Exhibit 10.21
 FOURTH AMENDMENT
 UTC PROPERTIES LLC CYPRESS
BIOSCIENCE, INC.
 RECITALS
 A.
    
    Landlord (as successor in interest to CA-Park Plaza Limited Partnership, a Delaware limited
partnership, as successor by conversion to EOP-Park Plaza, L.L.C., a Delaware limited
liability company) and Tenant are parties to that certain lease dated July 10, 2002, which
lease has been previously amended by a First Amendment dated September 6, 2006, Second
Amendment dated July 30, 2008 and a Third Amendment dated March 17, 2009 (collectively, the
Lease). Pursuant to the Lease, Landlord has leased to Tenant space currently containing
approximately 7,565rentable square feet (the Premises) described as Suite No. 315 (Suite
315), consisting of approximately 1,892 rentable square feet, and Suite No. 325, consisting
of approximately 5,673 rentable square feet, on the 3rd floor of the building
located at 4350 Executive Drive, San Diego, California (the Building).B.
    
    The Lease with respect to Suite 315 by its terms shall expire on December 31, 2009 (Suite
315 Extended Termination Date), the Lease with respect to Suite 325 by its terms shall expire
on July 31, 2012 and the parties desire to extend the Term of the Lease with respect to Suite
315 only, all on the following terms and conditions.
 NOW, THEREFORE
 I.
    
    Suite 315 Extension. The Term of the Lease with respect to Suite 315 only is hereby
extended and shall expire on December 31, 2010 (the Suite 315 Extended Expiration Date),
unless sooner terminated in accordance with the terms of the Lease. That portion of the Term
commencing the day immediately following the Suite 315 Extended Termination Date (Suite 315
Second Extension Date) and ending on the Suite 315 Extended Expiration Date shall be referred
to herein as the Suite 315 Second Extended Term.II.
    
    Suite 315 Base Rent. As of the Suite 315 Second Extension Date, the schedule of Base
Rent payable with respect to the Premises during the Extended Term is the following:
 Monthly Rate PerMonths of Term or Period
    
    Square Foot
    
    Monthly Base Rent1/01/10  12/31/10
    
    $2.45
    
    $4,635.00
 All such Base Rent shall be payable by Tenant in accordance with the terms of the Lease.
 III.
    
    Suite 315 Expenses and Taxes. For the period commencing on the Suite 315 Second
Extension Date and ending on the Suite 315 Extended Expiration Date, Tenant shall be obligated
to pay Tenants Pro Rata Share of Expenses and Taxes accruing in connection with Suite 315 in
accordance with the terms of the Lease, as previously amended in the Second Amendment.IV.
    
    Additional Security Deposit. No additional security deposit shall be required in
connection with this Amendment.V.
    
    Improvements to Premises.
 A.
    
    Condition of Suite 315. Tenant is in possession of the Premises and
accepts the same as is without any agreements, representations, understandings or
obligations on the part of Landlord to perform any alterations, repairs or
improvements, except as may be expressly provided otherwise in this Amendment.B.
    
    Any construction, alterations or improvements to Suite 315 shall be performed
by Tenant at its sole cost and expense using contractors selected by Tenant and
approved by Landlord and shall be governed in all respects by the provisions of Article
IX of the Lease.
 VI.
    
    Parking. During the Suite 315 Second Extended Term,      Tenant
shall continue to lease the Suite 315 parking spaces at
no charge through the Suite 315 Extended Expiration Date.
Thereafter, the stall charge shall be at Landlords scheduled
parking rates from time to time.VII.
    
    SDN List. Tenant hereby represents and warrants that neither
Tenant nor any officer, director, employee, partner, member or
other principal of Tenant (collectively, Tenant Parties) is
listed as a Specially Designated National and Blocked Person
(SDN) on the list of such persons and entities issued by the
U.S. Treasury Office of Foreign Assets Control (OFAC). In the
event Tenant or any Tenant Party is or becomes listed as an SDN,
Tenant shall be deemed in breach of
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this Lease and Landlord
shall have the right to terminate the Lease immediately upon
written notice to Tenant.VIII.
    
    GENERAL.
 A.
    
    Effect of Amendments. The Lease shall remain in full force and effect
except to the extent that it is modified by this Amendment.B.
    
    Entire Agreement. This Amendment embodies the entire understanding
between Landlord and Tenant and can be changed only by a writing signed by Landlord and
Tenant. There have been no additional oral or written representations or
agreements. Under no circumstances shall Tenant be entitled to any rent abatement,
improvement allowance, leasehold improvements, or any similar economic incentives that
may have been provided Tenant in connection with entering into the Lease, unless
specifically set forth in this Amendment.C.
    
    Counterparts. If this Amendment is executed in counterparts, each is hereby
declared to be an original; all, however, shall constitute but one and the same
amendment. In any action or proceeding, any photographic, photostatic, or other copy
of this Amendment may be introduced into evidence without foundation.D.
    
    Defined Terms. All words commencing with initial capital letters in
this Amendment and defined in the Lease shall have the same meaning in this Amendment
as in the Lease, unless they are otherwise defined in this Amendment.E.
    
    Authority. If Tenant is a corporation, limited liability company or
partnership, or is comprised of any of them, each individual executing this Amendment
for the corporation, limited liability company or partnership represents that he or she
is duly authorized to execute and deliver this Amendment on behalf of such entity and
that this Amendment is binding upon such entity in accordance with its terms.F.
    
    Attorneys Fees. The provisions of the Lease respecting payment of
attorneys fees shall also apply to this Amendment.G.
    
    Execution of Amendment. Submission of this Amendment by Landlord
is not an offer to enter into this Amendment but rather is a solicitation for such an
offer by Tenant. Landlord
shall not be bound by this Amendment until Landlord has executed and delivered the
same to Tenant.H.
    
    Nondisclosure of Terms. Tenant agrees that neither Tenant nor its
agents or any other parties acting on behalf of Tenant shall disclose any matters set
forth in this Amendment or disseminate or distribute any information concerning the
terms, details or conditions hereof to any person, firm or entity without obtaining the
express written consent of Landlord.
 IN WITNESS WHEREOF
 LANDLORD:
    
    
    
    TENANT:UTC PROPERTIES LLC,
    
    
    
    CYPRESS BIOSCIENCE, INC.,a Delaware limited liability company
    
    
    
    a Delaware corporationBy:
    
    /s/ Steven M. Case
    
    
    
    By:
    
    /s/  Sabrina Martucci JohnsonSteven M. Case
    
    
    
    Printed Name: Sabrina Martucci JohnsonExecutive Vice President, Leasing
Office Properties
    
    
    
    Title:
    
    COO and CFOBy:
    
    /s/  Michael T. Bennett
    
    
    
    By:
    
    /s/ Janna SipesMichael T. Bennett
    
    
    
    Printed Name: Janna SipesSenior Vice President, Operations
Office Properties
    
    
    
    Title:
    
    VP, Compliance Officer and
Human Resources Executive
 2