<PAGE>
                                                                   EXHIBIT 10.16


                           THIRD AMENDED AND RESTATED
                          REGISTRATION RIGHTS AGREEMENT

         This Third Amended and Restated Registration Rights Agreement (this
"Agreement") is made and entered into effective as of December 19, 2002, by and
between Kos Pharmaceuticals, Inc., a Florida corporation (the "Company"), Kos
Holdings, Inc., a Florida corporation ("Holdings"), Kos Investments, Inc., a
Florida corporation ("Investments"), and Michael Jaharis, an individual residing
in New York, New York ("Jaharis") and effectively amends and restates the Second
Amended and Restated Registration Rights Agreement entered into by the Company,
Holdings and Investments dated as of December 21, 1999.

                                    RECITALS

         A.       Holdings has acquired 10,000,000 shares (the "Holdings
                  Shares") of the Company's common stock, par value $.01 per
                  share (the "Common Stock"), under the terms of an Assignment
                  and Assumption Agreement dated as of June 30, 1996 between the
                  Company and Holdings (the "Assignment Agreement"). Pursuant to
                  the Assignment Agreement, the Company has agreed to grant
                  Holdings certain registration rights in accordance with the
                  terms of this Agreement.

         B.       The Company has issued a Promissory Note dated July 1, 1996
                  (the "Investments Note"), to Investments for an aggregate
                  principal amount of $15,000,000, which has been converted to
                  shares of Common Stock (the "Investments Shares"). The Company
                  has granted Investments certain registration rights in
                  accordance with the terms of this Agreement.

         C.       The Company has issued a Promissory Note dated as of September
                  1, 1999 (the "Supplemental Credit Facility Note") to Jaharis
                  for an aggregate principal amount of $50,000,000, which is
                  convertible to shares of Common Stock (the "Convertible Note
                  Shares"), and which was amended by that certain Amendment
                  Agreement dated as of July 21, 2001, between Borrower and
                  Michael Jaharis and Mary Jaharis, pursuant to which the
                  Supplemental Credit Facility Note was replaced by two separate
                  notes, one note from Borrower to Michael Jaharis in the amount
                  of $25,000,000 and one note from Borrower to Mary Jaharis in
                  the amount of $25,000,000 (the "Mary Jaharis Note"), which was
                  further amended by that certain Amendment Agreement dated as
                  of December 17, 2001, between Borrower and Wilson Point
                  Holdings, LP, a Delaware limited partnership ("Wilson Point"),
                  pursuant to which the Mary Jaharis Note was replaced by a note
                  from Borrower to Wilson Point in the amount of $25,000,000.



<PAGE>


         D.       Under the terms of the Supplemental Credit Facility Note, the
                  Company has granted Jaharis certain registration rights in
                  accordance with the terms of this Agreement.

         E.       The Company has issued a Promissory Note dated as of December
                  21, 1999 (the "Standby Facility Note") to Jaharis for an
                  aggregate principal amount of $50,000,000, pursuant to which
                  the Company has issued a warrant of even date therewith to
                  Jaharis (the "Standby Facility Warrant Agreement") pursuant to
                  which Jaharis will be entitled to purchase 6,000,000 shares of
                  Common Stock (the "Standby Facility Warrant Shares"). Under
                  the terms of the Standby Facility Warrant Agreement, the
                  Company has granted Jaharis certain registration rights in
                  accordance with the terms of this Agreement.

         F.       The Company is issuing a promissory note of even date herewith
                  (the "Additional Standby Facility Note") to Jaharis for an
                  aggregate principal amount of $30,000,000. In connection with
                  the Additional Standby Facility Note, the Company is issuing a
                  warrant of even date herewith to Jaharis (the "Additional
                  Standby Facility Warrant Agreement") pursuant to which Jaharis
                  will be entitled to purchase 1,000,000 shares of Common Stock
                  (the "Additional Standby Facility Warrant Shares", and,
                  together with the Holdings Shares, the Investments Shares, the
                  Convertible Note Shares and the Standby Facility Warrant
                  Shares, the "Shares") (The Standby Facility Warrant Agreement
                  and the Additional Standby Facility Warrant Agreement are
                  hereinafter referred to as the "Warrant Agreements"). Under
                  the terms of the Additional Standby Facility Warrant
                  Agreement, the Company will grant Jaharis certain registration
                  rights in accordance with the terms of this Agreement.

         NOW, THEREFORE, in consideration of the mutual promises and covenants
set forth herein, the parties hereto agree as follows:

         1. Definitions. The following terms shall have the meanings set forth
below:

                  a. "COMMISSION" means the Securities and Exchange Commission,
or any other Federal agency at the time administering the Federal securities
laws.

                  b. "CONVERSION" means Jaharis' right to convert indebtedness
owing under the Supplemental Credit Facility Note into the Convertible Note
Shares as provided in the Supplemental Credit Facility Loan Agreement and the
Supplemental Credit Facility Note.

                  c. "CUTBACK REGISTRATION" means any registration in connection
with an underwritten public offering in which the managing underwriter advises
the Company that marketing factors require a limitation of the number of the


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Company's securities to be underwritten in such public offering (including a
limitation to zero).

                  d. "1933 ACT" means the Securities Act of 1933, as amended, or
any similar federal statute, and the rules and regulations of the Commission
issued under such Act, as they each may, from time to time, be in effect.

                  e. "1934 ACT" means the Securities Exchange Act of 1934 or any
similar federal statute, and the rules and regulations of the Commission issued
under such Act, as they each may, from time to time, be in effect.

                  f. "REGISTRATION RIGHTS HOLDER" means either Holdings,
Investments, or Jaharis, individually (collectively referred to as the
"Registration Rights Holders").

                  g. "REGISTRATION STATEMENT" means a registration statement
filed by the Company with the Commission for a public offering and sale of
securities of the Company (other than any registration statement on Form S-4 or
Form S-8, or their successors, or any other form for a limited purpose, or any
registration statement covering only securities proposed to be issued in
exchange for securities or assets of another corporation or entity).

                  h. "REGISTRATION EXPENSES" means the expenses described in
Section 4.

                  i. "REGISTRABLE SHARES" means all of the Shares, and any other
shares of Common Stock or other securities of the Company or any other issuer
issued or issuable in respect of such Shares (because of stock splits, stock
dividends, reclassifications, recapitalizations, mergers, combinations or
similar events, if applicable); PROVIDED, HOWEVER, that the Shares which are
Registrable Shares shall cease to be Registrable Shares upon any sale or
transfer of such shares pursuant to a Registration Statement, Section 4(1) of
the 1933 Act, Rule 144 under the 1933 Act or otherwise, except that the Shares
which are Registrable Shares shall remain Registrable Shares notwithstanding any
transfer of the shares by Holdings or Investments to Jaharis or any of his
affiliates or by Jaharis or such affiliates to any member of Jaharis' immediate
family or to a trust established for the benefit of Jaharis or any family member
of Jaharis or to any corporation or other entity which is wholly owned by
Jaharis, such affiliates, such family members, or such trusts (Jaharis, such
affiliates, such family members such trusts and such entities referred to herein
collectively as "Permitted Transferees"). As a condition to effecting any
registration pursuant to this Agreement, the Company may require that Holdings,
Investments, Jaharis, or any Permitted Transferees, on whose behalf a
registration hereunder is being effected, execute an agreement further
acknowledging their obligations under Section 7 of this Agreement. All
references in this Agreement to the term "Holdings", "Investments" or "Jaharis"
shall be read to include any Permitted Transferee that owns or holds any
Registrable Shares.

                  j. "STANDBY FACILITY LOAN AGREEMENT" shall mean that certain
Revolving Credit and Loan Agreement dated as of December 21, 1999 between the



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<PAGE>

Company and Jaharis providing for an extension of credit by Jaharis to the
Company in the principal amount of $50,000,000.

                  k. "SUPPLEMENTAL CREDIT FACILITY LOAN AGREEMENT" shall mean
that certain Revolving Credit and Loan Agreement dated as of September 1, 1999
between the Company and Jaharis providing for an extension of credit by Jaharis
to the Company in the principal amount of $50,000,000.

         2. Registration Rights.

                  a. REQUIRED REGISTRATIONS.

                           i. Subject to the other provisions of this Agreement,
Holdings, Investments, and Jaharis shall each have the right to require the
Company, upon demand, whether before or after any indebtedness evidenced by the
Investments Note or the Supplemental Credit Facility Note shall become
convertible into Common Stock of the Company, or whether before or after Jaharis
shall exercise any warrants pursuant to the Warrant Agreements, or whether
before or after Investments or Jaharis shall have become a holder of any Common
Stock issued upon conversion without registration under the 1933 Act, to effect
unlimited registrations with respect to the Registrable Shares (each such
registration being a " Required Registration"). To effect a Required
Registration, a Registration Rights Holder shall make a written request (a
"Request Notice") to the Company with respect to his or its Shares which shall
describe in detail the contemplated sale of Registerable Securities, including
the number of Registerable Securities to be registered. The Company shall be
entitled to include in any Required Registration shares of Common Stock to be
sold by holders of either Common Stock or rights to acquire Common Stock to whom
the Company has previously granted or in the future does grant any registration
rights and shares of Common Stock to be sold by the Company for its own account,
provided that such inclusion shall not limit the number of Registrable Shares
included in such Registration Statement.

                           ii. Each Registration Rights Holder may revoke its
Request Notice in the event of a Cutback Registration that would limit the total
number of Registrable Shares that can be sold pursuant to such Requested
Registration to a number that is less than 90% of the number of the Registrable
Shares specified to be sold in the Request Notice.

                           The Company shall, as soon as practicable, but in no
event more than 120 days after receipt of a Request Notice, file a Registration
Statement covering the Registrable Shares to be included in the registration
requested by such Request Notice and cause such Registration Statement to become
effective as soon as practicable thereafter.

                  b. Piggyback Registration.


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<PAGE>


                           i. At any time and from time to time after the date
of this Agreement, whenever the Company proposes to file a Registration
Statement, the Company will prior to such filing give written notice to all
Registration Rights Holders of its intention to do so and, upon the written
request of any Registration Rights Holders given within fifteen (15) days after
the Company provides such notice, the Company shall use its good faith efforts
to cause all Registrable Shares of such Registration Rights Holder which the
Company has been requested by such Registration Rights Holder to register, to be
registered under the 1933 Act to the extent necessary to permit their sale or
other disposition in accordance with the intended methods of distribution
specified in the request of such Registration Rights Holder; provided that the
Company shall have the right to postpone or withdraw any registration effected
pursuant to this Section 2.b. without obligation to any Registration Rights
Holder.

                           ii. In connection with any registration under Section
2.b. involving an underwritten offering of the Company's securities, the Company
shall not be required to include any Registrable Shares of a Registration Rights
Holder in such underwriting unless such Registration Rights Holder accepts the
terms of the underwriting as agreed upon between the Company and the
underwriters selected by it, and then only in such quantity as will not, in the
sole discretion of the underwriters, jeopardize the success of the offering by
the Company. If in the sole discretion of the managing underwriter or
underwriters the registration of all, or part of, the Registrable Shares which a
Registration Rights Holder has requested to be included would adversely affect
such public offering, then the Company shall be required to include in the
underwriting only that number of Registrable Shares, if any, which the managing
underwriter or underwriters believe may be sold without causing such adverse
effect. If the number of Registrable Shares to be included in the underwriting
in accordance with the foregoing is less than the total number of shares which
such Registration Rights Holder has requested to be included, then such
Registration Rights Holder shall participate in the underwriting pro rata based
upon such Registration Rights Holder's total ownership of Registrable Shares
compared to the total number of shares held by any other Registration Rights
Holder or other affiliates of the Company for which registration has been
requested whether or not such shares are the subject of separate agreements with
the Company concerning registration rights.

         3. REGISTRATION PROCEDURES. When the Company is required by the
provisions of this Agreement to effect the registration of any of the
Registrable Shares under the 1933 Act, the Company shall:

                  a. file with the Commission a Registration Statement with
respect to such Registrable Shares and use its best efforts to cause that
Registration Statement to become and remain effective;




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<PAGE>

                  b. as expeditiously as possible prepare and file with the
Commission any amendments and supplements to the Registration Statement and the
prospectus included in the Registration Statement as may be necessary to keep
the Registration Statement effective until the earlier to occur of (i) such time
as all Registrable Shares included therein have been sold or (ii) the expiration
of two years;

                  c. as expeditiously as possible furnish to those Registration
Rights Holders whose Shares are being registered such reasonable numbers of
copies of the prospectus, including a preliminary prospectus and any amended or
supplemental prospectus, in conformity with the requirements of the 1933 Act,
and such other documents as such Registration Rights Holders may each reasonably
request in order to facilitate the public sale or other disposition of such
Registration Rights Holder's Registrable Shares; and

                  d. as expeditiously as possible use its best efforts to
register or qualify the Registrable Shares covered by the Registration Statement
under the securities or Blue Sky laws of such states as the Registration Rights
Holders shall reasonably request, and do any and all other acts and things that
may be necessary or desirable to enable the Registration Rights Holders to
consummate the public sale or other disposition of the Registrable Shares owned
by the Registration Rights Holders in such jurisdiction; PROVIDED, HOWEVER, that
the Company shall not be required in connection with this Section 3 to qualify
as a foreign corporation in any jurisdiction nor register or qualify the
securities in any state which as a condition to such registration or
qualification would impose material restrictions or other material conditions on
the Company or any of its officers, directors or shareholders (including with
respect to any shares held by such persons or entities) unless such restrictions
or other conditions are approved by the party adversely affected.

                  If the Company advises a Registration Rights Holder that any
         preliminary or final prospectus is no longer in compliance with the
         requirements of the 1933 Act, or that at such time it is otherwise a
         violation of any applicable securities laws to offer or sell securities
         pursuant to a preliminary or final prospectus, such Registration Rights
         Holder shall immediately cease offering or selling the Registrable
         Securities and, if requested, return all old prospectus to the Company.
         Such Registration Rights Holder may recommence offers and sales of
         Registrable Securities upon receipt from the Company of an amended
         prospectus, if applicable, or receipt of ratification from the Company
         that the offer and sale of Registrable Securities may resume.

         4. ALLOCATION OF EXPENSES. The Company will pay all Registration
Expenses of all registrations under this Agreement. The term "Registration
Expenses" shall mean all expenses incurred by the Company in complying with this
Agreement, including, without limitation, all registration and filing fees,
exchange listing fees, printing expenses, fees and disbursements of counsel for




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<PAGE>

the Company, state Blue Sky fees and expenses, and the expense of any special
audits incident to or required by any such registration, but excluding
underwriting discounts and selling commissions attributable to the Registrable
Shares and the fees and expenses of each Registration Rights Holder's own
counsel and accountants, which shall be borne by such Registration Rights
Holder.

         5. INFORMATION BY REGISTRATION RIGHTS HOLDERS. Each Registration Rights
Holder shall promptly furnish to the Company such information regarding such
Registration Rights Holder and the distribution proposed by such Registration
Rights Holder as the Company may request in writing and as shall be required in
connection with any registration, qualification or compliance referred to in
this Agreement.

         6. "LOCK-UP" AGREEMENT. If requested by an underwriter in connection
with an underwritten offering of Common Stock or other securities of the
Company, each Registration Rights Holder shall agree not to sell or otherwise
transfer or dispose of any Registrable Shares or other securities of the Company
held by such Registration Rights Holder for a specified period of time before
and/or after the effective date of a Registration Statement, PROVIDED that the
same request shall have been made of other holders of the Company's Common Stock
or other securities (including affiliates of the Company) and such other holders
have complied with such request. Such agreement shall be in writing in a form
satisfactory to the Company and any such underwriter. The Company may impose
stop transfer instructions with respect to the Registrable Shares or other
securities subject to the foregoing restriction until the end of the lock-up
period.

         7. INDEMNIFICATION.

                  a. BY THE COMPANY. In the event of any registration of any of
the Registrable Shares under the 1933 Act pursuant to this Agreement, the
Company will indemnify and hold harmless the sellers of such Registrable Shares
against any losses, claims, damages or liabilities, joint or several, to which
such sellers may become subject under the 1933 Act, 1934 Act, state securities
laws or otherwise, insofar as such losses, claims, damages or liabilities (or
actions in respect thereof) arise out of or are based upon any untrue statement
of any material fact contained in any Registration Statement under which such
Registrable Shares were registered under the 1933 Act, any preliminary
prospectus or final prospectus contained in the Registration Statement, or any
amendment or supplement to such Registration Statement, or arise out of or are
based upon the omission to state a material fact required to be stated therein
or necessary to make the statements therein not misleading; and the Company will
reimburse such sellers for any legal or any other expenses reasonably incurred
by such sellers in connection with investigating and defending any such loss,
claim, damage, liability or action; PROVIDED, HOWEVER, that the Company will not
be liable in any such case to the extent that any such loss, claim, damage,
liability or expense arises out of or is based upon any untrue statement or
omission made in such Registration Statement, preliminary prospectus or
prospectus, or any such amendment or supplement, in reliance upon and in
conformity with information furnished to the Company by or on behalf of such
sellers, specifically for use in the preparation thereof, or as a result of the
failure of such sellers, or any agent of such sellers, to deliver any amendments
and supplements to any Registration Statement and the prospectus included in any


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such Registration Statement (provided such amended or supplemental prospectus
has been delivered to sellers or their agent).

                  b. BY SELLERS OF REGISTRABLE SHARES. In the event of any
registration of any of the Registrable Shares under the 1933 Act pursuant to
this Agreement, each seller of Registrable Shares, severally and not jointly,
will indemnify and hold harmless the Company, each of its directors and officers
and each underwriter (if any) and each person, if any, who controls the Company
or any such underwriter within the meaning of the 1933 Act or the 1934 Act,
against any losses, claims, damages or liabilities, joint or several, to which
the Company, such directors and officers, underwriter or controlling person may
become subject under the 1933 Act, 1934 Act, state securities laws or otherwise,
insofar as such losses, claims, damages or liabilities (or actions in respect
thereof) arise out of or are based upon any untrue statement of a material fact
contained in any Registration Statement under which such Registrable Shares were
registered under the 1933 Act, any preliminary prospectus or final prospectus
contained in the Registration Statement, or any amendment or supplement to the
Registration Statement, or arise out of or are based upon any omission or
alleged omission to state a material fact required to be stated therein or
necessary to make the statements therein not misleading, and each seller of
Registrable Shares will reimburse the Company, each of its directors and
officers, each underwriter and each controlling person, severally and not
jointly, for any legal or other expenses reasonably incurred by the Company,
each director and officer, each underwriter and each controlling person in
connection with investigating and defending any such loss, claim, damage,
liability or action, if the statement or omission was made in reliance upon and
in conformity with information furnished to the Company by or on behalf of such
seller, specifically for use in connection with the preparation of such
Registration Statement, prospectus, amendment or supplement.

                  c. CLAIMS. Each party entitled to indemnification under this
Section 7 (the "Indemnified Party") shall give notice to the party required to
provide indemnification (the "Indemnifying Party") promptly after such
Indemnified Party has actual knowledge of any claim as to which indemnity may be
sought, and shall permit the Indemnifying Party to assume the defense of any
such claim or any litigation resulting therefrom; PROVIDED, that counsel for the
Indemnifying Party, who shall conduct the defense of such claim or litigation,
shall be approved by the Indemnified Party (whose approval shall not be
unreasonably withheld); and, PROVIDED, further, that the failure of any
Indemnified Party to give notice as provided herein shall not relieve the
Indemnifying Party of its obligations under this Section 7. The Indemnified
Party may participate in such defense at such party's expense. No Indemnifying
Party, in the defense of any such claim or litigation, except with the consent
of the Indemnified Party, shall consent to entry of any judgment or enter into
any settlement, which does not include as an unconditional term thereof the
giving by the claimant or plaintiff to such Indemnified Party of a release from
all liability in respect of such claim or litigation.


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<PAGE>


         8. MERGERS, ETC.

         The Company shall not, directly or indirectly, enter into any merger,
consolidation or reorganization in which the Company shall not be the surviving
corporation unless the proposed surviving corporation shall, prior to such
merger, consolidation or reorganization, agree in writing to assume the
obligations of the Company under this Agreement, and for that purpose references
hereunder to "Registrable Shares" shall be deemed to be references to the
securities which either Registration Rights Holder would be entitled to receive
in exchange for Registrable Shares under any such merger, consolidation or
reorganization; provided, however, that the provisions of this Section 8 shall
not apply in the event of any merger, consolidation or reorganization in which
the Company is not the surviving corporation if all Registration Rights Holders
and all other holders of Common Stock of the Company are entitled to receive in
exchange for their Registrable Shares consideration consisting solely of (i)
cash, (ii) securities of the acquiring corporation which may be immediately sold
to the public without registration under the Securities Act, or (iii) securities
of the acquiring corporation which the acquiring corporation has agreed to
register within 90 days of completion of the transaction for resale to the
public pursuant to the Securities Act.

         9. MISCELLANEOUS.

                  a. GOVERNING LAW. This Agreement shall be governed in all
respects by the laws of the State of Florida.

                  b. SUCCESSORS AND ASSIGNS. Except as otherwise expressly
provided herein, the provisions hereof shall inure to the benefit of, and be
binding upon, the successors, assigns, heirs, executors and administrators of
the parties hereto.

                  c. ENTIRE AGREEMENT; AMENDMENT; WAIVER. This Agreement
constitutes the full and entire understanding and agreement between the parties
with regard to the subjects hereof. Neither this Agreement nor any term hereof
may be amended, waived, discharged or terminated, except by a written instrument
signed by the Company, and each Registration Rights Holder affected by such
change. No waivers of or exceptions to any term, condition or provision of this
Agreement, in any one or more instances, shall be deemed to be, or construed as,
a further or continuing waiver of any such term, condition or provision.

                  d. NOTICES, ETC. All notices and other communications required
or permitted hereunder shall be in writing and shall be mailed by United States
first-class certified or registered mail, return receipt requested, postage
prepaid, or delivered personally by hand or nationally recognized courier
addressed as follows:




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         If to Holdings:

                  c/o Steven J. Aronoff, P.C.,
                  475 Park Avenue South, 23rd Floor
                  New York, New York 10016

         If to Investments:

                  c/o Steven J. Aronoff, P.C.,
                  475 Park Avenue South, 23rd Floor
                  New York, New York 10016

         If to Jaharis:

                  Michael Jaharis
                  c/o Steven J. Aronoff, P.C.,
                  475 Park Avenue South, 23rd Floor
                  New York, New York 10016

         If to the Company:

                  Kos Pharmaceuticals, Inc.
                  1001 Brickell Bay Drive
                  Suite 2502
                  Miami, Florida 33131
                  Facsimile No.  (305) 577-4596
                  Attention: Adrian Adams, President

or at such other address as a party shall have furnished to the other party in
writing. All such notices and other written communications shall be effective on
the earlier of the date of mailing or delivery.

                  e. SEVERABILITY. In case any provision of this Agreement shall
be invalid, illegal or unenforceable, the validity, legality and enforceability
of the remaining provisions shall not in any way be affected or impaired
thereby.

                  f. TITLES AND SUBTITLES. The titles of the paragraphs and
subparagraphs of this Agreement are for convenience of reference only and are
not to be considered in construing this Agreement.

                  g. COUNTERPARTS. This Agreement may be executed in any number
of counterparts, each of which shall be an original, and all of which together
shall constitute one instrument.




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<PAGE>

         IN WITNESS WHEREOF, the parties hereto have executed this Agreement
effective as of the day and year first above written.

                                      COMPANY

                                      KOS PHARMACEUTICALS, INC.


                                      By:
                                         --------------------------------------
                                          Adrian Adams
                                          President

                                      KOS HOLDINGS, INC.


                                      By:
                                         --------------------------------------


                                      KOS INVESTMENTS, INC.


                                      By:
                                         --------------------------------------
                                         MICHAEL JAHARIS



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