<PAGE>
                                                                   Exhibit 10.12

NEITHER THIS WARRANT NOR THE PREFERRED STOCK ISSUABLE UPON EXERCISE OF THIS
WARRANT HAVE BEEN REGISTERED UNDER THE SECURITIES ACT OF 1933, AS AMENDED (THE
"1933 ACT"), OR ANY APPLICABLE STATE SECURITIES LAWS, AND NEITHER THIS WARRANT
NOR THE PREFERRED STOCK ISSUABLE UPON EXERCISE OF THIS WARRANT MAY BE SOLD OR
TRANSFERRED UNLESS SUCH SALE OR TRANSFER IS IN ACCORDANCE WITH THE REGISTRATION
REQUIREMENTS OF SUCH ACT AND APPLICABLE LAWS, OR UNLESS THE COMPANY HAS RECEIVED
AN OPINION OF COUNSEL IN FORM AND SUBSTANCE REASONABLY SATISFACTORY TO THE
COMPANY TO THE EFFECT THAT SOME OTHER EXEMPTION FROM THE REGISTRATION
REQUIREMENTS OF SUCH ACT AND APPLICABLE LAWS IS AVAILABLE WITH RESPECT THERETO.

                        PREFERRED STOCK PURCHASE WARRANT

Warrant No. L-1                                         Number of Shares: 50,000
                                                        Series C Preferred Stock


                          ALNYLAM PHARMACEUTICALS, INC.

                         Effective as of March 30, 2004

                      Void after March 30, 2011, or earlier
                  in accordance with SECTION 7 of this Warrant

      1. ISSUANCE. This Preferred Stock Purchase Warrant (the "Warrant") is
issued to LIGHTHOUSE CAPITAL PARTNERS IV, L.P. by ALNYLAM PHARMACEUTICALS, INC.,
a Delaware corporation (hereinafter with its successors called the "Company").

      2. PURCHASE PRICE; NUMBER OF SHARES. The registered holder of this Warrant
(the "Holder"), commencing on the date hereof, is entitled upon surrender of
this Warrant with the subscription form annexed hereto duly executed, at the
principal office of the Company, to purchase from the Company, at a price per
share of $5.00 (the "Purchase Price"), 50,000 fully paid and nonassessable
shares of the Company's Series C Preferred Stock, $0.0001 par value (the
"Preferred Stock").

Until such time as this Warrant is exercised in full or expires, the Purchase
Price and the securities issuable upon exercise of this Warrant are subject to
adjustment as hereinafter provided. The person or persons in whose name or names
any certificate representing shares of Preferred Stock is issued hereunder shall
be deemed to have become the holder of record of the shares represented thereby
as at the close of business on the date this Warrant is exercised with respect
to such shares, whether or not the transfer books of the Company shall be
closed.

      3. PAYMENT OF PURCHASE PRICE. The Purchase Price may be paid (i) in cash
by wire transfer of immediately available funds, (ii) by certified check, (iii)
by the surrender by the Holder to the Company of any promissory notes or other
obligations issued by the Company to the Holder, with all such notes and
obligations so surrendered being credited against the Purchase Price in an
amount equal to the principal amount thereof plus accrued interest to the date
of surrender, or (iv) by any combination of the foregoing.

      4. NET ISSUE ELECTION. The Holder may elect to receive, without the
payment by the Holder of any additional consideration, shares of Preferred Stock
equal to the value of this Warrant or any portion hereof by the surrender of
this Warrant or such portion to the Company, with the net issue election notice
annexed hereto duly executed, at the principal office of the Company. Thereupon,
the Company shall issue to the Holder such number of fully paid and
nonassessable shares of Preferred Stock as is computed using the following
formula:


                                       1.
<PAGE>
                                    X= Y(A-B)
                                      -------
                                          A

      where:  X = the number of shares of Preferred Stock to be
                  issued to the Holder pursuant to this SECTION 4.

              Y = the number of shares of Preferred Stock covered by this
                  Warrant in respect of which the net issue election is made
                  pursuant to this SECTION 4.

              A = the Fair Market Value (defined below) of one share of
                  Preferred Stock, as determined at the time the net issue
                  election is made pursuant to this SECTION 4.

              B = the Purchase Price in effect under this Warrant at the time
                  the net issue election is made pursuant to this SECTION 4.

            "Fair Market Value" of a share of Preferred Stock (or fully paid and
nonassessable shares of the Company's common stock, $0.0001 par value (the
"Common Stock") if the Preferred Stock has been automatically converted into
Common Stock) as of the date that the net issue election is made (the
"Determination Date") shall mean:

            (I) If the net issue election is made in connection with and
contingent upon the closing of the sale of the Company's Common Stock to the
public in a public offering pursuant to a Registration Statement under the 1933
Act (a "Public Offering"), and if the Company's Registration Statement relating
to such Public Offering ("Registration Statement") has been declared effective
by the Securities and Exchange Commission, then the initial "Price to Public"
specified in the final prospectus with respect to such offering multiplied by
the number of shares of Common Stock into which each share of Preferred Stock is
then convertible.

            (II) If the net issue election is not made in connection with and
contingent upon a Public Offering, then as follows:

                  (A) If traded on a securities exchange or the Nasdaq National
Market, the fair market value of the Common Stock shall be deemed to be the
average of the closing or last reported sale prices of the Common Stock on such
exchange or market over the five day period ending five trading days prior to
the Determination Date, and the fair market value of the Preferred Stock shall
be deemed to be such fair market value of the Common Stock multiplied by the
number of shares of Common Stock into which each share of Preferred Stock is
then convertible;

                  (B) If otherwise traded in an over-the-counter market, the
fair market value of the Common Stock shall be deemed to be the average of the
closing ask prices of the Common Stock over the five day period ending five
trading days prior to the Determination Date, and the fair market value of the
Preferred Stock shall be deemed to be such fair market value of the Common Stock
multiplied by the number of shares of Common Stock into which each share of
Preferred Stock is then convertible; and

                  (C) If there is no public market for the Common Stock, then
fair market value shall be determined in good faith by the Company's Board of
Directors.

      5. PARTIAL EXERCISE. This Warrant may be exercised in part, and the Holder
shall be entitled to receive a new warrant, which shall be dated as of the date
of this Warrant, covering the number of shares in respect of which this Warrant
shall not have been exercised.

      6. FRACTIONAL SHARES. In no event shall any fractional share of Preferred
Stock be issued upon any exercise of this Warrant. If, upon exercise of this
Warrant in part or in its entirety, the Holder would, except as provided in this
SECTION 6, be entitled to receive a fractional share of Preferred Stock, then
the Company shall pay


                                       2.
<PAGE>
the Holder an amount in cash equal to such fraction of a share multiplied by the
Fair Market Value of a share of Preferred Stock at such time.

      7. EXPIRATION DATE; AUTOMATIC EXERCISE. This Warrant shall expire (the
"Expiration Date") at the earliest to occur of (i) the close of business on
March 30, 2011; (ii) the second anniversary of the effective date of the
Company's initial Public Offering on the NASDAQ or other stock exchange in the
United States; or (iii) the effective date of a Merger (as defined below), and
shall be void thereafter.

"Merger" means: (i) a sale of all or substantially all of the Company's assets
to an Unaffiliated Entity (as defined below), or (ii) the merger, consolidation
or acquisition of the Company with, into or by an Unaffiliated Entity (other
than a merger or consolidation for the principle purpose of changing the
domicile of the Company or a bona fide round of preferred stock equity
financing), that results in the transfer of fifty percent (50%) or more of the
outstanding voting power of the Company. "Unaffiliated Entity" means any entity
that is owned or controlled by parties who own less than twenty percent (20%) of
the combined voting power of the voting securities of the Company immediately
prior to such sale of assets, merger, consolidation or acquisition. The Company
agrees to give the Holder written notice of any proposed Merger in accordance
with SECTION 13, and agrees to give the Holder prompt written notice of
termination of any proposed Merger. Notwithstanding anything to the contrary in
this Warrant, the Holder may rescind any exercise of its purchase rights after a
notice of termination of the proposed Merger if the exercise of this Warrant
occurred after the Company notified the Holder that the Merger was proposed or
if the exercise was otherwise precipitated by such proposed Merger, provided,
however that such rescission right must be exercised within thirty (30) days of
receipt of such written notice of termination of the proposed Merger. In the
event of such rescission, this Warrant will continue to be exercisable on the
same terms and conditions.

Notwithstanding the foregoing, this Warrant shall automatically be deemed to be
exercised in full pursuant to the provisions of SECTION 4 hereof, without any
further action on behalf of the Holder, immediately prior to the time this
Warrant would otherwise expire pursuant to this SECTION 7.

      8. RESERVED SHARES; VALID ISSUANCE. The Company covenants that it will at
all times from and after the date hereof reserve and keep available such number
of its authorized shares of Preferred Stock and Common Stock free from all
preemptive or similar rights therein, as will be sufficient to permit,
respectively, the exercise of this Warrant in full and the conversion into
shares of Common Stock of all shares of Preferred Stock receivable upon such
exercise. The Company further covenants that such shares as may be issued
pursuant to such exercise and/or conversion will, upon issuance, be duly and
validly issued, fully paid and nonassessable and free from all taxes, liens and
charges with respect to the issuance thereof.

      9. STOCK SPLITS AND DIVIDENDS. If after the date hereof the Company shall
subdivide the Preferred Stock, by split-up or otherwise, or combine the
Preferred Stock, or issue additional shares of Preferred Stock in payment of a
stock dividend on the Preferred Stock, the number of shares of Preferred Stock
issuable on the exercise of this Warrant shall forthwith be proportionately
increased in the case of a subdivision or stock dividend, or proportionately
decreased in the case of a combination, and the Purchase Price shall forthwith
be proportionately decreased in the case of a subdivision or stock dividend, or
proportionately increased in the case of a combination.

      10. ADJUSTMENTS FOR DILUTING ISSUANCES. The antidilution rights applicable
to the Preferred Stock of the Company are set forth in the Amended and Restated
Certificate of Incorporation, as amended from time to time (the "Articles"), a
true and complete copy in its current form which is attached hereto as EXHIBIT
A. Until full exercise of the Warrant, such rights shall not be restated,
amended or modified in any manner which affects the Holder differently than the
holders of Preferred Stock without such Holder's prior written consent,
provided, however, that nothing herein shall be deemed to restrict the
restatement, amendment or modification of the Articles, in accordance with the
provisions of the Articles, in a manner that affects equally all holders of
Preferred Stock. The Company shall promptly provide the Holder hereof with any
restatement, amendment or modification to the Articles promptly after the same
has been made.

      11. RECLASSIFICATIONS. If after the date hereof the Company shall enter
into any Reorganization (as hereinafter defined), then, as a condition of such
Reorganization, lawful provisions shall be made, and duly executed documents
evidencing the same from the Company or its successor (if the Reorganization is
not a Merger as defined in SECTION 7) shall be delivered to the Holder, so that
the Holder shall thereafter have the right to purchase, at a total


                                       3.
<PAGE>
price not to exceed that payable upon the exercise of this Warrant in full, the
kind and amount of shares of stock and other securities and property receivable
upon such Reorganization by a holder of the number of shares of Preferred Stock
which might have been purchased by the Holder immediately prior to such
Reorganization, and in any such case appropriate provisions shall be made with
respect to the rights and interest of the Holder to the end that the provisions
hereof (including without limitation, provisions for the adjustment of the
Purchase Price and the number of shares issuable hereunder and the provisions
relating to the net issue election) shall thereafter be applicable in relation
to any shares of stock or other securities and property thereafter deliverable
upon exercise hereof. For the purposes of this SECTION 11, the term
"Reorganization" shall include without limitation any reclassification, capital
reorganization or change of the Preferred Stock (other than a Merger as defined
in SECTION 7, or as a result of or subdivision, combination or stock dividend
provided for in SECTION 9 hereof).

      12. CERTIFICATE OF ADJUSTMENT. Whenever the Purchase Price is adjusted, as
herein provided, the Company shall promptly deliver to the Holder a certificate
of the Company's chief financial officer setting forth the Purchase Price after
such adjustment and setting forth a brief statement of the facts requiring such
adjustment.

      13. NOTICES OF RECORD DATE, ETC. In the event of:

            (A) any taking by the Company of a record of the holders of any
class of securities for the purpose of determining the holders thereof who are
entitled to receive any dividend or other distribution, or any right to
subscribe for, purchase, sell or otherwise acquire or dispose of any shares of
stock of any class or any other securities or property, or to receive any other
right;

            (B) any reclassification of the capital stock of the Company,
capital reorganization of the Company, consolidation or merger involving the
Company, or sale or conveyance of all or substantially all of its assets; or

            (C) any voluntary or involuntary dissolution, liquidation or
winding-up of the Company;

then in each such event the Company will provide or cause to be provided to the
Holder a written notice thereof. Such notice shall be provided at least twenty
(20) business days prior to the date specified in such notice on which any such
action is to be taken.

      14. REPRESENTATIONS, WARRANTIES AND COVENANTS. This Warrant is issued and
delivered by the Company and accepted by each Holder on the basis of the
following representations, warranties and covenants made by the Company:

            (A) The Company has all necessary authority to issue, execute and
deliver this Warrant and to perform its obligations hereunder. This Warrant has
been duly authorized issued, executed and delivered by the Company and is the
valid and binding obligation of the Company, enforceable in accordance with its
terms.

            (B) The shares of Preferred Stock issuable upon the exercise of this
Warrant have been duly authorized and reserved for issuance by the Company and,
when issued in accordance with the terms hereof, will be validly issued, fully
paid and nonassessable.

            (C) The issuance, execution and delivery of this Warrant do not, and
the issuance of the shares of Preferred Stock upon the exercise of this Warrant
in accordance with the terms hereof will not violate or contravene the Company's
Articles or by-laws, or any law, statute, regulation, rule, judgment or order
applicable to the Company.

            (D) So long as this Warrant has not terminated, and at any time
prior to the Public Offering, Holder shall be entitled to receive such financial
and other information as the Holder would be entitled to receive under the Stock
Purchase Agreement applicable to the Preferred Stock if Holder were a holder of
that number of shares issuable upon full exercise of this Warrant.


                                       4.
<PAGE>
            (E) Attached hereto as EXHIBIT B is a capitalization table setting
forth the capitalization of the Company as of March 19, 2004.

      15. INTENTIONALLY OMITTED

      16. AMENDMENT. The terms of this Warrant may be amended, modified or
waived only with the written consent of the Company and the Holder.

      17. REPRESENTATIONS, WARRANTIES AND COVENANTS OF THE HOLDER. This Warrant
has been entered into by the Company in reliance upon the following
representations and covenants of the Holder, which by its execution hereof the
Holder hereby confirms:

            (A) INVESTMENT PURPOSE. The right to acquire Preferred Stock or the
Preferred Stock issuable upon exercise of the Holder's rights contained herein
will be acquired for investment and not with a view to the sale or distribution
of any part thereof, and the Holder has no present intention of selling or
engaging in any public distribution of the same except pursuant to a
registration or exemption.

            (B) ACCREDITED INVESTOR. This Warrant does not and will not
when exercised constitute a principal portion of the Holder's total assets
and Holder:

                  (i) is an "accredited investor" within the meaning of
Rule 501 of Regulation D of the 1933 Act, as presently in effect;

                  (ii) is a partnership, not formed with the specific purpose of
acquiring this Warrant or the shares of Preferred Stock issuable upon exercise
of this Warrant, with total assets in excess of $5 million;

                  (iii) has total assets of approximately $34 million and
aggregate capital commitment obligations from its general and limited partners
of approximately $230 million; and

                  (iv) is a "large institutional accredited investor," as used
in the letter from the Securities and Exchange Commission to Kenneth Koch of
Squadron, Ellenoff, Pleasant and Lehrer dated February 28, 1992.

            (C) PRIVATE ISSUE. The Holder understands (i) that the Preferred
Stock issuable upon exercise of the Holder's rights contained herein is not
registered under the 1933 Act or qualified under applicable state securities
laws on the ground that the issuance contemplated by this Warrant will be exempt
from the registration and qualifications requirements thereof, and (ii) that the
Company's reliance on such exemption is predicated on the representations set
forth in this SECTION 17.

            (D) FINANCIAL RISK. The Holder has such knowledge and experience in
financial and business matters as to be capable of evaluating the merits and
risks of its investment and has the ability to bear the economic risks of its
investment.

            (E) INFORMATION. The Holder acknowledges that it has been afforded
the opportunity to meet with the management of the Company and to ask questions
of, and receive answers from, such management about the business and affairs of
the Company and concerning the terms and conditions of the offering of this
Warrant, and to obtain any additional information, necessary to verify the
accuracy of the information otherwise obtained by or furnished to the Holder in
connection with the offering this Warrant. The Holder agrees that the Company
has furnished to the Holder all information which the Holder considered
necessary to form a decision concerning the purchase this Warrant, and no
request to the Company by the Holder for information of any kind about the
Company has been refused or denied by the Company or remains unfulfilled as of
the date hereof.

            (F) LEGENDS. The Holder acknowledges that certificates for
securities purchased under this Warrant shall bear the following legend or a
legend substantially similar thereto:


                                       5.
<PAGE>
            THE SHARES OF [SERIES C PREFERRED STOCK/COMMON STOCK] REPRESENTED BY
            THIS CERTIFICATE HAVE NOT BEEN REGISTERED UNDER THE SECURITIES ACT
            OF 1933, AS AMENDED, AND MAY NOT BE SOLD OR TRANSFERRED UNLESS THE
            REGISTRATION PROVISIONS OF THE SAID ACT HAVE BEEN COMPLIED WITH OR
            UNLESS THE COMPANY HAS RECEIVED AN OPINION OF COUNSEL IN FORM AND
            SUBSTANCE REASONABLY SATISFACTORY TO THE COMPANY TO THE EFFECT THAT
            COMPLIANCE WITH SUCH PROVISIONS IS NOT REQUIRED.

      18. NOTICES, TRANSFERS, ETC.

            (A) Any notice or written communication required or permitted to be
given to the Holder may be given by certified mail or delivered to the Holder at
the address most recently provided by the Holder to the Company.

            (B) Subject to compliance with applicable federal and state
securities laws, this Warrant may be transferred by the Holder with respect to
any or all of the shares purchasable hereunder; provided, however that (i) the
Holder may not transfer the right to purchase less than 25,000 shares at any one
time, as adjusted hereunder, (ii) the Holder has provided at least twenty (20)
business days notice to the Company prior to the proposed transfer, such notice
to include reasonable information regarding the proposed transferee, (iii) the
Company has approved such transfer, at its sole discretion, in writing prior to
the date of the proposed transfer, provided however that the Holder may transfer
this Warrant in full to an affiliate without the Company's prior written
consent, and (iv) the proposed transferee agrees in writing to be bound by all
provisions of this Warrant as if this Warrant was originally issued to such
proposed transferee. Upon surrender of this Warrant to the Company, together
with the assignment notice annexed hereto duly executed, for transfer of this
Warrant as an entirety by the Holder, and assuming that the previous sentence
has been complied with in full, the Company shall issue a new warrant of the
same denomination to the assignee. Upon surrender of this Warrant to the
Company, together with the assignment hereof properly endorsed, by the Holder
for transfer with respect to a portion of the shares of Preferred Stock
purchasable hereunder, and assuming that the first sentence of this SECTION
18(B) has been complied with in full, the Company shall issue a new warrant to
the assignee, in such denomination as shall be requested by the Holder hereof,
and shall issue to such Holder a new warrant covering the number of shares in
respect of which this Warrant shall not have been transferred.

            (C) In case this Warrant shall be mutilated, lost, stolen or
destroyed, the Company shall issue a new warrant of like tenor and denomination
and deliver the same (i) in exchange and substitution for and upon surrender and
cancellation of any mutilated Warrant, or (ii) in lieu of any Warrant lost,
stolen or destroyed, upon receipt of an affidavit of the Holder or other
evidence reasonably satisfactory to the Company of the loss, theft or
destruction of such Warrant

      19. NO IMPAIRMENT. The Company will not, by amendment of its Articles or
through any reclassification, capital reorganization, consolidation, merger,
sale or conveyance of assets, dissolution, liquidation, issue or sale of
securities or any other voluntary action, avoid or seek to avoid the observance
of performance of any of the terms of this Warrant, but will at all times in
good faith assist in the carrying out of all such terms and in the taking of all
such action as may be necessary or appropriate in order to protect the rights of
the Holder.

      20. GOVERNING LAW. The provisions and terms of this Warrant shall be
governed by and construed in accordance with the internal laws of the State of
Delaware without giving effect to its principles regarding conflicts of laws.

      21. SUCCESSORS AND ASSIGNS. This Warrant shall be binding upon the
Company's successors and assigns and shall inure to the benefit of the Holder's
successors, legal representatives and permitted assigns.

      22. BUSINESS DAYS. If the last or appointed day for the taking of any
action required or the expiration of any rights granted herein shall be a
Saturday or Sunday or a legal holiday in Massachusetts, then such action may


                                       6.
<PAGE>
be taken or right may be exercised on the next succeeding day which is not a
Saturday or Sunday or such a legal holiday.

      23. QUALIFYING PUBLIC OFFERING. If the Company shall effect a firm
commitment underwritten public offering of shares of Common Stock which results
in the conversion of the Preferred Stock into Common Stock pursuant to the
Company's Articles in effect immediately prior to such offering, then, effective
upon such conversion, this Warrant shall change from the right to purchase
shares of Preferred Stock to the right to purchase shares of Common Stock, and
the Holder shall thereupon have the right to purchase, at a total price equal to
that payable upon the exercise of this Warrant in full, the number of shares of
Common Stock which would have been receivable by the Holder upon the exercise of
this Warrant for shares of Preferred Stock immediately prior to such conversion
of such shares of Preferred Stock into shares of Common Stock, and in such event
appropriate provisions shall be made with respect to the rights and interest of
the Holder to the end that the provisions hereof (including, without limitation,
the provisions for the adjustment of the Purchase Price and of the number of
shares purchasable upon exercise of this Warrant and the provisions relating to
the net issue election) shall thereafter be applicable to any shares of Common
Stock deliverable upon the exercise hereof.

      24. NO DAMAGES. In no event shall Holder be liable to the Company for
special, incidental or consequential damages in connection with a breach by
Holder arising under this Warrant, even if Holder was advised of the possibility
of such losses or damages or if such losses or damages could have been
reasonably foreseen.

      25. STATUS OF HOLDER. Except as may be set forth herein or to the extent
the Holder may be entitled to certain rights pursuant to other agreements with
the Company or the Company's stockholders, this Warrant neither entitles the
Holder to any rights, voting or otherwise, nor subjects the Holder to any
responsibilities or liabilities, as a stockholder of the Company.

                Remainder of page intentionally left blank.


                                       7.
<PAGE>
                                          ALNYLAM PHARMACEUTICALS, INC.

                                          By:    /s/ David Neafus
                                                ------------------------

                                          Name:  David Neafus
                                                ------------------------

                                          Title: Interim VP Finance
                                                ------------------------


ACKNOWLEDGED AND AGREED:

LIGHTHOUSE CAPITAL PARTNERS IV, LP

By:  Lighthouse Management Partners IV, LLC, its General Partner

By:     /s/ Thomas Conneely
       ------------------------------
Name:   Thomas Conneely
       -----------------------------
Title:  Vice President
       -----------------------------


                                       8.
<PAGE>
                                  SUBSCRIPTION

To:
   ---------------------------

Date:
     -------------------------


The undersigned hereby subscribes for _________________ shares of Preferred
Stock covered by this Warrant. The certificate(s) for such shares shall be
issued in the name of the undersigned or as otherwise indicated below:

------------------------------
Signature

------------------------------
Name for Registration

------------------------------
Mailing Address


                                       1.
<PAGE>
                            NET ISSUE ELECTION NOTICE

To:                                                         Date:
   ---------------------------                                   -------------


The undersigned hereby elects under SECTION 4 to surrender the right to purchase
shares of Preferred Stock pursuant to this Warrant. The certificate(s) for such
shares issuable upon such net issue election shall be issued in the name of the
undersigned or as otherwise indicated below:

------------------------------
Signature

------------------------------
Name for Registration

------------------------------
Mailing Address


                                       1.
<PAGE>
                                   ASSIGNMENT

For value received _______________________________________________ hereby sells,
assigns and transfers unto  ____________________________________________________
________________________________________________________________________________
[Please print or typewrite name and address of Assignee]
________________________________________________________________________________
the within Warrant, and does hereby irrevocably constitute and appoint
____________________________________ its attorney to transfer the within Warrant
on the books of the within named Company with full power of substitution on the
premises.

Dated:
        ----------------------

------------------------------
Signature

------------------------------
Name for Registration

In the Presence of:

------------------------------


                                       1.
<PAGE>
                                    EXHIBIT A

             AMENDED AND RESTATED CERTIFICATE OF INCORPORATION



                               SEE ATTACHED PAGES.


                                       1.
<PAGE>
                                    EXHIBIT B

                              CAPITALIZATION TABLE


                                       1.
<PAGE>
WARRANT HAVE BEEN REGISTERED UNDER THE SECURITIES ACT OF 1933, AS AMENDED (THE
"1933 ACT"), OR ANY APPLICABLE STATE SECURITIES LAWS, AND NEITHER THIS WARRANT
NOR THE PREFERRED STOCK ISSUABLE UPON EXERCISE OF THIS WARRANT MAY BE SOLD OR
TRANSFERRED UNLESS SUCH SALE OR TRANSFER IS IN ACCORDANCE WITH THE REGISTRATION
REQUIREMENTS OF SUCH ACT AND APPLICABLE LAWS, OR UNLESS THE COMPANY HAS RECEIVED
AN OPINION OF COUNSEL IN FORM AND SUBSTANCE REASONABLY SATISFACTORY TO THE
COMPANY TO THE EFFECT THAT SOME OTHER EXEMPTION FROM THE REGISTRATION
REQUIREMENTS OF SUCH ACT AND APPLICABLE LAWS IS AVAILABLE WITH RESPECT THERETO.

                        PREFERRED STOCK PURCHASE WARRANT

Warrant No. L-2                                       Number of Shares: 50,000
                                                      Series C Preferred Stock


                          ALNYLAM PHARMACEUTICALS, INC.

                         Effective as of March 30, 2004

                      Void after March 30, 2011, or earlier
                  in accordance with SECTION 7 of this Warrant

      1. ISSUANCE. This Preferred Stock Purchase Warrant (the "Warrant") is
issued to LIGHTHOUSE CAPITAL PARTNERS V, L.P. by ALNYLAM PHARMACEUTICALS, INC.,
a Delaware corporation (hereinafter with its successors called the "Company").

      2. PURCHASE PRICE; NUMBER OF SHARES. The registered holder of this Warrant
(the "Holder"), commencing on the date hereof, is entitled upon surrender of
this Warrant with the subscription form annexed hereto duly executed, at the
principal office of the Company, to purchase from the Company, at a price per
share of $5.00 (the "Purchase Price"), 50,000 fully paid and nonassessable
shares of the Company's Series C Preferred Stock, $0.0001 par value (the
"Preferred Stock").

Until such time as this Warrant is exercised in full or expires, the Purchase
Price and the securities issuable upon exercise of this Warrant are subject to
adjustment as hereinafter provided. The person or persons in whose name or names
any certificate representing shares of Preferred Stock is issued hereunder shall
be deemed to have become the holder of record of the shares represented thereby
as at the close of business on the date this Warrant is exercised with respect
to such shares, whether or not the transfer books of the Company shall be
closed.

      3. PAYMENT OF PURCHASE PRICE. The Purchase Price may be paid (i) in cash
by wire transfer of immediately available funds, (ii) by certified check, (iii)
by the surrender by the Holder to the Company of any promissory notes or other
obligations issued by the Company to the Holder, with all such notes and
obligations so surrendered being credited against the Purchase Price in an
amount equal to the principal amount thereof plus accrued interest to the date
of surrender, or (iv) by any combination of the foregoing.

      4. NET ISSUE ELECTION. The Holder may elect to receive, without the
payment by the Holder of any additional consideration, shares of Preferred Stock
equal to the value of this Warrant or any portion hereof by the surrender of
this Warrant or such portion to the Company, with the net issue election notice
annexed hereto duly executed, at the principal office of the Company. Thereupon,
the Company shall issue to the Holder such number of fully paid and
nonassessable shares of Preferred Stock as is computed using the following
formula:


                                       1.
<PAGE>
                                    X= Y(A-B)
                                      -------
                                         A

      where:  X = the number of shares of Preferred Stock to be
                  issued to the Holder pursuant to this SECTION 4.

              Y = the number of shares of Preferred Stock covered by this
                  Warrant in respect of which the net issue election is made
                  pursuant to this SECTION 4.

              A = the Fair Market Value (defined below) of one share of
                  Preferred Stock, as determined at the time the net issue
                  election is made pursuant to this SECTION 4.

              B = the Purchase Price in effect under this Warrant at the time
                  the net issue election is made pursuant to this SECTION 4.

            "Fair Market Value" of a share of Preferred Stock (or fully paid and
nonassessable shares of the Company's common stock, $0.0001 par value (the
"Common Stock") if the Preferred Stock has been automatically converted into
Common Stock) as of the date that the net issue election is made (the
"Determination Date") shall mean:

            (I) If the net issue election is made in connection with and
contingent upon the closing of the sale of the Company's Common Stock to the
public in a public offering pursuant to a Registration Statement under the 1933
Act (a "Public Offering"), and if the Company's Registration Statement relating
to such Public Offering ("Registration Statement") has been declared effective
by the Securities and Exchange Commission, then the initial "Price to Public"
specified in the final prospectus with respect to such offering multiplied by
the number of shares of Common Stock into which each share of Preferred Stock is
then convertible.

            (II) If the net issue election is not made in connection with and
contingent upon a Public Offering, then as follows:

                  (A) If traded on a securities exchange or the Nasdaq National
Market, the fair market value of the Common Stock shall be deemed to be the
average of the closing or last reported sale prices of the Common Stock on such
exchange or market over the five day period ending five trading days prior to
the Determination Date, and the fair market value of the Preferred Stock shall
be deemed to be such fair market value of the Common Stock multiplied by the
number of shares of Common Stock into which each share of Preferred Stock is
then convertible;

                  (B) If otherwise traded in an over-the-counter market, the
fair market value of the Common Stock shall be deemed to be the average of the
closing ask prices of the Common Stock over the five day period ending five
trading days prior to the Determination Date, and the fair market value of the
Preferred Stock shall be deemed to be such fair market value of the Common Stock
multiplied by the number of shares of Common Stock into which each share of
Preferred Stock is then convertible; and

                  (C) If there is no public market for the Common Stock, then
fair market value shall be determined in good faith by the Company's Board of
Directors.

      5. PARTIAL EXERCISE. This Warrant may be exercised in part, and the Holder
shall be entitled to receive a new warrant, which shall be dated as of the date
of this Warrant, covering the number of shares in respect of which this Warrant
shall not have been exercised.

      6. FRACTIONAL SHARES. In no event shall any fractional share of Preferred
Stock be issued upon any exercise of this Warrant. If, upon exercise of this
Warrant in part or in its entirety, the Holder would, except as


                                       2.
<PAGE>
provided in this SECTION 6, be entitled to receive a fractional share of
Preferred Stock, then the Company shall pay the Holder an amount in cash equal
to such fraction of a share multiplied by the Fair Market Value of a share of
Preferred Stock at such time.

      7. EXPIRATION DATE; AUTOMATIC EXERCISE. This Warrant shall expire (the
"Expiration Date") at the earliest to occur of (i) the close of business on
March 30, 2011; (ii) the second anniversary of the effective date of the
Company's initial Public Offering on the NASDAQ or other stock exchange in the
United States; or (iii) the effective date of a Merger (as defined below), and
shall be void thereafter.

"Merger" means: (i) a sale of all or substantially all of the Company's assets
to an Unaffiliated Entity (as defined below), or (ii) the merger, consolidation
or acquisition of the Company with, into or by an Unaffiliated Entity (other
than a merger or consolidation for the principle purpose of changing the
domicile of the Company or a bona fide round of preferred stock equity
financing), that results in the transfer of fifty percent (50%) or more of the
outstanding voting power of the Company. "Unaffiliated Entity" means any entity
that is owned or controlled by parties who own less than twenty percent (20%) of
the combined voting power of the voting securities of the Company immediately
prior to such sale of assets, merger, consolidation or acquisition. The Company
agrees to give the Holder written notice of any proposed Merger in accordance
with SECTION 13, and agrees to give the Holder prompt written notice of
termination of any proposed Merger. Notwithstanding anything to the contrary in
this Warrant, the Holder may rescind any exercise of its purchase rights after a
notice of termination of the proposed Merger if the exercise of this Warrant
occurred after the Company notified the Holder that the Merger was proposed or
if the exercise was otherwise precipitated by such proposed Merger, provided,
however that such rescission right must be exercised within thirty (30) days of
receipt of such written notice of termination of the proposed Merger. In the
event of such rescission, this Warrant will continue to be exercisable on the
same terms and conditions.

Notwithstanding the foregoing, this Warrant shall automatically be deemed to be
exercised in full pursuant to the provisions of SECTION 4 hereof, without any
further action on behalf of the Holder, immediately prior to the time this
Warrant would otherwise expire pursuant to this SECTION 7.

      8. RESERVED SHARES; VALID ISSUANCE. The Company covenants that it will at
all times from and after the date hereof reserve and keep available such number
of its authorized shares of Preferred Stock and Common Stock free from all
preemptive or similar rights therein, as will be sufficient to permit,
respectively, the exercise of this Warrant in full and the conversion into
shares of Common Stock of all shares of Preferred Stock receivable upon such
exercise. The Company further covenants that such shares as may be issued
pursuant to such exercise and/or conversion will, upon issuance, be duly and
validly issued, fully paid and nonassessable and free from all taxes, liens and
charges with respect to the issuance thereof.

      9. STOCK SPLITS AND DIVIDENDS. If after the date hereof the Company shall
subdivide the Preferred Stock, by split-up or otherwise, or combine the
Preferred Stock, or issue additional shares of Preferred Stock in payment of a
stock dividend on the Preferred Stock, the number of shares of Preferred Stock
issuable on the exercise of this Warrant shall forthwith be proportionately
increased in the case of a subdivision or stock dividend, or proportionately
decreased in the case of a combination, and the Purchase Price shall forthwith
be proportionately decreased in the case of a subdivision or stock dividend, or
proportionately increased in the case of a combination.

      10. ADJUSTMENTS FOR DILUTING ISSUANCES. The antidilution rights applicable
to the Preferred Stock of the Company are set forth in the Amended and Restated
Certificate of Incorporation, as amended from time to time (the "Articles"), a
true and complete copy in its current form which is attached hereto as EXHIBIT
A. Until full exercise of the Warrant, such rights shall not be restated,
amended or modified in any manner which affects the Holder differently than the
holders of Preferred Stock without such Holder's prior written consent,
provided, however, that nothing herein shall be deemed to restrict the
restatement, amendment or modification of the Articles, in accordance with the
provisions of the Articles, in a manner that affects equally all holders of
Preferred Stock. The Company shall promptly provide the Holder hereof with any
restatement, amendment or modification to the Articles promptly after the same
has been made.

      11. RECLASSIFICATIONS. If after the date hereof the Company shall enter
into any Reorganization (as hereinafter defined), then, as a condition of such
Reorganization, lawful provisions shall be made, and duly executed documents
evidencing the same from the Company or its successor (if the Reorganization is
not a Merger as defined


                                       3.
<PAGE>
in SECTION 7) shall be delivered to the Holder, so that the Holder shall
thereafter have the right to purchase, at a total price not to exceed that
payable upon the exercise of this Warrant in full, the kind and amount of shares
of stock and other securities and property receivable upon such Reorganization
by a holder of the number of shares of Preferred Stock which might have been
purchased by the Holder immediately prior to such Reorganization, and in any
such case appropriate provisions shall be made with respect to the rights and
interest of the Holder to the end that the provisions hereof (including without
limitation, provisions for the adjustment of the Purchase Price and the number
of shares issuable hereunder and the provisions relating to the net issue
election) shall thereafter be applicable in relation to any shares of stock or
other securities and property thereafter deliverable upon exercise hereof. For
the purposes of this SECTION 11, the term "Reorganization" shall include without
limitation any reclassification, capital reorganization or change of the
Preferred Stock (other than a Merger as defined in SECTION 7, or as a result of
or subdivision, combination or stock dividend provided for in SECTION 9 hereof).

      12. CERTIFICATE OF ADJUSTMENT. Whenever the Purchase Price is adjusted, as
herein provided, the Company shall promptly deliver to the Holder a certificate
of the Company's chief financial officer setting forth the Purchase Price after
such adjustment and setting forth a brief statement of the facts requiring such
adjustment.

      13. NOTICES OF RECORD DATE, ETC. In the event of:

            (A) any taking by the Company of a record of the holders of any
class of securities for the purpose of determining the holders thereof who are
entitled to receive any dividend or other distribution, or any right to
subscribe for, purchase, sell or otherwise acquire or dispose of any shares of
stock of any class or any other securities or property, or to receive any other
right;

            (B) any reclassification of the capital stock of the Company,
capital reorganization of the Company, consolidation or merger involving the
Company, or sale or conveyance of all or substantially all of its assets; or

            (C) any voluntary or involuntary dissolution, liquidation or
winding-up of the Company;

then in each such event the Company will provide or cause to be provided to the
Holder a written notice thereof. Such notice shall be provided at least twenty
(20) business days prior to the date specified in such notice on which any such
action is to be taken.

      14. REPRESENTATIONS, WARRANTIES AND COVENANTS. This Warrant is issued and
delivered by the Company and accepted by each Holder on the basis of the
following representations, warranties and covenants made by the Company:

            (A) The Company has all necessary authority to issue, execute and
deliver this Warrant and to perform its obligations hereunder. This Warrant has
been duly authorized issued, executed and delivered by the Company and is the
valid and binding obligation of the Company, enforceable in accordance with its
terms.

            (B) The shares of Preferred Stock issuable upon the exercise of this
Warrant have been duly authorized and reserved for issuance by the Company and,
when issued in accordance with the terms hereof, will be validly issued, fully
paid and nonassessable.

            (C) The issuance, execution and delivery of this Warrant do not, and
the issuance of the shares of Preferred Stock upon the exercise of this Warrant
in accordance with the terms hereof will not violate or contravene the Company's
Articles or by-laws, or any law, statute, regulation, rule, judgment or order
applicable to the Company.

            (D) So long as this Warrant has not terminated, and at any time
prior to the Public Offering, Holder shall be entitled to receive such financial
and other information as the Holder would be entitled to receive under the Stock
Purchase Agreement applicable to the Preferred Stock if Holder were a holder of
that number of shares issuable upon full exercise of this Warrant.


                                       4.
<PAGE>
            (E) Attached hereto as EXHIBIT B is a capitalization table setting
forth the capitalization of the Company as of March 19, 2004.

      15. INTENTIONALLY OMITTED

      16. AMENDMENT. The terms of this Warrant may be amended, modified or
waived only with the written consent of the Company and the Holder.

      17. REPRESENTATIONS, WARRANTIES AND COVENANTS OF THE HOLDER. This Warrant
has been entered into by the Company in reliance upon the following
representations and covenants of the Holder, which by its execution hereof the
Holder hereby confirms:

            (A) INVESTMENT PURPOSE. The right to acquire Preferred Stock or the
Preferred Stock issuable upon exercise of the Holder's rights contained herein
will be acquired for investment and not with a view to the sale or distribution
of any part thereof, and the Holder has no present intention of selling or
engaging in any public distribution of the same except pursuant to a
registration or exemption.

            (B) ACCREDITED INVESTOR. This Warrant does not and will not
when exercised constitute a principal portion of the Holder's total assets
and Holder:

                  (i) is an "accredited investor" within the meaning of
Rule 501 of Regulation D of the 1933 Act, as presently in effect;

                  (ii) is a partnership, not formed with the specific purpose of
acquiring this Warrant or the shares of Preferred Stock issuable upon exercise
of this Warrant, with total assets in excess of $5 million;

                  (iii) has total assets of approximately $34 million and
aggregate capital commitment obligations from its general and limited partners
of approximately $365 million; and

                  (iv) is a "large institutional accredited investor," as used
in the letter from the Securities and Exchange Commission to Kenneth Koch of
Squadron, Ellenoff, Pleasant and Lehrer dated February 28, 1992.

            (C) PRIVATE ISSUE. The Holder understands (i) that the Preferred
Stock issuable upon exercise of the Holder's rights contained herein is not
registered under the 1933 Act or qualified under applicable state securities
laws on the ground that the issuance contemplated by this Warrant will be exempt
from the registration and qualifications requirements thereof, and (ii) that the
Company's reliance on such exemption is predicated on the representations set
forth in this SECTION 17.

            (D)   FINANCIAL RISK.  The Holder has such knowledge and
experience in financial and business matters as to be capable of
evaluating the merits and risks of its investment and has the ability to
bear the economic risks of its investment.

            (E) INFORMATION. The Holder acknowledges that it has been afforded
the opportunity to meet with the management of the Company and to ask questions
of, and receive answers from, such management about the business and affairs of
the Company and concerning the terms and conditions of the offering of this
Warrant, and to obtain any additional information, necessary to verify the
accuracy of the information otherwise obtained by or furnished to the Holder in
connection with the offering this Warrant. The Holder agrees that the Company
has furnished to the Holder all information which the Holder considered
necessary to form a decision concerning the purchase this Warrant, and no
request to the Company by the Holder for information of any kind about the
Company has been refused or denied by the Company or remains unfulfilled as of
the date hereof.

            (F) LEGENDS. The Holder acknowledges that certificates for
securities purchased under this Warrant shall bear the following legend or a
legend substantially similar thereto:


                                       5.
<PAGE>
            THE SHARES OF [SERIES C PREFERRED STOCK/COMMON STOCK] REPRESENTED BY
            THIS CERTIFICATE HAVE NOT BEEN REGISTERED UNDER THE SECURITIES ACT
            OF 1933, AS AMENDED, AND MAY NOT BE SOLD OR TRANSFERRED UNLESS THE
            REGISTRATION PROVISIONS OF THE SAID ACT HAVE BEEN COMPLIED WITH OR
            UNLESS THE COMPANY HAS RECEIVED AN OPINION OF COUNSEL IN FORM AND
            SUBSTANCE REASONABLY SATISFACTORY TO THE COMPANY TO THE EFFECT THAT
            COMPLIANCE WITH SUCH PROVISIONS IS NOT REQUIRED.

      18. NOTICES, TRANSFERS, ETC.

            (A) Any notice or written communication required or permitted to be
given to the Holder may be given by certified mail or delivered to the Holder at
the address most recently provided by the Holder to the Company.

            (B) Subject to compliance with applicable federal and state
securities laws, this Warrant may be transferred by the Holder with respect to
any or all of the shares purchasable hereunder; provided, however that (i) the
Holder may not transfer the right to purchase less than 25,000 shares at any one
time, as adjusted hereunder, (ii) the Holder has provided at least twenty (20)
business days notice to the Company prior to the proposed transfer, such notice
to include reasonable information regarding the proposed transferee, (iii) the
Company has approved such transfer, at its sole discretion, in writing prior to
the date of the proposed transfer, provided however that the Holder may transfer
this Warrant in full to an affiliate without the Company's prior written
consent, and (iv) the proposed transferee agrees in writing to be bound by all
provisions of this Warrant as if this Warrant was originally issued to such
proposed transferee. Upon surrender of this Warrant to the Company, together
with the assignment notice annexed hereto duly executed, for transfer of this
Warrant as an entirety by the Holder, and assuming that the previous sentence
has been complied with in full, the Company shall issue a new warrant of the
same denomination to the assignee. Upon surrender of this Warrant to the
Company, together with the assignment hereof properly endorsed, by the Holder
for transfer with respect to a portion of the shares of Preferred Stock
purchasable hereunder, and assuming that the first sentence of this SECTION
18(B) has been complied with in full, the Company shall issue a new warrant to
the assignee, in such denomination as shall be requested by the Holder hereof,
and shall issue to such Holder a new warrant covering the number of shares in
respect of which this Warrant shall not have been transferred.

            (C) In case this Warrant shall be mutilated, lost, stolen or
destroyed, the Company shall issue a new warrant of like tenor and denomination
and deliver the same (i) in exchange and substitution for and upon surrender and
cancellation of any mutilated Warrant, or (ii) in lieu of any Warrant lost,
stolen or destroyed, upon receipt of an affidavit of the Holder or other
evidence reasonably satisfactory to the Company of the loss, theft or
destruction of such Warrant

      19. NO IMPAIRMENT. The Company will not, by amendment of its Articles or
through any reclassification, capital reorganization, consolidation, merger,
sale or conveyance of assets, dissolution, liquidation, issue or sale of
securities or any other voluntary action, avoid or seek to avoid the observance
of performance of any of the terms of this Warrant, but will at all times in
good faith assist in the carrying out of all such terms and in the taking of all
such action as may be necessary or appropriate in order to protect the rights of
the Holder.

      20. GOVERNING LAW. The provisions and terms of this Warrant shall be
governed by and construed in accordance with the internal laws of the State of
Delaware without giving effect to its principles regarding conflicts of laws.

      21. SUCCESSORS AND ASSIGNS. This Warrant shall be binding upon the
Company's successors and assigns and shall inure to the benefit of the Holder's
successors, legal representatives and permitted assigns.

      22. BUSINESS DAYS. If the last or appointed day for the taking of any
action required or the expiration of any rights granted herein shall be a
Saturday or Sunday or a legal holiday in Massachusetts, then such action may


                                       6.
<PAGE>
be taken or right may be exercised on the next succeeding day which is not a
Saturday or Sunday or such a legal holiday.

      23. QUALIFYING PUBLIC OFFERING. If the Company shall effect a firm
commitment underwritten public offering of shares of Common Stock which results
in the conversion of the Preferred Stock into Common Stock pursuant to the
Company's Articles in effect immediately prior to such offering, then, effective
upon such conversion, this Warrant shall change from the right to purchase
shares of Preferred Stock to the right to purchase shares of Common Stock, and
the Holder shall thereupon have the right to purchase, at a total price equal to
that payable upon the exercise of this Warrant in full, the number of shares of
Common Stock which would have been receivable by the Holder upon the exercise of
this Warrant for shares of Preferred Stock immediately prior to such conversion
of such shares of Preferred Stock into shares of Common Stock, and in such event
appropriate provisions shall be made with respect to the rights and interest of
the Holder to the end that the provisions hereof (including, without limitation,
the provisions for the adjustment of the Purchase Price and of the number of
shares purchasable upon exercise of this Warrant and the provisions relating to
the net issue election) shall thereafter be applicable to any shares of Common
Stock deliverable upon the exercise hereof.

      24. NO DAMAGES. In no event shall Holder be liable to the Company for
special, incidental or consequential damages in connection with a breach by
Holder arising under this Warrant, even if Holder was advised of the possibility
of such losses or damages or if such losses or damages could have been
reasonably foreseen.

      25. STATUS OF HOLDER. Except as may be set forth herein or to the extent
the Holder may be entitled to certain rights pursuant to other agreements with
the Company or the Company's stockholders, this Warrant neither entitles the
Holder to any rights, voting or otherwise, nor subjects the Holder to any
responsibilities or liabilities, as a stockholder of the Company.

                Remainder of page intentionally left blank.

                                       7.
<PAGE>
                                          ALNYLAM PHARMACEUTICALS, INC.

                                          By:    /s/ David Neafus
                                                ------------------------

                                          Name:  David Neafus
                                                ------------------------

                                          Title: Interim VP Finance
                                                ------------------------


ACKNOWLEDGED AND AGREED:

LIGHTHOUSE CAPITAL PARTNERS IV, LP

By:  Lighthouse Management Partners IV, LLC, its General Partner

By:     /s/ Thomas Conneely
       ------------------------------
Name:   Thomas Conneely
       -----------------------------
Title:  Vice President
       -----------------------------


                                       8.
<PAGE>
                                  SUBSCRIPTION

To:
   ---------------------------

Date:
     -------------------------


The undersigned hereby subscribes for _________________ shares of Preferred
Stock covered by this Warrant. The certificate(s) for such shares shall be
issued in the name of the undersigned or as otherwise indicated below:

------------------------------
Signature

------------------------------
Name for Registration

------------------------------
Mailing Address


                                       1.
<PAGE>
                            NET ISSUE ELECTION NOTICE

To:                                                         Date:
   ---------------------------                                   -------------


The undersigned hereby elects under SECTION 4 to surrender the right to purchase
shares of Preferred Stock pursuant to this Warrant. The certificate(s) for such
shares issuable upon such net issue election shall be issued in the name of the
undersigned or as otherwise indicated below:

------------------------------
Signature

------------------------------
Name for Registration

------------------------------
Mailing Address


                                       1.
<PAGE>
                                   ASSIGNMENT

For value received _______________________________________________ hereby sells,
assigns and transfers unto  ____________________________________________________
________________________________________________________________________________
[Please print or typewrite name and address of Assignee]
________________________________________________________________________________
the within Warrant, and does hereby irrevocably constitute and appoint
____________________________________ its attorney to transfer the within Warrant
on the books of the within named Company with full power of substitution on the
premises.

Dated:
        ----------------------

------------------------------
Signature

------------------------------
Name for Registration

In the Presence of:

------------------------------


                                       1.