Exhibit 10.21
FOURTH AMENDMENT
     THIS FOURTH AMENDMENT (the “Amendment”) is made and entered into as of
December 29, 2009, by and between UTC PROPERTIES LLC, a Delaware limited
liability company, (“Landlord”) and CYPRESS BIOSCIENCE, INC., a Delaware
corporation (“Tenant”).
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 7,565 rentable 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, in consideration of the above recitals which by this
reference are incorporated herein, the mutual covenants and conditions contained
herein and other valuable consideration, the receipt and sufficiency of which
are hereby acknowledged, Landlord and Tenant agree as follows:

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 Per     Months of Term or Period   Square Foot  
Monthly Base Rent 1/01/10 – 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 and Tenant have duly executed this Amendment
as of the day and year first above written.

                      LANDLORD:       TENANT:    
 
                    UTC PROPERTIES LLC,       CYPRESS BIOSCIENCE, INC.,     a
Delaware limited liability company       a Delaware corporation    
 
                   
By:
  /s/ Steven M. Case       By:   /s/ Sabrina Martucci Johnson    
 
                        Steven M. Case       Printed Name: Sabrina Martucci
Johnson    
 
  Executive Vice President, Leasing
Office Properties       Title:   COO and CFO    
 
                   
By:
  /s/ Michael T. Bennett       By:   /s/ Janna Sipes    
 
                        Michael T. Bennett       Printed Name: Janna Sipes    
 
  Senior Vice President, Operations
Office Properties       Title:   VP, Compliance Officer and Human Resources
Executive    

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