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February 24, 2009

By EDGAR Transmission

Securities and Exchange Commission

Division of Corporate Finance

100 F Street, N.E., Mail Stop 6010

Washington, D.C. 20549

Attention: Christine Allen

    Re:

    Alnylam Pharmaceuticals, Inc.

Form 10-K for the Fiscal Year Ended December 31, 2007

File No. 000-50743

Ladies and Gentlemen:

On behalf of Alnylam Pharmaceuticals, Inc. (the “Company”), I am writing in response to comments
contained in the letter dated February 20, 2009 (the “Letter”) from Jim B. Rosenberg of the Staff
(the “Staff”) of the Securities and Exchange Commission (the “Commission”) to John M. Maraganore,
the Company’s Chief Executive Officer. The responses set forth below are keyed to the numbering of
the comments and the headings used in the Letter.

Intellectual Property Related to Fundamental Aspects and Uses of siRNA and RNAi related
Mechanisms, page 18

    1.

    In response to our previous comment 3, you state that you will include the expiration dates
of patents material to your business in future filings. Please respond with the disclosure
relating to these patents that you propose to include in future filings.

    Response:

    In response to previous comment 3, the Company intends to include a revised table,
including a column with expiration dates, and revised disclosure substantially similar
to that set forth below in its Form 10-K for the year ended December 31, 2008:

“Intellectual Property Related to Fundamental Aspects and Uses of siRNA and RNAi-related Mechanisms

In this category, we include United States and foreign patents and patent applications that claim
key aspects of siRNA architecture and RNAi-related mechanisms. Specifically included are patents
and patent applications covering targeted cleavage of mRNA directed by RNA-like oligonucleotides,
double-stranded RNAs of particular lengths and particular structural features,

Securities and Exchange Commission

February 24, 2009

Page 2

such as blunt and/or overhanging ends. Our strategy has been to secure exclusive rights where
possible and appropriate to key patents and patent applications we believe cover fundamental
aspects of RNAi. The following table lists patents and/or patent applications to which we have
secured rights that we regard as being fundamental for the use of siRNAs as therapeutics.

    Licensor/Patent

    First Priority

    Status

    Owner

    Subject Matter

    Date

    Inventors

    Patent Number

    Expiration Date*

    Alnylam Rights

    Isis

    Inactivation of
target mRNA

    6/6/1996 and
6/6/1997

    S. Crooke

    U.S. 5,898,031,
U.S. 6,107,094 &
U.S. 7,432,250

    06/06/2016

    Exclusive rights
for therapeutic
purposes related to
siRNAs**

    EP 0928290

    06/06/2017

    Additional applications pending in the
U.S. and several foreign jurisdictions

    Carnegie
Institution of
Washington

    Double-stranded
RNAs to induce RNAi

    12/23/1997

    A. Fire,
C. Mello

    U.S. 6,506,559

    12/18/2018

    Non-exclusive

rights for

therapeutic

purposes

    Additional applications pending in the
U.S. and several foreign jurisdictions

    Medical College of
Georgia Research
Institute, Inc.

    Methods for

inhibiting gene

expression using

double-stranded RNA

    1/28/1999

    Y. Li, M, Farrell,
M. Kirby

    AU 776150

(Australia)

    1/28/2020

    Exclusive rights

    Additional applications pending in the
U.S., Europe and Canada

    Alnylam

    Small double-

stranded RNAs as therapeutic

products

    1/30/1999

    R. Kreutzer, S.
Limmer

    EP 1214945

(revoked/to be

appealed) & EP

1550719,

CA 2359180

(Canada),

AU 778474

(Australia),

ZA 2001/5909 (South Africa)

DE 20023125 U1, DE

10066235 & DE

10080167 (Germany)

    01/29/2020

    Owned

    Additional applications pending in the
U.S. and several foreign jurisdictions

    Alnylam

    Composition and
methods for
inhibiting a target
nucleic acid with
double-stranded RNA

    4/21/1999

    C. Pachuk, C.
Satishchandran

    AU 781598

(Australia)

    4/19/2020

    Owned

    Additional applications pending in the
U.S. and many other additional countries
worldwide

    Cancer Research
Technology Limited

    RNAi uses in
mammalian oocytes,
preimplantation
embryos and somatic
cells

    11/19/1999

    M. Zernicka-Goetz,
M.J. Evans, D.M.
Glover

    EP 1230375

(revoked/to be

appealed), SG 89569

(Singapore),

AU 774285

(Australia)

    11/17/2020

    Exclusive rights

for therapeutic

purposes

    Additional applications pending in the
U.S. and several foreign jurisdictions

Securities and Exchange Commission

February 24, 2009

Page 3

    Licensor/Patent

    First Priority

    Status

    Owner

    Subject Matter

    Date

    Inventors

    Patent Number

    Expiration Date*

    Alnylam Rights

    Massachusetts
Institute of
Technology,
Whitehead
Institute, Max
Planck
Gesellschaft***

    Mediation of RNAi
by small RNAs 21-23
base pairs long

    3/30/2000

    D.P. Bartel, P.A.
Sharp, T. Tuschl,
P.D. Zamore

    AU 2001249622

(Australia)

    03/30/2020

    Non-exclusive

rights for

therapeutic

purposes***

    Additional applications pending in the
U.S. and many other additional countries
worldwide

    Max Planck

Gesellschaft

    Synthetic and
chemically modified
siRNAs as
therapeutic
products

    12/01/2000,
04/24/2004 and
04/27/2004

    T. Tuschl, S.
Elbashir, W.
Lendeckel

    U.S. 7,056,704 &
U.S. 7,078,196,
EP 1407044,
AU 2002235744
(Australia),
ZA 2003/3929 (South
Africa), SG 96891
(Singapore),
NZ 52588 (New
Zealand),
JP 4 095 895,
RU 2322500 (Russia)

    11/29/2021

    Exclusive rights

for therapeutic

purposes

    Additional applications pending in the
U.S. and many other countries worldwide

    Alnylam

    Methods for
inhibiting a target
nucleic acid via
the introduction of
a vector encoding a
double-stranded RNA

    1/31/2001

    T. Giordano, C.
Pachuk, C.
Satishchandran

    AU 785395

(Australia)

    1/31/2021

    Owned

    Additional applications pending in the
U.S., Australia and Canada

    Cold Spring Harbor

Laboratory

    RNAi uses in

mammalian cells

    3/16/2001

    D. Beach, G. Hannon

    Pending in the U.S. and  many countries
worldwide

    Non-exclusive

rights for

therapeutic

purposes

    Stanford University

    RNAi uses in vivo in mammalian liver

    7/23/2001

    M.A. Kay, A.P.
McCaffrey

    AU 2002326410

(Australia)

    7/23/2021

    Exclusive rights

for therapeutic

purposes

    Additional applications pending in the
U.S. and many other countries worldwide

    *

    For applications filed after June 7, 1995, the patent term generally
is 20 years from the earliest application filing date. However, under
the Drug Price Competition and Patent Term Extension Act of 1984,
known as the Hatch-Waxman Act, we may be able to apply for patent term
extensions for our U.S. patents. We cannot predict whether or not any
patent term extensions will be granted or the length of any patent
term extension that might be granted.

    **

    We hold co-exclusive therapeutic rights with Isis. However, Isis has
agreed not to license such rights to any third party, except in the
context of a collaboration in which Isis plays an active role.

    ***

    We hold exclusive rights to the interest owned by three co-owners. A
separate entity, the University of Massachusetts, has licensed its
purported interest separately to third parties.

Intellectual Property Related to Chemical Modifications

Our collaboration and license agreement with Isis provides us with rights to practice the
inventions covered by over 200 issued patents worldwide, as well as rights based on future
chemistry patent applications through March 2009. These patents will expire both in and outside the
United States generally between 2009 and 2029, subject to any potential patent term

Securities and Exchange Commission

February 24, 2009

Page 4

extensions and/or supplemental protection certificates extending such term extensions in countries
where such extensions may become available. These inventions cover chemical modifications we may
wish to incorporate into our RNAi therapeutic products. Under the terms of our license agreement,
Isis agreed not to grant licenses under these patents to any other organization for dsRNA products
designed to work through an RNAi mechanism, except in the context of a collaboration in which Isis
plays an active role.

Intellectual Property Related to siRNAs Directed to Specific Targets

We have filed a number of patent applications claiming specific siRNAs directed to various gene
targets that correlate to specific diseases. While there may be a significant number of competing
applications filed by other organizations claiming siRNAs to treat the same gene target, we were
among the first companies to focus and file on RNAi therapeutics, and thus, we believe that a
number of our patent applications may predate competing applications that others may have filed.
Reflecting this, in August 2005, the EPO granted a broad patent, which we call the Kreutzer-Limmer
II patent, with 103 allowed claims on therapeutic compositions, methods and uses comprising siRNAs
that are complementary to mRNA sequences in over 125 disease target genes. The Kreutzer-Limmer II
patent will expire on January 9, 2022, subject to any potential patent term extensions and/or
supplemental protection certificates extending such term extensions in countries where such
extensions may become available. Some of these claimed gene targets are being pursued by our
development and pre-clinical programs, such as those expressed by viral pathogens including RSV and
influenza virus. In addition, the claimed targets include oncogenes, cytokines, cell adhesion
receptors, angiogenesis targets, apoptosis and cell cycle targets, and additional viral disease
targets, such as hepatitis C virus and HIV. The Kreutzer-Limmer II patent series is pending in the
United States and many foreign countries.”

Material Agreements

    2.

    We note your response that you analyzed each agreement for materiality and that you
determined that the agreements are not material, and thus do not need to be filed as exhibits
as required by Item 601(b)(10) of Regulation S-K. Please provide us a comprehensive analysis,
including any relevant facts and circumstances you considered, that led to your conclusions
that these agreements are not material.

    Response:
    Item 601(b)(10)(ii)(B) of Regulation S-K clarifies that if an agreement is such as
ordinarily accompanies the kind of business conducted by the registrant, it will be
deemed to be made in the ordinary course of business, and therefore not required to be
filed, unless the agreement is, among other things, one “upon which the registrant’s
business is substantially dependent.”

    The Company has concluded that its license agreements with Tekmira
Pharmaceuticals Corporation (“Tekmira”) and the Massachusetts Institute of
Technology (“MIT”) were made in the ordinary course of the

Securities and Exchange Commission

February 24, 2009

Page 5

    Company’s business and that its business is not substantially dependent on
either agreement.

    Patent protection is critical to success in the research-based biotechnology
industry. Accordingly, license agreements are very much a part of the
ordinary course of business in the industry. In addition, as disclosed in
its periodic filings, including Forms 10-K and 10-Q, part of the Company’s
strategy is to identify and acquire rights to drug delivery technology for
its RNAi therapeutic candidates. As part of this strategy, the Company has
entered into, and intends to continue to enter into, agreements with respect
to delivery technology. The license agreements with Tekmira and MIT,
pursuant to which the Company has in-licensed delivery technology, are part
of this ordinary course business strategy.

    In considering the materiality of license agreements for purposes of the
exhibit requirements under Item 601(b)(10)(ii)(B), the Company considers the
following factors:

    •

    The impact to the Company’s business (including the freedom to
develop and commercialize RNAi therapeutics and the cost impact) in the
event the license was not available;

    •

    The applicability of the technology to the Company’s drug
development platform and/or drug development strategy;

    •

    The stage of development and value of the therapeutic(s) for which
the technology is relevant and the importance of such technology to the
successful development and commercialization of such therapeutics; and

    •

    The amount and timing of payments under the license agreement.

    By definition, the exhibit requirements under Item 601(b)(10)(ii)(B) do not
apply to licenses upon which the Company’s business is not substantially
dependent. The Company acknowledges that its business is substantially
dependent on licenses to fundamental patents applicable to all siRNAs and to
certain chemistry patents broadly applicable to siRNAs. However, the Company
does not currently believe its business is substantially dependent on
licenses to technology, such as the delivery technology in-licensed from
Tekmira and MIT, that is not broadly applicable to siRNAs.

    The Company believes it will likely be required to employ a different
delivery technology for each RNAi therapeutic candidate that it develops.
For example, while the Company is currently using the liposomal delivery
technology licensed under the Tekmira agreement in its Phase I ALN-VSP
product candidate, it will not use such technology with its lead product,

Securities and Exchange Commission

February 24, 2009

Page 6

    ALN-RSV. Furthermore, the Company does not yet know whether it will
successfully develop any therapies incorporating the technology licensed
under the Tekmira or MIT license agreement. Examples of other drug delivery
technologies that the Company will likely consider utilizing include (i)
polymers, (ii) cholesterol conjugates, (iii) carbohydrate conjugates, (iv)
antibodies and (v) peptides or other proteins.

    The annual payments that the Company made to each of Tekmira and MIT
represented less than 2% of the Company’s total operating expenses in 2007
and 2008. Until the Company is required to pay milestones or royalties, as
described below, its annual payment obligations under the agreements will
not increase.

    Under the Tekmira agreement, the Company will be required to make
development milestone payments totaling up to $10.0 million, sales milestone
payments totaling up to $6.0 million and royalty payments on sales, if any,
of products using the licensed technology. Under the MIT agreement, the
Company will be required to make development milestone payments totaling up
to $1.25 million and to pay royalties on sales, if any, of products using
the licensed technology. The Company expects that, if and when it is
required to make milestone or royalty payments under either the Tekmira or
MIT agreement, such payments will not represent a material percentage of its
operating expenses or cash, cash equivalents and marketable securities.
Accordingly, the Company does not believe that the payment of development or
sales milestones will be material to its results of operations or financial
condition, especially when considering that the payment of development
milestones would indicate positive developments that could lead to
additional revenue.

    The Company expects to explore numerous delivery technologies as it builds
its product pipeline and as drug delivery technologies evolve and also
expects to continue to enter into drug delivery license agreements in the
ordinary course of its business. The Company believes it is unlikely that
any such technology will be broadly applicable to RNAi therapeutics and,
therefore, does not currently anticipate that its business will be
substantially depend