RESTATED ISIS PHARMACEUTICALS, INC.
10B5-1 TRADING PLAN

        This 10b5-1 Trading Plan, (the "Trading Plan"), between Isis Pharmaceuticals, Inc. ("Isis") and Golden Triangle Securities llc ("Broker"), is entered into on February 22, 2002. Capitalized terms not otherwise defined herein will have the meanings given to them in Exhibit A attached hereto.

Recitals.

        (a)  This Trading Plan is entered into between Isis and Broker for the purpose of establishing a trading plan that complies with the requirements of Rule 10b5-1(c) under the Exchange Act.

        (b)  The purpose of this Trading Plan is to provide a mechanism by which eligible Sellers can orderly dispose of a portion of each Seller's holdings of Stock, including Stock that such Seller has the right to acquire under the Options.

        (c)  Isis and Broker hereby agree as follows:

Appointment. Isis hereby appoints and authorizes Broker to sell shares of Stock pursuant to the terms and conditions set forth below and in the applicable Sellers Plan. Subject to the terms and conditions set forth below, Broker hereby accepts such appointment.

Sellers Plans. Each Seller may establish up to three individual Sellers Plans with Broker in any Sales Period. In connection with such Sellers Plans, each Seller will establish an account at Broker in the name of and for the benefit of Seller (the "Plan Account"). Sales under each Sellers Plan cannot begin until the Broker receives (i) the Plan Shares, to the extent such Plan Shares are currently owned by Seller, (ii) a properly executed Seller Representation Letter and (iii) a properly completed and executed Sellers Plan, including an acknowledgment by Isis.

Obligations of Broker. With respect to each Sellers Plan, Broker will have the following obligations:

        (a)  Broker will sell the Plans Shares for the account of each Seller according to the terms of the Seller's Sellers Plan.

        (b)  Broker will not sell any Stock when broker is in possession of any material nonpublic information concerning Isis or its securities.

        (c)  Once a Sellers Plan becomes effective, Broker will not allow Seller to exercise, any influence over how, when or whether to effect sales of Stock pursuant to the Sellers Plan.

        (d)  Broker will withdraw Stock from Seller's Plan Account in order to effect sales of Stock under Seller's Sellers Plan. Broker will exercise Options to effect such sales according to the Seller's Option Priority Guidelines.

        (e)  Broker will deliver the proceeds from each sale of unrestricted Stock effected under a Sellers Plan to Seller's Account on a normal three-day settlement basis less any commission, commission equivalent, mark-up or differential and other expenses of sale to be paid to Broker. With respect to each sale of restricted Stock, Broker will deliver the net proceeds from such sales as soon as reasonably practicable.

        (f)    Broker will, in connection with the exercise of Options, remit to Isis the exercise price thereof along with such amounts as may be necessary to satisfy withholding obligations. These amounts will be deducted from the proceeds of the sale of the Stock.

        (g)  To the extent that any Stock remains in the Plan Account upon termination of the Sellers Plan, Broker agrees to return such Stock promptly to the Seller.

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        (h)  Broker agrees to conduct all sales pursuant to each Sales Plan in accordance with the manner of sale requirement of Rule 144 of the Securities Act and in no event will Broker effect any sale if such sale would exceed the then-applicable amount limitation under Rule 144 or will violate the "short-swing profit" provisions of Section 16 of the Exchange Act. Broker will file Forms 144 on behalf of Seller as required by applicable law.

        (i)    Promptly after each Sale, Broker will advise Seller in writing as to the number of shares of Stock sold, the date of each sale and the sales price.

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