in Section 4.3(b).

1.9     "AUSTRALIAN APPROVAL" means approval of a Product for marketing in
        Australia by the Therapeutic Goods Administration ("TGA"), without the
        requirement for price having been approved. If a Product can be sold in
        Australia without TGA approval, Australian Approval will be deemed to
        have been obtained on the first sale of a Product in Australia.

1.10    "CALENDAR QUARTER" means the respective periods of 3 consecutive
        calendar months ending on March 31, June 30, September 30 and December
        31.

1.11    "CALENDAR YEAR" means each successive period of 12 months commencing on
        January 1 and ending on December 31.

1.12    "COLLABORATION" has the meaning set forth in Section 2.1.

1.13    "COLLABORATION COMPOUND" means an Antisense Inhibitor of a Research
        Target that is discovered or developed by ISIS that (i) incorporates
        Antisense Technology; (ii) incorporates ISIS Standard Chemistry; (iii)
        is subject to a License to Research or License to Exploit hereunder; and
        (iv) is in Active Development, consistent with Section 1.2 herein.

1.14    "COLLABORATION COMPOUND PRODUCT" means a product containing a
        Collaboration Compound.

1.15    "COLLABORATION TERM" means the term of the Collaborative Research
        Program as set forth in Section 3.1.


                                      40
<Page>

1.16  "COLLABORATIVE RESEARCH PLAN" has the meaning set forth in Section 3.1,
      as further detailed in Exhibit 3.1.

1.17  "COLLABORATIVE RESEARCH PROGRAM" means the research program
      described in Article 3, as modified from time to time by the parties
      (e.g., via the JRC).

1.18  "CONFIDENTIAL INFORMATION" means information which is (a) of a
      confidential and proprietary nature; (b) designated by either party as
      Confidential Information or Proprietary Information; and (c) not readily
      available to that party's competitors and which, if known by a competitor
      of that party, might lessen any competitive advantage of that party or
      give such competitor a competitive advantage. Confidential Information
      which is disclosed in oral, written, graphic, electronic or any other form
      by one party to the other party that is clearly marked as "confidential"
      or "proprietary." Oral information must be reduced to writing and
      designated as "confidential" within 30 days of disclosure.

      For the purposes of this Agreement, "Confidential Information" includes,
      without limitation, (a) information that is proprietary or confidential or
      which is treated by that party as confidential and which relates either
      directly or indirectly to the business of that party regardless of the
      form in which that information is constituted, and which is not lawfully
      in the public domain; and (b) any confidential information in relation to
      Patents, technology, know-how, or any improvements owned or controlled by
      a party hereto.

      "Confidential Information" will not include any information that the
      receiving party can establish by written records:

      (i)   was known by it prior to the receipt of Confidential
            Information from the disclosing party;

      (ii)  was disclosed to the receiving party by a Third Party having
            the right to do so;

      (iii) was, or subsequently became, in the public domain through no fault
            of the receiving party, its officers, directors, employees or
            agents;

      (iv)  was concurrently or subsequently developed by personnel of the
            receiving party without having had access to the disclosing party's
            Confidential Information;

      (v)   was disclosed with the prior written consent of the disclosing
            party; or

      (vi)  was disclosed by the receiving party pursuant to any judicial or
            governmental request, requirement or order, so long as the receiving
            party provides the disclosing party with sufficient prior notice in
            order to allow the disclosing party to contest such request,
            requirement or order.

1.19  "CONSULTANT" means an individual who is not an employee of either party
      hereto, but who has been engaged by a party hereto in order to perform
      certain activities, wherein


                                      41
<Page>

      that individual has an obligation to assign to the engaging party, at the
      time an Invention is made, all rights that individual may have in such
      Invention.

1.20  "DERMATOLOGY TARGETS" means those Research Targets designated as
      Dermatology Targets, as listed in Section A of Exhibit 3.4.

1.21  "DEVELOPMENT MILESTONES" means the Development Milestones set forth in
      Section 1.2 hereinabove.

1.22  "DEVELOPMENT PLAN" means the plan for the development of any Antisense
      Inhibitor or Collaboration Compound hereunder.

1.23  "EC APPROVAL" means approval of a Product for marketing in the European
      Union by the European Commission ("EC") or, if ATL seeks approval through
      mutual recognition therein, by the Ministry of Health of the United
      Kingdom, France, Germany, Italy or Spain (each a "Major European
      Country"), without the requirement for price having been approved. If a
      Product can be sold in a Major European Country without EC or Ministry of
      Health approval, EC Approval will be deemed to have been obtained on the
      first sale of a Product in a Major European Country.

1.24  "GENETROVE," when used to refer to an organization, corporation or other
      business entity, means the functional genomics division of ISIS.

1.25  "GENETROVE INVESTIGATION" or "GENE FUNCTIONALIZATION ASSAY" has the
      meaning set forth in Section 3.8, as further described in Exhibit 3.8.

1.26  "GENE WALK" has the meaning set forth in Section 3.7, as further described
      in Exhibit 3.7.

1.27  [***].

1.28  [***].

1.29  "IND" means an Investigational New Drug Application or similar application
      or submission for approval to conduct human clinical investigations filed
      with or submitted to a Regulatory Authority or hospital ethics committee
      in conformity with applicable Regulatory Authority regulations.

1.30  "IND-ENABLING STUDIES" means, at a minimum, the pharmacokinetic and
      toxicology studies required to meet the safety regulations for filing an
      IND, as well as any additional studies required by a Regulatory Authority
      or hospital ethics committee as a prerequisite to filing an IND.

1.31  "INTEGRATED PRODUCT PLAN" or "IPP" means a plan for the development,
      commercialization and marketing of a Collaboration Compound hereunder. The
      IPP will


                                       42
<Page>

      include Product charter, strategic intent, a market analysis (event maps
      - demographics, market dynamics), label need and wants (based on the
      applicable Development Plan), Product life overview, geographic overview,
      and financial overview. In addition, a global marketing plan will be
      developed and incorporated into the IPP which includes analysis of market
      (disease overview, Product profile, archetype, patient segmentation),
      strategic ends (strategic intent, product positioning, brand character,
      core messages, critical success factors, marketing objectives) strategic
      means (global Product, place, price, promotion, launch, market research
      programs), operational plan (implementation plan, marketing activities)
      and budget for the execution of the plan. Each IPP will also include
      appropriate milestones and the dates upon which such milestones must be
      met by ATL, as agreed upon by the parties hereto.

1.32  "INVENTION" has the meaning set forth in Section 8.1 herein.

1.33  "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.

1.34  "ISIS 107248 DEVELOPMENT PLAN" means the plan for the development of ISIS
      107248 hereunder as set forth in Exhibit 2.2, as amended by the JDC from
      time to time.

1.35  "ISIS 107248 PATENT RIGHTS" means the Patents owned by ISIS as of the
      Effective Date or during the Collaboration Term that claim antisense
      oligonucleotides that modulate human CD49d, methods of making such
      oligonucleotides for therapeutic use, or methods of using such
      oligonucleotides for therapeutic applications. The ISIS 107248 Patent
      Rights are the Patents listed in Exhibit 1.35.

1.36  "ISIS C5-PROPYNE PATENT RIGHTS" means all Patents owned by ISIS as of the
      Effective Date or during the Collaboration Term that claim any of the
      5-(1-propynyl) pyrimidine phosphoramidite compounds listed in Exhibit
      1.37.

1.37  "ISIS CORE TECHNOLOGY PATENT RIGHTS" means the Patents owned by ISIS as of
      the Effective Date or during the Collaboration Term that claim ISIS
      Standard Chemistry, the cellular mechanisms of action by which
      phosphorothioate antisense oligonucleotides exert their effect, or to
      methods of treatment using such oligonucleotides. ISIS Core Technology
      Patent Rights also include the ISIS C-5 Propyne Patent Rights. The ISIS
      Core Technology Patent Rights are the Patents listed in Exhibit 1.37.

1.38  "ISIS FORMULATION PATENT RIGHTS" means the Patents owned by ISIS as of the
      Effective Date or during the Collaboration Term that claim topical
      formulations incorporating antisense oligonucleotides made using ISIS
      Standard Chemistry, methods of making formulations containing such
      oligonucleotides for topical administration, or methods of treatment using
      such topical formulations. The ISIS Formulation Patent Rights are the
      Patents listed in Exhibit 1.38.

1.39  "ISIS FTE RATE" means [***].


                                      43
<Page>

1.40  "ISIS INVENTION" has the meaning set forth in Section 8.1(b).

1.41  "ISIS NET ROYALTY" means the [***].

1.42  "ISIS PATENT" has the meaning set forth in Section 8.1(b).

1.43  "ISIS PATENT RIGHTS" means all rights in Patents owned by ISIS that are
      within the ISIS Core Technology Patent Rights, the Manufacturing Patent
      Rights, the ISIS Formulation Patent Rights, or the Research Target Patent
      Rights.

1.44  "ISIS STANDARD CHEMISTRY" means the technology, whether or not subject to
      a Patent, that is owned, acquired or controlled by ISIS as of the
      Effective Date or during the Collaboration Term that claims or covers
      linkages and sugar units in an antisense oligonucleotide, wherein such
      linkages include phosphorothioate linkages and such sugar units include a
      combination of deoxy sugar units and 2'-O-[methoxyethyl] (MOE) modified
      sugar units with natural and methyl substituted heterocycle bases ("MOE
      Gapmer Technology"). ISIS Standard Chemistry also includes the technology
      owned, acquired or controlled by ISIS as of the Effective Date that claims
      or covers the cellular mechanisms of action by which MOE Gapmer Technology
      antisense oligonucleotides exert their effect. ISIS Standard Chemistry
      does not include any target gene-specific technology.

1.45  "JAPANESE APPROVAL" means the approval of a Product for marketing in
      Japan by the Japanese Ministry of Health and Welfare (or any future
      equivalent process), together with any other approval necessary to make
      and sell Product commercially in Japan without the requirement for price
      having been approved. If a Product can be sold in Japan without Ministry
      of Health and Welfare approval, Japanese Approval will be deemed to have
      been obtained on the first sale of a Product in Japan.

1.46  "LICENSE TO EXPLOIT" has the meaning set forth in Section 4.2.

1.47  "LICENSE TO RESEARCH" has the meaning set forth in Section 4.1.

1.48  "LICENSE TERM" has the meaning set forth in Section 4.0.

1.49  "MAJOR MARKET" means any one of the following countries: the United
      States, Australia, Japan, the United Kingdom, France, Germany,
      Italy or Spain.

1.50  "MANUFACTURE" OR "MANUFACTURING" OR "MANUFACTURED" means all operations
      involved in the manufacturing, quality control testing (including
      in-process, release and stability testing, if applicable), releasing,
      and shipping a Product.

1.51  "MANUFACTURING PATENT RIGHTS" means the Patents owned by ISIS as of the
      Effective Date or during the Collaboration Term that claim the
      Manufacturing Technology. The


                                       44
<Page>

      Manufacturing Patent Rights as of the Effective Date are the Patents
      listed in Exhibit 1.51.

1.52  "MANUFACTURING PROCESS" means the process steps set forth in master
      batch records for ISIS 107248 in the version existing as of the
      Effective Date, including reasonable minor variants and extensions of
      process steps thereof.

1.53  "MANUFACTURING TECHNOLOGY" means any and all scientific and technical
      data and information including without limitation formulas, methods,
      techniques, protocols, and processes owned or controlled by ISIS as of
      the Effective Date or during the Collaboration Term which are necessary
      or useful for performing the Manufacturing Process.

1.54  "MARKETING APPROVAL" means the act of a Regulatory Authority necessary
      for the marketing and sale of the Product in a country or regulatory
      jurisdiction, including, without limitation, the approval of the NDA by
      the FDA, Australian Approval, EC Approval, and Japanese Approval.

1.55  "NDA" means New Drug Application or similar application or submission
      for approval to market and sell a new pharmaceutical product filed with
      or submitted to a Regulatory Authority in conformity with applicable
      Regulatory Authority regulations.

1.56  "NET SALES" means, with respect to a Product, the gross amount invoiced
      by ATL or ISIS, as appropriate, or by their Affiliates or sublicensees,
      to unrelated Third Parties for the Product, less:

      (a)      Trade, quantity and cash discounts allowed;

      (b)      Commissions, discounts, refunds, rebates, chargebacks,
               retroactive price adjustments, and any other allowances
               which effectively reduce the net selling price;

      (c)      Credits for actual Product returns;

      (d)      Any tax imposed on the production, sale, delivery or use of
               the Product, including, without limitation, sales, use,
               excise or value added taxes;

      (e)      Allowance for distribution expenses at levels customary in
               the industry; and

      (f)      Any other similar and customary deductions.


      "NET SALES" excludes:

      (i)   The transfer of reasonable and customary quantities of free samples
            of Product(s) and the transfer of Product(s) as clinical trial
            materials, other than for subsequent resale;
      (ii)  Sales or transfers of Product(s) among ATL and its Affiliates,
            unless the receiving party is the consumer or user of the
            Product; and


                                       45
<Page>

      (iii) Use by ATL or its Affiliates or sublicensees of 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 Product (unless such Product is subsequently
            sold).

1.57  [***].

1.58  "PATENT" or "PATENTS" means (a) patent applications (including
      provisional applications and applications for certificates of
      invention); (b) any patents issuing from such patent applications
      (including certificates of invention); (c) all patents and patent
      applications worldwide based on, corresponding to, or claiming the
      priority date(s) of any of the foregoing; (d) any reissues,
      substitutions, confirmations, registrations, validations,
      re-examinations, additions, continuations, continued prosecution
      applications, continuations-in-part, requests for continued examination,
      or divisions of or to any of the foregoing; and (e) term extension or
      other governmental action which provide exclusive rights to a Product
      beyond the original patent expiration date.

1.59  "PRODUCT" means a Collaboration Compound Product or a Research
      Target Compound Product.

1.60  "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, the United
      States Food and Drug Administration ("FDA") and any successor government
      authority having substantially the same function, and foreign
      equivalents thereof.

1.61  "RESEARCH TARGET" means a gene product - usually, a protein - that may
      be modulated by another molecule, such as an antisense drug. Modulation
      of a Research Target may be accomplished in a variety of ways including,
      without limitation, the modulation of the synthesis, function or
      degradation of a Research Target, or the expression of the corresponding
      gene.

1.62  "RESEARCH TARGET COMPOUND" means a compound that modulates a Research
      Target or Abandoned Research Target that was discovered by ATL alone or
      as part of a bona fide drug discovery collaboration with a Third Party
      in which ATL played a significant role.

1.63  "RESEARCH TARGET COMPOUND PRODUCT" means a product containing a
      Research Target Compound.

1.64  "RESEARCH TARGET PATENT RIGHTS" means the Patents owned by ISIS as of
      the Effective Date or during the Collaboration Term that claim antisense
      oligonucleotides that modulate a Research Target, methods of making such
      oligonucleotides, or methods of treatment using such oligonucleotides.
      The Research Target Patent Rights thus include the ISIS 107248 Patent
      Rights. The Research Target Patent Rights are the Patents listed in
      Exhibit 1.64, which will be amended from time to time as new Patents are
      added.


                                       46
<Page>

1.65  "SUBLICENSEE" means any Third Party (including a distributor) to which
      ATL or any of its Affiliates grants any right to make, use, market, or
      import and sell a Product. A Third Party who is granted only the right
      to import and sell a Product (such as a wholesaler) will not be
      considered a Sublicensee.

1.66  "SUBLICENSE INCOME" means all consideration paid to ATL from
      Sublicensees pursuant to a sublicense by ATL or an Affiliate of ATL
      including, without limitation, up-front license fees, milestones, and
      royalties.. If non-monetary consideration is received from Sublicensees
      by ATL or its Affiliates, then a commercially reasonable monetary value
      will be assigned for purposes of calculating Sublicense Income.

1.67  "TECHNOLOGY" means inventions (whether or not patentable), know-how,
      trade secrets, research tools, materials, and technical information,
      including but not limited to information in the form of research data,
      databases, experimental procedures, designs, formulas, and process
      information.

1.68  "THIRD PARTY" means any party other than ISIS or ATL and their
      respective Affiliates.

1.69  "THIRD PARTY INTELLECTUAL PROPERTY" means any intellectual property
      owned by a Third Party.

1.70  "THIRD PARTY PATENT RIGHTS" means the [***].

1.71  [***].


                                       47
<Page>


                                  EXHIBIT 1.27

                                     [***]


                                  EXHIBIT 1.28

                                     [***]


                                  EXHIBIT 1.35

                            ISIS 107248 PATENT RIGHTS


-  U.S. Patent No. 5,968,826, issued October 19, 1999, entitled "Antisense
   Modulation of Integrin Alpha 4 Expression."

-  U.S. Patent No. 6,258,790, issued July 10, 2001, entitled "Antisense
   Modulation of Integrin Alpha 4 Expression."


                                       48
<Page>



                                  EXHIBIT 1.37

                       ISIS CORE TECHNOLOGY PATENT RIGHTS

[***]
                                  EXHIBIT 1.38

                         ISIS FORMULATION PATENT RIGHTS


[***]


                                  EXHIBIT 1.51

                           MANUFACTURING PATENT RIGHTS


[***]


                                       49
<Page>



                                  EXHIBIT 1.57

[***]


                                  EXHIBIT 1.64

                          RESEARCH TARGET PATENT RIGHTS

                                   [***]



                                  EXHIBIT 1.71

[***]


                                       50
<Page>




                                   EXHIBIT 2.2


                          ISIS 107248 DEVELOPMENT PLAN

[***]


                                       51
<Page>


                                   EXHIBIT 3.4
                                RESEARCH TARGETS
[***]


                                       52
<Page>





                                   EXHIBIT 3.7

                                   GENE WALKS

[***]


                                       53
<Page>



                                   EXHIBIT 3.8

                            GENETROVE INVESTIGATIONS:
                          GENE FUNCTIONALIZATION ASSAYS


[***]




                                    CONFIDENTAIL TREATMENT REQUESTED UNDER
                                    17 C.F.R. SECTIONS 200.80(b)4 AND 240.24B-2


                                       54