<PAGE>

                                                                   EXHIBIT 10.24

          CONFIDENTIAL MATERIALS OMITTED AND FILED SEPARATELY WITH THE
         SECURITIES AND EXCHANGE COMMISSION. ASTERISKS DENOTE OMISSIONS.

                           STRATEGIC COLLABORATION AND
                                LICENSE AGREEMENT

           This Strategic Collaboration and License Agreement (the "Agreement")
is effective as of March 11, 2004 (the "Effective Date") between Isis
Pharmaceuticals, Inc., a Delaware corporation having an address at 2292 Faraday
Avenue, Carlsbad, CA 92008 ("Isis") and Alnylam Pharmaceuticals, Inc., a
Delaware corporation having an address at 790 Memorial Drive, Suite 202,
Cambridge, MA 02139 (together with its wholly owned subsidiaries Alnylam U.S.,
Inc., a Delaware corporation, and Alnylam Europe AG, a company organized under
the laws of Germany, "Alnylam"). Isis and Alnylam may be referred to herein as
the "Parties," or each individually as a "Party."

                               GUIDING PRINCIPLES

           Isis is the leader in RNA-based drug discovery, has created
technology, intellectual property, expertise, facilities and resources to
discover and develop oligonucleotide drugs;

           Alnylam is the leader in RNAi therapeutics, has developed and
acquired intellectual property, expertise and technology in RNAi therapeutics,
and is conducting research and drug discovery focused on Double Stranded RNA
drugs;

           Isis and Alnylam desire to create a long-term strategic relationship
that will enhance the positions of both companies in RNA-based drug discovery;

           Isis will continue to pursue RNA-based drug discovery technology very
broadly including all potential mechanisms of action. Isis will work with
Alnylam as Isis' primary means of participating in the potential value of Double
Stranded RNA Products, and will not enter into any collaborations with Third
Parties the primary purpose of which is to discover Double Stranded RNA
Products; and

           Alnylam will focus on RNAi therapeutics and the use of Double
Stranded RNA.

      The objectives of the strategic relationship are to:

-     Enhance the leadership of Alnylam in RNAi therapeutics.

-     Enhance the potential of Alnylam to develop Double Stranded RNA drugs.

-     Defer Alnylam investments in Chemistry, Manufacturing and Controls (CMC).

-     Enhance the patent positions of each Party with respect to Double Stranded
      RNA drugs.

-     Provide Isis with a means for participating in the success of RNAi
      therapeutics.

                                   ARTICLE 1

                                       1
<PAGE>
                       DEFINITIONS; EXHIBITS AND SCHEDULES

      1.1 Capitalized terms used herein and not defined elsewhere herein have
the meanings set forth in Exhibit 1.1.

      1.2 On or before March 19, 2004, the Parties shall both execute a mutually
satisfactory addendum transmittal instrument (the "Addendum Transmittal")
delivering all Exhibits and Schedules identified herein as attached to the
Addendum Transmittal.

                                   ARTICLE 2

                                EQUITY INVESTMENT

      2.1 Isis will purchase from Alnylam Pharmaceuticals, Inc., and Alnylam
Pharmaceuticals, Inc. will sell to Isis, 1,666,667 shares of Series D Preferred
Stock, at $6.00 per share (i.e., at an aggregate purchase price of $10,000,002),
on the terms contained in the Equity Documents.

                                   ARTICLE 3

                       MANUFACTURING SERVICES RELATIONSHIP

      3.1 At Alnylam's request, on the terms and conditions of the Manufacturing
Services Term Sheet attached hereto as Exhibit 3.1 attached to the Addendum
Transmittal, Isis and Alnylam will negotiate in good faith a manufacturing
services agreement (the "Manufacturing Services Agreement"), pursuant to which
Isis will provide Alnylam with manufacturing and related services relating to
Double Stranded RNA Products.

                                   ARTICLE 4

                         COLLABORATIVE RESEARCH EFFORTS

      4.1 Research Management Committee.

            (A) To promote the success of the collaboration objectives and RNAi
technology, the Parties will establish a Research Management Committee ("RMC"),
which will be comprised of equal numbers of representatives of each of the
Parties and will meet at least twice per calendar year, alternating venues
between the vicinities of Cambridge, Massachusetts and Carlsbad, California, to
share scientific direction and data, to coordinate basic research experiments,
and to facilitate the guiding principles of the collaboration.

            (B) Intellectual property representatives of each Party will be
invited to participate in RMC meetings and such meetings will provide a forum to
discuss patent prosecution and enforcement issues and to allocate responsibility
for the filing and prosecution of any Joint Patents.

            (C) The Parties will use the RMC as a forum to update one another
regarding their respective Future Chemistry and Motif and Mechanism Patents.

                                       2
<PAGE>
            (D) The RMC will establish a clearance policy that will govern any
publication or presentation by a Party in which such Party proposes to include
any previously undisclosed information or intellectual property Controlled by
the other Party.

            (E) The RMC will continue in existence for three (3) years after the
Effective Date, subject to extension by mutual agreement of the Parties. Upon
termination of the RMC, the Parties will agree upon a strategy to make decisions
about the items in Sections 4.1 (b), (c), and (d).

                                   ARTICLE 5

                       LICENSES GRANTED BY ISIS TO ALNYLAM

      5.1 License Grants. Subject to the terms and conditions of this Agreement,
including, but not limited to, the restrictions set forth in Section 5.3, Isis
grants Alnylam the following licenses:

            (A) Under Isis Current Motif and Mechanism Patents and Isis Current
Chemistry Patents, a license to research, develop, make, have made, use, import,
offer to sell and sell Double Stranded RNA and Double Stranded RNA Products.

            (B) Subject to the terms of Section 11.8, under Isis Future Motif
and Mechanism Patents, Isis Future Chemistry Patents and Isis' rights in Joint
Patents, a license to research, develop, make, have made, use, import, offer to
sell and sell Double Stranded RNA and Double Stranded RNA Products.

            (C) Under the Isis Current Motif and Mechanism Patents and Isis
Current Chemistry Patents, a license to research, develop, make, have made, use,
import, offer to sell and sell MicroRNA Products.

            (D) Subject to the terms of Section 11.8, under the Isis Future
Motif and Mechanism Patents and Isis Future Chemistry Patents, a license to
research, develop, make, have made, use, import, offer to sell and sell MicroRNA
Products.

            (E) A royalty-free, fully paid, license to practice any Know-How
disclosed to Alnylam during the performance of this Agreement, subject to the
non-disclosure but not the non-use provisions contained in Article 12.

            (F) A fully paid, royalty-free nonexclusive license under Isis
Manufacturing Patents to research, develop, make, have made, use and import
Alnylam Products for Research Use.

      5.2 License Exclusivity, Territory and Sublicenses.

                                       3
<PAGE>
            (A) Subject to the terms and conditions of this Agreement, including
the restrictions set forth in Section 5.3, the licenses from Isis to Alnylam
granted in Sections 5.1(a) and (b) are worldwide and co-exclusive (with Isis),
with the exclusive right to grant Naked Sublicenses, and the licenses from Isis
to Alnylam granted in Sections 5.1 (c), (d), (e) and (f) are worldwide and
nonexclusive. Alnylam is not permitted to grant sublicenses under the licenses
granted in Sections 5.1(a) through 5.1(e), except that Alnylam is permitted to
grant (i) sublicenses in connection with a Bona Fide Drug Discovery
Collaboration, (ii) sublicenses in connection with a Development Collaboration,
(iii) Naked Sublicenses and (iv) sublicenses under the license granted in
Section 5.1(e) in connection with the discovery, development or
commercialization of any product. Alnylam is not permitted to grant sublicenses
under the licenses granted in Section 5.1(f).

            (B) If Alnylam, on its own or through an Affiliate or collaborator
in a Bona Fide Drug Discovery Collaboration, has not reached the [**] stage of
development with any Alnylam Product by [**], the exclusive right to grant Naked
Sublicenses under the licenses granted in Sections 5.1(a) and 5.1(b) will
convert to a nonexclusive right.

            (C) Alnylam cannot sublicense its right to grant Naked Sublicenses
under this Agreement except that Alnylam may permit its sublicensees to grant
further sublicenses in connection with an Alnylam Product.

            (D) Notwithstanding the foregoing, Isis may (i) [**] provided that
[**] for the manufacture and sale of [**] for research use only and (ii)
continue to grant licenses to Third Parties for the purpose of manufacturing and
selling oligonucleotides; provided that, to the extent such licenses cover
Double Stranded RNA, Isis will restrict such licenses to non-therapeutic uses.

      5.3 Limitations on Licenses.

            (A) The licenses granted under Section 5.1 above are not intended to
grant any rights to Alnylam to practice the Isis Excluded Technology. If Alnylam
wishes to license any Isis Excluded Technology for which Isis has the right to
grant a license or sublicense, Isis will negotiate in good faith an appropriate
license.

            (B) Notwithstanding the licenses granted to Alnylam under Section
5.1, Isis retains its rights in the Isis Patent Rights and in the Joint Patents
(i) exclusively for the Isis Exclusive Targets and (ii) exclusively for the Isis
Encumbered Targets. Once a particular contractual restriction expires on an Isis
Encumbered Target, Alnylam's licenses under Section 5.1 will no longer be
limited under this Section 5.3(b) for such target and such target shall no
longer be an Isis Encumbered Target. Isis will update [**] Alnylam [**] to
remove targets that are no longer Isis Encumbered Targets promptly upon receipt
of a written request from Alnylam [**], but will not be required to update [**]
more frequently than once a calendar quarter.

            (C) Licenses to Isis Patent Rights that are joint patents with Third
Parties (i.e., invented by one or more Isis inventors and one or more non-Isis
inventors) are licensed subject to the retained rights of any non-Isis inventors
and their assignees and licensees. Any

                                       4
<PAGE>
such retained rights of non-Isis inventors and their assignees and licensees
existing as of the Effective Date are set forth in Exhibit 5.3(c) attached to
the Addendum Transmittal.

            (D) Licenses to Isis Patent Rights that are subject to contractual
obligations between Isis and Third Parties in effect as of the Effective Date
are licensed subject to the restrictions and other terms described in Exhibit
5.3(d) attached to the Addendum Transmittal. Alnylam hereby agrees to comply,
and to cause its sublicensees to comply, with such restrictions and other terms.

      5.4 Alnylam Covenant Regarding Sublicensing of Isis Patent Rights. Alnylam
shall use good faith efforts to include sublicenses under the licenses under the
Isis Patent Rights granted to Alnylam in Sections 5.1(a) and 5.1(b) in any Third
Party collaboration or license agreement in which Alnylam grants rights to
develop and commercialize Double Stranded RNA Products, unless the technology
covered by such licensed Isis Patent Rights would not reasonably be expected to
advance the goals of such Third Party collaboration or license relationship.

                                   ARTICLE 6

                       LICENSES GRANTED BY ALNYLAM TO ISIS

      6.1 License Grants. Subject to the terms and conditions of this Agreement,
including, but not limited to, the restrictions set forth in Section 6.5,
Alnylam grants Isis the following licenses:

            (A) A fully-paid, royalty-free, nonexclusive license under Alnylam
Current Motif and Mechanism Patents and Alnylam Current Chemistry Patents to
research, develop, make, have made, use and import Isis Products for Research
Use.

            (B) Subject to the terms of Section 11.8, a fully paid, royalty-free
nonexclusive license under Alnylam Future Motif and Mechanism Patents and
Alnylam Future Chemistry Patents to research, develop, make, have made, use and
import Isis Products for Research Use.

            (C) A nonexclusive license under Alnylam Current Motif and Mechanism
Patents and Alnylam Current Chemistry Patents to research, develop, make, have
made, use, import, offer to sell and sell Isis Single Stranded Products

            (D) Subject to the terms of Section 11.8, a nonexclusive license
under Alnylam Future Motif and Mechanism Patents and Alnylam Future Chemistry
Patents to research, develop, make, have made, use, import, offer to sell and
sell Isis Single Stranded Products.

            (E) Under the Alnylam Current Motif and Mechanism Patents and
Alnylam Current Chemistry Patents, a nonexclusive license to research, develop,
make, have made, use, import, offer to sell and sell MicroRNA Products.

                                       5
<PAGE>
            (F) Subject to the terms of Section 11.8, under the Alnylam Future
Motif and Mechanism Patents and Alnylam Future Chemistry Patents, a nonexclusive
license to research, develop, make, have made, use, import, offer to sell and
sell MicroRNA Products.

            (G) A worldwide, royalty-free, fully paid, nonexclusive license to
practice any Know-How disclosed to Isis during the performance of this
Agreement, subject to the non-disclosure but not the non-use provisions
contained in Article 12.

      6.2 License Option. For each Gene Target in the Isis Target Pool (as
further described below) Alnylam grants Isis an exclusive option to obtain (on a
Reserved Target-by-Reserved Target basis), subject to the terms and conditions
of this Agreement, including, but not limited to, the restrictions set forth in
Section 6.5, a license under (i) Alnylam Current Motif and Mechanism Patents and
Alnylam Current Chemistry Patents and (ii) subject to the terms of Section 11.8,
Alnylam Future Motif and Mechanism Patents, Alnylam Future Chemistry Patents and
Alnylam's rights in Joint Patents, to research, develop, make, have made, use,
import, offer for sale and sell Double Stranded RNA and Double Stranded RNA
Products.

            (A) This license, when the option is exercised, will be exclusive
with respect to Isis Exclusive Targets and co-exclusive (with Alnylam) with
respect to Isis Co-Exclusive Targets.

            (B) This option will expire on a Reserved Target-by-Reserved Target
basis if Isis has not paid Alnylam the option fee set forth in Section 8.1 below
before the earlier of (i) [**], (ii) the [**] anniversary of the date [**] or
the [**] anniversary of the date [**] and Isis is [**] or (iii) the date [**]
with respect to such Reserved Target.

            (C) For any Reserved Target for which Isis obtains a license from
Alnylam under this Section 6.2, Isis will use Commercially Reasonable Efforts
(either on its own or in an Antisense Drug Discovery Program or Development
Collaboration) to develop and commercialize Double Stranded RNA Products that
modulate such Reserved Target.

      6.3 Sublicenses.

            (A) With respect to any license granted by Alnylam pursuant to
Section 6.1(a), 6.1(b) or 6.2, Isis may only grant a sublicense to a Third Party
solely for the purpose of enabling such Third Party to collaborate with Isis in
an Antisense Drug Discovery Program or to develop and commercialize an Isis
Product in a Development Collaboration. With respect to any license granted by
Alnylam pursuant to Section 6.1(c), 6.1(d), 6.1(e), 6.1(f) or 6.1(g), Isis may
grant a sublicense to a Third Party in connection with the discovery,
development or commercialization of any product.

            (B) Notwithstanding anything in this Agreement to the contrary, Isis
may not enter into any drug discovery collaboration the primary purpose of which
is to discover Double Stranded RNA Products and/or to develop Double Stranded
RNA Products to any point up to the [**].

      6.4 Target Pool.

                                       6
<PAGE>
            (A) Reserved Target Slots. Initially, Isis will have a pool (the
"Isis Target Pool") containing up to [**] slots for which Isis can designate
certain Gene Targets solely for Antisense Drug Discovery Programs (each such
slot, a "Target Slot" and any Gene Target occupying such a slot, a "Reserved
Target"); provided, however, that on January 1 of each year starting with
January 1, [**], Isis will [**] per each additional Target Slot, which
additional Target Slot shall be a Co-Exclusive Target Slot except as otherwise
provided in Section 6.4(f). These rights are cumulative and, subject to Section
17.2(c) do not expire during the License Term. Furthermore, in the event that
Isis pays the $[**] license option fee for a Reserved Target pursuant to section
8.1, such Reserved Target will be considered to have graduated from the Isis
Target Pool, and, subject to Section 6.4(e), Isis will be permitted to designate
a new Reserved Target to fill the open Target Slot in the Isis Target Pool.

            (B) Initial Designations; Conversion of Target Slots. Initially,
subject to Section 6.4(e), Isis can designate up to [**] Reserved Targets as
Isis Exclusive Targets (the "Isis Exclusive Targets", and each Target Slot
occupied by an Isis Exclusive Target, an "Exclusive Target Slot") and up to [**]
Reserved Targets as Isis Co-Exclusive Targets (the "Isis Co-Exclusive Targets",
and each Target Slot occupied by an Isis Co-Exclusive Target, a "Co-Exclusive
Target Slot"). On January 1 of each year starting with January 1, [**], [**]
initial Co-Exclusive Target Slots will convert into an Exclusive Target Slot
such that the initial [**] Target Slots will all be Exclusive Target Slots by
January 1, [**]. Subject to section 6.4(f), the Isis Co-Exclusive Target in a
Co-Exclusive Target Slot that converts to an Exclusive Target Slot will become
an Isis Exclusive Target.

            (C) Removing/Adding/Redesignating Targets. After the Effective Date
and no more than [**] period (a "Target Reallocation Period"), Isis may do any
of the following:

                  (i) Remove a Gene Target from the Isis Target Pool (which,
                  following such removal will create an open Target Slot);

                  (ii) Add a new Gene Target to any open Target Slot (subject to
                  the procedures and provisions of Section 6.4(e); or

                  (iii) Redesignate an Isis Co-Exclusive Target as an Isis
                  Exclusive Target, provided that (A) an open Exclusive Target
                  Slot is available, which may be made available by Isis's
                  simultaneous redesignation of an Isis Exclusive Target as an
                  Isis Co-Exclusive Target, and (B) Alnylam does not have an
                  Active Program with respect to such Isis Co-Exclusive Target
                  or has not entered into a Bona Fide Drug Discovery
                  Collaboration or Development Collaboration that prevents
                  Alnylam from granting Isis an exclusive license with respect
                  to such Isis Co-Exclusive Target.

            Notwithstanding the foregoing provisions of this Section 6.4(c), in
any Target Reallocation Period, Isis cannot remove or redesignate, or any
combination thereof, a number of Reserved Targets that exceeds the number
calculated by dividing the then current number of Target Slots by [**]and
rounding down to the nearest whole number. For the purpose of the limitation
described in the immediately preceding sentence, (x) removing a Gene Target from
the Isis Target Pool and then filling the open Target Slot created by such
removal shall

                                       7
<PAGE>
count as a single removal and (y) redesignating an Isis Co-Exclusive Target as
an Isis Exclusive Target and simultaneously redesignating an Isis Exclusive
Target as an Isis Co-Exclusive Target in order to make available an open
Exclusive Target Slot to permit the former redesignation shall count as a single
redesignation. Once Isis removes a Gene Target from the Isis Target Pool, Isis
will be prevented from later adding such Gene Target to the Isis Target Pool
until [**] have passed from the date Isis removed such Gene Target.

            (D) New Target Request. When Isis wishes to add a new Gene Target to
occupy a vacant Target Slot, it will provide Alnylam with written notice (the
"Request Notice") of the Gene Target it wishes to add (the "Proposed Reserved
Target"). The Request Notice will include the gene name, the NCBI accession
number or nucleic acid sequence for the Proposed Reserved Target and whether
Isis wants the Proposed Reserved Target, if accepted, to be an Isis Exclusive
Target or an Isis Co-Exclusive Target.

            (E) New Target Rejection/Approval. Within [**] of receipt of the
Request Notice, Alnylam will give Isis written notice if any of the criteria set
forth below applied to such Proposed Reserved Target at the time of Alnylam's
receipt of the Request Notice. If, at such time, the Proposed Reserved Target is
(i) subject to Alnylam's own Active Program [**], (ii) encumbered by a
contractual obligation between Alnylam and a Third Party that would preclude
Alnylam from granting a license under Section 6.2 with respect to the Proposed
Reserved Target or (iii) the subject of Alnylam's good faith negotiations to
enter into a contractual obligation within the [**] following receipt of the
Request Notice with a Third Party (as supported by a written request from such
Third Party) that would preclude Alnylam from granting a license under Section
6.2 with respect to the Proposed Reserved Target, then the Proposed Reserved
Target will be rejected and will not become a Reserved Target. If the Proposed
Reserved Target is not rejected under this subsection (e), the Proposed Reserved
Target will become an Isis Co-Exclusive Target or an Isis Exclusive Target (as
set forth in the Request Notice). If Alnylam can only grant a license to a
Proposed Reserved Target on a co-exclusive basis, it will notify Isis in
writing. Isis will then have the option to accept the Proposed Reserved Target
as one of its Isis Co-Exclusive Targets. Alnylam will promptly notify Isis in
writing if a rejected Proposed Reserved Target later becomes available to be
designated as a Reserved Target or if an Isis Co-Exclusive Target later becomes
available to be designated as an Isis Exclusive Target.

            (F) Target Redesignation Procedures. In each year that a
Co-Exclusive Target Slot converts to an Exclusive Target Slot pursuant to
section 6.4(b), Isis will provide Alnylam with written notice designating which
Isis Co-Exclusive Target (the "Proposed Redesignated Target") it wishes to
become an Isis Exclusive Target occupying the new Exclusive Target Slot. Alnylam
will have [**] after the receipt of such notice either to confirm that the
Proposed Redesignated Target has become an Isis Exclusive Target or to disallow
such redesignation. Alnylam may only disallow such redesignation if, at the time
of Alnylam's receipt of Isis' notice regarding the Proposed Redesignated Target,
Alnylam has an Active Program with respect to such Proposed Redesignated Target
or has entered into a contractual obligation with a Third Party that prevents
Alnylam from granting Isis an exclusive license with respect to such Proposed
Redesignated Target. In the event that Alnylam disallows the redesignation of a
Proposed Redesignated Target, Isis will use the same procedure to designate
another Isis Co-Exclusive Target as a Proposed Redesignated Target, and Alnylam
will follow the same procedure to confirm or disallow the redesignation

                                       8
<PAGE>
of such Proposed Redesignated Target as an Isis Exclusive Target. In the event
that Isis has proposed all of the then-existing Isis Co-Exclusive Targets as the
Proposed Redesignated Target and Alnylam has disallowed each such proposal, then
(i) if the calendar year is [**], Isis will have the right to [**], or (ii) if
the calendar year is [**] pursuant to section 6.4(a) will become a right to
purchase an Exclusive Target Slot in such year, or (iii) if the calendar year is
[**] or later, Isis's right to [**] pursuant to section 6.4(a) will become a
right to [**], provided, however, that in no event shall the number of Exclusive
Target Slots held by Isis exceed [**].

            (G) Diligence on Rejected Targets. If (i) Alnylam rejects a Proposed
Reserved Target under Section 6.4(e) above and (ii) Alnylam has [**] by the [**]
anniversary of the date Alnylam rejected such Proposed Reserved Target if
Alnylam is working on such target alone, or the [**] anniversary of the date
Alnylam rejected such Proposed Reserved Target if such rejected Proposed
Reserved Target is subject to a contractual obligation between Alnylam and a
Third Party that would preclude Alnylam from granting a license under Section
6.2 with respect to the rejected Proposed Reserved Target but Alnylam is [**],
then [**] such rejected Proposed Reserved Target [**].

            (H) Diligence Obligations in Third Party Contractual Obligations.
With the goal of minimizing contractual encumbrances on Alnylam Patent Rights
with respect to Gene Targets in the absence of a reasonable intent to discover
and develop products that modulate such Gene Targets by Third Parties with which
Alnylam enters into such contractual obligations, Alnylam intends to seek
reasonable diligence obligations from Third Parties in negotiating contracts
between Alnylam and such Third Parties that would constitute contractual
obligations of Alnylam that would preclude Alnylam from granting licenses to
Isis under Section 6.2 with respect to Proposed Reserved Targets or that would
prevent Alnylam from granting Isis exclusive licenses with respect to Proposed
Redesignated Targets; [**].

            (I) Confidentiality. The fact that Isis has designated or removed a
particular Gene Target within the Isis Target Pool is Confidential Information
of Isis, or that Alnylam has rejected a particular Gene Target proposed for a
Target Slot or disallowed the redesignation of a particular Gene Target is
Confidential Information of Alnylam, subject to the provisions of Article 12.
Neither Party shall disclose such Confidential Information of the other Party to
any Third Party, including its Third Party collaborators, or use such
Confidential Information of the other Party to guide its own (or its Third Party
collaborators') decisions to pursue particular Gene Targets, but Alnylam can use
such Confidential Information of Isis to decline a Third Party's request for a
license to such Gene Target.

      6.5 Limitations on Licenses.

            (A) The licenses granted under Sections 6.1 and 6.2 above are not
intended to grant any rights to Isis to practice the Alnylam Excluded
Technology. If Isis wishes to license any Alnylam Excluded Technology for which
Alnylam has the right to grant a sublicense, Alnylam will negotiate in good
faith an appropriate license.

            (B) Licenses to Alnylam Patent Rights that are joint patents with
Third Parties (i.e., invented by one or more Alnylam inventors and one or more
non-Alnylam inventors)

                                       9
<PAGE>
are licensed subject to the retained rights of any non-Alnylam inventors and
their assignees and licensees. There are no Alnylam Current Chemistry Patents or
Alnylam Current Motif and Mechanism Patents subject to such retained rights.

            (C) Licenses to Alnylam Patent Rights that are subject to
contractual obligations between Alnylam and Third Parties in effect as of the
Effective Date are licensed subject to the restrictions and other terms
described in Exhibit 6.5(c) attached to the Addendum Transmittal. Isis hereby
agrees to comply, and to cause its sublicensees to comply, with such
restrictions and other terms.

            (D) Notwithstanding anything to the contrary herein, the licenses to
Alnylam Patent Rights hereunder initially shall not include licenses to Patents
licensed by Alnylam from [**] under any agreement between Alnylam and [**] in
effect as of the Effective Date; provided that if any such licensed Patents
become issued Patents, Isis shall have the option of expanding its licenses to
Alnylam Patent Rights hereunder to include such issued Patents by notifying
Alnylam of such election and agreeing to pay to Alnylam, in addition to all
amounts otherwise payable to Alnylam hereunder (and without any right under
Section 8.2 to reduce such otherwise payable amounts as a consequence of such
additional payment amounts), all amounts that (i) become payable by Alnylam to
[**] as a result of such expansion of Isis' licenses and Isis' (and its
Affiliates' and sublicensees') exercise of its rights thereunder and (ii) are
described on Exhibit 6.5(d) attached hereto.

                                   ARTICLE 7

                   LICENSE FEES AND ROYALTIES PAYABLE TO ISIS

      7.1 License Fees. Alnylam will pay an initial, irrevocable, noncreditable
and non-refundable license fee of $5,000,000 to Isis, $3,000,000 of which will
be due within 5 business days of the Effective Date and the remaining $2,000,000
of which will be due on [**].

      7.2 Royalties. Subject to the terms and conditions of, and during the term
of, this Agreement, Alnylam will pay to Isis royalties on sales of Alnylam
Products by Alnylam, its Affiliates or sublicensees (except Naked Sublicensees)
equal to [**]% of Net Sales. Alnylam may reduce the royalty due under this
section by [**]% of any additional royalties that Alnylam owes to Third Parties
on such Alnylam Product that arise from Alnylam acquiring access to new
technologies after the Effective Date; provided, however that (a) the royalty
due under this section can never be less than a floor of [**]% and (b)
additional royalties arising as the result of the addition, pursuant to Section
11.8, of Isis Future Chemistry Patents or Isis Future Motif and Mechanism
Patents to the Isis Patent Rights licensed to Alnylam cannot be used to reduce
the royalty.

      7.3 Development Milestones.

            (A) Alnylam, its Affiliates or sublicensees (except Naked
Sublicensees) will pay to Isis the following milestone payments for each Alnylam
Product within [**] after the first achievement of each of the following events:

                                       10
<PAGE>
<TABLE>
<CAPTION>
                      MILESTONE EVENT                                    MILESTONE PAYMENT
                      ---------------                                    -----------------
<S>                                                                      <C>
[**]                                                                               US$[**]
[**]                                                                               US$[**]
[**]                                                                               US$[**]
[**]                                                                               US$[**]
</TABLE>

Each milestone payment under this Section 7.3(a) will only be due on [**]
Alnylam Product that modulates a particular Gene Target to trigger such
milestone payment, whether such milestone is achieved by Alnylam or an Affiliate
or sublicensee of Alnylam.

            (B) Alnylam, its Affiliates or sublicensees will pay to Isis a
milestone payment of US$[**] for [**] within [**] after such [**], and not for
any other [**].

      7.4 Sublicensing Revenue on Naked Sublicenses. Alnylam will pay Isis [**]%
of Sublicense Revenue from Naked Sublicenses granted by Alnylam and its
Affiliates under this Agreement.

      7.5 Technology Access Fees from Bona Fide Collaborations.

            (A) Alnylam will pay Isis a percentage of Technology Access Fees
received by Alnylam and its Affiliates pursuant to Bona Fide Drug Discovery
Collaborations and Development Collaborations entered into between Alnylam and a
Third Party. Such percentage will be calculated based on the year in which
Alnylam executes such Bona Fide Drug Discovery Collaboration or Development
Collaboration agreement using the following table:

<TABLE>
<CAPTION>
                     YEAR                   2004/2005                2006               2007             2008+
                     ----                   ---------                ----               ----             -----
<S>                                         <C>                      <C>                <C>              <C>
            APPLICABLE PERCENTAGE             [**]%                  [**]%              [**]%             [**]%
</TABLE>

            (B) Notwithstanding the foregoing, for any Bona Fide Drug Discovery
Collaboration or Development Collaboration agreement, Alnylam will pay Isis a
minimum fee, payable upon the first Alnylam Product developed pursuant to such
Bona Fide Drug Discovery Collaboration agreement reaching [**] or within [**]
after the execution of such Development Collaboration agreement, equal to the
lesser of (i) $[**] or (ii) [**]% of the Technology Access Fees from such
collaboration; provided, however that Alnylam may credit any amounts paid Isis
pursuant to Section 7.5(a) above as the result of the same Bona Fide Drug
Discovery Collaboration or Development Collaboration agreement against this
minimum fee with such amounts credited only once, and provided further that if
following such payment, additional Technology Access Fees are owed to Isis for
such Bona Fide Drug Discovery Collaboration or Development Collaboration, the
amounts paid under this Section 7.5(b) (after crediting of any previous
Technology Access Fees paid under Section 7.5(a) in accordance with the
immediately preceding proviso) will be creditable against such future Technology
Access Fees. [**] the Effective Date [**] the Effective Date, Alnylam [**]
Alnylam [**]; provided, however, that [**] Alnylam [**] Alnylam [**] the
Effective Date, [**] subject to all the terms and conditions of this Agreement,
including but not limited to the

                                       11
<PAGE>
terms of this Section 7.5; provided further, however, that [**] Alnylam in this
Agreement [**] Alnylam pursuant to [**] the provisions of section 7.5(a).

                                   ARTICLE 8

                  LICENSE FEES AND ROYALTIES PAYABLE TO ALNYLAM

      8.1 Option Fee. For each Isis Reserved Target for which Isis exercises its
option granted pursuant to Section 6.2, Isis will pay Alnylam an irrevocable,
noncreditable and non-refundable option fee of $[**] due upon the date of
exercise. Isis may credit any $[**] payment made under Section 6.4(a) for the
Target Slot occupied by such Reserved Target against this option fee. The option
fee is only payable once per Gene Target.

      8.2 Royalties. Subject to the terms and conditions of, and during the term
of, this Agreement, Isis will pay to Alnylam royalties on sales of Isis Products
by Isis, its Affiliates or sublicensees equal to [**]% of Net Sales. Isis may
reduce the royalty due under this section by [**]% of any additional royalties
that Isis owes to Third Parties on such Isis Product that arise from Isis
acquiring access to new technologies after the Effective Date; provided, however
that that (a) the royalty due under this section can never be less than a floor
of [**]%, (b) additional royalties arising as the result of the addition,
pursuant Section 11.8, of Alnylam Future Chemistry Patents or Alnylam Future
Motif and Mechanism Patents to the Alnylam Patent Rights licensed to Isis, or as
the result of an expansion of Isis' licenses pursuant to Section 6.5(d), cannot
be used to reduce the royalty and (c) Isis shall not be entitled to reduce,
pursuant to this sentence, its royalty obligation to Alnylam below a royalty
obligation equal to the lesser of (i) Alnylam's aggregate royalty obligations
[**] existing as of the Effective Date [**] and (ii) Alnylam's aggregate royalty
obligations [**] as such obligations may be reduced from time to time after the
Effective Date.

      8.3 Development Milestones.

            (A) Isis, its Affiliates or sublicensees will pay to Alnylam the
following milestone payments for each Isis Product within [**] after the first
achievement of each of the following events:


<TABLE>
                      MILESTONE EVENT                                    MILESTONE PAYMENT
                      ---------------                                    -----------------
<S>                                                                      <C>
[**]                                                                               US$[**]
[**]                                                                               US$[**]
[**]                                                                               US$[**]
[**]                                                                               US$[**]
</TABLE>

Each milestone payment under this Section 8.3(a) will only be due on [**] Isis
Product that modulates a particular Gene Target to trigger such milestone
payment, whether such milestone is achieved by Isis or an Affiliate or
sublicensee of Isis.

            (B) Isis, its Affiliates or sublicensees will pay to Alnylam a
milestone payment of US$[**] for the [**] that is an Isis Product that [**]
within [**] after such [**], and not for any other [**].

                                       12
<PAGE>
            (C) Isis, its Affiliates or sublicensees will pay to Alnylam a
milestone payment of US$[**] for the [**] that is an Isis Product that [**]
within [**] after such [**], and not for any other [**].

                                    ARTICLE 9

                               OTHER PAYMENT TERMS

      9.1 Payments. All payments by a Party 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 Alnylam or Isis, from
time to time. Royalties payable under Sections 7.2 and 8.2 shall be payable on a
quarterly basis within 45 days after the end of each calendar quarter. The Party
with such royalty obligation (the "Royalty-Paying Party") shall provide the
other Party with a report setting forth (i) gross sales of Alnylam Products or
Isis Products, as applicable, by the Royalty-Paying Party, its Affiliates and
sublicensees, (ii) all deductions from such gross sales taken in calculating Net
Sales, (iii) Net Sales of Alnylam Products or Isis Products, as applicable, by
the Royalty-Paying Party, its Affiliates and sublicensees, (iv) royalties
payable based on such Net Sales and (v) all other information relevant to the
calculation of such royalties, on a product-by-product and country-by-country
basis, for each calendar quarter within [**] after the end of such calendar
quarter.

      9.2 Late Payments; Collections. In the event that any payment, including
royalty, milestone, Sublicense Revenue or Technology Access Fee payments, due
hereunder is not made when due, the payment will bear interest from the date due
at the lesser of (i) 1.5% 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 a Party disputes in writing the
amount of an invoice presented by the other Party within [**] of receipt of such
invoice, interest will only be due on 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, each Party agrees to pay all external costs of collection, including
reasonable attorneys' fees, incurred by the other Party in enforcing the payment
obligations after a due date has passed under this Agreement.

      9.3 Audit Rights.

            (A) Upon the written request of Isis or Alnylam, as the case may be,
and not more than once in each calendar year, Isis or Alnylam will permit the
other Party's independent certified public accountant to have access upon
reasonable advance notice and during normal business hours to its records 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 the auditing Party only whether
the royalty reports are correct or incorrect, the specific details concerning
any discrepancies, and the corrected amount of Net Sales and royalty payments.
No other information will be provided to the auditing Party. Once a Party has
audited a particular calendar year under this section, the Party will be
precluded from subsequently auditing such calendar year. In any sublicense
granted by a Party under this Agreement, such Party will

                                       13
<PAGE>
endeavor to secure a similar audit right and if reasonably requested by the
other Party will enforce such audit right.

            (B) If such accounting firm concludes that additional royalties were
owed during such period, the delinquent Party will pay the additional royalties
within 90 days of the date such Party receives the accounting firm's written
report. The fees charged by such accounting firm will be paid by the auditing
Party unless the additional royalties, milestones or other payments owed by the
audited Party exceed 5% of the royalties, milestones or other payments paid for
the time period subject to the audit, in which case the audited Party will pay
the reasonable fees and expenses charged by the accounting firm.

            (C) Each Party will treat all financial information subject to
review under this Section 9.3 or under any sublicense agreement in accordance
with the confidentiality provisions of Article 12, and will cause its accounting
firm to enter into an acceptable confidentiality agreement obligating such firm
to retain all such financial information in confidence pursuant to such
confidentiality agreement.

      9.4 Taxes. If laws, rules or regulations require withholding of income
taxes or other taxes imposed upon payments set forth in Article 7 or 8, each
Party will make such withholding payments as required and subtract such
withholding payments from the payments set forth in Article 7 or 8. Each Party
will submit appropriate proof of payment of the withholding taxes to the other
Party within a reasonable period of time. The Parties will cooperate to obtain
the appropriate tax clearance and/or recover any such withholdings if possible.

                                   ARTICLE 10

             ALNYLAM RIGHT OF FIRST NEGOTIATION; PREFERRED LICENSEE

      10.1 Right of First Negotiation. Isis will notify Alnylam in writing once
(i) Isis, on its own with no subsequent rights to Third Parties, intends to
initiate [**]or (ii) if a Third Party with which Isis has a Development
Collaboration or a collaboration on [**] before or during clinical development
or commercialization with no subsequent rights to Third Parties. Alnylam will
have [**] from the receipt of such notice to notify Isis in writing whether or
not Alnylam wishes to negotiate with Isis regarding the development and/or
commercialization of such Isis Product. If Alnylam fails to respond to Isis'
notice within the [**] or if Alnylam declines in writing to exercise its right
of first negotiation, then Isis will be free to develop and commercialize
(either on its own or with a Third Party) the Isis Product. If Alnylam wishes to
negotiate a license or development or commercialization rights in such Isis
Product, the Parties will negotiate in good faith the terms of the license or
collaboration agreement. If, despite good faith negotiations, Alnylam and Isis
do not reach agreement within [**] from Alnylam's exercise of its right of first
negotiation, then Isis will be free to develop and commercialize (either on its
own or with a Third Party) the Isis Product; provided that during the period
prior to the latest of (x) the [**] the Isis Product, (y) the [**] for the Isis
Product or (z) in the case of an Isis Product [**], Isis shall not enter into a
license or collaboration agreement with a Third Party for such Isis Product on
terms (the "More Favorable Terms") that are in the aggregate materially more
favorable to the Third Party than

                                       14
<PAGE>
the terms on which Isis most recently offered in writing to grant such rights to
Alnylam without first offering the More Favorable Terms to Alnylam.

      10.2 Preferred Licensee. If, after the Effective Date, Alnylam grants to
any Third Party that is not a Major Pharmaceutical Company a license under the
Alnylam Patent Rights to develop and commercialize Double Stranded RNA Products,
then if (a) either (i) the [**] terms of such license are more favorable to the
Third Party than the [**] terms hereunder with respect to Isis Products are to
Isis or (ii) the [**] covered by such license exceeds the [**] potentially
licensed to Isis hereunder for development and commercialization of Double
Stranded RNA Products, and (b) the roles to be played by Alnylam and such Third
Party in the development and commercialization of Double-Stranded RNA Products
under such Third Party license, the nature of the Gene Targets covered by such
Third Party license and any other relevant terms of such Third Party license do
not collectively justify the conditions described in the preceding clauses
(a)(i) and/or (a)(ii), then Alnylam shall modify the terms of its licenses to
Isis hereunder with respect to such conditions so that they are reasonably
equivalent to those granted to the Third Party.

                                   ARTICLE 11

                              INTELLECTUAL PROPERTY

      11.1 Ownership of Inventions.

            (A) Each Party will solely own all inventions, technology,
discoveries, or other proprietary property (collectively, "Inventions") that are
made (as determined by U.S. rules of inventorship) solely by employees of or
consultants to that Party under this Agreement.

            (B) Isis and Alnylam 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 Alnylam, 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
Alnylam 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.

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

      11.2 Filing and Prosecution of Isis and Alnylam Patent Rights.

            (A) Isis and Alnylam will work closely, through their interactions
on the RMC to ensure that, to the greatest degree permitted by United States and
foreign patent laws, Patents for inventions relating to all aspects of Double
Stranded RNA are obtained and shared.

                                       15
<PAGE>
            (B) Isis will be responsible for preparing, filing, prosecuting,
maintaining and taking such other actions as are reasonably necessary or
appropriate with respect to the Isis Patent Rights.

            (C) Alnylam will be responsible for preparing, filing, prosecuting,
maintaining and taking such other actions as are reasonably necessary or
appropriate with respect to the Alnylam Patent Rights.

            (D) Each Party will endeavor in good faith to coordinate its efforts
with those of the other Party to minimize or avoid interference with the
prosecution of the other Party's Patents. Neither Party will initiate or
participate in any opposition, reexamination, interference, litigation or other
proceeding for the purpose of narrowing or invalidating any claim in a Patent of
the other Party. Promptly after the Effective Date, Isis shall discontinue its
participation in the opposition proceeding relating to the following Patent
Controlled by Alnylam: EP 1,144,623 (Inventors: R. Kreutzer and S. Limmer).

            (E) At either Party's request, the other Party will keep the
requesting Party continuously informed of and provide documentation of all
significant matters relating to the preparation, filing, prosecution and
maintenance of any designated Patent.

      11.3 Filing and Prosecution of Jointly Owned Patents.

            (A) The Research Management Committee will designate one of the
Parties as being the responsible Party for preparing, filing, prosecuting,
maintaining and taking such other actions as are reasonably necessary or
appropriate with respect to any Joint Patent.

            (B) Each Party will keep the other Party continuously informed of
all significant matters relating to the preparation, filing, prosecution and
maintenance of Joint Patents, and shall provide the other Party with copies of
any substantial prosecution papers within thirty days of receipt.

      11.4 Costs and Expenses.

            (A) Each Party will bear its own costs and expenses in filing,
prosecuting, maintaining and extending the Alnylam Patent Rights and Isis Patent
Rights, respectively.

            (B) The Parties will pay equal shares of all costs and expenses in
filing, prosecuting, maintaining and extending the Joint Patents.

      11.5 Enforcement.

            (A) Each Party will promptly advise the other of any suspected or
actual infringement of the Isis Patent Rights, Alnylam Patent Rights, or Joint
Patents by any person that reasonably affects the other Party's business. The
notice shall set forth the facts of such infringement or misappropriation in
reasonable detail.

            (B) Subject to subsections (c) and (h) below, Alnylam will have the
sole and exclusive right, in its sole discretion and at its expense, to assert
and enforce any Isis Patent Rights, Alnylam Patent Rights or Joint Patents
against any party engaging in an unlicensed or

                                       16
<PAGE>
unauthorized making, having made, using, selling, offering for sale or importing
of any allegedly infringing Double Stranded RNA.

            (C) For any enforcement by Alnylam under subsection (b) above that
includes Isis Patent Rights covering a [**], Isis will actively participate in
the planning and conduct of such enforcement and will take the lead of such
enforcement to the extent that the scope or validity of any such Isis Patent
Rights covering a [**] is at risk.

            (D) Except as set forth in Sections 11.5(b) and (h),

                  (I) Isis will have the sole and exclusive right, in its sole
discretion and at its expense, to assert and enforce any Isis Patent Rights;

                  (II) Alnylam will have the sole and exclusive right, in its
sole discretion and at its expense, to assert and enforce any Alnylam Patent
Rights; and

                  (III) The RMC will agree in advance on the enforcement of any
Joint Patent and will apportion enforcement responsibilities and recoveries
amongst the parties.

            (E) The rights granted hereunder to Alnylam to enforce certain
licensed in or jointly owned Isis Patent Rights are further limited as described
in Exhibit 5.3(d) attached to the Addendum Transmittal. The rights granted
hereunder to Isis to enforce certain licensed in or jointly owned Alnylam Patent
Rights are further limited as described in Exhibit 6.5(c) attached to the
Addendum Transmittal.

            (F) The nonenforcing Party will have the right, at its own expense,
to participate in the conduct of the enforcement action and to be represented in
such action by its own counsel.

            (G) The enforcing Party will not enter into any settlement that
impacts the scope or interpretation of any claim of any Joint Patent or of any
Patent of the nonenforcing Party without prior written authorization of the
nonenforcing Party.

            (H) If the Party with enforcement rights under section (b) or (d)
above (the "Enforcing Party") fails to initiate proceedings against any actual
or suspected infringement within [**] of receipt of written request for
enforcement from the other Party (the "Nonenforcing Party") and if the infringer
is directly competing with a Product (the "Affected Product") of such
Nonenforcing Party, then (i) if the license granted in this Agreement under
which the Nonenforcing Party is selling the Affected Product is exclusive or
co-exclusive, the Nonenforcing Party will have the right to assert and enforce
the patents that are allegedly being infringed, or (ii) if the license granted
in this Agreement under which the Nonenforcing Party is selling the Affected
Product is non-exclusive, the Nonenforcing Party [**] during the period [**];
provided that the provisions of the immediately preceding clause (ii) shall not
apply if the Enforcing Party elects to grant the Nonenforcing Party enforcement
rights with respect to such infringement. The Enforcing Party will not grant a
license to any such infringing Third Party with respect to any directly
competitive infringing product on terms materially more favorable (milestones
and royalties) than the terms of the license granted hereunder to the
Nonenforcing Party or, solely with

                                       17
<PAGE>
respect to the Affected Product, will adjust the terms of such license so that
they are not materially less favorable than the terms of the license granted to
the infringing Third Party.

            (I) Except as otherwise agreed to by the Parties as part of a
cost-sharing arrangement, any recovery realized as a result of such litigation,
after reimbursement of any reasonable litigation expenses of Isis and Alnylam,
shall be retained by the Party or Parties that brought and controlled such
litigation for purposes of this Agreement, except that any recovery realized as
a result of such litigation shall be treated as Net Sales of Isis Products or
Net Sales of Alnylam Products and distributed as such Net Sales would have been
distributed.

      11.6 Manufacturing Patents. All provisions relating to Manufacturing
Patents shall be governed by the Manufacturing Services Agreement.

      11.7 Third Party Patents. The Parties will consult about the need to
license any patents Controlled by Third Parties that would be useful or
necessary for either Party to research, develop, make, have made, use, sell,
offer for sale or import Double Stranded RNA Products. If it is agreed that
there is a desire to obtain a license or to acquire any such patent, the Parties
will negotiate in good faith regarding (i) the share of the financial
obligations relating to the license or acquisition that each Party will bear;
(ii) the compensation of any acquisition costs incurred in connection with
obtaining the Patent rights; and (iii) an agreement by the Parties to abide by
all terms of the agreement under which the patent rights are granted.

      11.8 Future Licenses. If after the Effective Date, a Party (the
"Controlling Party") later invents or acquires rights or title to an invention
claimed by a Patent that (i) would be included in the Isis Future Chemistry
Patents or Isis Future Motif and Mechanism Patents if such Party is Isis or in
the Alnylam Future Chemistry Patents or Alnylam Future Motif and Mechanism
Patents if such Party is Alnylam (the "Additional Rights") and (ii) carry
financial or other obligations, then the Controlling Party must promptly notify
the non-Controlling Party of such acquisition or invention. If the
non-Controlling Party wishes to include such Additional Rights under the
licenses granted pursuant to Article 5 or 6, as applicable, the non-Controlling
Party will notify the Controlling Party of its desire to do so and will assume
all financial and other obligations to the Controlling Party's licensors or
collaborators, if any, arising from the grant to the non-Controlling Party of
such license. Any Additional Rights that do not carry financial or other
obligations shall be automatically included under the licenses granted pursuant
to Article 5 or 6, as applicable. If a Party pays any upfront payments or
similar acquisition costs to access Additional Rights, the Parties will
negotiate in good faith regarding sharing such acquisition costs and payments.
When acquiring or creating such Additional Rights, each Party will endeavor in
good faith to secure the right to sublicense such Additional Rights to the other
Party.

                                   ARTICLE 12

                                       18
<PAGE>
                                 CONFIDENTIALITY

      12.1 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.

      12.2 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 any adjudicative body as required by law, provided that prior
to such disclosure, the Party subject to such disclosure obligation (the
"Notifying Party") promptly notifies the other Party of such requirement so that
such other Party can seek a protective order, confidential treatment or other
appropriate remedy; and provided, further, that in the event that no such
protective order, confidential treatment or other remedy is obtained, or that
such other Party waives compliance with this section, the Notifying Party will
furnish only that portion of the other Party's Confidential Information that it
is advised by counsel it is legally required to furnish;

            (C) to Affiliates, sublicensees, agents, consultants, and/or other
Third Parties for the development, manufacturing and/or marketing of Isis
Products or Alnylam Products (or for such parties to determine their interest in
performing such activities) in accordance with this Agreement on the condition
that such Affiliates, sublicensees and Third Parties agree to be bound by the
confidentiality obligations contained in this Agreement;

            (D) if such disclosure is required by law or regulation (including
without limitation by rules or regulations of any securities exchange or
NASDAQ), provided that prior to such disclosure, the Notifying Party promptly
notifies the other Party of such requirement so that such other Party can seek a
protective order, confidential treatment or other appropriate remedy; and
provided, further, that in the event that no such protective order, confidential
treatment or other remedy is obtained, or that such other Party waives
compliance with this section, the Notifying Party will furnish only that portion
of the other Party's Confidential Information that it is advised by counsel it
is legally required to furnish; or

            (E) as necessary if embodied in products to develop and
commercialize such products.

Either Party may disclose (i) a copy of this Agreement on a confidential basis
to prospective lenders and investors, (ii) a mutually agreed upon redacted copy
of this Agreement on a confidential basis to prospective collaborators and (iii)
the terms of this Agreement as required under applicable securities laws or
regulations (including without limitation under rules or regulations of any
securities exchange or NASDAQ); provided, however, that,

                                       19
<PAGE>
subject to Section 6.4(i), Alnylam shall not disclose Isis' past or current
Reserved Targets without the express prior written consent of Isis.

      12.3 Announcements; Publicity.

      (A) Each Party understands that this Agreement is likely to be of
significant interest to investors, analysts and others, and that either Party
therefore may make public announcements with respect to this Agreement. The
Parties agree that any such announcement will not contain confidential business
or technical information unless disclosure of confidential business or technical
information is required by law or regulation, in which case they will make
reasonable efforts to minimize such disclosure of confidential business or
technical information to that required by law or regulation. Each Party agrees
to provide to the other Party a copy of any such public announcement as soon as
reasonably practicable under the circumstances prior to its scheduled release.
Except under extraordinary circumstances, each Party shall provide the other
with an advance copy of any press release at least two (2) business days prior
to the scheduled disclosure. The other Party shall have the right to
expeditiously review and recommend changes to any announcement regarding this
Agreement or the subject matter of this Agreement, provided that such right of
review and recommendation shall only apply for the first time that specific
information is to be disclosed, and shall not apply to the subsequent disclosure
of information that (i) is substantially similar to a previously reviewed
disclosure and (ii) in the context of the subsequent disclosure, does not carry
a substantially different qualitative message than that carried by the
previously reviewed disclosure. The Party whose press release has been reviewed
shall in good faith consider any changes that are timely recommended by the
reviewing Party.

      (B) Each Party will (i) use reasonable, good faith efforts to provide the
other Party with at least 5 business days' prior notice (which notice may be
given orally to a senior executive officer of the other Party) before such Party
publicly announces the execution of a Naked Sublicense, Bona Fide Drug Discovery
Collaboration agreement or Development Collaboration agreement (or any material
amendments thereto) that could reasonably be expected to be of strategic or
financial importance to the other Party's business and (ii) cooperate with the
other Party to enable the other Party to develop appropriate mutually beneficial
public announcements regarding such transactions.

                                   ARTICLE 13

                                 INDEMNIFICATION

      13.1 Indemnification by Alnylam. Alnylam 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 expense
(including reasonable attorneys' fees) arising out of Third Party claims or
suits related to (a) Alnylam's performance of its obligations under this
Agreement; (b) breach by Alnylam of its representations and warranties set forth
in Article 15; or (c) the discovery, development, manufacture, use, importation
or commercialization (including marketing and sale) of Alnylam Products.

                                       20
<PAGE>
      13.2 Indemnification by Isis. Isis will indemnify, defend and hold Alnylam
and its Affiliates and each of their respective agents, employees, officers and
directors (the "Alnylam Indemnitees") harmless from and against any and all
liability, damage, loss, cost or expense (including reasonable attorneys' fees)
arising out of Third Party claims or suits related to (a) Isis' performance of
its obligations under this Agreement; (b) breach by Isis of its representations
and warranties set forth in Article 15; or (c) the discovery, development,
manufacture, use, importation or commercialization (including marketing and
sale) of Isis Products.

      13.3 Notification of Claims; Conditions to Indemnification Obligations. A
Party entitled to indemnification under this Article 13 shall (a) promptly
notify the other Party as soon as it becomes aware of a claim or action for
which indemnification may be sought pursuant hereto, (b) cooperate with the
indemnifying Party in the defense of such claim or suit, and (c) permit the
indemnifying Party to control the defense of such claim or suit, including
without limitation the right to select defense counsel; provided that if the
Party entitled to indemnification fails to promptly notify the indemnifying
Party pursuant to the foregoing clause (a), the indemnifying Party shall only be
relieved of its indemnification obligation to the extent prejudiced by such
failure. 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, or which imposes obligations on the indemnified Party
other than financial obligations that are covered by the indemnifying Party's
indemnification obligation, without the prior written consent of the indemnified
Party. The indemnifying Party will have no liability under this Article 13 with
respect to claims or suits settled or compromised without its prior written
consent.

                                   ARTICLE 14

                        TERM AND TERMINATION OF AGREEMENT

      14.1 Term and Termination of Agreement. This Agreement will be effective
as of the Effective Date and unless terminated earlier pursuant to Sections 14.2
or 14.3 below, the term of this Agreement will continue in effect until
expiration of the License Term.

      14.2 Termination upon Material 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 material breach of its obligations
hereunder and has not cured such breach within 90 days after written notice
requesting cure of the breach; provided, however, that (a) in the event of a
good faith dispute with respect to the existence of such a material breach, the
90-day cure period will be stayed until such time as the dispute is resolved
pursuant to Section 17.6 hereof, (b) so long as the breaching Party takes
substantial steps to cure the breach promptly after receiving notice of the
breach from the non-breaching Party and thereafter diligently prosecutes the
cure to completion as soon as is practicable, the non-breaching Party may not
terminate this Agreement, and (c) any license granted under this Agreement with
respect to an Isis or Alnylam Product that has at least reached IND-Enabling
Studies may not be terminated for a material breach under this Section 14.2
(except for an uncured failure to make any undisputed portion of any payment
obligation under Article 7 or

                                       21
<PAGE>
8 with respect to such Isis or Alnylam Product) to the extent such license is
necessary to develop, make and have made, sell and import such Isis or Alnylam
Product.

      14.3 Termination upon Bankruptcy; Rights in Bankruptcy.

            (A) This Agreement may be terminated with written notice by either
Party at any time during the term of this Agreement upon the filing or
institution of bankruptcy, reorganization, liquidation or receivership
proceedings by or against the other Party or upon an assignment of a substantial
portion of its assets for the benefit of creditors by the other Party; provided,
however, in the case of any involuntary bankruptcy proceeding such right to
terminate will only become effective if the Party consents to the involuntary
bankruptcy or such proceeding is not dismissed within 90 days of the filing
thereof.

            (B) All rights and licenses granted under or pursuant to this
Agreement by Isis or Alnylam 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 therefore, 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 therefore by the non-subject Party.

      14.4 Accrued Rights and Surviving Obligations.

            (A) Expiration or termination of the Agreement will not relieve the
Parties of any obligation accruing prior to such expiration or termination,
including, but not limited to, financial obligations under Article 7 or 8.
Sections 9.2, 9.3 and 11.1, and Articles 1, 12, 13, 14 and 17 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. No
expiration of this Agreement will relieve a Party of its obligation to pay
milestones, royalties, or a percentage of Technology Access Fees or Sublicense
Revenue.

            (B) The rights of any sublicensee under any permitted sublicense
granted in accordance with Section 5.2 or 6.3 will survive the termination of
this Agreement.

                                       22
<PAGE>
                                   ARTICLE 15

                   REPRESENTATIONS AND WARRANTIES; DISCLAIMER

      15.1 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 of 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 sufficient right, power and authority to enter
into this Agreement, to perform its obligations under this Agreement and to
grant the licenses granted hereunder.

      15.2 Disclaimers. 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 16

                                     NOTICE

      16.1 Notice. All notices which are required or permitted hereunder will be
in writing and sufficient if delivered personally, sent by facsimile (and
confirmed by telephone), sent by nationally-recognized overnight courier or sent
by registered or certified mail, postage prepaid, return receipt requested,
addressed as follows:

<TABLE>
<S>                             <C>
            if to Isis, to:     Isis Pharmaceuticals, Inc.
                                Carlsbad Research Center
                                2292 Faraday Avenue
                                Carlsbad, CA 92008
</TABLE>


                                         23
<PAGE>

<TABLE>
<S>                             <C>
                                Attention:  Executive Vice President
                                Fax No.: +1 (760) 603-4652

            with a copy to:     Attention: General Counsel
                                Fax No.: +1 (760) 268-4922

            if to Alnylam, to:  Alnylam Pharmaceuticals, Inc.
                                790 Memorial Drive, Suite 202
                                Cambridge, MA  02139
                                Attention:  President
                                Fax No.: +1 (617) 252-0011

            with a copy to:     Hale and Dorr LLP
                                60 State Street
                                Boston, Massachusetts 02109
                                Attention:  Steven D. Singer, Esq.
                                Fax No.: +1 (617) 526-5000
</TABLE>

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.

                                   ARTICLE 17

                            MISCELLANEOUS PROVISIONS

      17.1 Relationship of the Parties. It is expressly agreed that Isis and
Alnylam will be independent contractors and that the relationship between the
two Parties will not constitute a partnership, joint venture or agency. Neither
Isis nor Alnylam 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.

      17.2 Successors and Assigns.

            (A) Neither this Agreement nor any interest hereunder may be
assigned or otherwise transferred (whether by sale of stock, sale of assets or
merger), 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 a Party may,
without such consent, assign this Agreement and its rights and obligations
hereunder to an Affiliate or in connection with an Acquisition.

            (B) Notwithstanding the provisions of Section 17.2(a), if Alnylam is
the subject of an Acquisition [**] after the time of the Acquisition, then [**].

            (C) Notwithstanding the provision of Section 17.2(a), if Isis is the
subject of an Acquisition, [**] such Acquisition [**].


                                       24
<PAGE>
            (D) Any permitted assignee will assume all obligations of its
assignor under this Agreement. Any attempted assignment not in accordance with
this Section 17.2 will be void.

      17.3 Entire Agreement; Amendments. This Agreement, together with the
Equity Documents, contains the entire understanding of the Parties with respect
to the license, development and commercialization of Products 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. This Agreement may be amended, or any term hereof
modified, only by a written instrument duly executed by both Parties hereto.

      17.4 Force Majeure. Neither Party will be held liable or responsible to
the other Party nor be deemed to have defaulted under or breached this Agreement
for failure or delay in fulfilling or performing any term of this 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,
acts of terrorism, 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.

      17.5 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.

      17.6 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:

<TABLE>
<S>                           <C>
            For Isis:         Executive Vice President
            For Alnylam:      Senior Vice President of Business Development
</TABLE>

If the dispute is not resolved as provided above, the President of Isis and the
President of Alnylam will meet for attempted resolution by good faith
negotiations within 15 days after the expiration of the preceding 30 day period.

            (B) In the event the designated executive officers are not able to
resolve such dispute during such 15-day period, then any such dispute shall be
resolved through binding arbitration under the Commercial Arbitration Rules of
the American Arbitration Association by a panel of three arbitrators appointed
in accordance with such rules. The Parties shall be entitled to the same
discovery as permitted under the U.S. Federal Rules of Civil Procedure; provided
that the panel shall be entitled in its discretion to grant a request


                                       25
<PAGE>
from a Party for expanded or more limited discovery. The award of the
arbitrators shall be the sole and exclusive remedy between the Parties regarding
any such dispute. An award rendered in connection with an arbitration pursuant
to this Section 17.6 shall be final and binding upon the Parties and any
judgment upon such award may be entered and enforced in any court of competent
jurisdiction. Any arbitration pursuant to this Section 17.6 shall be conducted
in San Diego, California if Alnylam initiates the arbitration or in Boston,
Massachusetts if Isis initiates the arbitration. Nothing in this Section 17.6
shall be construed as limiting in any way the right of a Party to seek an
injunction or other equitable relief with respect to any actual or threatened
breach of this Agreement or to bring an action in aid of arbitration. Should any
Party seek an injunction or other equitable relief, or bring an action in aid of
arbitration, then for purposes of determining whether to grant such injunction
or other equitable relief, or whether to issue any order in aid of arbitration,
the dispute underlying the request for such injunction or other equitable
relief, or action in aid of arbitration, may be heard by the court in which such
action or proceeding is brought.

      17.7 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.

      17.8 Captions. The captions to the several Articles and Sections hereof
are not a part of this Agreement, but are merely a convenience to assist in
locating and reading the several Articles and Sections hereof.

      17.9 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.

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

      17.11 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.

      17.12 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


                                       26
<PAGE>
Agreement. Accordingly, the rule of construction that any ambiguity in this
Agreement will be construed against the drafting Party will not apply.

      17.13 Counterparts. This 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.

      17.14 Performance by Affiliates. To the extent that this Agreement imposes
obligations on Affiliates of a Party, such Party agrees to cause its Affiliates
to perform such obligations.

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

<TABLE>
<S>                                       <C>
ISIS PHARMACEUTICALS, INC.                ALNYLAM PHARMACEUTICALS, INC.

By: /s/ B. Lynne Parshall                 By: /s/ Vincent J. Miles
    --------------------------------         ---------------------------------

Name: B. Lynne Parshall                   Name: Vincent J. Miles
     -------------------------------           -------------------------------

Title:  Executive Vice President          Title: Senior Vice President,
      ------------------------------            ------------------------------
                                                 Business Development
                                                ------------------------------
</TABLE>


                                       27
<PAGE>
                                   EXHIBIT 1.1

                                   DEFINITIONS

1.    "Acquisition" means any of the following events: (a) the acquisition by
      any Person or group, other than a Person or group controlling such Party
      as of the Effective Date, of "beneficial ownership" (as defined in Rule
      13d-3 under the United States Securities Exchange Act of 1934, as
      amended), directly or indirectly, of fifty percent (50%) or more of the
      shares of such Party's voting stock; (b) the approval by the shareholders
      of such Party of a merger, share exchange, reorganization, consolidation
      or similar transaction of such Party (a "Transaction"), other than a
      Transaction which would result in the voting stock of such Party
      outstanding immediately prior thereto continuing to represent (either by
      remaining outstanding or by being converted into voting securities of the
      surviving entity) more than fifty percent (50%) of the voting stock of
      such Party or such surviving entity immediately after such Transaction; or
      (c) approval by the shareholders of such Party of a complete liquidation
      of such Party or a sale or disposition of all or substantially all of the
      assets of such Party.

2.    "Active Program" means with respect to a Gene Target, [**] directed to
      such Gene Target.

3.    "Affiliate" with respect to either Party means Person controlling,
      controlled by, or under common control with such Party. For purposes of
      this definition, "control" refers to the possession, directly or
      indirectly, of the power to direct the management or policies of a Person,
      whether through the ownership of voting securities, by contract or
      otherwise, of a Person.

4.    "Alnylam Current Chemistry Patents" means all Chemistry Patents Controlled
      by Alnylam as of the Effective Date, including without limitation the
      Patents listed on Schedule 1-4 attached to the Addendum Transmittal,
      except Patents that constitute Alnylam Excluded Technology.

5.    "Alnylam Current Motif and Mechanism Patents" means all Motif and
      Mechanism Patents Controlled by Alnylam as of the Effective Date,
      including without limitation the Patents listed on Schedule 1-5 attached
      to the Addendum Transmittal, except Patents that constitute Alnylam
      Excluded Technology.

6.    "Alnylam Excluded Technology" means inhibitors to specific genes or gene
      families, manufacturing and analytical technologies, formulation and
      delivery technologies and the specific technology listed on Schedule 1-6
      attached to the Addendum Transmittal.

7.    "Alnylam Future Chemistry Patents" means all Chemistry Patents Controlled
      by Alnylam after the Effective Date and having an earliest priority date
      of no later than [**] years from the Effective Date or that is necessary
      to practice a Patent licensed hereunder; provided, however that (a) for
      any such Chemistry Patents


                                       28
<PAGE>
      that are acquired, licensed or invented that include financial or other
      obligations to a Third Party, the provisions of Section 11.8 will govern
      whether such Patent will be included as an Alnylam Future Chemistry Patent
      and (b) Alnylam Future Chemistry Patents do not include Patents that
      constitute Alnylam Excluded Technology.

8.    "Alnylam Future Motif and Mechanism Patents" means all Motif and Mechanism
      Patents Controlled by Alnylam after the Effective Date and having an
      earliest priority date of no later than [**] years from the Effective Date
      or that is necessary to practice a Patent licensed hereunder; provided,
      however that (a) for any such Motif and Mechanism Patents that are
      acquired, licensed or invented that include financial or other obligations
      to a Third Party, the provisions of Section 11.8 will govern whether such
      Patent will be included as an Alnylam Future Motif and Mechanism Patent
      and (b) Alnylam Future Motif and Mechanism Patents do not include Patents
      that constitute Alnylam Excluded Technology.

9.    "Alnylam Patent Rights" means Alnylam Current Motif and Mechanism Patents,
      Alnylam Future Motif and Mechanism Patents, Alnylam Current Chemistry
      Patents and Alnylam Future Chemistry Patents.

10.   "Alnylam Product" means a Double Stranded RNA Product or MicroRNA Product
      discovered or developed by Alnylam, its Affiliates or sublicensees, the
      manufacture, sale or use of which is covered by a Valid Claim within the
      Isis Patent Rights.

11.   "Antisense Drug Discovery Program" means an antisense drug discovery
      program that investigates multiple different mechanisms of modulating a
      Gene Target to identify a drug candidate, with a predominant emphasis on
      potential drug candidates that are single-stranded.

12.   "Bona Fide Drug Discovery Collaboration" means a collaboration involving
      the discovery and development of Double Stranded RNA Products in which a
      Party plays an integral role in the experimentation and an important,
      though not necessarily dominant or co-equal, role in the decision-making,
      relating to the discovery and development of Double Stranded RNA Products
      from the point in time at which the relevant Gene Target has been
      designated through [**]. A Bona Fide Drug Discovery Collaboration may
      continue beyond [**]. For Isis Products that are Double Stranded RNA
      Products, a Bona Fide Drug Discovery Collaboration must be an Antisense
      Drug Discovery Program. For each Party, collaborations that do not include
      or involve Patents licensed from the other Party hereunder shall not
      constitute Bona Fide Drug Discovery Collaborations. A Party's
      experimentation relating to the discovery and development of Double
      Stranded RNA Products that modulate a relevant Gene Target prior to the
      commencement of a collaboration shall be deemed to have been conducted in
      the course of the collaboration for purposes of determining whether the
      collaboration is a Bona Fide Drug Discovery Collaboration. A series of
      related collaborations and/or license agreements involving the discovery
      and development of Double


                                       29
<PAGE>
      Stranded RNA Products with the same sublicensee or related sublicensees
      that includes a Bona Fide Drug Discovery Collaboration agreement will be
      aggregated to constitute a single Bona Fide Drug Discovery Collaboration.

13.   "Chemistry Patent" means any Patent that covers (a) an oligomeric compound
      having a chemical composition that differs from a native oligonucleotide
      composition or (b) any modification to the base, sugar or internucleoside
      linkage of the oligomeric compound, and specifically, but without
      limitation, includes covalently linked conjugates and other such moieties.

14.   "Commercially Reasonable Efforts" means the diligent efforts, expertise
      and resources normally used by a Party to develop, manufacture and
      commercialize a product or compound owned by it or to which it has rights,
      which is of similar market potential at a similar stage in its development
      or product life, taking into account issues of safety, and efficacy,
      product profile, difficulty in developing the product or compound,
      competitiveness of the marketplace for the product, the proprietary
      position of the compound or product, the regulatory structure involved,
      the potential total profitability of the applicable product(s) marketed or
      to be marketed and other relevant factors affecting the cost, risk and
      timing of development and the total potential reward to be obtained if a
      product is commercialized, but not less than reasonably diligent efforts.
      In determining whether Commercially Reasonable Efforts have been
      satisfied, the fact that a Party is required to pay the other Party a
      royalty or milestones shall not be a factor weighed (i.e., a Party may not
      apply lesser resources or effort to a Product because it must pay a
      royalty or milestones to the other Party).

15.   "Control" or "Controlled" means, with respect to any Patent or other
      intellectual property right, possession of the right (whether by
      ownership, license or otherwise), to assign, or grant a license,
      sublicense or other right to or under, such Patent or right as provided
      for herein without violating the terms of any agreement or other
      arrangement with any Third Party.

16.   "Confidential Information" means information which is (a) of a
      confidential and proprietary nature; and (b) 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 includes, without limitation, (x) 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 (y) 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:


                                       30
<PAGE>
      (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; or

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

17.   "Development Collaboration" means a collaboration by either Party with a
      Third Party whose purpose is the further development and/or
      commercialization of a Double Stranded RNA Product and that begins at or
      after the initiation of IND-Enabling Studies for such Product. For each
      Party, collaborations that do not include or involve Patents licensed from
      the other Party hereunder shall not constitute Development Collaborations.

18.   "Double Stranded RNA" means a composition designed to act primarily
      through an RNAi mechanism that is not a MicroRNA Construct and which
      consists of either (a) two separate oligomers of native or chemically
      modified RNA that are hybridized to one another along a substantial
      portion [**] of their lengths, or (b) a single oligomer of native or
      chemically modified RNA that is hybridized to itself by self-complementary
      base-pairing along a substantial portion [**] of its length to form a
      hairpin.

19.   "Double Stranded RNA Product" means a pharmaceutical composition that
      contains a Double Stranded RNA.

20.   "Equity Documents" means the Series D Convertible Preferred Stock Purchase
      Agreement and the Investor Rights Agreement by and between the Parties
      executed as of the Effective Date.

21.   "Gene Target" means a transcriptional unit of a gene, including any
      protein product of such transcriptional unit, and including all splice
      variants.

22.   "IND" means an Investigational New Drug Application or similar foreign
      application or submission for approval to conduct human clinical
      investigations.

23.   "IND-Enabling Studies" means the pharmacokinetic and toxicology studies
      required to meet the regulations for filing an IND.

24.   "Initiation of Phase I Trial" means the dosing of the first patient in the
      first human clinical trial conducted and designed to evaluate safety of a
      product.


                                       31
<PAGE>
25.   "Initiation of Phase III Trial" means the dosing of the first patient in
      the first pivotal human clinical trial the results of which could be used
      to establish safety and efficacy of a Product as a basis for an
      application for marketing approval or that would otherwise satisfy the
      requirements of 21 CFR 3 12.21I or its foreign equivalent.

26.   "Isis Co-Exclusive Target" has the meaning set forth in Section 6.4(b).

27.   "Isis Current Chemistry Patents" means all Chemistry Patents Controlled by
      Isis as of the Effective Date, including without limitation the Patents
      listed on Schedule 1-27 attached to the Addendum Transmittal, except
      Patents that constitute Isis Excluded Technology.

28.   "Isis Current Motif and Mechanism Patents" means all Motif and Mechanism
      Patents Controlled by Isis as of the Effective Date, including without
      limitation the Patents listed on Schedule 1-28 attached to the Addendum
      Transmittal, except Patents that constitute Isis Excluded Technology.

29.   "Isis Encumbered Target" means a Gene Target (a) to which Isis has a
      contractual obligation to a Third Party existing as of the Effective Date
      that precludes Isis from granting a license under Section 5 with respect
      to such Gene Target and (b) [**]. When and if such restrictions lapse a
      Gene Target will cease to be an Isis Encumbered Target.

30.   "Isis Excluded Technology" means (a) RNase H mechanisms, RNase H motifs
      and RNase H oligonucleotides when utilized in an RNase H mechanism, assays
      and methods thereof; (b) modulators of specific genes, gene families or
      proteins; (c) manufacturing technologies; (d) analytical technologies,
      kits and assays, including without limitation methods, systems and
      compositions of matter for amplifying, quantifying, detecting,
      characterizing or identifying nucleic acids or nonoligomeric ligands
      thereto; (e) formulation and delivery technologies; and (f) the specific
      technology listed on Schedule 1-30 attached to the Addendum Transmittal.

31.   "Isis Exclusive Target" has the meaning set forth in Section 6.4(b).

32.   "Isis Future Motif and Mechanism Patents" means all Motif and Mechanism
      Patents Controlled by Isis after the Effective Date and having an earliest
      priority date of no later than [**] years from the Effective Date or that
      is necessary to practice a Patent licensed hereunder; provided, however
      that (a) for any such Motif and Mechanism Patents that are acquired,
      licensed or invented that include financial or other obligations to a
      Third Party, the provisions of Section 11.8 will govern whether such
      Patent will be included as an Isis Future Motif Mechanism Patent and (b)
      Isis Future Motif and Mechanism Patents do not include Patents that
      constitute Isis Excluded Technology.

33.   "Isis Future Chemistry Patents" means the Chemistry Patents Controlled by
      Isis after the Effective Date and having an earliest priority date of no
      later than [**]


                                       32
<PAGE>
      years from the Effective Date or that is necessary to practice a Patent
      licensed hereunder; provided, however that (a) for any such Chemistry
      Patents that are acquired, licensed or invented that include financial or
      other obligations to a Third Party, the provisions of Section 11.8 will
      govern whether such Chemistry Patents will be included as an Isis Future
      Chemistry Patent, except Patents that constitute Isis Excluded Technology
      and (b) Isis Future Chemistry Patents do not include Patents that
      constitute Isis Excluded Technology.

34.   "Isis Manufacturing Patents" means the Patents specifically listed on
      Schedule 1-34 attached to the Addendum Transmittal. The Parties may agree
      in writing from time to time to add additional Patents to Schedule 1-34
      attached to the Addendum Transmittal.

35.   "Isis Patent Rights" means Isis Current Motif and Mechanism Patents, Isis
      Future Motif and Mechanism Patents, Isis Current Chemistry Patents and
      Isis Future Chemistry Patents.

36.   "Isis Product" means any Isis Single Stranded Product, MicroRNA Product or
      Double Stranded RNA Product, discovered or developed by Isis, its
      Affiliates or sublicensees, the manufacture, sale or use of which is
      covered by a Valid Claim within the Alnylam Patent Rights.

37.   "Isis Single Stranded Product" means any single stranded oligomeric
      compound (a) that hybridizes in whole or in part with a target RNA and
      modulates the Gene Target, (b) is not a Double Stranded RNA or Double
      Stranded RNA Product and (c) the manufacture, sale or use of which is
      covered by a Valid Claim within the Alnylam Patent Rights.

38.   "Joint Invention" has the meaning set forth in Section 11.1(b).

39.   "Joint Patent" has the meaning set forth in Section 11.1(b).

40.   "Know-How" means all tangible or intangible know-how, discoveries,
      processes, formulas, data, clinical and preclinical results, non-Patented
      Inventions, Inventions for which Patents are in preparation, trade
      secrets, and any physical, chemical, or biological material or any
      replication of any such material in whole or in part that are not
      otherwise covered by the Isis Patent Rights or the Alnylam Patent Rights

41.   "License Term" means the period from the Effective Date until the date of
      expiry of the last to expire of the Patents licensed hereunder.

42.   "Major Pharmaceutical Company" means a Person that, together with all of
      its affiliated Persons, had annual pharmaceutical product sales during the
      most recently completed calendar year in excess of $[**].

43.   "Manufacturing Services Agreement" has the meaning set forth in Section
      3.1.


                                       33
<PAGE>
44.   "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, EC Approval, and Japanese Approval.

45.   "MicroRNA Construct" is a construct having the chemical and physical
      description of a Double Stranded RNA that is either (a) designed to target
      a[**]precursor microRNA or a microRNA, thereby to inhibit the production
      or function of the microRNA, or (b) designed to function by mimicking the
      translational repressor function of a naturally occurring microRNA, and
      which, in relation to its target RNA, has been demonstrated in vitro and,
      to the extent reasonably feasible, in vivo, to function solely as a
      translational repressor and not via cleavage of such target RNA.

46.   "MicroRNA Product" means a pharmaceutical product that contains a MicroRNA
      Construct.

47.   "Motif and Mechanism Patents" means any Patent that covers an oligomeric
      structure or composition of matter, or any method of using or
      incorporating such oligomeric structure or composition of matter in vitro
      or in vivo, including without limitation for therapeutic use, in which
      target RNA levels are modulated by any mechanism other than RNase H.

48.   "Naked Sublicense" means a license for Double Stranded RNA that includes
      rights to the Isis Patent Rights that is not a license in connection with
      (a) a Development Collaboration or (b) a Bona Fide Drug Discovery
      Collaboration. A series of Naked Sublicenses to the same sublicensee or
      related sublicensees will be aggregated to constitute a single Naked
      Sublicense. For the avoidance of doubt, where this Agreement grants
      Alnylam exclusive rights to grant Naked Sublicenses, such exclusive rights
      preclude Isis from granting licenses to the Isis Patent Rights to Third
      Parties for Double Stranded RNA even though such license grants by Isis
      would technically be license grants and not sublicense grants. Licenses
      that do not include or involve rights to Isis Patents shall not constitute
      Naked Sublicenses.

49.   "Naked Sublicensee" means a Third Party that obtains a Naked Sublicense
      from Alnylam in accordance with the terms of this Agreement.

50.   "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.

51.   "Net Sales" will mean the gross invoice price of Products sold by Alnylam
      or Isis (as applicable), their respective Affiliates and sublicensees (but
      with respect to Alnylam does not include Naked Sublicensees) to a Third
      Party less the following items: (i) trade discounts, credits or
      allowances, (ii) credits or allowances additionally granted upon returns,
      rejections or recalls, (iii) freight, shipping and insurance charges, (iv)
      taxes, duties or other governmental tariffs (other than


                                       34
<PAGE>
      income taxes) and (v) government-mandated rebates and (vi) [**]. Except in
      the cases of Products used to conduct clinical trials, [**] or similar
      uses, a Party, its Affiliates or sublicensees will be treated as having
      sold Products for an amount equal to the fair market value of Products if:
      (a) Products are used by such Party, its Affiliates or sublicensees
      without charge or provision of invoice, or (b) Products are provided to a
      Third Party by such Party, its Affiliates or sublicensees without charge
      or provision of invoice and used by such third party.

      In the event the Product is sold as part of a Combination Product (as
      defined below), the Net Sales from the Combination Product, for the
      purposes of determining royalty payments, shall be determined by
      multiplying the Net Sales (as determined without reference to this
      paragraph) of the Combination Product, during the applicable royalty
      reporting period, by the fraction, A/A+B, where A is the average sale
      price of the Product when sold separately in finished form and B is the
      average sale price of the other product(s) included in the Combination
      Product when sold separately in finished form, in each case during the
      applicable royalty reporting period or, if sales of both the Product and
      the other product(s) did not occur in such period, then in the most recent
      royalty reporting period in which sales of both occurred. In the event
      that such average sale price cannot be determined for both the Product and
      all other products(s) included in the Combination Product, Net Sales for
      the purposes of determining royalty payments shall be calculated by
      multiplying the Net Sales of the Combination Product by the fraction of
      C/C+D where C is the fair market value of the Product and D is the fair
      market value of all other product(s) included in the Combination Product.
      As used above, the term "Combination Product" means any pharmaceutical
      product which consists of a Product and other therapeutically active
      pharmaceutical compound or any delivery technology that embodies
      substantial intellectual property rights Controlled by the selling Party
      (e.g., a common syringe would not constitute a delivery technology that
      embodies substantial intellectual property rights Controlled by the
      selling Party, but an implantable delivery device such as a stent would
      constitute such a delivery technology).

52.   "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 based on,
      corresponding to, or claiming the priority date(s) of any of the
      foregoing; (d) any substitutions, extensions (including supplemental
      protection certificates), registrations, confirmations, reissues,
      divisionals, continuations, continuations-in-part, re-examinations,
      renewals and foreign counterparts thereof; and (e) all patents claiming
      overlapping priority therefrom.

53.   "Person" means any person, organization, corporation or other business
      entity.

54.   "Product" means either an Alnylam Product or an Isis Product as the case
      may be.

55.   "Regulatory Authority" means any applicable government regulatory
      authority involved in granting approvals for the marketing and/or pricing
      of a Product


                                       35
<PAGE>
      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.

56.   "Research Use" means discovering, developing and optimizing an Alnylam
      Product or an Isis Product, as applicable, up to, but not including, [**],
      and/or conducting pilot manufacturing studies of an Alnylam Product or an
      Isis Product, as applicable. Research Use may include small pilot
      toxicology studies. With respect to Isis, Research Use does not include
      studies [**] for potential drug targets, but does include studies [**] for
      development of Double Stranded RNA Products from among potential targets
      for which a reasonable scientific basis exists for believing that such
      potential targets are associated with a particular disease or condition.

57.   "Reserved Target" has the meaning set forth in Section 6.4(a).

58.   "Series D Preferred Stock" means Series D Convertible Preferred Stock of
      Alnylam as further defined in the Equity Documents.

59.   "Sublicense Revenue" means any payments that Alnylam receives from a
      sublicensee in consideration of a Naked Sublicense, including, but not
      limited to, license fees, royalties, milestone payments, and license
      maintenance fees, but excluding: (i) payments made in consideration of
      equity or debt securities of Alnylam at fair market value and (ii)
      payments specifically committed to reimburse Alnylam for the
      fully-burdened cost of research and development. If Alnylam receives any
      non-cash Sublicense Revenue, Alnylam will pay Isis, at Isis' election,
      either (x) a cash payment equal to the fair market value of Isis'
      appropriate portion of the Sublicense Revenue or (y) the in-kind portion,
      if practicable, of the Sublicense Revenue.

60.   "Technology Access Fee" means any payments that Alnylam receives from
      granting a Third Party access (through sublicense or otherwise) to the
      Isis Patent Rights as part of a Bona Fide Collaboration or Development
      Collaboration agreement, including, but not limited to, [**], but
      excluding the following payments: (i) payments [**], (ii) payments [**],
      (iii) payments [**], including without limitation [**], (iv) [**]
      payments, (v) payments [**], and (vi) payments [**]. If Alnylam receives
      any non-cash Technology Access Fees, Alnylam will pay Isis, at Isis'
      election, either (x) a cash payment equal to the fair market value of
      Isis' appropriate portion of the Technology Access Fee or (y) the in-kind
      portion, if practicable, of the Technology Access Fee.

61.   "Third Party" means any party other than Isis or Alnylam and their
      respective Affiliates.

62.   "Valid Claim" means (i) an issued claim of an unexpired Patent that has
      not been withdrawn, canceled or disclaimed, or held invalid or
      unenforceable by a court of competent jurisdiction in an unappealed or
      unappealable decision, or (ii) a claim


                                       36
<PAGE>
      of a patent application which has been pending for less than [**] years
      from the earliest priority date for such application.


                                       37
<PAGE>
                                 EXHIBIT 6.5(D)

          DESCRIPTION OF POTENTIAL PASS-THROUGH AMOUNTS PAYABLE TO [**]

The passages shown below are excerpted from the License Agreement between [**]
and Alnylam Pharmaceuticals, Inc. dated [**]. These passages were selected to
provide Isis with sufficient information to understand its potential obligation
to [**]pursuant to Section 6.5(d) of the Agreement.

DEFINITIONS

2.5   "Licensed Field of Use" means delivery of ex-vivo synthesized siRNA
      Molecules for research, development and therapeutic uses (including a
      diagnostic necessary for development, sale or reimbursement of a
      therapeutic Licensed Product). The Licensed Field of Use specifically
      excludes delivery of any system producing in vivo expressed siRNAs for
      therapeutic use, including but not limited to episomal and integrated
      vectors, and recombinant viruses.

2.7   "Co-Exclusive" means that, subject to Article 4, [**] will only grant one
      further license in the Licensed Territory in the Licensed Field of Use.

GRANT

3.2   CO-EXCLUSIVITY. The license is Co-Exclusive, including the right to
      sublicense pursuant to Article 13, in the Licensed Field of Use for a term
      beginning on the Effective Date, and ending, on a country-by-country
      basis, on the expiration of the last to expire of Licensed Patents.

3.4   EXCLUSIVITY.

      (A)   If the other Co-Licensee discontinues licensing this Field of Use,
            then the Field of Use will become exclusive for Alnylam.

      (B)   If the other Co-Licensee discontinues any other therapeutic license
            under the Licensed Patents, [**] shall so inform Alnylam and Alnylam
            shall have the option to obtain an exclusive, worldwide
            sublicensable license to such therapeutic field. The terms of any
            such license shall be negotiated in good faith by [**] and Alnylam.
            This option may be exercised by Alnylam by written notice to [**] at
            any time during a period of ninety (90) days after notification by
            [**].

ROYALTIES

6.3   EARNED ROYALTY. In addition, Alnylam will pay [**] earned royalties on Net
      Sales as follows:

      (A)   [**]% of Net Sales for a Licensed Product subject to the following;.


                                       38
<PAGE>
      (B)   Such royalty payments shall be reduced up to [**]% (from [**]% of
            Net Sales down to [**]% of Net Sales) by the amount of royalty paid
            to access additional intellectual property necessary in order to
            sell Licensed Products ("Additional Earned Royalties").

      (C)   Such royalty payments shall be reduced as follows:

            (1)   [**]% if Additional Earned Royalties are [**]% or less.

            (2)   [**]% if Additional Earned Royalties are greater than [**]%
                  but less than [**]%.

            (3)   [**]% if Additional Earned Royalties are equal to or greater
                  than [**]% but less than [**]%.

            (4)   [**]% if Additional Earned Royalties are equal to or greater
                  than [**]% but less than [**]%.

            (5)   [**]% if Additional Earned Royalties are equal to or higher
                  than [**]%.

      (D)   Only one royalty is due on each Licensed Product sold by Alnylam or
            its sublicensees regardless of whether its manufacture, use,
            importation or sale are or shall be covered by more than one patent
            or patent application included in Licensed Patents under this
            Agreement, and no further royalties will be due for use of such
            Licensed Product by Alnylam or its sublicensee's customers.

6.4   CREDITABLE PAYMENTS. Creditable payments under this Agreement will be an
      offset to Alnylam against each earned royalty payment which Alnylam would
      be required to pay under Section 6.3 until the entire credit is exhausted.

6.5   MILESTONE PAYMENTS.

      (A)   For the first Licensed Product, Alnylam will make the following
            payments for the filing of [**] ("Milestone Payments"):

            (1)   $[**] for [**].

            (2)   $[**] for [**].

            (3)   $[**] for [**].

            (4)   $[**] for [**]

      (B)   For the second Licensed Product, Alnylam will make the following
            Milestone Payments:

            (1)   $[**] for [**].

            (2)   $[**] for [**].


                                       39
<PAGE>
            (3)   $[**] for [**].

            (4)   $[**] for [**].

      (C)   For the third and every subsequent Licensed Product, Alnylam will
            make the following Milestone Payments:

            (1)   $[**] for [**].

            (2)   $[**] for [**].

            (3)   $[**] for [**].

            (4)   $[**] for [**].

      (D)   Notwithstanding the above, at the time that [**] receives a
            Milestone Payment from Alnylam on behalf of a sublicensee under
            13.6, the corresponding Milestone Payment under this Section 6.5
            will not be due.

6.6   OBLIGATION TO PAY ROYALTIES. If this Agreement is not terminated in
      accordance with other provisions, Alnylam will be obligated to pay
      royalties on all Licensed Product that is either sold or produced under
      the license granted in Article 3, whether or not the Licensed Product is
      produced before the Effective Date of this Agreement or sold after the
      Licensed Patent has expired.

13    SUBLICENSING

13.1  PERMITTED SUBLICENSING FOR LICENSED CO-EXCLUSIVE FIELD OF USE. Alnylam may
      grant sublicenses in the Co-exclusive Licensed Field of Use during the
      Co-Exclusive period:

      (A)   only in conjunction with intellectual property under Alnylam's
            control; and

      (B)   only if Alnylam is developing or selling Licensed Products in the
            Co-Exclusive Licensed Field of Use.

13.3  SUBLICENSE REQUIREMENTS. Any sublicense granted by Alnylam under this
      Agreement will be subject and subordinate to terms and conditions of this
      Agreement, except:

      (A)   Sublicense terms and conditions will reflect that any sublicensee
            will not further sublicense, with the exception that sublicensee may
            further sublicense rights under Licensed Patents only as needed or
            implied in the course of distribution or performance of service as
            required for the sale to an end user of Licensed Products; and


                                       40
<PAGE>
       (B)  The earned royalty rate specified in the sublicense may be at
            different rates than the rates in this Agreement.

13.4  SUBLICENSES REVERT TO [**]. Any sublicense will expressly include the
      provisions of Articles 7, 8, and 9 for the benefit of [**] [Note: these
      provisions are detailed in Exhibit 6.5(c)]. If a sublicensee desires that
      its sublicense survive the termination of this agreement, [**] agrees that
      the sublicense will revert to [**] subject to the transfer of all
      obligations, including the payment of royalties specified in the
      sublicense, to [**] or its designee, if this Agreement is terminated.

13.5  COPY OF SUBLICENSES. Alnylam will provide [**] in confidence a copy of all
      relevant portions of any sublicenses granted pursuant to this Article 13.

13.6  SHARING OF SUBLICENSING INCOME. In addition to the earned royalties
      defined in Article 6, Alnylam will pay [**] percent ([**]%) of the amount
      received by Alnylam, that is specifically attributable to the Licensed
      Patents, from a sublicensee in

            (A) up-front license fees, and

            (B) clinical Milestone Payments as defined in Article 6.5.

13.7  ROYALTY-FREE SUBLICENSES. Alnylam may grant royalty-free or noncash
      sublicenses or cross-licenses if Alnylam pays all royalties due [**] from
      sublicensee's Net Sales.


                                       41
<PAGE>
                                 EXHIBIT 8.2(C)

      DESCRIPTION OF ALNYLAM ROYALTY OBLIGATIONS TO [**]EXISTING AS OF THE
                                 EFFECTIVE DATE

As of the Effective Date, Alnylam has the following royalty obligations to [**]:

Alnylam is obligated to pay [**] running royalties on NET SALES (as defined in
Alnylam's agreements with [**]) of therapeutic and prophylactic LICENSED
PRODUCTS (as defined in Alnylam's agreements with [**]) by Alnylam and its
SUBLICENSEES (as defined in Alnylam's agreements with [**]) that range from
[**]% ([**] percent) to [**]% ([**] percent) of NET SALES, depending on the
level of NET SALES. Royalties payable by Alnylam to [**] are subject to the
following Royalty Stacking provision:

"5.3 Royalty Stacking

(a) Third Party Licenses
In the event COMPANY or a SUBLICENSEE takes, for objective commercial and/or
legal reasons, a license from any third party under any patent applications or
patents that dominate the PATENT RIGHTS or is dominated by the PATENT RIGHTS in
order to develop, make, use, sell or import any LICENSED PRODUCT (explicitly
excluding, without limitation, any third party patents and patent applications
for formulation, stabilization and delivery), then COMPANY is allowed to deduct
[**]% ([**] percent) of any additional running royalties to be paid to such
third party up to [**]% ([**] percent) of the running royalties stated in
Section 5.2, from the date COMPANY has to pay running royalties to such third
party. However, the running royalties stated in Section 5.2 shall not be reduced
to less than a minimum of [**]% ([**] percent) of NET SALES in any case.

For avoidance of doubt, if COMPANY or a SUBLICENSEE takes a license to a third
party target, COMPANY is in no event allowed to deduct any license fees for such
target from running royalties due to [**] under this Agreement."

Because Alnylam's right to reduce its royalty obligations to [**] pursuant to
the foregoing royalty stacking provision is not co-extensive with Isis' right to
reduce its royalty obligations to Alnylam pursuant to Section 8.2 of this
Agreement, Isis' right to reduce its royalty obligations to Alnylam pursuant to
Section 8.2 of this Agreement is limited, pursuant to Section 8.2(c) of this
Agreement, to the extent necessary to ensure that Isis' royalty obligations to
Alnylam are never less than Alnylam's royalty obligations to [**] with respect
to sales by Isis, its Affiliates and its sublicensees of any Isis Product.


                                       42
<PAGE>

                              ADDENDUM TRANSMITTAL

      Reference is hereby made to the Strategic Collaboration and License
Agreement executed as of March 11, 2004 (the "Agreement"), between Isis
Pharmaceuticals, Inc., a Delaware corporation, and Alnylam Pharmaceuticals,
Inc., a Delaware corporation.

      Capitalized terms used herein and not defined herein shall have the
meanings ascribed to them in the Agreement.

      The Parties hereby acknowledge and agree that this document constitutes
the Addendum Transmittal.

      Attached hereto are the following Exhibits and Schedules:

                  Exhibit 3.1
                  Exhibit 5.3(c)
                  Exhibit 5.3(d)
                  Exhibit 6.5(c)
                  Schedule 1-4
                  Schedule 1-5
                  Schedule 1-6
                  Schedule 1-27
                  Schedule 1-28
                  Schedule 1-30
                  Schedule 1-34

      IN WITNESS WHEREOF, the Parties have executed this Addendum Transmittal as
of this 19th day of March, 2004.

<TABLE>
<S>                                         <C>
ISIS PHARMACEUTICALS, INC.                  ALNYLAM PHARMACEUTICALS, INC.

By: /s/ B. Lynne Parshall                   By: /s/ Vincent J. Miles
   ------------------------------------        --------------------------------

Name: B. Lynne Parshall                     Name: Vincent J. Miles
     ----------------------------------          ------------------------------

Title:  Executive Vice President            Title: Senior Vice President,
      ---------------------------------           -----------------------------
                                                   Business Development
                                                  -----------------------------
</TABLE>
<PAGE>
                                  SCHEDULE 1-4
                        ALNYLAM CURRENT CHEMISTRY PATENTS

Alnylam Current Chemistry Patents include all claims of the patents and patent
applications listed below that do not claim inhibitors to specific genes or gene
families.

<TABLE>
<CAPTION>
Case No.    Filing Date     Country      Serial No.     Status     Title
--------    -----------     -------      ----------     ------     -----
<S>         <C>             <C>          <C>            <C>        <C>
  [**]          [**]          [**]          [**]         [**]      [**]
  [**]          [**]          [**]          [**]         [**]      [**]
  [**]          [**]          [**]          [**]         [**]      [**]
  [**]          [**]          [**]          [**]         [**]      [**]
  [**]          [**]          [**]          [**]         [**]      [**]
  [**]          [**]          [**]          [**]         [**]      [**]
  [**]          [**]          [**]          [**]         [**]      [**]
  [**]          [**]          [**]          [**]         [**]      [**]
  [**]          [**]          [**]          [**]         [**]      [**]
  [**]          [**]          [**]          [**]         [**]      [**]
  [**]          [**]          [**]          [**]         [**]      [**]
  [**]          [**]          [**]          [**]         [**]      [**]
  [**]          [**]          [**]          [**]         [**]      [**]
  [**]          [**]          [**]                       [**]      [**]
  [**]          [**]          [**]          [**]         [**]      [**]
  [**]          [**]          [**]          [**]         [**]      [**]
</TABLE>

<PAGE>
                                  SCHEDULE 1-5
                   ALNYLAM CURRENT MOTIF AND MECHANISM PATENTS

Alnylam Current Motif and Mechanism Patents include all claims of the patents
and patent applications listed below that do not claim inhibitors to specific
genes or gene families.

<TABLE>
<CAPTION>
   Case No.  Filing Date  Country   Serial No.     Status    Title
   --------  -----------  -------   ----------     ------    -----
<S>          <C>          <C>       <C>            <C>       <C>
     [**]        [**]       [**]       [**]         [**]     [**]
     [**]        [**]       [**]                    [**]     [**]
     [**]        [**]       [**]       [**]         [**]     [**]
     [**]        [**]       [**]       [**]         [**]     [**]
     [**]        [**]       [**]       [**]         [**]
     [**]        [**]       [**]       [**]         [**]
     [**]        [**]       [**]       [**]         [**]
     [**]        [**]       [**]       [**]
     [**]        [**]       [**]       [**]
     [**]        [**]       [**]       [**]
     [**]        [**]       [**]       [**]
     [**]        [**]       [**]       [**]
     [**]        [**]       [**]       [**]
     [**]        [**]       [**]       [**]
     [**]        [**]       [**]       [**]
     [**]        [**]       [**]       [**]
     [**]        [**]       [**]       [**]
     [**]        [**]       [**]       [**]
     [**]        [**]       [**]       [**]
     [**]        [**]       [**]       [**]
     [**]        [**]       [**]       [**]         [**]
     [**]        [**]       [**]       [**]         [**]
     [**]        [**]       [**]       [**]         [**]
     [**]        [**]       [**]       [**]         [**]
     [**]        [**]       [**]       [**]         [**]
     [**]        [**]       [**]       [**]         [**]
     [**]        [**]       [**]       [**]         [**]
     [**]        [**]       [**]       [**]         [**]
     [**]        [**]       [**]       [**]         [**]
     [**]        [**]       [**]       [**]         [**]     [**]
     [**]        [**]       [**]       [**]         [**]
     [**]        [**]       [**]       [**]         [**]
     [**]        [**]       [**]       [**]         [**]
     [**]        [**]       [**]       [**]         [**]
     [**]        [**]       [**]       [**]         [**]
     [**]        [**]       [**]       [**]         [**]
     [**]        [**]       [**]       [**]         [**]
     [**]        [**]       [**]       [**]         [**]
     [**]        [**]       [**]       [**]         [**]
     [**]        [**]       [**]       [**]         [**]             [**]
     [**]        [**]       [**]       [**]         [**]
     [**]        [**]       [**]       [**]         [**]
</TABLE>



<PAGE>
<TABLE>
<S>          <C>          <C>       <C>            <C>       <C>
     [**]        [**]       [**]       [**]         [**]
     [**]        [**]       [**]       [**]         [**]
     [**]        [**]       [**]       [**]         [**]
     [**]        [**]       [**]       [**]         [**]
     [**]        [**]       [**]       [**]         [**]
     [**]        [**]       [**]       [**]         [**]
     [**]        [**]       [**]       [**]         [**]
     [**]        [**]       [**]       [**]         [**]
     [**]        [**]       [**]       [**]         [**]
     [**]        [**]       [**]       [**]         [**]
     [**]        [**]       [**]       [**]         [**]
     [**]        [**]       [**]                    [**]
     [**]        [**]       [**]       [**]         [**]
     [**]        [**]       [**]       [**]         [**]
     [**]        [**]       [**]       [**]         [**]
     [**]        [**]       [**]       [**]         [**]
     [**]        [**]       [**]       [**]         [**]
     [**]        [**]       [**]       [**]         [**]     [**]
     [**]        [**]       [**]       [**]         [**]
     [**]        [**]       [**]       [**]         [**]     [**]
     [**]        [**]       [**]       [**]         [**]
     [**]        [**]       [**]       [**]         [**]
     [**]        [**]       [**]       [**]         [**]
     [**]        [**]       [**]       [**]         [**]
     [**]        [**]       [**]       [**]         [**]
     [**]        [**]       [**]       [**]         [**]
     [**]        [**]       [**]       [**]         [**]
     [**]        [**]       [**]       [**]         [**]
     [**]        [**]       [**]       [**]         [**]
     [**]        [**]       [**]       [**]         [**]
     [**]        [**]       [**]       [**]         [**]
     [**]        [**]       [**]       [**]         [**]
     [**]        [**]       [**]       [**]         [**]
     [**]        [**]       [**]       [**]         [**]
     [**]        [**]       [**]       [**]         [**]     [**]
     [**]        [**]       [**]       [**]         [**]     [**]
     [**]        [**]       [**]       [**]         [**]
     [**]        [**]       [**]       [**]         [**]     [**]
     [**]        [**]       [**]       [**]         [**]     [**]
     [**]        [**]       [**]       [**]         [**]
     [**]        [**]       [**]       [**]         [**]
     [**]        [**]       [**]       [**]         [**]             [**]
     [**]        [**]       [**]       [**]         [**]
     [**]        [**]       [**]       [**]         [**]
     [**]                   [**]                    [**]
     [**]                   [**]                    [**]
     [**]                              [**]         [**]
     [**]        [**]       [**]                    [**]
     [**]        [**]       [**]       [**]         [**]
</TABLE>

[**]+ Note that Alnylam's license to this series of patent applications
   specifically excludes claims [**] and the equivalent claims in any patent
   applications and patents


<PAGE>
   resulting from this PCT application. The application contains claims relating
   to [**]. The claims excluded from Alnylam's license are those that [**].

*  Subject to the provisions of section 6.5(d).
<PAGE>
                                  SCHEDULE 1-6
                           ALNYLAM EXCLUDED TECHNOLOGY

   1. All Patent rights licensed to Alnylam under the license agreements
      between [**] dated [**], and between [**] and Alnylam dated [**].

   2. All Patent rights licensed to Alnylam under the license agreement
      between [**] and Alnylam dated [**].

   3. All Patent rights licensed to Alnylam under the license agreement
      between [**] and Alnylam dated [**].
<PAGE>
                                EXHIBIT 6.5(c)

 RESTRICTIONS IMPOSED BY AGREEMENTS BETWEEN ALNYLAM AND THIRD PARTIES EXECUTED
                           PRIOR TO THE EFFECTIVE DATE

Because of agreements in effect with Third Parties as of the Effective Date, the
following restrictions and other terms apply to Alnylam Patent Rights with
respect to which Isis is granted a license, or option to obtain a license, under
this Agreement.

RIGHTS LICENSED FROM [**]

The rights licensed from [**] ("**") relate to the "[**]" and "[**]" patents.

 "[**] patent" means the pending patent applications listed in Schedule 1-5 with
the following case numbers: [**].

"[**] patent" means the pending patent applications listed in Schedule 1-5 with
the following case numbers, excluding claims [**] (case number [**]) and the
equivalent claims in any patent applications and patents resulting from this PCT
application: [**].

The restrictions on, and other terms relating to, the rights available to Isis
under the Agreement are described in the following clauses excerpted from the
Co-Exclusive License executed between Alnylam and [**] on [**].

      "ARTICLE 2 - GRANT OF RIGHTS

      2.4  Sublicenses

      .... Immediately after the signature of each sublicense granted under this
      Agreement, COMPANY shall provide [**] with a copy of the signed sublicense
      agreement, and COMPANY shall confirm in writing to [**] that COMPANY shall
      be liable for payment of royalties on NET SALES of the SUBLICENSEE in
      accordance with Sections 5.2 and 5.3.

      ARTICLE 4 - COMPANY DILIGENCE OBLIGATIONS AND REPORTS

      4.1  Activity Requirements

      COMPANY shall use commercially reasonable efforts, and shall oblige its
      SUBLICENSEES to use commercially reasonable efforts, to develop and to
      introduce into the commercial market LICENSED PRODUCTS at the earliest
      practical date.

      4.2  Development Reports

      Commencing with the beginning of 2003, COMPANY shall furnish, and shall
      oblige its SUBLICENSEES to furnish to COMPANY for inclusion in its reports
      to [**], to [**] in writing, within 30 (thirty) days after the end of each
      calendar quarter with COMPANY's standard R&D report, as provided to the
      investors
<PAGE>
      pursuant to the Amended and Restated Investor's Rights Agreement Series B,
      on the progress of its efforts during the immediately preceding calendar
      quarter to develop and commercialize LICENSED PRODUCTS for each indication
      and sub-indication within the FIELD. The report shall also contain a
      discussion of intended R&D efforts for the calendar quarter in which the
      report is submitted.

      4.4  Liability for SUBLICENSEES

      If SUBLICENSEES of COMPANY develop, manufacture, use and/or sell LICENSED
      PRODUCTS under the PATENT RIGHTS, COMPANY warrants and is liable towards
      [**] that the SUBLICENSEES perform their sublicense agreement in
      accordance with this Agreement, and COMPANY shall be responsible and
      liable for royalty payments and reports of the SUBLICENSEES.

      4.5  Effect of Failure

      In the event that [**] determines that COMPANY or any of its SUBLICENSEES
      has failed to fulfill any of its obligations under this Section 4, then
      [**] may treat such failure as a material breach in accordance with
      Section 11.7.

      ARTICLE 5 - SHARES, Royalties and Payment Terms

      5.2  Running Royalties

      COMPANY shall pay to [**] the following running royalties on NET SALES of
      therapeutic and prophylactic LICENSED PRODUCTS by COMPANY and its
      SUBLICENSEES:

            [[**]% ([**] percent) to [**]% ([**]%) of NET SALES depending on
            level of NET SALES].

      In the event that COMPANY or a SUBLICENSEE develops [**] LICENSED
      PRODUCTS, COMPANY shall initiate negotiations with [**] at least 3 (three)
      months prior to the intended first commercial sale of each [**]
      LICENSED PRODUCT. COMPANY and [**] shall negotiate in good faith royalties
      on reasonable market terms for such [**] LICENSED PRODUCT.

      .... Non-cash consideration shall not be accepted by COMPANY or any
      SUBLICENSEE for LICENSED PRODUCTS without the prior written consent
      of [**].

      5.3  Royalty Stacking

      (a) Third Party Licenses

      In the event COMPANY or a SUBLICENSEE takes, for objective commercial
      and/or legal reasons, a license from any third party under any patent
      applications or patents that dominate the PATENT RIGHTS or is dominated by
      the PATENT RIGHTS in order to develop, make, use, sell or import any
      LICENSED PRODUCT [**], then COMPANY is allowed to deduct [**]% ([**]
      percent) of
<PAGE>
      any additional running royalties to be paid to such third party up to
      [**]% ([**] percent) of the running royalties stated in Section 5.2, from
      the date COMPANY has to pay running royalties to such third party.
      However, the running royalties stated in Section 5.2 shall not be reduced
      to less than a minimum of [**]% ([**] percent) of NET SALES in any case.

      For avoidance of doubt, if COMPANY or a SUBLICENSEE takes a license [**],
      COMPANY is in no event allowed to deduct any license fees [**] from
      running royalties due to [**] under this Agreement.

      (b) PATENT RIGHTS Coverage

      In the event that (i) COMPANY or its SUBLICENSEES sell a LICENSED PRODUCT
      in a country where no PATENT RIGHTS are issued and no patent applications
      that are part of the PATENT RIGHTS are pending that have not been pending
      for less than [**] years after filing national patent applications in the
      country in question, and (ii) such LICENSED PRODUCT is manufactured in a
      country where PATENT RIGHTS are issued or patent applications that are
      part of the PATENT RIGHTS are pending that have not been pending for more
      than [**] years after filing national patent applications in the country
      in question, the royalties stated in Section 5.2 will be reduced by [**]%
      ([**] percent) for such LICENSED PRODUCT, until the expiration or
      abandonment of all issued patents and filed patent applications within the
      PATENT RIGHTS in the country in which the LICENSED PRODUCT is
      manufactured.

      5.4  Reports

      Within 30 (thirty) days of the end of each calendar half year, COMPANY
      shall deliver a detailed report to [**] for the immediately preceding
      calendar half year showing at least (i) the number of LICENSED PRODUCTS
      sold by COMPANY and its SUBLICENSEES in each country, (ii) the gross price
      charged by COMPANY and its SUBLICENSEES for each LICENSED PRODUCTS in each
      country, (iii) the calculation of NET SALES, and (iv) the resulting
      running royalties due to [**] according to those figures. If no running
      royalties are due to [**], the report shall so state.

      5.6  Bookkeeping and Auditing

      COMPANY is obliged to keep, and shall oblige its SUBLICENSEES to keep,
      complete and accurate books on any reports and payments due to [**] under
      this Agreement, which books shall contain sufficient information to permit
      [**] to confirm the accuracy of any reports and payments made to [**].
      [**], or [**] appointed agents, is authorized to check the books of
      COMPANY, and, upon [**] request, COMPANY, or agents appointed by [**] for
      COMPANY, shall check the books of its SUBLICENSEES for [**], [**]. The
      charges for such a check shall be borne by [**]. In the event that such
      check reveals an underpayment in excess of 5% (five percent), COMPANY
      shall bear the full cost of such check and shall remit any amounts due to
      [**] within thirty days of receiving notice thereof from [**].
<PAGE>
      The right of auditing by [**] under this Section shall expire five years
      after each report or payment has been made. Sublicenses granted by COMPANY
      shall provide that COMPANY shall have the right to check the books of its
      SUBLICENSEES according to this Section 5.6.

      5.7  No Refund

      All payments made by COMPANY or its SUBLICENSEES under this [**] Agreement
      are nonrefundable and noncreditable against each other.

      ARTICLE 6 - Patent Prosecution AND Infringement

      6.3  Infringement

      COMPANY shall inform [**] promptly in writing of any alleged infringement
      of the PATENT RIGHTS by a third party and of any available evidence
      thereof.

      Subject to COMPANY's right to join in the prosecution of infringements set
      forth below, the OWNERS shall have the right, but not the obligation, to
      prosecute in their own discretion and at their own expense, all
      infringements of the PATENT RIGHTS. The total cost of any such sole
      infringement action shall be borne by the OWNERS, and the OWNERS shall
      keep any recovery or damages derived therefrom. In any such infringement
      suits, COMPANY shall, at the OWNERS' expense, cooperate in all respects.

      COMPANY shall have the right to join the OWNERS' prosecution of any
      infringements of the PATENT RIGHTS: In any such joint infringement suits,
      the OWNERS and COMPANY will cooperate in all respects. The OWNERS and
      COMPANY will agree in good faith on the sharing of the total cost of any
      such joint infringement action and the sharing of any recovery or damages
      derived therefrom.

      In the event that the OWNERS decide not to prosecute infringements of the
      PATENT RIGHTS, neither solely nor jointly with COMPANY, GI shall offer to
      COMPANY to prosecute any such infringement in its own discretion and at
      its own expense. .... The OWNERS shall, at COMPANY'S expense, cooperate.
      The total cost of any such sole infringement action shall be borne by
      COMPANY, and COMPANY shall keep any recovery or damages derived therefrom.

      In the event that COMPANY intends to make any arrangements with the
      infringer to settle the infringement (such as sublicenses), and solely the
      OWNERS or the OWNERS jointly with COMPANY have prosecuted the
      infringement, any such settlement needs the prior written approval of GI,
      which shall not unreasonably be withheld; reasons to withheld include,
      without limitation, that the settlement is financially disadvantageous for
      the OWNERS or [**]. Any infringer to which COMPANY grants such sublicenses
      shall be a SUBLICENSEE under this Agreement.
<PAGE>
      ARTICLE 8 - CONFIDENTIALITY

      8.2  Obligation for [**]

      The content of this Agreement and any information marked confidential
      which is disclosed to [**] under this Agreement by COMPANY or its
      SUBLICENSEES shall be treated confidential by [**] during the TERM and for
      [**] years thereafter. [**] shall not use such information for any
      purposes other than those necessary to directly further the purpose of
      this Agreement. [**] may disclose such information to the OWNERS, provided
      however, that the OWNERS are obliged to confidentiality to the same extent
      as [**].

      The confidentiality obligation shall not apply to information which is (i)
      publicly available or becomes publicly available through no fault of [**],
      or (ii) obtained by [**] from another source without a duty of
      confidentiality, or (iii) demonstrably independently developed or
      possessed by [**], or (iv) is required by law, regulation, accounting
      principles or an order of a court or government agency to be disclosed.

      ARTICLE 10 - General Compliance with Laws

      10.2  Non-Use of OWNERS Names

      Neither COMPANY nor its SUBLICENSEES shall use the name of [**] or any
      variation, adaptation, or abbreviation thereof, or of any of its trustees,
      officers, faculty, students, employees, or agents, or any trademark owned
      by any of the OWNERS, in any promotional material or other public
      announcement or disclosure without the prior written consent of the OWNERS
      or in the case of an individual, the consent of that individual. The
      foregoing notwithstanding, without the consent of the OWNERS, COMPANY may
      state generally that it is co-exclusively licensed by the OWNERS under the
      PATENT RIGHTS.

      ARTICLE 11 - EFFECTIVENESS AND TERMINATION

      11.5  Attack on PATENT RIGHTS

      [**] shall have the right to terminate this Agreement immediately upon
      written notice to COMPANY, if COMPANY attacks, or has attacked or supports
      an attack through a third party, the validity of any of the PATENT RIGHTS.
      To the extent legally enforcable, sublicenses granted by COMPANY shall
      provide that in the event the SUBLICENSEE attacks, or has attacked or
      supports an attack through a third party, the validity of any of the
      PATENT RIGHTS, COMPANY shall have the right to terminate the sublicense
      agreement immediately; upon request of [**], COMPANY shall have the
      obligation to terminate such sublicense agreement.

      11.8  Effect of Termination

      .... In no event shall termination of this Agreement release COMPANY or
      its SUBLICENSEES from the obligation to pay any amounts that became due on
      or before the effective date of termination.
<PAGE>
      In the event that any license granted to COMPANY under this Agreement is
      terminated, any sublicense under such license granted prior to termination
      of said license shall remain in full fore and effect, provided that:

      (a) the SUBLICENSEE is not then in breach of its sublicense agreement, and

      (b) the SUBLICENSEE agrees to be bound to [**] as licensor under the terms
      and conditions of the sublicense agreement, provided that [**] shall have
      no other obligation than to leave the sublicense granted by COMPANY in
      place."

RIGHTS LICENSED FROM [**]

The rights licensed from [**] ("[**]") relate to the pending patent applications
listed in Schedule 1-5 with the following case numbers: [**].

The restrictions on, and other terms relating to, the rights available to Isis
under the Agreement are described in the following clauses excerpted from the
agreement executed between Alnylam and [**] on [**]. Articles 7, 8 and 9 of such
agreement are included in these excerpts because clause 13.4 of such agreement
states that "Any sublicense will expressly include the provisions of Articles 7,
8, and 9 for the benefit of [**]."

      "7    ROYALTY REPORTS, PAYMENTS, AND ACCOUNTING

      7.1 QUARTERLY EARNED ROYALTY PAYMENT AND REPORT. Beginning with the first
      sale of a Licensed Product, Alnylam will make written reports (even if
      there are no sales) and earned royalty payments to [**] within thirty days
      after the end of each calendar quarter. This report will be in the form of
      the report of Appendix B and will state the number, description, and
      aggregate Net Sales of Licensed Product during the completed calendar
      quarter, and resulting calculation pursuant to Section 6.3 of earned
      royalty payment due [**] for the completed calendar quarter. With each
      report, Alnylam will include payment due [**] of royalties for the
      completed calendar quarter."

      7.2 TERMINATION REPORT. Alnylam will make a written report to [**] within
      ninety days after the license expires under Section 3.2. Alnylam will
      continue to make reports after the license has expired, until all Licensed
      Product produced under the license have been sold or destroyed. Concurrent
      with the submittal of each post-termination report, Alnylam will pay [**]
      all applicable royalties.

      7.3 ACCOUNTING. Alnylam will keep and maintain records for a period of
      three years showing the manufacture, sale, use, and other disposition of
      products sold or otherwise disposed of under the license. Records will
      include general-ledger records showing cash receipts and expenses, and
      records that include production records, customers, serial numbers, and
      related information in sufficient detail to enable Alnylam to determine
      the royalties payable under this Agreement.
<PAGE>
      7.4 AUDIT BY [**]. Alnylam will permit an independent certified public
      accountant selected by [**] and acceptable to Alnylam to examine Alnylam's
      books and records from time to time (but no more than one time a year) to
      the extent necessary to verify reports provided for in Sections 7.1 and
      7.2. [**] will pay for the cost of such audit, unless the results of the
      audit reveal an underreporting of royalties due [**] of five percent or
      more, in which case, Alnylam will pay the audit costs.

      8 NEGATION OF WARRANTIES

      8.1 To the best of [**] OTL knowledge, [**] is the sole owner of Licensed
      Patent and has the right to enter into this Agreement and to grant the
      rights and licenses set forth herein.

      8.2 NEGATION OF WARRANTIES. Nothing in this Agreement is construed as:

            (A)   [**] warranty or representation as to the validity or scope of
                  any Licensed Patent;

            (B)   A warranty or representation that anything made, used, sold,
                  or otherwise disposed of under any license granted in this
                  Agreement is or will be free from infringement of patents,
                  copyrights, and other rights of third parties;

            (C)   An obligation to bring suit against third parties for
                  infringement, except as described in Article 12;

            (D)   Granting by implication, estoppel, or otherwise any licenses
                  or rights under patents or other rights of [**] or other
                  persons other than Licensed Patent, regardless of whether the
                  patents or other rights are dominant or subordinate to any
                  Licensed Patent; or

            (E)   An obligation to furnish any technology or technological
                  information.

      8.3 NO WARRANTIES. Except as expressly set forth in this Agreement, [**]
      makes no representations and extends no warranties of any kind, either
      express or implied. There are no express or implied warranties of
      merchantability or fitness for a particular purpose, or that Licensed
      Product will not infringe any patent, copyright, trademark, or other
      rights, or any other express or implied warranties.

      8.4 SPECIFIC EXCLUSION. Nothing in this Agreement grants Alnylam any
      express or implied license or right under or to [**] entitled [**] or any
      patent application corresponding thereto.

      9     INDEMNITY
<PAGE>
      9.1 INDEMNIFICATION. Alnylam will indemnify, hold harmless, and defend
      [**] and [**] Hospitals and Clinics, and their respective trustees,
      officers, employees, students, and agents against all claims for death,
      illness, personal injury, property damage, and improper business practices
      arising out of the manufacture, use, sale, or other disposition of
      Invention, Licensed Patent, Licensed Product, by Alnylam or any
      sublicensee, or their customers except to the extent such claims are due
      to the gross negligence or willful misconduct of [**]. [**] agreed to
      promptly notify Alnylam in writing of any such claim and Alnylam shall
      manage and control, at its own expense, the defense of such claim and its
      settlement. Alnylam agrees not to settle any such claim against [**]
      without [**] written consent where such settlement would include any
      admission of liability on the part of [**], where the settlement would
      impose any restriction on the conduct by [**] of any of its activities, or
      where the settlement would not include an unconditional release of [**]
      from all liability for claims that are the subject matter of such claim.

      9.2 NO LIABILITY. Subject to Section 9.1, neither party will be liable to
      each other for any loss profit, expectation, punitive or other indirect,
      special, consequential, or other damages whatsoever, in connection with
      any claim arising out of or related to this Agreement whether grounded in
      tort (including negligence), strict liability, contract, or otherwise.

      9.3 WORKERS' COMPENSATION. Alnylam will at all times comply, through
      insurance or self-insurance, with all statutory workers' compensation and
      employers' liability requirements covering all employees with respect to
      activities performed under this Agreement.

      9.4 INSURANCE. Alnylam will maintain, during the term of this Agreement,
      Comprehensive General Liability Insurance, including Product Liability
      Insurance prior to commercialization, with a reputable and financially
      secure insurance carrier to cover the activities of Alnylam and its
      sublicensees. Upon initiation of human clinical trials of Licensed
      Product, such insurance will provide minimum limits of liability of Five
      Million Dollars and will include [**] and [**] Hospitals and Clinics, and
      their respective trustees, directors, officers, employees, students, and
      agents as additional insureds. Insurance will be written to cover claims
      incurred, discovered, manifested, or made during or after the expiration
      of this Agreement and must be placed with carriers with ratings of at
      least A- as rated by A.M. Best. Alnylam will furnish a Certificate of
      Insurance evidencing primary coverage and additional insured requirements
      and requiring thirty (30) days prior written notice of cancellation or
      material change to [**]. Alnylam will advise [**], in writing, that it
      maintains excess liability coverage (following form) over primary
      insurance for at least the minimum limits set forth above. All insurance
      of Alnylam will be primary coverage; insurance of [**] and [**] Hospitals
      and Clinics will be excess and noncontributory.
<PAGE>
      12    INFRINGEMENT BY OTHERS: PROTECTION OF PATENTS

      12.1  INFRINGEMENT ACTION.

            (A)   The parties will promptly inform each other of any suspected
                  infringement of any Licensed Patent by a third party.

            (B)   [**], Licensee and the other Co-Exclusive licensee will
                  meet to discuss the matter during the Co-Exclusive period of
                  this Agreement.

            (C)   If the Field-of-Use becomes Exclusive for Licensee, [**]
                  and Licensee will meet to discuss the matter during the
                  Exclusive period of this Agreement.

            (D)   If [**] does not choose to institute suit against said
                  third party within sixty days of notification, then the suit
                  may be brought in both Licensee's and the other Co-Exclusive
                  licensee's names, and [**] name if necessary and the
                  out-of-pocket costs thereof shall be borne equally by Licensee
                  and the other Co-Exclusive licensee and any recovery or
                  settlement shall be shared equally between Licensee and the
                  other Co-Exclusive licensee. In such situation, Licensee and
                  the other Co-Exclusive licensee shall agree to the manner in
                  which they exercise control over such action and if either
                  party desires to also be represented by separate counsel of
                  its own selection, the fees for such counsel shall be paid by
                  such party.

            (E)   If both [**] and the other Co-Exclusive licensee, or
                  [**] if there is no other Co-Exclusive Licensee, choose
                  not to institute suit against said third party within sixty
                  days of notification, then Licensee shall have the right to
                  institute suit in its own name or if necessary, in [**]
                  name, to enjoin such infringement. Licensee shall bear the
                  entire cost of such litigation and shall be entitled to retain
                  the entire amount of any recovery or settlement. However, any
                  recovery in excess of litigation/settlement costs will be
                  considered Net Sales and Licensee will pay [**] royalties
                  as indicated in Article 6 hereof. [**] shall provide
                  reasonable assistance to Licensee in the prosecution of any
                  such suit brought by Licensee, at Licensee's expense.

      13    SUBLICENSING

      13.1  PERMITTED SUBLICENSING FOR LICENSED CO-EXCLUSIVE FIELD OF USE.
            Alnylam may grant sublicenses in the Co-exclusive Licensed Field of
            Use during the Co-Exclusive period:
<PAGE>
                  (A)   only in conjunction with intellectual property under
                        Alnylam's control; and

                  (B)   only if Alnylam is developing or selling Licensed
                        Products in the Co-Exclusive Licensed Field of Use.

      13.2  REQUIRED SUBLICENSING FOR LICENSED CO-EXCLUSIVE FIELD OF USE.

                  (A)   If Alnylam or its sublicensee(s) is unable or unwilling
                        to serve or develop a potential market or market
                        territory for which there is a willing sublicensee,
                        Alnylam will, at [**] request, negotiate in good
                        faith a sublicense under the Licensed Patents, provided
                        that the same request has been made of the other
                        Co-Exclusive licensee.

                  (B)   Bona fide business concerns of Alnylam will be
                        considered in any good faith negotiations for a
                        sublicense under this Agreement and Alnylam shall not be
                        required to license/sublicense any other intellectual
                        property to such sublicensee.

                  (C)   If the other Co-Exclusive licensee itself or through its
                        sublicensees is already developing a product in the
                        market or market territory for which there is a willing
                        sublicensee, Alnylam will not be required to sublicense
                        to such party.

                  (D)   In case that any other issue arises in the context of
                        Required Sublicensing, [**] will discuss and try to
                        resolve such issue with Alnylam in good faith.

      13.3  SUBLICENSE REQUIREMENTS. Any sublicense granted by Alnylam under
            this Agreement will be subject and subordinate to terms and
            conditions of this Agreement, except:

                  (A)   Sublicense terms and conditions will reflect that any
                        sublicensee will not further sublicense, with the
                        exception that sublicensee may further sublicense rights
                        under Licensed Patents only as needed or implied in the
                        course of distribution or performance of service as
                        required for the sale to an end user of Licensed
                        Products; and

                  (B)   The earned royalty rate specified in the sublicense [**]
                        in this Agreement.

      13.4  SUBLICENSES REVERT TO [**]. Any sublicense will expressly
            include the provisions of Articles 7, 8, and 9 for the benefit of
            [**]. If a sublicensee desires that its sublicense survive the
            termination of this
<PAGE>
            agreement, [**] agrees that the sublicense will revert to
            [**] subject to the transfer of all obligations, including the
            payment of royalties specified in the sublicense, to [**] or its
            designee, if this Agreement is terminated.

      13.5  COPY OF SUBLICENSES. Alnylam will provide [**] in confidence a
            copy of all relevant portions of any sublicenses granted pursuant to
            this Article 13.

      13.6  SHARING OF SUBLICENSING INCOME. In addition to the earned royalties
            defined in Article 6, Alnylam will pay [**] [**] percent ([**]%)
            of the amount received by Alnylam, that is specifically attributable
            to the Licensed Patents, from a sublicensee in

                  (A)   [**], and

                  (B)   [**] as defined in [**].

      13.7  ROYALTY-FREE SUBLICENSES. Alnylam may grant royalty-free or noncash
            sublicenses or cross-licenses if Alnylam pays all royalties due
            [**] from sublicensee's Net Sales."
<PAGE>
                                 EXHIBIT 5.3(D)

                          ISIS ENCUMBERED PATENT RIGHTS

      The following schedule of encumbered Patents is provided by Isis
Pharmaceuticals, Inc. to Alnylam Pharmaceuticals, Inc., in connection with the
Strategic Collaboration and License Agreement between Alnylam and Isis (the
"AGREEMENT"). Capitalized terms used but not otherwise defined herein have the
meanings given to such terms in the Agreement.

      This schedule and the information and disclosures contained in this
schedule are intended only to qualify and limit the licenses granted by Isis to
Alnylam in the Agreement and do not expand in any way the scope or effect of any
such licenses.

1.    MERCK

The Patents identified by Isis docket numbers [**] cover the incorporation of
certain Merck-proprietary [**].

The licenses from Isis to Alnylam with respect to these Patents are limited to
the Isis Field. In addition, Merck has a research license to practice these
Patents in the Isis Field.

"Isis Field" means the use of [the Merck [**]] solely for the purposes of
developing [**].

Reference is made to the discussion regarding Merck nucleosides on the Excluded
Technology schedule.

2.    GILEAD SCIENCES, INC.

Gilead has retained exclusive rights in the Patents identified by a "Gilead" in
the Third Party column to make, have made, use, import, export or sell compounds
and other subject matter claimed within the scope of the patents which are [**].

In addition, Gilead has a non-exclusive, non-sublicensable, non-assignable
license under such Patents to make and use CodeBlocker Compounds and
Oligonucleotide Delivery Systems for internal research purposes, but not for any
commercial purpose.

"Codeblocker Compound" means an oligonucleotide that binds directly to DNA or
RNA within a cell on a selective basis determined by the nucleotide sequence of
the target DNA or RNA and exerts its biological activity predominantly through
binding to DNA or RNA to inhibit the transcription or replication of the target
DNA or RNA or binding to RNA to inhibit the translation, processing, packaging
or regulatory activity of the target RNA. A Codeblocker Compound may also have a
mechanism of action or biological activity other than one conferred through
direct binding to RNA or DNA provided that (i) the compound originally was
designed to bind a target DNA or RNA and (ii) the final
<PAGE>
compound or any compounds used to derive the final compound were not identified
using selective purification and polymerase amplification in any fashion. An
oligonucleotide, is [**]. An oligonucleotide includes RNA or DNA fragments, and
may be composed of naturally occurring or non-naturally occurring bases, sugars
or intersugar linkages. An oligonucleotide may have [**]. Oligonucleotides may
be made such that adjacent nucleoside or nucleoside fragments are linked
together by [**] linkages to form the [**] in the linkage.

"Oligonucleotide Delivery System" means any [**] which was developed by Gilead
on or prior to [**], and which (i) enhances the [**] of a Codeblocker Compound,
(ii) selectively delivers a Codeblocker compound to the intended [**], (iii)
provides [**], or (iv) otherwise favorably alters the [**] so as to enhance its
pharmacological activity of clinical value. "Oligonucleotide Delivery System"
includes [**].

Glaxo Smith Kline has retained rights (originally granted from Gilead to GSK) in
the Patents identified by a "Gilead" in the Third Party column to (i) conduct
research and development within the GSK Field and (ii) make, have made, use,
offer for sale, sell, supply and import within the GSK Field any form or dosage
of a GSK Codeblocker Compound and any GSK Codeblocker Delivery System used in
connection therewith.

GSK may grant sublicenses only (a) to affiliates, for any use within the GSK
Field, and (b) to non-affiliates only to the extent necessary to enable such
sublicensee to make, have made, use, offer for sale, sell, supply and import a
GSK Codeblocker Compound developed by GSK or a research or development
collaborator of GSK during the term of such collaboration and for which GSK
(alone or in conjunction with a commercialization partner for such compound) has
commenced or is prepared to commence human clinical trials.

"GSK Field" means research with respect to, and the development and use of, GSK
Codeblocker Compounds for the diagnosis, prevention or treatment of conditions
or diseases in humans.

"GSK Codeblocker Compound" means any material which (i) binds directly to DNA or
RNA within a cell on a selective basis determined by the nucleotide sequence of
the target DNA or RNA and exerts its biological activity predominantly through
binding to DNA or RNA to inhibit the transcription or replication of the target
DNA or RNA or binding to RNA to inhibit the translation, processing, packaging
or regulatory activity of the target RNA, and (ii) is a molecule [**], and (iii)
is not a naturally occurring protein that binds to DNA to regulate
transcription, or a peptide derived from such a naturally occurring protein, and
(iv) is [**], and (v) was not known by GSK prior to [**].

"GSK Codeblocker Delivery System" means any [**] which is developed by GSK or
Gilead pursuant to their Collaborative Research Agreement dated March 25, 1996,
and which (i) [**] a GSK Codeblocker Compound, (ii) [**] to the intended target
[**], (iii) provides [**] a GSK Codeblocker Compound from [**], or (iv)
otherwise [**] a GSK Codeblocker Compound so as to [**].
<PAGE>
3.    [**], INC.

Alnylam cannot grant Naked Sublicenses with respect to the Patents identified by
a "[**]" in the Third Party column or the Patents listed on Annex 3. In
addition, [**] has the first right to defend and enforce such Patents if it is
facing the greatest competitive threat from infringement.

Alnylam must notify Isis if it grants a sublicense of any kind to a Third Party
with respect to such Patents.

The [**] has the first right to defend and maintain the Patents with a docket
number containing "[**]."

Isis also has access to certain other [**] technology to the extent it is useful
for Antisense Products and Antisense Technology (both as defined in Annex 3).
However, in addition to the restrictions described above, this technology
carries certain other use restrictions depending on how the technology is
characterized under the in-license agreement. We do not believe that such
technology will be useful to Alnylam, but have provided a description of the
technology and its related encumbrances on Annex 3 attached hereto.

4.    TULLIS PATENTS.

The Patents identified by a "Tullis" in the Third Party column can only be
sublicensed in combination with a product that (i) uses such Patents and (ii)
employs as a material element other Isis Patent Rights.

5.    AMGEN, GSK, CHIRON AND PFIZER.

Amgen, Inc., Glaxo Smith Kline, Chiron Corporation and Pfizer, Inc. each have a
license to use some or all of the Patents identified by a "TV" in the Third
Party column for their own internal target validation research.

6.    INTEGRATED DNA TECHNOLOGIES, INC.

With respect to the Patents identified by an "IDT" in the Third Party column,
Integrated DNA Technologies, Inc. has a nonexclusive license to make, have made,
use, import, offer to sell, sell and have sold oligonucleotides and other
related research products to the Academic Market.

"Academic Market" means end-users employed by and located at or in academic,
university, government, and other 501(c)(3) registered not-for-profit
organizations; provided however that specifically excluded from this definition
shall be those end-users at such institutions whose research is directly funded
by a for-profit corporation for the purpose of drug discovery, drug development,
or target validation/gene functionalization
<PAGE>
wherein the funding corporation has a specific legal interest or right to the
data and information of the funded research

7.    TRILINK BIOTECHNOLOGIES, INC.

TriLink Biotechnologies, Inc. has a non-exclusive license to the Patents
identified by a "TriLink" in the Third Party column to (i) make, use, distribute
and sell Licensed Products to purchasers who have signed a form license
agreement and (ii) have [**] in the manufacture of Licensed Products.

"Licensed Product" means [**]

      -     "Propyne" means any of the following [**]

[**]
<PAGE>
                                     ANNEX 3

If the Patents marked with either a B1 or B2 restriction are [**] prevails in
the [**] and [**] for such Patents broadly cover [**], the licenses under such
Patents are limited to discover, develop, make, have made, use, sell, have sold,
offer to sell, import and have imported Antisense Products and to practice
Antisense Technology; provided that the license will only extend to the issued
claims corresponding to the [**] and shall not extend to any other claim of such
Patents.

The licenses under the Patents marked with an F restriction are limited (i) to
discover, develop, make, have made, use, sell, have sold, offer to sell, import
and have imported Antisense Products which contain modifications which have
[**], (ii) to practice Antisense Technology using oligonucleotides [**] in such
oligonucleotides, and (iii) to discover, develop, make, have made, use, sell,
have sold, offer to sell, import and have imported Antisense Products which
target genes involved in [**].

The licenses under the Patents marked with a C or D restriction are limited to
discover, develop, make, have made, use, sell, have sold, offer to sell, import
and have imported Antisense Products and practice Antisense Technology, provided
that neither such Antisense Products nor such Antisense Technology use, or are
used with, [**].

The licenses under the Patents marked with an A restriction are limited to
discover, develop, make, have made, use, sell, have sold, offer to sell, import
and have imported Antisense Products and practice Antisense Technology, provided
that such Antisense Products and Antisense Technology use, or are used with, the
technology covered by the claims of such Patents solely for the [**] purposes
only.

The licenses under the Patents marked with an M restriction are limited to
discover, develop, make, have made, use, sell, have sold, offer to sell, import
and have imported Antisense Products and practice Antisense Technology, which
Antisense Products and Antisense Technology primarily act [**].

The licenses under the Patents marked with a K restriction are limited to
discover, develop, make, have made, use, sell, have sold, offer to sell, import
and have imported Antisense Products and practice Antisense Technology;
provided, however, that such licenses will not extend to [**].

For purposes of this description:

      -     Antisense Products means oligonucleotides or oligonucleotide analogs
            or mimics thereof targeted to a specific sequence of RNA that
            hybridize to such sequence and through such hybridization modulate
            the production of the targeted gene product. The term Antisense
            Products shall not include Ribozymes."
<PAGE>
      -     Antisense Technology means the use of any oligonucleotide or
            oligonucleotide analog or mimic thereof targeted to a specific
            sequence of RNA that hybridizes to such sequence and through such
            hybridization modulates the production of the targeted gene product.
            The term Antisense Technology shall not include Ribozyme technology.

      -     Ribozymes means oligonucleotides or oligonucleotide analogs or
            mimics containing a catalytic core having a bulge or stem loop and
            regions flanking the catalytic core that hybridize to a targeted RNA
            and modulate the targeted RNA by cleavage at a site next to a
            specific ribonucleotide triplet by an oligonucleotide catalyzed
            transesterification reaction.

      -     Ribozyme Technology means the use of any oligonucleotides or
            oligonucleotide analogs or mimics thereof containing a catalytic
            core having a bulge or stem loop and regions flanking the catalytic
            core that hybridize to a targeted RNA and modulate the targeted RNA
            by cleavage at a site next to a specific ribonucleotide triplet by
            an oligonucleotide catalyzed transesterification reaction.

<TABLE>
<CAPTION>
 PATENT #          HYBN #                      TITLE                        PATENT GROUP         INVENTORS      RESTRICTION
 --------          ------                      -----                        ------------         ---------      -----------
<S>                <C>         <C>                                        <C>                  <C>              <C>
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]                           [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
</TABLE>
<PAGE>
<TABLE>
<S>                <C>         <C>                                        <C>                  <C>              <C>
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
                   [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
</TABLE>
<PAGE>
<TABLE>
<S>                <C>         <C>                                        <C>                  <C>              <C>
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]               [**]        [**]                                       [**]                 [**]                  [**]
[**]                           [**]                                       [**]                 [**]                  [**]
[**]                           [**]                                       [**]                 [**]                  [**]
</TABLE>
<PAGE>
                                  SCHEDULE 1-30

                               EXCLUDED TECHNOLOGY

      The following schedule of Excluded Technology is provided by Isis
Pharmaceuticals, Inc. to Alnylam Pharmaceuticals, Inc., in connection with the
Strategic Collaboration and License Agreement between Alnylam and Isis (the
"AGREEMENT"). Capitalized terms used but not otherwise defined herein have the
meanings given to such terms in the Agreement.

      This schedule and the information and disclosures contained in this
schedule are intended only to qualify and limit the licenses granted by Isis to
Alnylam in the Agreement and do not expand in any way the scope or effect of any
such licenses.

      In the event of a conflict between this schedule of Excluded Technology
and any other schedule or terms of the Agreement, this schedule will govern.

      1.    INTELLECTUAL PROPERTY COVERING:

            - RNA processing, including modulation of [**]

            - PNA chemistry licensed or acquired from (i) [**];

            - [**] chemistry licensed or acquired from [**];

            - [**] a Gene Target.



      2.    [**]/4'-THIO CHEMISTRY.

            4'-thio chemistries including patents licensed in from [**]



<PAGE>





     In addition, the following Patents in-licensed from the Centre National De
La Recherche Scientifique are excluded:


<TABLE>
<CAPTION>
ISIS DOCKET                                            PATENT          GRANTED
 NUMBER                COUNTRY         STATUS          NUMBER           DATE           TITLE

<S>                    <C>             <C>             <C>          <C>      <C>       <C>
[**]                     [**]            [**]           [**]                 [**]      [**]
[**]                     [**]            [**]           [**]                 [**]      [**]
[**]                     [**]            [**]           [**]                 [**]      [**]
[**]                     [**]            [**]           [**]          [**]             [**]
[**]                     [**]            [**]           [**]                 [**]      [**]
[**]                     [**]            [**]           [**]                 [**]      [**]
[**]                     [**]            [**]           [**]                 [**]      [**]
[**]                     [**]            [**]           [**]                 [**]      [**]
[**]                     [**]            [**]           [**]          [**]             [**]

</TABLE>
<PAGE>
<TABLE>
<S>                      <C>             <C>             <C>          <C>    <C>       <C>
[**]                     [**]            [**]           [**]                 [**]      [**]
[**]                     [**]            [**]           [**]                 [**]      [**]
[**]                     [**]            [**]           [**]                 [**]      [**]
[**]                     [**]            [**]           [**]                 [**]      [**]
[**]                     [**]            [**]           [**]                 [**]      [**]
[**]                     [**]            [**]           [**]          [**]             [**]
[**]                     [**]            [**]           [**]                 [**]      [**]
[**]                     [**]            [**]           [**]                 [**]      [**]
[**]                     [**]            [**]           [**]                 [**]      [**]
[**]                     [**]            [**]           [**]                 [**]      [**]
[**]                     [**]            [**]           [**]          [**]             [**]
</TABLE>
<PAGE>
<TABLE>
<S>                      <C>             <C>             <C>          <C>              <C>
[**]                     [**]            [**]           [**]          [**]             [**]
[**]                     [**]            [**]           [**]          [**]             [**]
[**]                     [**]            [**]           [**]          [**]             [**]
[**]                     [**]            [**]           [**]          [**]             [**]
[**]                     [**]            [**]           [**]          [**]             [**]
[**]                     [**]            [**]           [**]          [**]             [**]
[**]                     [**]            [**]           [**]          [**]             [**]
[**]                     [**]            [**]           [**]          [**]             [**]
[**]                     [**]            [**]           [**]          [**]             [**]
[**]                     [**]            [**]           [**]          [**]             [**]
[**]                     [**]            [**]                                          [**]

</TABLE>

<PAGE>
3.    GEN-PROBE AND NIH. (A)

The following Patents in-licensed from Gen-Probe Inc. and the National Institute
of Health are excluded:



U.S. Patent No. [**] entitled: [**];

U.S. Patent No. [**] entitled: [**]; and

U.S. Patent No. [**] entitled: [**]



4.    MCGILL UNIVERSITY (B)

      In addition to certain manufacturing technology excluded by definition,
the following Patents in-licensed from McGill University are excluded:

<TABLE>
<CAPTION>
ISIS DOCKET
 NUMBER          COUNTRY         STATUS      TITLE
<S>              <C>             <C>         <C>
[**]               [**]           [**]       [**]
[**]               [**]           [**]       [**]
</TABLE>


5.    UNIVERSITY OF MASSACHUSETTS (B)

The following Patents in-licensed from the University of Massachusetts are
excluded:

      [**] Patent No. [**] entitled [**];

      [**] Patent Application [**] entitled "[**];

      [**] Patent Application [**] entitled [**]; and

      [**] Patent No. [**] entitled [**].
<PAGE>
6.    WALDER PATENTS (B)

The Walder Patents are excluded. "Walder Patents" means and includes [**].
Patent Nos. [**]; [**] Patent No. [**], and [**] Patent Application No. [**]
(allowed).



7.    MERCK NUCLEOSIDE

Single nucleosides, nucleotides or monomers claimed in Patents filed as of the
Effective Date which are prosecuted by Merck and Co. are excluded. However if
such Patents are necessary for Alnylam to practice the licenses granted under
Section 5.1 with respect to a specific Alnylam Product, then Isis will include
such necessary Patents in the licenses granted under Section 5.1.
<PAGE>
8.    AJINOMOTO

Isis believes the agreement under which Isis received a license to the Ajinomoto
Patents listed below [**]. However, there is a dispute regarding [**].

<TABLE>
<CAPTION>
  ISIS DOCKET       COUNTRY        STATUS        PATENT      GRANT DATE       TITLE
    NUMBER                                       NUMBER
<S>              <C>            <C>            <C>              <C>           <C>
                 [**]           [**]           [**]             [**]          [**]
[**]             [**]           [**]           [**]             [**]          [**]
[**]             [**]           [**]           [**]             [**]          [**]
[**]             [**]           [**]           [**]             [**]          [**]
[**]             [**]           [**]           [**]             [**]          [**]
[**]             [**]           [**]           [**]             [**]          [**]
[**]             [**]           [**]           [**]             [**]          [**]
[**]             [**]           [**]           [**]             [**]          [**]
[**]             [**]           [**]           [**]             [**]          [**]
[**]             [**]           [**]           [**]             [**]          [**]
</TABLE>
<PAGE>
<TABLE>
<S>              <C>            <C>            <C>                   <C>   <C>
[**]             [**]           [**]           [**]                  [**]  [**]
[**]             [**]           [**]           [**]                  [**]  [**]
[**]             [**]           [**]           [**]                  [**]  [**]
[**]             [**]           [**]           [**]                  [**]  [**]
[**]             [**]           [**]           [**]                  [**]  [**]
[**]             [**]           [**]           [**]                  [**]  [**]
[**]             [**]           [**]           [**]                  [**]  [**]
[**]             [**]           [**]           [**]                  [**]  [**]
[**]             [**]           [**]           [**]                  [**]  [**]
[**]             [**]           [**]           [**]                  [**]  [**]
[**]             [**]           [**]           [**]                  [**]  [**]

</TABLE>


----------
(A)   Isis cannot sublicense the technologies marked with this footnote.

(B)   Although, Isis can sublicense the technologies marked with this footnote,
      such a sublicense carries additional financial and other obligations. Isis
      is willing to negotiate a separate sublicense agreement for these
      technologies.
<PAGE>
                                   EXHIBIT 3.1

                              ISIS PHARMACEUTICALS
                             ALNYLAM PHARMACEUTICALS
                            CLINICAL SUPPLY AGREEMENT
                        MANUFACTURING SERVICES TERM SHEET

      At Alnylam's request, Isis will provide Alnylam services in the categories
described below. Alnylam will compensate Isis for such services on a cost plus
[**]% basis.

1.    For each drug candidate for which Alnylam wishes to engage Isis's
      services, Isis and Alnylam will enter into a Manufacturing Agreement
      pursuant to which Isis will [**] as may be mutually agreed by the parties.

2.    Each year, in advance, Isis and Alnylam will detail a mutually agreed plan
      of the services, if any, to be provided by Isis to Alnylam, including a
      written estimate of the amount of API Alnylam will require for the drug
      candidate during the subsequent calendar year.

3.    Such plan will also detail manufacturing support services to be provided
      by Isis in connection with the drug candidate, including process
      development, analytical methods development and formulation services.

4.    The Manufacturing Agreement will also specify which party will be
      responsible for the Drug Master File for the drug candidate.

5.    At the end of [**] or such other stage mutually agreed under paragraph (1)
      above, the parties will agree either that Isis will continue to
      manufacture the drug candidate or that Isis will transfer the
      manufacturing process for such drug candidate to a third party
      manufacturer designated by Alnylam on commercially reasonable license
      terms.
<PAGE>
                  SCHEDULE 1-27 ISIS CURRENT CHEMISTRY PATENTS

<TABLE>
<CAPTION>
    ISIS
   DOCKET   COUNTRY              PATENT   GRANT                                                              3RD        3RD
   NUMBER      NAME    STATUS     NUMBER   DATE    ISISCASETYPE  CURRENTOWNER   ISISATTYAGENT     TITLE      PARTY      PARTY
<S>         <C>        <C>       <C>      <C>      <C>           <C>            <C>               <C>       <C>         <C>
                                                    DELETED

</TABLE>
<PAGE>
             SCHEDULE 1-28 ISIS CURRENT MOTIF AND MECHANISM PATENTS

<TABLE>
<CAPTION>
 ISIS DOCKET                        PATENT     GRANT    ISIS   CURRENT  ISIS                              3RD     3RD
    NUMBER    COUNTRY    STATUS     NUMBER     DATE     CASE    OWNER   ATTY   CODE  COMMENTS   TITLE    PARTY   PARTY
<S>           <C>        <C>        <C>        <C>      <C>    <C>      <C>    <C>   <C>        <C>      <C>     <C>


                                     DELETED

</TABLE>
<PAGE>
                                  SCHEDULE 1-34
                           ISIS MANUFACTURING PATENTS

The Parties have not yet agreed to a specific list of Manufacturing Patents as
of the date of the Addendum Transmittal. However, the Parties agree to work
together to develop a list of Manufacturing Patents by [**].
<PAGE>
                                 SCHEDULE 1-34
                           ISIS MANUFACTURING PATENTS

The Parties have not yet agreed to a specific list of Manufacturing Patents as
of the date of the Addendum Transmittal. However, the Parties agree to work
together to develop a list of Manufacturing Patents by [**].