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REPORTOF INDEPENDENTREGISTEREDPUBLICACCOUNTINGFIRM
TheBoardofDirectors andStockholders of Isis Pharmaceuticals, Inc.
We have audited Isis Pharmaceuticals, Inc.’s internal control over financial reporting as ofDecember 31, 2013, basedon criteria
established in Internal Control—IntegratedFramework issuedby theCommittee of SponsoringOrganizations of theTreadway
Commission (1992 framework) (theCOSO criteria). Isis Pharmaceuticals, Inc.’smanagement is responsible formaintaining effective
internal control over financial reporting, and for its assessment of the effectiveness of internal control over financial reporting included
in the accompanyingManagement’sReport on Internal Control over Financial Reporting. Our responsibility is to express anopinion
on the company’s internal control over financial reportingbasedonour audit.
We conductedour audit in accordancewith the standards of thePublicCompanyAccountingOversight Board (UnitedStates). Those
standards require thatwe plan andperform the audit toobtain reasonable assurance aboutwhether effective internal control over
financial reportingwasmaintained in allmaterial respects. Our audit includedobtaining anunderstandingof internal control over
financial reporting, assessing the risk that amaterial weakness exists, testing and evaluating the design and operating effectiveness of
internal control basedon the assessed risk, andperforming suchother procedures aswe considerednecessary in the circumstances.
We believe that our audit provides a reasonable basis for our opinion.
A company’s internal control over financial reporting is a process designed toprovide reasonable assurance regarding the reliabilityof
financial reporting and the preparationof financial statements for external purposes in accordancewithgenerally accepted accounting
principles. A company’s internal control over financial reporting includes those policies andprocedures that (1) pertain to the
maintenance of records that, in reasonable detail, accurately and fairly reflect the transactions anddispositions of the assets of the
company; (2) provide reasonable assurance that transactions are recorded as necessary to permit preparationof financial statements in
accordancewithgenerally accepted accounting principles, and that receipts and expenditures of the company are beingmade only in
accordancewith authorizations ofmanagement anddirectors of the company; and (3) provide reasonable assurance regarding
preventionor timelydetectionof unauthorized acquisition, use, or dispositionof the company’s assets that couldhave amaterial effect
on the financial statements.
Because of its inherent limitations, internal control over financial reportingmay not prevent or detectmisstatements. Also, projections
of any evaluation of effectiveness to future periods are subject to the risk that controlsmaybecome inadequate because of changes in
conditions, or that the degree of compliancewith the policies or proceduresmaydeteriorate.
Inour opinion, Isis Pharmaceuticals, Inc.maintained, in allmaterial respects, effective internal control over financial reporting as of
December 31, 2013, basedon theCOSO criteria.
We alsohave audited, in accordancewith the standards of thePublicCompanyAccountingOversight Board (UnitedStates), the
consolidatedbalance sheets of Isis Pharmaceuticals, Inc. as ofDecember 31, 2013 and 2012, and the related statements of operations,
comprehensive loss, stockholders’ equity, and cash flows for each of the three years in the period endedDecember 31, 2013of Isis
Pharmaceuticals, Inc. andour report datedFebruary28, 2014 expressed anunqualifiedopinion thereon.
/s/ ERNST&YOUNGLLP
SanDiego, California
February28, 2014
