Document:

FIRST AMENDMENT TO AGREEMENT DATED 12-11-2001

 

Exhibit 4.7

State of São Paulo Government

	 	 	 
	 

	 	FIRST AMENDMENT TO THE INSTRUMENT OF ACKNOWLEDGMENT, PAYMENT COMMITMENT AND
OTHER COVENANTS, ENTERED INTO BETWEEN COMPANHIA DE SANEAMENTO BÁSICO DO ESTADO
DE SÃO PAULO – SABESP AND THE STATE OF SÃO PAULO, THROUGH ITS STATE DEPARTMENT
OF FINANCE.

The parties hereinbelow:

	1.	 	COMPANHIA DE SANEAMENTO BÁSICO DO ESTADO DE SÃO PAULO – SABESP, a private
legal entity and basic sanitation utility concessionaire, with head-office
at Rua Costa Carvalho, no 300, in the Capital of São Paulo State, enrolled
with the CNPJ (National Registry of Legal Entities) under no
43.776.517/0001-80, herein collectively represented by Mr. Dalmo do Valle
Nogueira Filho, Chief Executive Officer, and Mr. Rui de Britto Álvares
Affonso, Economic-Financial and Investor Relations Officer (hereinafter
referred to as SABESP); and
	 
	2.	 	STATE OF SÃO PAULO, a public legal entity, through its State Department
of Finance, herein represented by the State Secretary, Mr. Eduardo
Refinetti Guardia (hereinafter referred to as STATE);

WHEREAS

	 	 	 
	I

	 	on December 11, 2001 the STATE and SABESP entered into the
“Instrument for Acknowledgment and Restatement of Debts, Payment
Commitment and other Covenants” (hereinafter referred to as
INSTRUMENT OF ACKNOWLEDGMENT), the Department of Water and Electric
Power – DAEE being also an interested party to the agreement;
	 
	 	 
	II

	 	the INSTRUMENT OF ACKNOWLEDGMENT, among other things, restated the
STATE’s debt to SABESP, comprising the water supply and sewer
collection bills related to buildings and premises occupied by
several agencies of the direct, independent and foundation management
entities, overdue and unpaid until December 01, 2001, as well as the
amounts disbursed by SABESP by way of complementary retirement and
pension benefits granted under State Law no. 4819/58 and subject to
recovery by the STATE;
	 
	 	 
	III

	 	through Official Letter P-0389/2003, of April 29, 2003, SABESP
decided to rectify the amount of the consolidated debt mentioned in
the INSTRUMENT OF ACKNOWLEDGMENT, which as from them was three
hundred and twenty-four million, five hundred and sixty-three
thousand, forty-seven reais and seventy-one cents

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	 	(R$324,563,047.71)
relating to the water supply and sewer collection accounts overdue
and unpaid until December 01, 2001;
	 
	 	 
	IV

	 	the INSTRUMENT OF ACKNOWLEDGMENT set forth an exception allowing the
installments of the consolidated debt to be repaid by transfer of
rights over the areas and equipment related to the reservoirs owned
by the DAEE, which would then become a STATE creditor for the same
amount, for further settlement of accounts;
	 
	 	 
	V

	 	the assets owned by the DAEE were duly evaluated as three hundred
million, eight hundred and eighty thousand, one hundred and
sixty-eight reais and seventy cents), on reference date June 30,
2002, notwithstanding the fact that the assignment of the respective
rights to SABESP has not yet been formally carried out, nor the STATE
has started the payment of the consolidated debt installments;
	 
	 	 
	VI

	 	new debts owed by the STATE have arisen, by reason of the non-payment
of water supply and sewer collection occurred after the execution of
the INSTRUMENT OF ACKNOWLEDGMENT, the amounts thereof have been
already duly ascertained;
	 
	 	 
	VII

	 	payment has not been effected to the STATE of interests on the net
equity relating to fiscal years prior to 2003, already declared and
paid by SABESP to the other company’s shareholders;
	 
	 	 
	VIII

	 	SABESP decided to pay other amounts by way of interests on net
equity, on account of fiscal year 2003, the amount of which will be
available to the shareholders only on a date subsequent to the
general meeting of shareholders;
	 
	 	 
	IX

	 	it is convenient to give a specific treatment to the STATE’s debt
arising out of water supply and sewer collection services provided by
SABESP, by netting the same against part of the credits held by the
STATE with SABESP, on account of interests on net equity already
declared, however not yet necessarily payable;
	 
	 	 
	X

	 	the above referred specific treatment is in line with the “Memorandum
of Understanding” entered into between the STATE and SABESP on
September 30, 1997;
	 
	 	 
	XI

	 	it is also advisable to adopt a more equitable and uniform criterion
for monetary updating of the consolidated debt, thus allowing its
impact to be distributed along the period being considered;

NOW, THEREFORE, the parties have decided to enter into this instrument, called
“First Amendment”, which shall be governed by the following clauses and
conditions, being binding upon the parties themselves and/or their eventual
successors.

SECTION ONE

The debt acknowledged by the STATE, arising out of water supply and sewer
collection services provided by SABESP, shall hereinafter be five hundred and
eighty-one million, seven hundred and seventy-eight thousand, eight hundred and
seventy-eight reais and seventy-five cents (R$581,778,878.75), including
therein all the amounts referred to in Section One of the INSTRUMENT OF
ACKNOWLEDGMENT, as well as other invoices due after December 01, 2001 and until
February 29, 2004, as listed in the table included in Annexes I and IA.

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Paragraph one

The water supply and sewer collection bills due until February 29, 2004 have
been monetarily adjusted also until February 2004, pursuant to the annual
variation of the Reference Rate – TR, by end of each calendar year.

Paragraph two

The STATE has the right, through accredited employees of the State Department
of Finance, to audit the amounts stated in Annexes I and IA, within one hundred
and eighty (180) days, and proceed to the applicable adjustments, for more or
less, should any inconsistency be found out.

SECTION TWO

SABESP acknowledges to owe to the STATE, as of this date, the total amount of
five hundred and eighteen million, seven hundred and thirty-two thousand, two
hundred and two reais and twenty-one cents (R$518,732,202.21), by way of
interests on net equity, which comprises the amount of one hundred and
fifty-eight million, sixty-four thousand, seven hundred and fifty-one reais and
thirty-four cents (R$ 158,064,751.34) related to the income for fiscal years
prior to 2003 and since now deemed to be payable, and the amount of three
hundred and sixty million, six hundred and sixty-seven thousand, four hundred
and fifty reais and eighty-seven cents (R$ 360,667,450.87) related to the
income for fiscal year 2003, which shall become payable on a date subsequent to
the next general meeting of shareholders.

Sole paragraph

The amount of one hundred and fifty-eight million, sixty-four thousand, seven
hundred and fifty-one reais and thirty-four cents (R$ 158,064,751.34) includes
the amounts due by way of interests on net equity relating to shares issued by
SABESP previously owned by the DAEE and transferred to the STATE by force of
State Law no. 6851, of May 03, 1990, having been monetarily adjusted pursuant
to the annual variation of the IPC/FIFE (Consumer Prices Index calculated by
the Economic Research Institute Foundation), as from December of the calendar
year in which it became payable, and until February 2004.

SECTION THREE

The STATE and SABESP and transferred to the STATE by force of State Law no.
6851, of May 03, 1990, having been monetarily adjusted pursuant to the annual
variation of the IPC/FIFE (Consumer Prices Index calculated by the Economic
Research Institute Foundation), as from December of the calendar year in which
it became payable, and until February 2004.

SECTION THREE

The STATE and SABESP shall give mutual and reciprocal release to each other for
their respective credits, up to the limit of three hundred and sixty million,
six hundred and sixty-seven thousand, four hundred and fifty reais and
eighty-seven cents (R$ 360,667,450.87), corresponding to interests on net
equity related to the income for fiscal year 2003, which shall become payable
on a date subsequent to the general meeting of shareholders.

Sole paragraph

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The mutual release up to the limit of three hundred and sixty million, six
hundred and sixty-seven thousand, four hundred and fifty reais and eighty-seven
cents (R$ 360,667,450.87) shall
be acknowledged by the parties, for accounting and budget purposes, in seven
monthly, equal and consecutive installments, from June to December 2004.

SECTION FOUR

The balance of two hundred and twenty-one million, one hundred and eleven
thousand, four hundred and twenty-seven reais and eighty-eight cents (R$
221,111,427.88) of the consolidated debt owed by the STATE, as herein
acknowledged, which is not settled under the terms of the preceding section,
shall be paid in sixty (60) monthly, equal and consecutive installments, in the
amount of three million, six hundred and eighty-five thousand, one hundred and
ninety reais and forty-six cents (R$ 3,685,190.46) each, the first one maturing
on May 30, 2004, and the other ones on the same day of the subsequent months
or, should that be a bank holiday, on the immediately following business day.

Paragraph One – Exceptionally, the twelve installments shall be due for their
respective face value, in the total amount of forty-four million, two hundred
and twenty-two thousand, two hundred and eighty-five reais and eighty-five
cents (R$ 44,222,285.58), without any addition whatsoever by way of monetary
adjustment or interests.

SECTION FIVE

The amount of one hundred and fifty-eight million, sixty-four thousand, seven
hundred and fifty-one reais and thirty-four cents (R$ 158,064,751.34), related
to interests on net equity stated in fiscal years prior to 2003 and since now
deemed to be payable, shall be entailed to the settlement of the total amount
of forty-four million, two hundred and twenty-two thousand, two hundred and
eighty-five reais and fify-eight cents (R$ 44,222,285.58), referred to in the
second paragraph of the preceding clause, which shall be deemed to be paid, for
accounting and budget effects, in seven monthly, equal and consecutive
installments, from June to December 2004.

Sole paragraph

The balance of the amount related to interests on net equity stated in fiscal
years prior to 2003 and since now deemed to be payable, and not used for
settlement of the amounts referred to in Section Five, shall be subject to
monetary adjustment in accordance with the monthly variation of the IPCA-IBGE,
added by 0.5% per month, relating to the period from March 2004 until the month
of the respective payment or netting, whether total or partial, and shall be
allocated to the settlement of invoices arising out of water supply and sewer
collection services provided by SABESP to the STATE, which become due after
this date and are not paid in cash by the STATE.

SECTION SIX

The debt acknowledged by the STATE pursuant to Section Two of the INSTRUMENT OF
ACKNOWLEDGMENT, referring to the recovery of complementary retirement and
pension benefits provided for in State Law no. 4819/58, shall continue being
subject to the ascertainment, adjustment and payment conditions set forth
therein, save as otherwise expressly agreed to between the parties.

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SECTION SEVEN

All other clauses and conditions of the INSTRUMENT OF ACKNOWLEDGMENT not
expressly amended hereby shall continue in full force and effect.

Sole paragraph

This instrument does not affect the rights and obligations undertaken by the
DAEE under the INSTRUMENT OF ACKNOWLEDGMENT, which shall be entirely complied
with as set forth therein.

SECTION EIGHT

The STATE shall adopt the applicable actions in order to ensure sufficient
budget availability, in such a way as to enable the settlement of the
consolidated debt installments payable by the STATE.

In witness whereof, the parties execute this instrument, called as “First
Amendment”, in two counterparts of the same contents and form, in the presence
of the two undersigned witnesses.

São Paulo, March 22, 2004.

COMPANHIA DE SANEAMENTO BÁSICO DO

ESTADO DE SÃO PAULO – SABESP

	 	 	 
	[signature]

	 	[signature]
	Dalmo do Valle Nogueira Filho

	 	Rui de Britto Álvares Affonso
	Chief Executive Officer

	 	Economic-Financial and Investor Relations
Officer

STATE OF SÃO PAULO

[signature]

Eduardo Refinetti Guardia

State Finance Secretary

	 	 	 
	[signature]

	 	[signature]
	First Witness

	 	Second Witness
	Name: Daniel Sonder

	 	Name: Iassuo Hagy
	I.D.: 24.448.000

	 	I.D.: 5.377.233

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\

Annex I

COMPANHIA DE SANEAMENTO BÁSICO DO ESTADO DE SÃO PAULO – SABESP

GESP X SABESP AGREEMENT

Adjustment pursuant to the Latest BTN/TR of the Yearly Total Debts

	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	Adjustment Base
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	Total up to	 	Adjusted Total
	 	 	1994
	 	1995
	 	1996
	 	1997
	 	1998
	 	1999
	 	2000
	 	12/01/2001
	 	12/01/2001
	 	until 02/2004

	(1) Unadjusted Value to
Date of Debts
	 	 	9,485,166.41	 	 	 	13,312,301.45	 	 	 	14,366,659.30	 	 	 	21,041,738.47	 	 	 	36,024,480.51	 	 	 	41,453,179.22	 	 	 	63,199,480.89	 	 	 	125,680,131.46	 	 	 	324,563,047.71	 	 	 	 	 
	(2) BTN/TR Value on 12/31
	 	 	0.6640	 	 	 	0.8872	 	 	 	0.9768	 	 	 	1.0676	 	 	 	1.1573	 	 	 	1.2291	 	 	 	1.2574	 	 	 	1.2849	 	 	 	 	 	 	 	 	 
	(3) Amount of BTN/TR
	 	 	14,284,889.17	 	 	 	15,004,848.34	 	 	 	14,707,790.03	 	 	 	19,709,384.11	 	 	 	31,128,039.84	 	 	 	33,726,449.62	 	 	 	50,262,033.47	 	 	 	97,813,161.69	 	 	 	276,636,596.27	 	 	 	 	 
	(4) BTN/TR Value in
02/2004
	 	 	1.3868	 	 	 	1.3868	 	 	 	1.3868	 	 	 	1.3868	 	 	 	1.3868	 	 	 	1.3868	 	 	 	1.3868	 	 	 	1.3868	 	 	 	 	 	 	 	 	 
	(5) Amount Adjusted until
02/2004
	 	 	19,810,284.30	 	 	 	20,808,723.68	 	 	 	20,396,763.22	 	 	 	27,332,973.88	 	 	 	43,168,365.65	 	 	 	46,771,840.33	 	 	 	69,703,388.02	 	 	 	135,647,292.63	 	 	 	—	 	 	 	383,639,631.71	 

     Calculation Criteria

	 	(1)	 	Unadjusted value to date ascertained from the data base transmitted by
the CSI through the FTP of the accounts cadastradas as State Public
Entities;
	 
	 	(2)	 	BTN/TR Value on 12/31 for the respective years
	 
	 	(3)	 	Amount of BTN/TR on 12/31 of the respective years: (1) divided by (2) =
(3)
	 
	 	(4)	 	BTN/TR Value on 02/29/04
	 
	 	(5)	 	Amount ascertained in (1) divided by the BTN/TR of 12/31 of the
respective years (2), and multiplied by the BTN/TR of 02/2004 (4): (3)
multiplied for (4) = (5)

	 	 	 	 	 
	Total Face Value
	 	 	521,530,274.20	 
	Adjustment pursuant to BTN/TR
	 	 	60,248,604.55	 
	Total
	 	 	581,778,878.75	 

E-6

 

Annex I A

COMPANHIA DE SANEAMENTO BÁSICO DO ESTADO DE SÃO PAULO – SABESP

GESP X SABESP AGREEMENT

Adjustment pursuant to the Latest BTN/TR of the Yearly Total Debts

	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	Total 2001 to	 	Adjusted Total
	Adjustment Base
	 	2001
	 	2002
	 	2003
	 	2004
	 	02/2004
	 	until 02/2004

	(1) Unadjusted Value to Date of Debts
	 	 	29,565.99	 	 	 	13,519,500.69	 	 	 	148,476,969.75	 	 	 	34,941,190.06	 	 	 	196,967,226.49	 	 	 	 	 
	(2) BTN/TR Value on 12/31
	 	 	1.2849	 	 	 	1.3188	 	 	 	1.3824	 	 	 	1.3868	 	 	 	 	 	 	 	 	 
	(3) Amount of BTN/TR
	 	 	23,010.34	 	 	 	10,251,365.40	 	 	 	107,405,215.39	 	 	 	25,195,550.95	 	 	 	142,875,142.08	 	 	 	 	 
	(4) BTN/TR Value in 02/2004
	 	 	1.3868	 	 	 	1.3868	 	 	 	1.3868	 	 	 	1.3868	 	 	 	 	 	 	 	 	 
	(5) Amount Adjusted until 02/2004
	 	 	31,910.74	 	 	 	14,216.593.54	 	 	 	148,949,552.70	 	 	 	34,941,190.06	 	 	 	—	 	 	 	198,139.247.04	 

Calculation Criteria

	(1)	 	Unadjusted value to date ascertained from the data base transmitted by
the CSI through the FTP of the accounts cadastradas as State Public
Entities;
	 
	(2)	 	BTN/TR Value on 12/31/2001, 2002 and 2003, to 02/29/2004
	 
	(3)	 	Amount of BTN/TR for the respective years: (1) divided by (2) = (3)
	 
	(4)	 	BTN/TR Value on 02/29/04
	 
	(5)	 	Amount ascertained in (1) divided by the BTN/TR of the respective years
(2), and multiplied by the BTN/TR of 02/2004 (4): (3) multiplied for (4) =
(5)

E-7

 

Annex I

COMPANHIA DE SANEAMENTO BÁSICO DO ESTADO DE SÃO PAULO – SABESP

GESP X SABESP AGREEMENT

Adjustment pursuant to the Latest BTN/TR of the Yearly Total Debts

E-8<PAGE>

                                                                    EXHIBIT 10.1

      Portions of this Exhibit have been redacted and are the subject of a
confidential treatment request filed with the Secretary of the Securities and
Exchange Commission.

<PAGE>

                                 AMENDMENT NO. 1

                                       TO

                DEVELOPMENT AND MARKETING COLLABORATION AGREEMENT

      THIS AMENDMENT NO. 1 TO DEVELOPMENT AND MARKETING COLLABORATION AGREEMENT
(this "Amendment"), dated as of the 4th day of June 2004 (the "Amendment
Effective Date"), by and between OSI Pharmaceuticals, Inc., a Delaware
corporation ("OSI"), and Genentech, Inc., a Delaware corporation ("Genentech"),
amends the Development and Marketing Collaboration Agreement (the "Collaboration
Agreement"), dated as of January 8, 2001, by and between OSI and Genentech. The
Collaboration Agreement as amended by this Amendment shall be referred to herein
as the "Agreement". Capitalized terms undefined herein shall have the meanings
given to them in the Collaboration Agreement.

                                   WITNESSETH

      WHEREAS, the Collaboration Agreement provides, among other things, that
OSI and Genentech have differing roles and obligations with respect to certain
promotion, marketing, and other activities.

      WHEREAS, pursuant to the Collaboration Agreement, OSI has the right,
subject to certain conditions and criteria, to co-promote the Licensed Product.

      WHEREAS, the Parties now wish to amend the Collaboration Agreement to
modify, clarify and more fully define their rights and responsibilities with
respect to the post-approval development of Licensed Product and co-promotion of
Licensed Product by OSI, all as more fully set forth herein.

<PAGE>

      NOW, THERFORE, in consideration of the foregoing recitals and the
covenants contained herein, OSI and Genentech hereby agree as follows:

                      AMENDMENT TO COLLABORATION AGREEMENT

1     JOINT COMMERCIAL INTEGRATION TEAM, JOINT CLINICAL SUBTEAM AND JOINT
CLINICAL TRIALS REVIEW COMMITTEE

A.    Section 3.2(b) of the Collaboration Agreement is hereby deleted in its
entirety and replaced with the following:

      (b)   JOINT PROJECT TEAM RESPONSIBILITIES.

            (i) The Joint Project Team shall be responsible for formulating
      overall development plans and an annual development budget, for making
      overall decisions regarding the priority and design of all clinical trials
      for new indications (except for Registry Studies and ISTs, defined below),
      for recommending to the JSC which Party will be responsible for
      implementing clinical studies for each indication (other than Registry
      Studies), for developing a publication strategy and a calendar of key
      scientific and clinical meetings and other events for Licensed Product,
      for exchanging information and facilitating cooperation and coordination
      between the Parties as they exercise their respective rights and meet
      their respective obligations under this Agreement, for determining the
      priority with respect to seeking Regulatory Approval of Licensed Product,
      for approving third party manufacturing and supply agreements, for
      recommending to the JSC or the GDC (via the OSI-774 Liaison Team, in the
      case of the GDC), as the case might be, new Lifecycle Initiatives
      hereunder, and for implementing all activities approved by the JSC or the
      GDC, as the case might be.

                                       2
<PAGE>

            (ii) In addition, the Joint Project Team may designate subteams as
      appropriate to facilitate coordination and cooperation in key areas.
      Specifically, the Joint Project Team will designate a Joint Regulatory
      Subteam to coordinate efforts as may be necessary for NDA filing and other
      regulatory activities. The Joint Project Team will also designate a
      subteam called the Joint Commercial Integration Team ("JCIT"), which will
      be chaired by the Genentech Director of Licensed Product Marketing or
      Sales. There shall be two OSI representatives on the JCIT, consisting of
      an OSI commercial director assigned to Licensed Product at a level
      comparable to the chair of the JCIT and a sales director assigned to
      Licensed Product at a level comparable to the OSI commercial director. OSI
      shall be permitted to propose that an additional OSI staff member(s)
      attend specific portions of JCIT meetings to address particular agenda
      items, and such additional staff members may only attend for such agenda
      items after good faith consideration by, and agreement of, the Genentech
      JCIT chairperson. The functions of the JCIT are as follows:

                  a.    to provide a forum to update OSI on Genentech's
      commercial activities with respect to Licensed Product and any issues
      related thereto and for OSI to provide feedback with respect thereto for
      Genentech's consideration;

                  b.    to provide a forum for OSI to give input to Genentech
      with respect to Co-promotion (as defined below) related matters to be
      included in the Commercialization Plan;

                  c.    to review and discuss Co-promotion-related matters,
      including without limitation, assignment of Physician Call Targets (as
      hereinafter defined) in accordance with Section 5.2A(b) below, sales force
      bonus criteria alignment, and sales force training, and also to act as a
      forum to which a Party may bring up for discussion

                                        3
<PAGE>

      other Co-promotion related matters listed on Appendix A attached hereto
      and incorporated herein and entitled "Licensed Product Commercial Roles
      and Responsibilities";

                  d.    to resolve disputes arising from routine "day-to-day"
      Co-promotion-related operational matters that cannot be resolved by the
      field sales managers of the Parties; and

                  e.    to carry out such other matters assigned to the JCIT by
      the JSC. "Co-promotion" and "Co-promote" as used in this Agreement shall
      mean performing sales calls by OSI sales representatives to Physician Call
      Targets and to medical staff associated with those Physician Call Targets,
      and having OSI sales representatives at OSI promotional exhibit booths at
      medical meetings and tradeshows, all solely for the purpose of the sale of
      Licensed Product under the Trademark, as more specifically described in
      and to the extent permitted by Section 5.2A below. Co-promotion shall not
      be included within the term marketing as such term is used within the
      Agreement.

            The JCIT shall meet quarterly either in person or telephonically, or
      as otherwise agreed by the JCIT, however the JCIT members of the Parties
      with direct responsibility for implementing Co-promotion activities shall
      communicate and meet as often as they reasonably deem necessary to achieve
      their objectives under the Commercialization Plan.

            (iii) The Joint Project Team will also designate a subteam called
      the Joint Clinical Subteam, which will be co-chaired by one representative
      from each Party. The functions of the Joint Clinical Subteam are as
      follows:

                  a.    to review protocols for all clinical trials (other than
      ISTs) and to approve protocols for all clinical trials (other than
      Registry Studies and ISTs), related to

                                        4
<PAGE>

      Licensed Product and sponsored by Genentech or OSI (usually under their
      respective INDs), whether or not such protocols constitute Lifecycle
      Initiatives (as hereinafter defined);

                  b.    to review clinical trial studies related to Licensed
      Product (other than ISTs) that are conducted by cooperative groups or
      under the Cancer Therapy Evaluation Program (CTEP), and to approve
      clinical trial studies related to Licensed Product conducted by
      cooperative groups or under CTEP (other than ISTs and Registry Studies,
      which are approved as more fully described below) ;

                  c.    to update the Parties on on-going Licensed Product
      clinical programs, and

                  d.    to resolve and settle any disagreement of the JCTRC
      regarding IST review or approval.

      The Joint Clinical Subteam shall meet monthly either in person or
      telephonically, or as otherwise agreed by the Joint Clinical Subteam
      leaders.

            The Joint Clinical Subteam will designate a subteam called the Joint
      Clinical Trials Review Committee ("JCTRC"). The sole function of the JCTRC
      will be to review and approve all clinical trial proposals, protocols and
      clinical trial concept sheets provided by or solicited from external
      sponsor-investigators, including, without limitation, sponsoring
      cooperative groups and CTEP (to the extent not governed by Section
      3.2(b)(iii)(b) above), for clinical trials evaluating Licensed Product
      (collectively, "ISTs"), including, without limitation, ISTs within a
      Lifecycle Initiative pursued and funded solely by one Party under Section
      4.3A(b)(ii) below. For clarity, "ISTs" hereunder are clinical trials
      evaluating Licensed Product that are sponsored by third party

                                       5
<PAGE>

      sponsor-investigators, or cooperative group sponsors, as the terms
      "sponsor-investigator" and "sponsor" are defined in Section 312.3(b) of
      Title 21 of the U.S. Code of Federal Regulations. The membership of the
      JCTRC shall include the heads of clinical teams or their designees from
      each Party and Medical Science Liaisons from each Party. The JCTRC shall
      meet monthly either in person or telephonically or as otherwise agreed by
      the JCTRC. The Parties' respective commercial, marketing and sales groups
      shall not vote on or control decisions of the JCTRC regarding any IST or
      other matter discussed at any JCTRC meeting. Decisions to approve ISTs
      shall be based on medical, scientific, strategic and budgetary
      considerations, provided that a Party has not reasonably objected that an
      IST could adversely affect the Licensed Product. Only ISTs approved by the
      JCTRC can be funded and/or supplied Licensed Product by either Party for
      the purpose of such ISTs. In general the JCTRC will operate by consensus.
      In the event that the JCTRC members do not reach consensus regarding an
      IST decision, the JCTRC representatives of each Party shall collectively
      have one vote, with decisions made by unanimous vote. If the JCTRC cannot
      agree with respect to an IST decision, such disputed IST may be referred
      to the Joint Clinical Subteam by either Party. In the case of such
      referral, all decisions regarding ISTs shall be finally decided by the
      Joint Clinical Subteam and shall not be subject to further review or
      escalation. If the JCTRC approves an IST based on medical, scientific and
      strategic considerations but one Party does not wish to fund such IST,
      such IST may be funded and/or provided Licensed Product drug by the other
      Party at its sole cost. Similarly, if the JCTRC approves an IST based on
      medical, scientific and strategic considerations and such IST is solely
      within a Lifecycle Initiative pursued and funded solely by one Party under
      Section 4.3A(b)(ii) below), then

                                       6
<PAGE>

      such Party may pursue and fund such IST under such Lifecycle Initiative.
      Any adverse event safety data occurring during ISTs funded solely by one
      Party shall be part of the Licensed Product SAE database. Data from ISTs
      funded solely by one Party or provided Licensed Product at one Party's
      sole cost shall be subject to Section 4.3 if such IST is within a
      Lifecycle Initiative or a GNE/OSI Initiative for which the Parties are
      sharing costs. Data from ISTs funded solely by one Party, or provided
      Licensed Product at the cost solely of one Party, under Section
      4.3A(b)(ii) below shall not be shared except as provided therein.

            (iv) The Joint Project Team will prepare a draft Development
      Budget/Plan, and draft an annual development budget by August 15 of the
      then-current calendar year, and a final Development Budget/Plan shall be
      presented by the Joint Project Team to the JSC for approval by September
      15 of the then-current calendar year. The Development Budget/ Plan shall
      include specific budgets for OSI/GNE Initiatives (as hereinafter defined).
      In addition, the Joint Project Team Leaders will participate in the
      OSI-774 Liaison Team, described in Section 3.4 below, to exchange
      information, and facilitate cooperation and coordination, between the
      Parties and Roche, pursuant to the Tripartite Agreement.

            (v) Annually, on or about August 15, the OSI commercial director,
      the Genentech marketing director and the heads of OSI's and Genentech's
      clinical teams shall meet to discuss and approve the general budget for
      ISTs, which budget shall then be included in the Commercialization Budget
      (as hereinafter defined) submitted by Genentech to the JSC for approval as
      provided in Section 5.1 below.

                                       7
<PAGE>

B.    Section 3.2(c) of the Collaboration Agreement is hereby amended by adding
the following two sentences immediately after the last sentence of such
subsection:

      "The foregoing provisions of this Section 3.2(c) shall also apply to the
      Joint Clinical Subteam, which shall be subject to the dispute resolutions
      procedures set forth in Article 16 for matters other than the resolution
      of disagreements of the JCTRC.

2.    POST-APPROVAL DEVELOPMENT ACTIVITIES.

      Article 4 of the Collaboration Agreement is hereby amended by inserting
the following new Sections 4.3A, 4.3B and 4.3C immediately after Section 4.3:

      "4.3A POST-APPROVAL DEVELOPMENT ACTIVITIES.

            (a)   As part of the updating of the Global Development Plan under
      the Tripartite Agreement, which updating is required by the Tripartite
      Agreement, OSI and Genentech shall each use commercially reasonable
      efforts to cause the GDC to create a lifecycle plan ("Lifecycle Plan")
      which will identify specific Lifecycle Initiatives. "Lifecycle
      Initiatives" shall mean development opportunities with estimable
      probabilities of technical and commercial success and defined budgets,
      that are designed to provide an estimable increase to the overall value of
      Licensed Product. Lifecycle Initiatives will include one or more of the
      following: a new medical indication (for example, an indication within
      **), a new therapy within indications being pursued under the existing
      Global Development Plan or Development Plan (for example, studies for **).
      The Lifecycle Plan will include the following details with respect to each
      Lifecycle Initiative in order to achieve the purposes of such Lifecycle
      Initiative: scope of clinical trials

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                                       8
<PAGE>

      (including, without limitation, the size of trials), the purpose of each
      trial (for example, **), the number of clinical trials and the phase of
      each trial (e.g. Phase I, II, or III), the number of investigators
      required to conduct each such trial, whether the trial(s) will be
      sponsored and conducted by Genentech, OSI or Roche or by a cooperative
      group investigator or through CTEP, and the estimated costs of such
      trials. The Lifecycle Plan will be submitted by the OSI-774 Liaison Team
      to the GDC for review and approval of the Lifecycle Initiatives by the GDC
      in accordance with the procedures set forth under the Tripartite
      Agreement. Accordingly, it is expected that the GDC will determine which
      Lifecycle Initiatives, if any, or which part of each Lifecycle Initiative,
      will be approved and funded under the Global Development Plan as Global
      Development Costs. If the GDC approves the funding of a Lifecycle
      Initiative, in accordance with the Tripartite Agreement, the GDC is to
      determine each company's responsibilities for such Lifecycle Initiative,
      which shall be comprised of some or all of the clinical study activities
      described in Section 4.3A(b)(i) below. To the extent that Lifecycle
      Initiatives put forward by the OSI-774 Liaison Team to the GDC have not
      been approved, such Lifecycle Initiatives shall be handled pursuant to
      Section 4.3A(b) below. Similarly, if the Tripartite Agreement is
      terminated, the Parties shall operate in accordance with Section 4.3A(b)
      below.

      (b)   If the GDC does not approve the funding of a Lifecycle Initiative,
            or if Roche opts out pursuant to Section A.4 of Exhibit A to the
            Tripartite Agreement (provided that neither Party or Roche
            reasonably has objected to such Lifecycle Initiative, and such
            Lifecycle Initiative does not adversely affect the goals of the
            Global Development Plan, pursuant to Section 10.13 of the Tripartite
            Agreement), or if the

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                                        9
<PAGE>

            Tripartite Agreement is terminated, the JSC shall consider such
            Lifecycle Initiative (or, in the event that the Tripartite Agreement
            is terminated, a Lifecycle Initiative created by Genentech and OSI
            as part of their annual lifecycle plan) and determine whether to
            fund such Lifecycle Initiative under the Development Budget/Plan,
            provided that neither Party reasonably has objected to such
            Lifecycle Initiative during JSC review and such Lifecycle Initiative
            does not adversely affect the goals of the Development Budget/Plan
            under the Agreement.

                  (i)   If such Lifecycle Initiative is approved by the JSC
                        (thereafter, an "OSI/GNE Initiative"), the JSC shall
                        determine which Party shall have the lead responsibility
                        for such OSI/GNE Initiative and the Joint Project Team
                        shall propose the responsibilities of each Party with
                        respect to such OSI/GNE Initiative, which proposals
                        shall be subject to JSC approval. Except as otherwise
                        agreed by the Parties, activities assigned to a Party
                        with respect to each such OSI/GNE Initiative shall be:
                        1) specific clinical studies sponsored and conducted by
                        such Party to directly further such OSI/GNE Initiative,
                        2) specific studies conducted by cooperative groups that
                        directly further such OSI/GNE Initiative, 3) specific
                        ISTs that directly further such OSI/GNE Initiative, 4)
                        specific studies conducted by such Party or the Parties
                        in collaboration with another sponsor that directly
                        further such OSI/GNE Initiative and/or 5) FDA mandated
                        Phase IV studies for Licensed Product within such
                        OSI/GNE Initiative. As used herein, "directly further"
                        shall mean that the study is designed to show
                        feasibility, efficacy and/or safety of

                                       10
<PAGE>

                        Licensed Product within the applicable OSI/GNE
                        Initiative. Studies under OSI/GNE Initiatives, or under
                        a Lifecycle Initiative above, shall not include: 1)
                        Registry Studies, as defined herein (which shall only be
                        conducted by Genentech but which are nonetheless subject
                        to review by the Joint Clinical Subteam, as described in
                        Section 4.3A(c) below), 2) ISTs outside the scope of an
                        OSI/GNE Initiative or Lifecycle Initiative (for example,
                        unsolicited requests for IST funding for an indication
                        outside of the OSI/GNE Initiatives), which are subject
                        to JCTRC approval, or 3) marketing or other
                        commercialization activities. The costs for any clinical
                        study activities within OSI/GNE Initiatives shall be
                        treated as OSI/GNE Development Costs in accordance with
                        Section 4.6 of this Agreement, except for the costs of
                        ISTs borne by one Party. The provisions of Section 4.3
                        above shall apply to any clinical trials conducted by
                        the Parties or external sponsors as part of such OSI/GNE
                        Initiatives, except for clinical trials sponsored and
                        funded solely by one Party within a rejected Lifecycle
                        Initiative under Section 4.3A(b)(ii) below. Safety
                        reports and safety data from all clinical trials,
                        however, shall be shared and centralized, however, in
                        accordance with Section 4.3. The costs for any Registry
                        Studies (subject to the last sentence of Section 4.3A(c)
                        below) and for jointly funded ISTs outside the scope of
                        an OSI/GNE Initiative or Lifecycle Initiative shall be
                        treated as **, in accordance with Exhibit B to the
                        Agreement.

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                                       11
<PAGE>

                  (ii)  The JSC may reject such Lifecycle Initiative in whole or
                        in part and/or the corresponding budget for pursuit
                        under the Agreement. In such case, either Party may
                        pursue such Lifecycle Initiative or rejected part
                        thereof at its own expense. Any serious adverse event
                        safety data occurring during the activities of such
                        Lifecycle Initiative shall be part of the Licensed
                        Product SAE database. If such Lifecycle Initiative is
                        for an additional indication and the Tripartite
                        Agreement is in effect, then such Lifecycle Initiative
                        so pursued by only one Party will be subject to the
                        applicable terms, if any, of the additional indication
                        opt out-opt back in provisions in Section A.4 of Exhibit
                        A to the Tripartite Agreement. For Lifecycle Initiatives
                        other than for an additional indication, or if the
                        Tripartite Agreement is no longer in effect, then for
                        such Lifecycle Initiative pursued by only one Party at
                        its own expense, the following will apply: If the other
                        Party that did not pursue such Lifecycle Initiative
                        wishes to regain its rights to such Lifecycle
                        Initiative, including the use of and access to data and
                        results (including, without limitation, all data and
                        results for ISTs within such Lifecycle Initiative), then
                        it may regain such rights by electing to do so within
                        ninety (90) days of delivery of a final study report for
                        the pivotal trial for such Lifecycle Initiative to the
                        non-participating Party and by paying within thirty days
                        ** of the total costs the non-participating Party would
                        have incurred had the non-participating Party
                        participated (i.e.

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                                       12
<PAGE>

                        shared costs, and thereafter assuming from the opt back
                        in date its ongoing obligations as if no opt out had
                        occurred.

                  (iii) From time to time, if a Party desires to pursue
                        Lifecycle Initiatives which have not been evaluated by
                        the GDC or JSC, as applicable, or included under the
                        current Lifecycle Plan, such Lifecycle Initiatives shall
                        be brought to the GDC, or if the Tripartite Agreement
                        has been terminated, to the JSC, for evaluation pursuant
                        to this Section 4.3A.

      (c)   "Registry Study", for purposes of the Agreement, shall mean a
            prospective, observational study of the process and outcomes of care
            in a population of patients designated by a common condition, status
            or treatment, usually descriptive in nature, and usually without a
            control or comparator arm, in which treatment is not dictated beyond
            "standard of care." The Parties agree that Registry Studies shall
            only be conducted by Genentech, but will be nonetheless subject to
            review and good faith consideration (but not approval) by the Joint
            Clinical Subteam. If the Joint Clinical Subteam does not agree
            whether a proposed Registry Study should be supported or conducted,
            the final decision regarding such Registry Study shall be made by
            Genentech without further review discussion or escalation under the
            Agreement. If the OSI members of the Joint Clinical Subteam do not
            agree that a Registry Study, which has been approved by Genentech,
            should be conducted or supported, then such Registry Study shall be
            conducted by Genentech at its sole cost, however, OSI shall not be
            entitled to obtain or review the data or results from such Registry
            Study prior to publication in a scientific journal or otherwise made

                                       13
<PAGE>

            available to the public, nor will OSI be allowed to participate in
            registry investigator meetings.

      4.3B MEDICAL SCIENCE LIAISON (MSL) ACTIVITIES.

      "Medical Science Liaisons" or "MSLs" are defined as field-based clinical
      research employees of each of the Parties whose main function is to
      support clinical investigators in developing and conducting clinical
      trials. OSI MSLs may conduct activities with respect to Licensed Product
      only for so long as OSI is conducting clinical study activities within a
      OSI Lifecycle Initiatives (as defined in Section 4.3B(a) below in
      accordance with the following:

      (a)   With respect to Licensed Product, OSI MSLs may only make calls to
            potential or current investigators for the purpose of discussing
            clinical studies within: (i) OSI/GNE Initiatives, (ii) Lifecycle
            Initiatives under the Tripartite Agreement, (iii) ongoing
            development activities under the Global Development Plan for which
            OSI is assigned the responsibility of executing or managing the
            status of under the Tripartite Agreement, and (iv) Lifecycle
            Initiatives which OSI is conducting and funding on its own either as
            permitted under the Tripartite Agreement or under Section
            4.3A(b)(ii) above (such Initiatives and Global Development Plan
            activities collectively hereafter referred to as the "OSI Lifecycle
            Initiatives"), but only to the extent reasonably expected to be
            necessary in order to execute such OSI Lifecycle Initiatives. In
            addition, OSI MSLs may also make calls to investigators for the
            purpose of discussing ISTs which have been approved by the JCTRC but
            which are not included within OSI/GNE Initiatives and for which OSI
            has been assigned responsibility by the JCTRC, but only to the
            extent reasonably expected to be

                                       14
<PAGE>

            necessary in order to execute such ISTs. With respect to such
            potential investigators, OSI may make such calls only to a number of
            potential investigators that is reasonable, given the total number
            of investigators that will be participating in each such clinical
            study. For all inquiries with respect to Licensed Product or
            clinical studies other than the foregoing, OSI MSLs shall refer such
            inquiries to the appropriate Genentech MSL.

      (b)   With respect to Licensed Product, Genentech MSLs may make call to
            potential or current investigators for any purpose, other than for
            the purpose of discussing OSI Lifecycle Initiatives. Genentech MSLs
            shall respond to inquiries regarding clinical studies within OSI
            Lifecycle Initiatives by referring such inquiries to the appropriate
            OSI MSL.

      (c)   With respect to Licensed Product, OSI shall ensure that OSI MSLs are
            fully trained by OSI, under guidelines agreed upon by the Parties,
            to handle unsolicited queries, to respond to unsolicited study
            proposals and to discuss clinical studies within OSI Initiatives in
            accordance with applicable law and regulations and the following:

                  (i)   Any clinical study proposals received by OSI MSLs that
                        are directly within OSI Lifecycle Initiatives will be
                        reviewed by OSI for potential submission to the JCTRC.

                                       15
<PAGE>

                  (ii)  OSI will forward clinical study proposals that are not
                        directly within OSI Lifecycle Initiatives to a Genentech
                        MSL for follow-up and review by Genentech for potential
                        submission to the JCTRC.

                  (iii) Any clinical study proposals directly within OSI
                        Lifecycle Initiatives that are forwarded to OSI by
                        Genentech will be reviewed by OSI for potential
                        submission to the JCTRC.

      (d)   With respect to Licensed Product, Genentech shall ensure that
            Genentech MSLs are fully trained, under its standard guidelines, to
            handle unsolicited queries and to respond to unsolicited proposals
            in accordance with applicable law and regulations and the following:

                  (i)   Any clinical study proposals received by Genentech MSLs
                        that are not directly within OSI Lifecycle Initiatives
                        will be reviewed by Genentech for potential submission
                        to the JCTRC.

                  (ii)  Genentech will forward clinical study proposals that are
                        directly within OSI Lifecycle Initiatives to an OSI MSL
                        for follow-up and review by OSI for potential submission
                        to the JCTRC.

                  (iii) Any clinical study proposals forwarded to Genentech by
                        OSI will be reviewed by Genentech for potential
                        submission to the JCTRC.

                                       16
<PAGE>

      (e)   Genentech MSLs will be the primary liaisons for Licensed Product
            with cooperative groups and professional societies other than the
            Cancer Therapy Evaluation Program (CTEP) for which OSI shall be the
            primary liaison as set forth in Section 4.3C. Representatives of OSI
            shall jointly participate with Genentech in all significant meetings
            and telephone calls (for example, those involving or expected to
            involve strategy, clinical trial design and/or safety issues) with
            cooperative groups and professional societies relating to Licensed
            Product. Genentech shall promptly forward to OSI copies of any
            significant cooperative group and professional society
            correspondence related to Licensed Product sent or received by
            Genentech and any research data sent by a cooperative group or
            professional society investigator to Genentech.

      (f)   Subject to Section 5.3A(b), Genentech MSLs will be responsible for
            Licensed Product education and disease state education (including,
            without limitation, medical and professional disease state
            education), and unrestricted Licensed Product medical education
            grants.

      4.3C CANCER THERAPY EVALUATION PROGRAM (CTEP). OSI shall be the primary
      liaison for the Parties' relationship with CTEP with respect to Licensed
      Product. Representatives of Genentech shall jointly participate with OSI
      in all meetings and significant telephone calls (for example, those
      involving or expected to involve strategy, clinical trial design and/or
      safety issues) with CTEP relating to Licensed Product. OSI shall promptly
      forward to Genentech copies of any CTEP correspondence relating to

                                       17
<PAGE>

      Licensed Product sent or received by OSI and any research data sent to OSI
      by a CTEP investigator.

3.    INDS AND DRUG APPROVAL APPLICATIONS.

      Section 4.4 is hereby amended by adding a new subsection 4.4(d) to the end
of Section 4.4 as follows:

4.4 (d) Notwithstanding anything to the contrary herein, the Joint Regulatory
Subteam will develop and agree on the strategy and proposed wording for Licensed
Product labels and package inserts, including, without limitation, strategy for
discussions related thereto with regulatory agencies. Decisions on all such
matters will be made by consensus. In the event that the Joint Regulatory
Subteam does not agree on any such matter, the matter in dispute will be
escalated to the Vice President (or Party officer of similar title) in charge of
the regulatory function of each Party, and notwithstanding any other provision
in this Agreement, the final decision on the matter in dispute will be made by
such two Vice Presidents. Members of the Joint Regulatory Subteam from both
Parties will participate in meetings and teleconferences with regulatory
authorities in which such labels or package inserts are discussed or negotiated,
with the number of members attending such meetings to be determined by the Joint
Regulatory Subteam.

4.    COMMERCIALIZATION PLAN/ BUDGET

      Article 5 of the Collaboration Agreement is hereby amended by deleting the
last two sentences of Section 5.1 and replacing them with the following:

                                       18
<PAGE>

      "Within thirty (30) days after NDA submission, the Genentech marketing
director for Licensed Product shall present, for discussion, to the OSI
commercial director for Licensed Product the first detailed annual commercial
budget for the commercialization of Licensed Product in the Territory, which
shall include the budget for activities listed in the definition of Marketing
Costs and Sales Costs under Exhibit B of the Agreement (the "Commercialization
Budget"). The Genentech marketing director and OSI commercial director will
conduct a discussion of such draft Commercialization Budget and attempt to reach
consensus on such budget during that discussion. If consensus has been reached
during that discussion that requires revisions to such draft Commercialization
Budget, the Genentech marketing director will prepare a new draft
Commercialization Budget reflecting such consensus. To the extent that consensus
has not been reached during that discussion, the Genentech marketing director
will take into consideration, in good faith, the comments of the OSI commercial
director to the Commercialization Budget. The Genentech marketing director shall
then prepare the final Commercialization plan and Commercialization Budget
("together, the Commercialization Plan") and submit it to the JSC for approval.
The OSI commercial director may attend the JSC meeting to discuss such
Commercialization Budget. Thereafter, Genentech shall update the
Commercialization Plan (including the Commercialization Budget) on a yearly
basis, in accordance with the procedures set forth in the preceding five (5)
sentences and the following two sentences. Genentech shall provide to OSI, on or
about August 15, a preliminary budget. On or about September 15, Genentech shall
provide a draft of the detailed Commercialization Budget to the OSI commercial
director for comment, and thereafter to the JSC for review and approval on or
about October 15. The timing of submission of the Commercialization Budget to

                                       19
<PAGE>

the JSC shall be coordinated with the submissions of the development and
manufacturing budgets, whenever possible.

5.    CO-PROMOTION.

A.    Article 5 of the Collaboration Agreement is hereby amended by inserting
the following new Sections 5.2A and 5.2B immediately after Section 5.2:

      "5.2A CO-PROMOTION. OSI shall be entitled to Co-promote (as defined
      hereinabove) Licensed Product as follows:

      (a)   For so long as OSI is Co-promoting Licensed Product, OSI will be
            entitled to Co-promote only as specifically described in Sections
            5.2A(a) through 5.2A(i). OSI shall assign certain OSI sales force
            representative Full Time Equivalents ("FTEs") to Co-promote Licensed
            Product (consisting of a percentage of time, determined by OSI, for
            each OSI sales force representative to devote to Licensed Product
            Co-promotion but in any case such percentage shall not be less that
            an average of sixty-five percent (65%) for such OSI sales force
            representatives, unless first approved by the JSC, and provided that
            such percentage for each such OSI sales force representative shall
            not be less than fifty percent (50%)). Such OSI sales force
            representatives shall be employees of OSI. OSI sales force
            representatives for Licensed Product will call on a subset of the
            physicians also called upon by the Genentech Licensed Product sales
            force, as provided in Section 5.2A(b) below. Sales territories for
            the OSI sales force FTEs for Licensed Product will be

                                       20
<PAGE>

            determined by OSI, provided that OSI will assign one representative
            to each Genentech Licensed Product sales territory, and further
            provided that OSI may assign an additional representative to each
            such sales territory with approval of Genentech, such approval not
            to be unreasonably withheld. OSI sales territories for Licensed
            Product need not be identical to the Genentech sales territories for
            Licensed Product. It is expressly understood by the Parties that
            Genentech sales representatives may also call on physicians in the
            OSI sales territories in which OSI's sales representative are
            operating.

      (b)   OSI sales force FTEs for Licensed Product shall call on specific
            customer targets, generally defined as potential high volume
            oncology/hematology prescribers for Licensed Product (i.e., within
            the top three to four deciles of prescribers within Genentech sales
            territories, with criteria of such deciles to be identical for the
            determination of such OSI and Genentech call targets) ("Physician
            Call Targets") in order to increase sales call frequency on such
            customer accounts. Genentech shall determine such Physician Call
            Targets after discussion at the JCIT and its good faith
            consideration of JCIT comments. If OSI provides in good faith a
            reasonable reason to decline a Physician Call Target it may do so
            and such customer account will be removed from the list of Physician
            Call Targets. In such event, then OSI may propose replacements for
            such declined Physician Call Targets to the JCIT, which shall then
            discuss the proposed replacements. Final decisions for adding such
            replacement Physician Call Targets shall be made by Genentech after
            good faith consideration of OSI's proposed replacements. Physician
            Call Targets will be

                                       21
<PAGE>

            updated by Genentech, after review and comment by the JCIT and
            Genentech's good faith consideration of such JCIT comments and the
            needs of the Licensed Product business, provided, however, that
            Genentech may change the list of Physician Call Targets no more than
            once per calendar year and by not more than 20 percent for each such
            change, unless otherwise agreed by the Parties or unless regulatory
            approval is obtained to sell a new Licensed Product or to sell an
            existing marketed Licensed Product for a new indication.

      (c)   Genentech shall determine the total number of FTEs which will
            comprise the combined OSI/Genentech sales force for Licensed Product
            and the ratio of OSI sales force FTEs to Genentech's sales force
            FTEs, provided, however, that the OSI sales force FTEs for Licensed
            Product shall not be required to be less than 25% of the combined
            OSI/Genentech sales force FTEs. Genentech's proposal shall be made
            in good faith based upon a sales force sizing analysis, which shall
            be conducted by Genentech by **. Such sizing analysis shall be
            conducted by Genentech as frequently as Genentech determines in good
            faith is needed. Any proposed adjustment to the total number of FTEs
            which will comprise the combined OSI/Genentech sales force for
            Licensed Product and the ratio of OSI sales force FTEs to
            Genentech's sales force FTEs as a result of such sizing analysis
            shall be part of, or a modification to, the Commercialization Plan.

      (d)   Genentech shall have final decision making authority with respect to
            overall sales force activities, except as otherwise expressly
            provided in this Amendment

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** This portion has been redacted pursuant to a confidential treatment request.

                                       22
<PAGE>

            or Appendix A hereto. Genentech shall coordinate overall sales force
            activities through the JCIT (which shall not require JCIT approval,
            however), to ensure a consistent and unified voice to the customer,
            including plan of action meetings, call reach and frequency goals,
            customer targets and messages. Genentech will determine the
            execution of sales training of the OSI and Genentech sales force
            representatives pertaining to Licensed Product.

      (e)   Licensed Product shall be the primary detail by the OSI Licensed
            Product sales force FTEs calling upon Physician Call Targets. The
            sales force representatives for each Party assigned to Licensed
            Product hereunder shall not promote a product competitive with
            Licensed Product. A competitive product shall mean a product that is
            designed to replace a Licensed Product for treatment of an approved
            disease indication. A product that can potentially be used in
            combination with such Licensed Product, regardless of whether such
            combination is approved by regulatory authorities, shall be deemed
            not competitive. In any event, competitive products **.

      (f)   OSI shall report call activity of OSI sales force FTEs for Licensed
            Product to Genentech on a **. OSI shall report in a format
            compatible with the Genentech call reporting system as of the
            Amendment Effective Date, or as otherwise agreed upon by the
            Parties.

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                                       23
<PAGE>

      (g)   The components and criteria for sales force bonus remuneration
            directly related to Licensed Product shall be aligned for OSI and
            Genentech representatives for Licensed Product, through discussion
            at the JCIT.

      (h)   Genentech shall maintain sole responsibility for Licensed Product
            sales data collection and reporting, and shall make such sales data
            available to OSI on the following basis. Genentech will provide to
            OSI daily reports of Licensed Product shipments (quantities),
            monthly reports of Licensed Product sales by geography, and such
            other sales data mutually agreed upon by the Parties. Such shipment
            and sales reports will be for OSI's internal use only and not for
            public disclosure.

      (i)   The sales force budgets allocated for sales territories for OSI and
            Genentech representatives shall be aligned, and will be part of the
            Commercialization Budget prepared by Genentech and approved by the
            JSC. In accordance with Section 5.2 above, OSI shall be responsible,
            for **. Genentech will discuss with OSI the projected dollar amounts
            of such OSI share of Sales Costs, during Genentech's preparation of
            the Commercialization Budget.

      "5.2B. TERMINATION OF CO-PROMOTION. (a) If OSI (i) materially breaches
this Amendment and fails to cure such breach within thirty 30 days following
written notice from Genentech or (ii) fails to cure, within thirty (30) days
following written notice from Genentech, circumstances or conditions which have
resulted in a pattern of several similar breaches of this Amendment, regardless
of materiality of the individual breaches (such as a failure on the part of

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                                       24
<PAGE>

an OSI sales representative to spend at least 50% of his or her time on Licensed
Product promotion or the failure of an OSI MSL to refer a matter to a Genentech
MSL as required under this Amendment), for which OSI has also received written
notices thereof, Genentech shall have the right to terminate all of OSI's
Co-promotion rights granted under the Agreement by written notice, subject to
the terms of this Section 5.2B The parties acknowledge and agree that because
the materiality of any specific breach must be measured as of the time of the
breach and is dependent on the performance obligations and conditions at such
time, the examples above are for purposes of reference and are not intended to
change the applicable legal principles governing materiality. OSI will have five
(5) days after its receipt of Genentech's notice of termination to notify
Genentech in writing that it will challenge the termination, and OSI may not
challenge such termination if it does not give such notice to Genentech. If OSI
does challenge the termination, then notwithstanding anything to the contrary in
the Agreement, such dispute shall be resolved through the Expedited Arbitration
Procedure set forth in Section 16.4 below. The termination shall be effective on
the later of (A) ninety (90) days after Genentech's notice of termination, if
OSI fails to challenge the claim upon which the termination has been based, or
(B) sixty (60) days after receipt of an arbitration decision affirming the
termination in the Expedited Arbitration Procedure set forth hereinbelow,
regardless of any pending judicial proceedings related thereto. For purposes of
the "Expedited Arbitration Procedure" set forth in Section 16.4 below, Genentech
and OSI agree (1) that the time periods in Section 16.1 of the Agreement will be
reduced by 50%, and (2) if such dispute cannot be resolved during such reduced
time periods, the dispute shall be resolved as set forth in Section 16.4 below.
The Parties acknowledge that time is of the essence in resolving termination of
Co-promotion. Should OSI be found by the arbitrator to have delayed such
procedures for purposes of delaying

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<PAGE>

a decision on the termination, Genentech shall be entitled to reasonable
attorney fees and, at the sole discretion of the arbitrator, exemplary damages
for the delay. The Parties agree that the Expedited Arbitration Procedure set
forth in Section 16.4 is solely for purposes of affirming or reversing the
Co-promotion termination decision and claims for damages directly related to the
breach resulting in such Co-promotion termination and is not the exclusive
remedy for any breaches or damages contemplated herein. The Expedited
Arbitration Procedure does not apply to any other dispute or claim under the
Agreement.

      (b) Such termination of OSI's Co-promotion rights shall also be subject to
OSI's ability to assert, under Section 5.2 of the Agreement, its participation
in Co-promotion again pursuant to the terms of this Amendment, such assertion
not to be made until at least two (2) calendar years after the later of: (i) the
effective date of such termination or (ii) the effective date of the final
arbitration decision upholding such termination, described above.

B.    Section 5.3 of the Collaboration Agreement is hereby amended by deleting
the second and third sentences of Section 5.3 in their entirety. A new Section
5.3A is hereby added to the Agreement immediately after Section 5.3 as follows:

      "Genentech shall have the responsibility for design of Licensed Product
      advertising and promotional materials and sales training materials.
      Genentech shall file such advertising and promotional materials with the
      FDA as required under applicable law. Genentech will be designated by OSI
      as the Party responsible for filing such materials to OSI's NDA. Genentech
      will provide, in a timely manner, the draft of such advertising and
      promotional materials to OSI, and a senior member of OSI's regulatory
      function will be

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<PAGE>

      able to attend Genentech's internal regulatory review of such materials
      through Genentech's Promotional Review Committee ("PRC") meetings (or
      similar successor Genentech regulatory committee review if the PRC ceases
      to exist). During such meetings the OSI regulatory representative may
      raise any reasonable concern of OSI regarding such materials only with
      respect to any particular potential violation of a law or FDA regulation
      governing pharmaceutical product promotion, which Genentech has not
      addressed. Decisions at the PRC meeting regarding any such OSI regulatory
      concern will be made by consensus. In the event that such PRC members and
      the OSI regulatory representative do not agree on such regulatory
      compliance of any such materials, the materials in dispute will be
      reviewed and discussed at Genentech's PRC Oversight Committee (or similar
      successor Genentech committee if the PRC Oversight Committee ceases to
      exist), which will include participation by the OSI Vice President (or
      officer of similar title) in charge of OSI's regulatory function. In the
      event that the OSI Vice President and the Genentech members of such PRC
      Oversight Committee do not agree and resolve such regulatory dispute for
      the materials, the materials and regulatory issue will be referred for
      resolution to the Vice President (or Party officer of similar title) in
      charge of the regulatory function of each Party. If such two Vice
      Presidents together cannot resolve such regulatory issue in dispute, then
      notwithstanding anything to the contrary in this Agreement, such dispute
      will be finally resolved by the Party which will hold the NDA for the
      particular Licensed Product for which such materials are prepared."

C.    The following sentence is hereby added to the end of Section 5.3 of the
Collaboration Agreement:

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<PAGE>

      "For further clarification, each Party will have the responsibility for
      execution of and decision making responsibility for, Licensed Product
      commercialization activities as specified on Appendix A hereto."

D.    Section 5.3 of the Collaboration Agreement is further amended by deleting
the fourth sentence in its entirety and replacing it with the following
sentence: "Except as otherwise expressly provided in this Amendment or in
Appendix A hereto, Genentech shall have the final decision making authority with
respect to commercialization matters."

6.    MARKETING ACTIVITIES OF LICENSED PRODUCT.

A.    Article 5 of the Collaboration Agreement is hereby amended by inserting
the following new Section 5.3B immediately after Section 5.3:

      "5.3B MARKETING ACTIVITIES.

      (a) Except as otherwise stated in Appendix A hereto or otherwise expressly
      provided in the Agreement, Genentech shall have the sole responsibility
      for setting the overall commercial strategy for Licensed Product and for
      designing and implementing all marketing activities related to Licensed
      Product, including, without limitation, branding, positioning, advertising
      and promotional materials (subject to OSI's regulatory review under
      Section 5.3), medical and professional disease state education (subject to
      Section 5.3B(b) below), Licensed Product public relations (except as
      provided in Appendix A hereto or otherwise expressly provided in the
      Agreement), relationships with opinion leaders and professional societies,
      medical meeting and tradeshow activities (except as set forth in the
      following sentence) and Licensed Product market research, except for

                                       28
<PAGE>

      those activities expressly assigned to OSI in Appendix A hereto or by
      Genentech. Notwithstanding the foregoing, OSI shall be entitled to use at
      medical meetings and tradeshows specific Licensed Product promotional
      materials and exhibit panels that have been previously approved in writing
      by Genentech and, with respect to which, OSI has confirmed through the
      JCIT that have not been updated. Except for OSI's role in decision making
      with respect to regulatory review under Section 5.3A above and as
      otherwise provided in Appendix A hereto or otherwise expressly provided in
      the Agreement, all final decision making for all Licensed Product
      marketing activities shall reside with Genentech. Genentech shall manage
      the Commercialization Budget and will also manage all relationships with
      vendors for Licensed Product commercial activities.

      (b) Notwithstanding Section 4.3B(f) above, either Party shall be entitled
      to make unrestricted medical education grants and to conduct continuing
      medical education ("CME") accredited medical and professional disease
      state education (and continuing education accredited professional disease
      state education for nurses and pharmacists) that: (i) are not designed to
      provide but may include education on Licensed Product and (ii) are
      designed to provide general education in oncology or another general
      disease state area, and (iii) are funded from such Party's own budget
      (which shall not be subject to any cost sharing under the Agreement). All
      unrestricted medical education grants and CME accredited disease state
      education shall be made in accordance with applicable laws and regulations
      and the PhRMA Code on Interactions with Healthcare Professionals.

B.    Article 5 of the Collaboration Agreement is hereby amended by adding a new
Section 5.6 immediately after Section 5.5 as follows:

                                       29
<PAGE>

      "5.6 USE OF LOGO. All Licensed Product-related materials, including,
      without limitation, marketing, promotional, medical and training materials
      for Licensed Product and all sponsorships related to Licensed Product for
      or on which the names and/or logo of a Party are to be included shall bear
      the names and/or logos of both Genentech and OSI, as provided by the
      Parties to each other, in comparable prominence (size, emphasis and
      position), to the extent permitted under applicable law and regulations.
      Use of a Party's name and/or logo for such purposes shall be in accordance
      with all requirements of such Party with respect to such use, and neither
      Party shall otherwise use the name or logo of the other Party unless
      expressly provided in the Agreement or expressly permitted by such Party.

7.    EXPEDITED ARBITRATION

      Article 16 of the Collaboration Agreement is hereby amended by adding a
new Section 16.4 immediately after Section 16.3 as follows:

      "16.4 EXPEDITED ARBITRATION PROCEDURE. In the event of disputes under
Section 5.2B(a) as to which the Expedited Arbitration Procedure herein applies,
Sections 16.2 and 16.3 shall apply, except as expressly set forth below:

      (a)   The Parties agree that issues under the Expedited Arbitration
Procedure will be determined by one arbitrator. Within ten (10) days after the
commencement of procedures under Section 16.1, the Parties shall attempt to
agree to and rank in order of preference no fewer than three (3) qualified
arbitrators. In the event the Parties cannot agree on such a list within such

                                       30
<PAGE>

ten-day period, either Party may request the American Arbitration Association
("AAA") to appoint for purposes of ranking no fewer the three (3) such
arbitrators (including a request that the AAA do so within fifteen (15) days of
such request) and such appointments shall be final and binding on the Parties.
Whether the arbitrators are chosen by the Parties or the AAA is asked to appoint
such arbitrators, (i) all appointees must have at least ten (10) years
experience as an attorney and experience in the pharmaceuticals industry so as
to better understand the legal, business and scientific issues addressed in the
arbitral proceeding, and (ii) the Parties will separately rank the proposed
arbitrators and the average ranking of the Parties will determine the order for
purposes of subsection (b) below (in the event of a tie, the Parties will rank
the tying arbitrators based on random selection).

      (b)   Upon such initiation, the Parties will jointly contact the first
ranking arbitrator and determine whether that person is available to serve
within the time frame set forth herein. If that person is not available on those
terms, the next ranking arbitrator will be contacted, and so forth down the
ranking. Upon agreement by an arbitrator to take the case, and upon completion
of the procedures set for in Section 16.1 as expedited, the Expedited
Arbitration Process will be deemed commenced ("Commencement"), and the following
sequence of proceedings will occur:

      i.    Within ** after Commencement, OSI shall serve a brief on Genentech

and the arbitrator setting forth its factual and legal arguments with regard to
the termination dispute and providing all documents it proposes to use at
hearing in support of its position. Within ** after service of OSI's brief,
Genentech shall serve a brief on OSI and the arbitrator setting forth its
factual and legal arguments with regard to the termination dispute and providing
all documents it proposes to use at hearing in support of its position. Within
** after service of Genentech's brief,

--------------
** This portion has been redacted pursuant to a confidential treatment request.

                                       31
<PAGE>

the Parties shall request any discovery that it believes is critical to a fair
resolution of the issues in dispute.

      ii.   Within twenty (20) days after Commencement, the arbitrator shall (1)
grant such discovery as deemed appropriate and require that it be completed
within no more than **; (2) identify the issues that will be subject to a
hearing; and (3) set a date for a hearing as to the pending termination dispute
no more than ten (10) days after the completion of all allowed discovery or
twenty (20) days after the issues are identified in the event no discovery is
allowed. In no event shall the hearing begin any later than two (2) months after
the Commencement.

      iii.  The arbitrator shall provide a hearing of sufficient length for each
Party to present its case but in no event longer than five (5) days total
duration. At the completion of said hearing the arbitrator may allow
post-hearing briefs to be filed within no more than ten (10) days after the
hearing.

      iv.   Within ten (10) days after completion of hearing, or within ten (10)
days after the submission of post-hearing briefs, if allowed, the arbitrator
shall render a decision on the termination dispute affirming or reversing the
Co-promotion termination. There shall not be a reasoned decision. In no event
shall the decision be issued any later than three (3) months after Commencement.

8.    LEGAL COMPLIANCE

      Section 17.2 of the Collaboration Agreement is hereby amended by adding
the following sentence at the end of Section 17.2:

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** This portion has been redacted pursuant to a confidential treatment request.

                                       32
<PAGE>

      "The Parties shall each reasonably cooperate with the other by providing
information reasonably necessary in order to enable the other Party to meet its
reporting obligations, under applicable law or regulation, to which it may be
subject as a result of its responsibilities under this Agreement."

9.    COLLABORATION AGREEMENT.

      Except as expressly amended herein, all provisions of the Collaboration
Agreement remain in full force and effect.

10.   GOVERNING LAW.

      This Amendment shall be governed by, and construed in accordance with, the
laws of the State of New York.

11.   COUNTERPARTS.

      This Amendment may be executed in two or more counterparts, each of which
shall be deemed an original, but all of which together shall constitute one and
the same instrument.

                                       33
<PAGE>

      IN WITNESS WHEREOF the Parties have executed this Amendment as of the
Amendment Effective Date by their duly authorized representatives.

OSI PHARMACEUTICALS, INC.                       GENENTECH, INC.

By:   /s/ Robert L. Van Nostrand                By:    /s/ Susan D. Hellmann
      --------------------------                       ---------------------
      Name: Robert L. Van Nostand                      Name: Susan D. Hellmann

      Title: Vice President and Chief                  Title: President, Product
      Financial Officer                                Developement

                                       34
<PAGE>

                                   APPENDIX A

                                       **

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** This portion has been redacted pursuant to a confidential treatment request.

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