GEORGE J. GILLESPIE, m

THOMAS R. BROME

ROBERT D. JOFFE

ALLEN FINKELSON

RONALD S. ROLFE

PAUL C. SAUNDERS

DOUGLA D. BROADWATER

ALN C. STEPHENSON

MAX R. SHULMAN

STUART W. GOLD

JOHN W. WHITE

..OHN E. BEERBOWER

EVAN R. CHESLER

PATRICIA GEOGHEGAN

D. COLLIER KIRKHAM

MICHAEL L SCHLER

KRIS F. H EI NZELMAN

B. ROBBINS KIESSLING

ROGER D. TURNER

PHILIP A. GELSTON

RORY O. MILLSON

NEIL P. WETREICH

FRANCIS P. BARRON

RICHARD W. CLARY

WILLIAM P. ROGERS . ..R.

JAMES D. COOPER

STEPHEN L. GORDON

DANIEL L MOSLEY

GREGORY M. SHAW

PETER S. WILSON

JAMES C. VARDELL. m

ROBERT H. BARON

KEVIN oJ. GREHAN

W. CLAYTON ..OHNSON

STEPHEN S. MADSEN

C. ALLEN PARKER

MARC S. ROSENBERG

WILLIAM B. BRANNAN

LEWIS R. STEINBERG

SUSAN WEBSTER

TIMOTHY G. MASSA

DAVID MERCADO

ROWAN D. WILSON

..OHN T. GAFFNEY

Dear Ms. Schenof:

CRAVATH SWAINE & MOORE LLP

JULIE T. SPELLMAN

RONALD CAMI

MARK I. GREENE

SARKIS .. EBE. IAN

JAMES C. WOOLERY

DAVID R. MARRIOTT

MICHAEL A. PASKIN

ANDREW J. PITTS

MICHAEL T. REYNOLDS

ANTONY L RYAN

GEORGE E. ZOBITZ

GEORGE A. STEPHANAKIS

SPECIAL COUNSEL

SAMUEL C. BUTLER

THOMAS D. BARR

OF COUNSEL

ROBERT ROSENMAN

CHRISTINE BESHAR

CONFIDENTIA TREATMENT REQUESTED

Termation.

Carboplatin ANA Filers

April 29, 2004

Bristol-Myers Squibb Company ("BMS") submits ths letter and the

enclosed materials in response to the requests for additional inormation contained 

your letter of April 20, 2004, and made durng recent conversations with outside counsel

for BMS and/or Teva Pharmaceuticals USA, Inc. ("Teva

WORLDWIDE PLAZA

825 EIGHTH AVENUE

NEW YORK, NY 10019-7475

PETER T. BARBUR

SANDRA C. GOLDSTEIN

PAUL MICHALSKI

THOMAS G. RAF"FERT

MICHAEL S. GOLDMAN

RICHAD HALL

ELIZABETH L. GRAYER

..ULIE A. NORTH

STEPHEN L BURNS

KATHERINE B. FORREST

KEITH R. HUMMEL

DANIEL SLlFKIN

JEFFREY A. SMITH

ROBERT I. TOWNSEND. m

WILLIAM J. WHELAN, m

SCOTT A. SARSHAY

PHILIP ... aOECKMAN

ROGER G. BROOKS

WILLIAM V. FOGG

FAIZA... SAEED

RICHARD J. STARK

THOMAS E. DUNN

TELEPHONE: (212) 474- 1000

F'ACSIMILE: (212) 474-3700

CITYPOINT

ONE ROPE MAKER STREET

LONDON EC2Y 9HR

TELEPHONE: 44-207-453-1000

FACSIMILE: 44-207-860.1150

WRITER S DIRECT DIAL NUMBER

(212) 474- 1564

Carboplatin

You asked us to consider modifying the term ofT eva s distrbutorship

rights to provide that Teva s distrbutorship rights expire at the earlier of some period

after Teva receives Food and Drg Admstration ("FDA") approval of its ANA

(perhaps 30 or 60 days) or June 24 2005.

The paries addressed ths request in Aricle 9 of the Distrbution and

Supply Agreement between BMS and Teva, dated April 26, 2004, (the "Distrbution and

Supply Agreement") submitted to the FTC on April 27, 2004. BMS respectfully refers

you to the following specific provisions of the Distrbution and Supply Agreement:

Sections 9. 1.1 5 and 9. 6.1 (c).

You requested that BMS identify, by the form and dose specified in the

Agreement, which companes have fied an ANA for carboplatin.

CONFIDENTIAL
Enclosed is a list of generic companes that, to BMS' s knowledge, have

filed ANDAs for carboplatin. BMS does not generally have knowledge of ANDA filings

prior to tentative approval unless it receives notice that a company filed an ANDA

containing a paragraph IV certification. It is therefore possible that other generic

companies have filed ANDAs for carboplatin about which BMS does not have

knowledge.

BMS' s Annual Sales ofParaplatin

You requested that BMS identify its annual sales of carboplatin.

Enclosed is a chart that provides annual domestic net sales for Paraplatin i!

in lyophilized and solution form, by dose, for 2003. BMS also markets a 600 Mgs

solution product. This product launched earlier this year and accordingly no net sales

figures for this dosage are included.

Claims and Potential Claims that are Resolved by the Agreements

You requested a copy of any counterclaims asserted by Teva that would be

dismissed as part of the resolution of the litigation at issue.

Pharachemie B.V. ("Pharachemie ) filed three answers in which it

asserted counterclaims. In its most recent answer, the Amended Answer and

Counterclaim to Consolidated Amended Complaint, dated October 22, 2002, Teva

asserted only one counterclaim for declaratory judgment of patent invalidity. A copy of

the Amended Answer and Counterclaim to Consolidated Amended Complaint is

enclosed.

REDACTED

Pharachemie has also argued that it could obtain approval of ANDA 76-

162 notwithstanding BMS' s pending pediatric exclusivity. BMS disagreed, and continues

to disagree, with this contention.

The language in the agreements relevant to the resolution of the claims

and potential claims of the paries may be found in paragraphs 2, 3 and 4 of the

Settlement Agreement between BMS, Teva and Research Corporation Technologies

Inc., dated April 26, 2004, submitted to the FTC on April 27, 2004, and section 2. 1.4 of

the Distribution and Supply Agreement.

CONFIDENTIAL
Teva s Corporate Strctue.

You requested information regarding Teva s corporate strctue and the

relationship between Teva and Pharachemie.

Teva and Pharachemie are both subsidiares of Teva Pharaceutical

Industres Ltd., an Israeli company that does not do business in the United States.

Pharachemie is a Europea company that does not directly distrbute products in the

United States and relies upon Teva and others physically to sell and distrbute products in

the United States.

To aid in the FTC's understadig of the corporate strctue ofTeva, I am

enclosing a printout from Mergent Online that provides additional information

concerng Teva Pharaceutical Industres Ltd.

Confdential treatment of ths letter and the enclosed materials is

respectfully requested.

Than you for your consideration and assistance. If you have any

questions, please do not hesitate to call me at the number above.

Respectfully,

Richard J. Stark

Ane Schenof, Esq.

Bureau of Competition

Federal Trade Commission

601 New Jersey Avenue, N.

Washington, DC 20580

Encls.

FEDERA EXPRESS

Copies wi encls. to:

Alan Bar, Esq.

Assistat Attorney General

Office of the Attorney General

200 Saint Paul Place

Antitrst Division, 19th Floor

Baltimore, MD 21202-2202

CONFIDENTIA
Richard L. Schwar, Esq.

Assistant Attorney General

Offce of the Attorney General of New York

Antitrst Bureau

120 Broadway

Suite 26-

New York, NY 10271

Wiliam Shieber, Esq.

Assistat Attorney General

Antitrst Section

Offce of the Attorney General

300 W. 15th Street

Austin, TX 78701

Alan C. Witten, Esq.

Antitrst Section

Ohio Attorney General

150 East Gay Street, 20th Floor

Columbus, OH 43215-3130

Meredyt Smith Andrs, Esq.

Assistant Attorney General

Office of the Attorney General

Antitrst Division

200 St. Paul Place

Baltimore, MD 21202

Nicholas J. Weilhammer, Esq.

Assistat Attorney General

Offce of the Attorney General

The Capitol, PL 01

Tallahassee, FL 32399

FEDERA EXPRESS

CONFIDENTIA
Carboplatin

Known AND A Filers

Caboplatin Injection USP Mayne Phara ANA 3/30/04 Solution FDA

10 mglmL, Rx 76-517 Website

Tentatively Approved

Carboplatin Injection USP Faulding ANDA 4/16/03 Lyophilized FDA

, 150 and 450 mg, Rx Pharaceutical 76-473 Website

Tentatjvely Approved

Carboplati Injection USP American ANA 5/22/02 Lyophilized FDA

, 150 or 450 mg, Rx Pharaceutical 76-235 Website

Tentatively Approved Parers, Inc.

Carboplati Injection USP Gensia Sicor ANDA 8/12/02 Solution FDA

10 mglmL, Rx Pharaceuticals, 76-227 Website

Tentatively Approved Inc.

Carboplati Injection USP Pharachemie ANDA 1/14/03 Lyophilzed FDA

, 150 or 450 mg, Rx B.V. 76- 162 Website

Tentatively Approved

Carboplati Injection Pharachemie ANDA N/A Solution Notice of

10 mglmL, 5 mL, 15 mL B.V. 76-292 Paragraph IV

and 45 mL vials Certfication

Statu Unknown

Carboplatin Injection USP Bedford ANDA 6/6/03 Solution FDA

10 mglmL, Rx Laboratories 76-039 Website

Tentatively Approved

Carboplatin Injection USP Bedford ANDA 9/18/02 Lyophilized FDA

, 150 & 450 mg, Rx Laboratories 76-099 Website

Tentatively Approved

Carboplatin Injection Spectr Unkown N/A Unkown Public Press

Dosage Unknown Pharaceuticals Release

Status Unknown Inc.

CONFIDENTIA
Paraplatin 

2003 Domestic Net Sales

REDACTED

CONFIDENTIAL
, 

- Mergent Online Page 1 of2

MERGENT ..

Home: I Basic Search: I Search Results: I Company Details

Teva Pharmaceutical Industries Ltd. (Israel) (NMS: TEVA)

I Company Detailsl Company Financial Create Report EDGA New

Synopsis I Highlights I History I Joint Ventures I Business I Propert

Debt I Executives I Capital Stock

Teva Pharmaceutical

Industries Ltd. (Israel)

5 Basel St.

Petach Tikva, 49131 Israel

Incorporated: 1944, Israel

Number of

Employees: 10,960

(Approximate Full-Time as of

12/31/2003)

Country: Israel

Ticker: TEVA

Primary SIC: 2834 -

Pharmaceutical preparations

Primary NAICS: 325412-

Pharmaceutical Preparation

Manufacturing

Number of

Shareholders: 1 600 (as of

01/30/2004)

Closing Stock Price: As of

4/212004 $64.47

PE Ratio N/A

Company Website:

ww.tevapharm.com

Mergent Dividend

Achiever

Annual Meeting:

Other Search Tools

EDGAR

CONTACT US I HELP

MUtiE:-r

I Company Analysls List (0) Expand

I Subsidiaries I Long Term

Business Summary Custom Report List

to Custom Reportng List

to Company Analysis List Teva Pharmaceutical Industes Limited is a global

pharmaceutical company producing drugs in all major

treatment categories. Co. utilizes its production and

research capabilites to establish a global pharmaceutical

operation focused on supplying the growing demand for

generic drugs and on the opportnities for proprietary

branded products for specifc niche categories, such as its

branded drug Copaxon r multple sclerosis. Co. 's actve

pharmaceutical ingredients (API) business provides both

significant revenues and profis from sales to third part

manufacturers and strtegic benefits to Co. 's own

pharmaceutical production through its timely delivery of

signifcant raw materials.

Financial Highlights (In USD as of 12/1/2003) Total Revenue 3,276,400,000 Net Income 691,000,000 Total Assets 5,915,900,000 Current Assets 3,716,400,000

Total Liabilties 2,626,500,000

Current Liabilites 1,694,900,000

Long Term Debt 449,900,000

Stockholders' Equit 3, 289,400,000

Key Executives

Eli Hurvitz - Chmn.

Israel Makov - Pres., C.EO.

Principal Offces Auditor

5 Basel St.

Petach Tikva, 49131

Israel

Kesselman & Kesselman

legal Counsel

Tulchinsky - Stem & Co.

Willkie Farr & Gallagher

Pricing Information

htt://:fsonlinel.fisonline.comfcomDdetaiLa.'m?comn nv mp.t= '\Rt\7 &r.nmn nv=_ Li/1 /' (\(\Li
. Mergent Online

kPage 2 of2

Ticker: TEV A Exchange: NMS

Closing Price As of 4/212004 $64.

Weeks Ending

04/03/2004 03/27/2004 03/20/2004 03/13/2004

Open

Price 64.

High

Price 64.

Low

Price 61.

Last

Price 62.

Total

Volume 8,714 800

Average

Volume

for Past

30 days 62

52-

Week 55.14-

Range 67.

COPYRIGHT 2003 MERGENT I PRIVACY POLICY I FEEDBACK

64. 64. 63.

62. 63. 65.

61. 62. 61.

61. 62. 64.

375,200 8,421,200 12,287,000

htt://fisonlinel.fisonline.com/compdetal.asn?cornnanvmer- 4\Rf\7 nmn!'n'=- A/1,/,)f\l\A
Mergent Online: Teva Pharmaceutical Industries Ltd. (Israel) (NMS: TEVA)

History

Incorporated in Israel on Feb. 13, 1944. Present Co. estalished in 1976 upon the merger of thee companes, Teva, Zori and

Assia, which were originaly established in Isrel in the 1930'

In Mar. and Apr. 1980, Co. acquid Ikphar Ltd., a phareutical manufactur (merged effective Mar. 31 , 1982), and Dr.

N. Premiger Ltd. (now Promedco Ltd.) an importer of medicines and medical equipment.

In Feb. 1986, Co., though its U.S. joint ventue company, acqud Lemmon Company, a U.S. producer and maketer of

generic drgs.

On Apr. 10, 1987, Co. sold Promedico to foreign investors for US$4 000 000.

On Jan. 21, 1988, Co. purchased from Baxter-Interntional Inc., a U.S. company, al of the issued and outstadig shares of

Travenol Laboratories (Israel) Ltd. The shares of the above two companes were purchased for a tota of approx.

US$8 200 000.

On Mar. 29, 1988, Co. acquied the remag outstadig shares ofMigad Ltd. and Ada Ltd., Israeli companes which

were previously 45% owned and 50% controlled, for approx. US$I,OOO OOO.

On Oct. 11 , 1988, Co. acquied approx. 98% of the equity of the issued and outstadig shars of Abic Ltd., an Israeli

corporation which, diectly and indiectly, though subsidiares;'manufactues and markets pharaceutical and veteri

products, for approx. US$26,6000,000.

In 1989, Travenol Laboratories and Migada Ltd, subsidiares of Co., were merged.

In Jan. 1991 , Co. acquied the remaig 49.8% interest in TAG Pharaceuticals, Inc. from W.R. Grace &Co. for

US$20 000,000, plus up to US$4 000,000 payable based on the operatig results of TAG until the year 2000.

In 1992, Co. acquied 100% of the share capita ofProchemia S.d. and is subsidiares for a tota payment ofUS$23 200,000.

In 1994, Co. acquied 34% of the share capital of Pro grph ar Laboratories for consideration ofUS$7,200,000 and 30% of

the share capital of Portan Pharceuticals Inc. in consideration of US$ 1 500 000.

In Oct. 1995, Co. acquied Industre Chiche Itaane S.

In Nov. 1995, Co. acquied 78% of Biogal Phaaceutical W odes.

In 1996, Co. acquied Approved Prescription Services Ltd., a U.K. generic drg company, for US$52.2 millon.

On July 1, 1998, Co. acquired ful ownership and control ofPharchemie N.V. for approx. US$83 millon.

On Sept. 21 1999, Co. acquied Copley Pharaceutical, Inc. for US$220 mion (includig acquisition costs).

In Apr. 2000, Co. acquired Novophar Ltd. In consideration, the vendor was issued 2. 1 millon ordiar shares of Co. and 6.3

millon special shares that are exchangeable into ordiar shares of Co. at his discretion on a one-to-one ratio.

On Dec. 31 , 2000, Co. acquied the shares in a subsidiar of Novophar from the miority shareholders in ths subsidiar, for

a total amount of US$12 millon.

In June 2002, Co. acquied fu control and ownership of Honeywell Phaaceutical Fine Chemical S.d. (subsequently

renamed Teva Pharaceutical Fine Chemicals S. ) in Itay and Bayer Classics S.A. (subsequently renamed Teva Classics

) in France, as well as a shareholders' loan ofUS$34 millon grted to the acquied company by the vendor. Tota
Mergent Online: Teva Pharmaceutical Industries Ltd. (Israel) (NMS: TEVA)

consideration paid for the two acquisitions (includig the shareholder s loan mentioned above and acquisition costs) was

US$168 millon in cash. Co. accounted for these acquisitions by the purchase method.

On Jan. 22, 2004, Co. acquied Sicor Inc. The purchase price paid by Co. amounted to approxitely $3 460,000,000 in a

combintion of cash and Co. shares.

Joint Ventures

Subsidiaries

; ; ::; :::

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Mexico
2 ,

STERNS & WEINOTH

A Professional Corporation

50 West State Street

Suite 1400

. Trenton, NJ 08607

KC-0848

Attorneys for Defendant

Phanachemie B.

UNTED STATES DISTRICT COURT

FOR THE DISTRICT OF NEW JERSEY

BRISTOL-MYERS SQUIBB

COMPANY and

RESEARCH CORPORATION

TECHNOLOGIES, INC.

Plaintiffs

PHACHEMIE B.

Defendant.

. .

I CIVIL ACTION No. 01-3751 (MLC)

I (Civil Action No. 02- 1270 has been

I consolidated herewith)

AMNDED ANSWER AN COUNTERCLAIM TO

CONSOLIDATED AMNDED COMPLAIT
.!:

Defendant Phanachemie Pharmachemie answers the

correspondingly numbered paragraphs of plaintiffs' Amended Complaint for

Patent Inmngement as follows:

Pharachemie is without lrowledge or information sufficient to

form a belief as to the trth of the allegations of Paragraph 1 , except that it

believes that Bristol-Myers Squibb Company ("BMS" is a Delaware

corporation with a principal place of business in New York, New York.

Pharachemie is without knowledge or information sufficient to

form a belief as to the trth of the allegations of Paragraph 2, except that it

believes that Research Corporation Technologies, Inc. ("RCT") is a Delaware

corporation with a principal place of business in Tucson, Arzona.

Admts.

Admts.

Pharachemie admits that it designated an agent for service of

process in New Jersey in connection with the originally filed Civil Action

No. 01-3751 (MLC) and fuher admts, for puroses of this action only, that

Phanachemie is subject to personal jursdiction in this judicial distrct and that

venue is proper in this. Cour under 28 D. C. 1391(c) and 1400(b).

Phanachemie denies the remaining allegations of Paragraph 5.
Pharachemie admts that United States Patent No. 4 657 927

(hereinafter the "' 927 patent") issued on April 14, 1987, and that copies of the

927 patent and Certficates of Correction are attached to the Amended

Complaint as Exhbit A. Phanachemie is without lrowledge or information

sufficient to form a belief as to the trth of the remaining allegations of

Paragraph 6.

Pharmachemie is without knowledge or information sufficient to

form a belief as to the trth of the allegations of Paragraph 7.

Pharmachemie is without lrowledge or information sufficient to

form a belief as to the trth of the allegations of Paragraph 8.

Pharachemie admits that it filed an abbreviated new drg

application ("ANDA") with the United States Food and Drug Administration

FDA") for approval to market powder for injection products containing

carboplatin as their active ingredient; that its ANDA included a certfication

under 505G)(2)(A)(vii)(IV) of the Federal Food, Drug and Cosmetic Act that

the ' 927 patent is invalid, unenforceable, or will not be infrnged; and that RCT

and BMS received notice of the certfication on June 26, 2001. Pharachemie

denies the remaining allegations of Paragraph 9.

10. Pharachemie admits that it filed an ANA with the FDA for

approval to market injection products containing carboplatin as their active
ingredient (together with the powder for injection products which are the subject

of 9 above referred to as "Phanachemie Carboplatin Products ); that its

ANA included a certfication under 505(j)(2)(A)(vii)(IV) of the Federal

Food, Drug and Cosmetic Act that the ' 927 patent is invalid, unenforceable, or

will not be infunged; and that BMS received notice of the certfication on

February 25 , 2002. Furher answering, Pharachemie states that RCT received

notice of the certfication on Februar 27, 2002. Phanachemie denies the

remaining allegations of Paragraph 10.

11. Phanachemie admts that if the ' 927 patent is valid, its filing of

the ANDAs referenced in 9 and 10 constitutes an act of infrgement of 

. least one claim of the ' 927 patent pursuant to 35 D. C. 271(e)(2)(A) entitling

plaintiffs to an order that the effective date. of the approval of both of

Phanachemie s ANDAs be a date which is not earlier than the April 14, 2004

expiration date of the '927 patent. Pharachemie denies the remaining

allegations of Paragraph 11.

FIST AFTI DEFENSE

Claims 1 and 3 of the '927 patent are invalid and unenforceable against

Phanachemie by reason of obviousness-tye double patenting.
COUNRCLAI

DECLARTORY JUGMENT OF

PATENT INALIDITY

For its counterclaim Pharachemie alleges the following:

Pharachemie is a Netherlands corporation with a -pricipal place

of business in Haarlem, The Netherlands.

On infoffation and belief, BMS is a Delaware corporation with a

pricipal place of business in New York, New York.

On infoffation and belief, RCT is a D ware corporation with a

principal place of business in Tucson, Arzona.

Subject matter jurisdiction exists pursuant to 28 D. C. g 1331 and

g 1338.

Phannachemie incorporates by reference the statements in

paragraph 5 of its Answer establishing venue over this action in this Court.

THE RCT/BMS PATENTS

S. Patent No. 4 140 707 (the "'707 patent"), issued on

Februar 20, 1979, identifies the inventors of that patent as Michael Cleare

James Hoeschele, Barett Rosenberg, and Loretta VanCamp. The patent was

subject to reexamination and a Reexamination Certficate issued on December

, 1989. The tenn of the ' 707 patent was extended by 916 days under 35
C. 9 156 in response to an application submitted to the United States Patent

and Trademark Office by RCT based on the period of time required by FDA to

review BMS' application for approval to market its carboplatin products in the

United States. Copies of the ' 707 patent, the Reexamation Certficate and the

Certficate Extending Patent Term are attached as Exhbit A.

The ' 707 patent expired on August 24, 1998.

Claims 1 , 5 6 and 7 of the ' 707 patent, after Reexamination, claim

diammineplatium(II) dicarboxylate compounds. Claim 7 is limited to

carboplatin.

The '927 patent issued on April 14, 1987, and identifies the

inventors of that patent as the same inventors identified in the ' 707 patent:

Michael Cleare, James Hoeschele, Barett Rosenberg, and Loretta Van Camp.

Unless declared invalid or unenforceable, the ' 927 patent will continue in force

until April 14, 2004, when it is currently scheduled to expire.

10. Claims 1 and 3 of the '927 patent generally claim compositions

containing, and a method of treatment using, compounds, including those

claimed in claims 1 , 5 , 6 and 7 of the '707 patent, to be admnistered

parenterally. More specifically, Claim 1 of the ' 927 patent claim a method for

treatig a specified malignant tumor which "comprises parenterally

admnistering to an animal affected with said malignant tumor a solution
containing in an amount sufficient to cause regression of.the tuor. . . (one of

the diammneplatinum(II) dicarboxylate compounds claimed in the ' 707 patent

and other (platinum(II) and) platinum(IV) compounds) . . . ." Claim 3 of the

927 patent claims a "composition suitable for parenteral admnistration to an

animal affected with a . . (specified malignant) tumor

. comprising a

pharaceutically acceptable carer and 

. . . 

(one of the diammneplatium(II)

dicarboxylate compounds claimed in the '707 patent and other (platinum(II)

and) platinum(IV) compounds) . . . .

THE PHAACHEMIE CAROPLATIN PRODUCTS

11. The Pharachenre Carboplatin Products are 1) powder for

injection products containing carboplatin as their active ingredient which, if

approved for marketing in the United States, will be available in strengths of

50mg per vial 150mg per vial and 450mg per vial; and 2) injection products

containing carboplatin as their active ingredient which, if approved for

marketing in the United States, will be available in 10mg/mL, 5mL, 15mL and

45mL vials.

12. On or about April 16, 2001 , Pharachemie filed with the FDA an

ANA seekig approval to market the powder for . injection form of the

Pharmachemie Carboplati Products in the United States. On or about

December 6, 2001 Pharachemie filed with the FDA an ANDA seeking
approval to market the injection fonn of the Pharachemie CarboplatiProducts in the United States.

13. Pursuant to the Federal Food, Drug and Cosmetic Act, each ANA

contaed a certfication by Pharachemie that, in its opinion, the '927 patent

was invalid, unenforceable or not infrnged. By letter dated June 20, 2001

notice of the certfication in the April 16, 200 I ANDA submission setting fort

the factual and legal basis for the opinion regarding the ' 927 patent was sent to

RCT and BMS. By letter dated February 20, 2002, notice of the certification in

. . . 

the December 6, 200 I ANDA submission setting fort the factual and legal

basis for the opinion regarding the ' 927 patent was sent to RCT and BMS.

14. BMS and RCT have asserted and are continuing to assert that the

Phanachemie Carboplatin Products will infrnge claims 1 and 3 of the ' 927

patent.

15. Pharmachemie seeks a declaratory judgment that claims 1 and 3 of

the ' 927 patent are invalid based on obviousness-tye double patenting and

therefore, the Phanachemie Carboplatin Products, when marketed in the United

States, will not infrge those claims.

16. The only difference between the subject matter of the earlier issued

claims in the ' 707 patent and the subject matter of the later issued claims 1 and 3

of the ' 927 patent, with respect to the compounds claimed in the ' 707 patent, is
. .

the parenteral use of a solution containing such compounds to treat a specified

malignant tuor (claim I) and a composition that includes such compounds

together with a "pharaceutically acceptable carer (claim 3). The

admnistration of such compounds to regress the tumors specified in those

claims, and the manufactue or use of a composition containing such compounds

in an amount suffcient to regress such tuors, would have been, to a person of

ordinar skill in the relevant art and in light of the prior art, an obvious

modification of the inventions claimed in the ' 707 patent. -

17. actual controversy exists between RCT/BMS and

Phanachemie with respect to invalidity of claims I and 3 of the ' 927 patent by

reason of obviousnesstye double patenting.

WHEREFORE, Phanachemie prays for judgment against BMS and RCT:

(a)

(b)

Dismissing the Amended Complaint herein;

Declarng that claims I and 3 of the '927 patent are invalid and

unenforceable based on obviousnesstye double patenting; and
(c) Pennanently enjoinng RCT/BMS, their offcers, agents, directors

servants, employees, subsidiares and assigns, and all those acting under the

authority of or in privity with them or with any of them, from assertg or

otherwse seekig to enforce the '927 patent against Phanachemie.

PHARMACHEMIE B.

By its attorneys

STERNS & WEINROTH

A Professional Corporation

50 West State Street

Suite 1400 . 

Trenton, NJ 08607

Dated: October 22, 2002

OF COUNSEL:

Francis C. Lynch

Laure S. Gill

PALMER & DODGE LLP

III Huntigton Avenue

Boston, MA 02199
United States Patent (19)

Oeare et &1.

(11)

(45)

140 707

Feb. 20, 1979

(54) MALO ATO PLATINUM ANI-TUMOR

COt\IPOUNDS

(75) Inventors: Micbael J. Oeae; James D.

Hoeele; Barett Rosenberg;

Lorett L VBJ Cap, aD of Eat

Laing, Mich-

(73) Assignee: Reseach Corpration, New Yotk

(21) Appl. No.: 778,955

(22) I:ilcd: Mar. 18, 1977

(63)

Related U.s. Applicaon Data

Continuation of Ser- No. 260.989, Jun B, 1972.

ab.su!onr.

(51) Int. 0. ...____n...___n-.__._..n.....-_-'- C0 15/00

(52) U.s. a. _n""n-_'-'-----"'-"-' 26/429 R; 424n45;

424/287; 54/4

(5&) Field of Secb _n...__..n",,,,__,,"n'_' 260/429 

Referce aled

PUBUCA nONS

Ward ct aI-. CaccTre.tmnt Repom. vol. 60, No. II,

1675-1678 (1976). 

Rosenbeg Pial Meta Rev. IS, 42-47 (1971).

Lcb ct aI_, J. Pha3CUt Scince, 65, No. 3 (1976),

pp. .

3IS-320.

Roscnberg ct 21, Natue 222. 385-386 (1969).

(56)

Prnu Eran:iner-Helc: M. S. Snc:

Artomq. Agmt. ar .fm:-Dcu. P. Clake

(57) ABCf

MaJonato platinum cOrdintion compounds and a

method of treatig JDgnt tuors comprig the

p3rteral adti:l to 3D afected an of a .

solution of the compot:

4 a., No Ih-awi
num (IV) forms d2 3 coordination compounds which

have an octahedra arrangement ir space.

The coordination compounds of the. invention indude thc cis d tra.'!, isomers of platium 01) and

platinum (I whicb conlz the bidentate malonato

ligand which may be lubstituted or.unsubstituted. Tbe

maonato ligand may contan substituents sc:ected from

the group consising oflower aJkyl. (e.g., methyl, ethyl,

propyl, isopropyl, n-butyl, etc.); arl, (e.g., phenyl;

10 lower alkyl., lower alkenyl-, halo-, nino-, lower aJkoxysubituted phenyl and naphthyl); aralkyl, (e.g-, pbenylmethyl (benzyl). 2-(l-n:.phthy1)methyl); alkenyl, (e_

4-ami:IO- butene. allyl); cycloakyl. (e.g cyclopropyl,

cydo e:t) I, etc.); cydoalk=nyl, (e. , 2-cyclopcntcnIS I-yl. 2-cyc1obexcn- yl); alkoxy, (e. , mctboxy, ethoxy,

etc.), and bydroxy. Also suitable are the . I-cydoaJkylenedi ar\;oxylic acids, (e. , I I-cyclopropanedicaob"ylic acid, l l-cyclobutanedicarboxylic

acid. e:c.) and the 1,I-cyc1oal1:nyldicuboxylic acids

20 (e. , I,I-cyclopropenedicaboxylic acid, 1

cyclobut ncdicarbo"ylic acid..dc.

The cordination compounds of the invention also wherein: cont3i Iwo monodcnbt"e amonia or priary or heter- -

acyclic amie ligands, i.e., when x in the above formul

x =.1 .or 2; ,2S is 2 or one bideDtatc amine ligand, i. , when. x is I. y = I or 2: Suitable monodentate ame ligands indude lower z = 0, I or 2. alk).1 amincs, (e. , methyl., ethyl-, n-propyl-, ispropylprovided that when y = 2, Z = 0 and when y I, Z is , butyl- 3Jines, etc.), aryl amincs (e.g.. aniline), arat- greater tban 0; 1:yl amines, (e.g:, bczylaine), hydroxy lower all

Rand RJ are. selected from the group consisting of H. 30 ames, (e_g., ethaolame, propanolame; etc), bylower alkyl, aryl. aralkyl, al1:enyl, cydoalkyl, cy- droxybmi , lower alk ?, ames (e.g., methxylac1o:.lkenyl. alkoxy, OH, or are combined \lith the ca. , etc.). aJkoxyalkyl es , lIethox3?.etbylabon atom to fonn a cycloa1yl or c)"c1oaJkenyl group, etc.), and h:krocycli IIcs (e. , pyn me and

and substituted derivaives thrcof andme). -A Included are the 3I0 acid, ie.,

when x = I, A is HR2 CHRr-H NRsH 3S Rr-Cm-'Hl OOH wherein R is H, lower alkyl

and when x = 2, A is H NR6a heterocyclic amine or an (e.g.. methyl, ISpropyl. ele.), hydroxy lower alyl (e.

g.,

amino acid, wherein Rz, R), . :a R, are the sae or hydroxymethyl, hydroxyeth).I, etc.). aralkyl (e.g., bendifferent and are selected from rhe group consisg of zyl, eIe).

. .

H. CH . C H,. hydroxy and lower alkoxy provided thaI It 15 to be r.ders ood Ilt. the roordll lIo comR and R may also be ary) or ar I. and each R is the .& p?und of the: mve:nl1o may uaclude two Idenllca or

-' Y dlfT rent monode:nbte: bgands sae or dIfferent and IS se ecku from regroup consast- Ulta", e . L I enta e amme: gan s IDC u e t e su ta- IDg 0 H, tower alkyl, arl, aralkyl, h)"woxy lower U e an WI tuuo pnmary an secon alkyl, hydroxyl and al oxyl annes. alkoxy!akylanncs th I cd ' 0 t: th f th 

\; 

wherein all of sad alyl groups are lower alkyls and e y n =?:So. De or 0 r on a oms 0

bs' ts ' I d' 'd N 4S the: ethyleneda..rune: may contam subslltuents such as eteroc c IC su ntuen anc u IDg S3 as a nog lo",

er aJkyl (e. , methyl, ethyl), hydroxyl, aloxy (e.g. member

, .

. - methox)., ethoxy, etc). Secondary ethylenedies

when z = I, L !S a bJdenlate anlont d, and wherein one or more of the ame groups conta sub-

. z = , L IS a monodentate amomc h d. stNents sueh as lisJed above for the carbon atoms of the The IDventlo . also elatcs to a C SJlJOn and SO primar ame a.'!d arl (e.g., phenyl) and aralkyl Co e.g. od for treating mal &?ant. tUors In unaJs com- benzyl) may al be utilied.

lDg pa entcraJly admmastea;ng to an.a?lma aff ted The Pt (II) coordintion compounds specifed herein

\V1Ih a. ma!lgnaot tumor a solution O!mral g a plat!num do not ext as geometrica ismer; however, the 

coordllallon ompound as defint: hereanabove 10 an OV) compounds ext as cis and tran ismers. II is to be

amount suffCIent to caus regrason of the .tumor. SS furr understoo that the inventin is inclusie oftbe

DETAILED DESCRIPTION OF TIE . ci and tr-iomcrs. INVNTON The PI (I cordintioa compounds may also con-

. .

ra tw monoeDtate or one bidentate anioni ligand

Iatlnum l!' compounds and methods for where only one malonato ligad is present, i.e.. where y

rhe r producpon are desn'bd by J. C.. Baiu, Jr.. The 60 = I in the above fonnula.

Che"!ir ry of the Coordination Compounds R:Wold Saiitable monodentate anionc ligads include cbJoPubbshang Corp-, N.Y.. 1956, Chap. 2; J. LeWI eI ai, ride. brolle. iodide. oitrte.- hydroxide, nitrate sulfModern. Coordina CItmistry Prnciples and Method Jlt:, etc. A:ong the bideDtatc aionic ligands which

Intersclence Pubbshers Inc., N.Y., 1960 and Kauffma may be present are oxakte, pyrophosphate, dithioxaIrrorganic Synthtsis 7, McGraw-Hil .Book Co., Inc., 6S late- .

- N.Y., 1963. It is to be understood that the invention includes

Platinum (II) fonns dsp2 cordination compounds thos coordination compounds contanig mixed mono.

which have a square planar arrangement iD space. Plati- dent3!e anonic ligads;;

140 707

MALONATO PLATINUM ANTI-TtIOR

COMPOl;1'"DS

Tbe invention described .herein was made in the S

cou of work under a grant or award from the Dc.

parJme:nt of Healtb, Education and Welfare. .

This is a continuation, of application Ser. No.

260.989, fied June 8, 1972, now abandon

BACKGROUND OF THE INVENTON

The pre:sent invention rc:ate:s to novel malonato plaunum coordination compounds and to thc:r use in cancer

chemotherapySUMMARY OF THE INVENTION

The invention provides platinum coordination compounds having the fonnula:

(P\(II)A (OOI..CRR.l Dr

ci, or ,nn,IP,(JVIA (OOCh-CRRlhLzl
140,707 -

The preferred compounds are those wherein R and (to avoid "bumping ) on the bot plate until white crys.

Rt in Ibe above formuJa are H, metbyl or ethyl

. i_ tas of Ihe produci started to form in greal quatity.-The

malonatopleUnum. methylmaloDatopb.tioum ard ethyl- miture was then cooled to room temperature and Ihe

maJon:topl:lunum cordination eompoWlds- The most product fIlered ofT. The: filr;ole: W2 rebeated for 5-10

preferred Pt (I compounds arc Ibose mzonato- 5 miUles and coled to 0' C. 10 col1cct a furlher crop.

platium (II) compounds of the abovc f~rmula ",hcrein The crde yield at ths stage Sg (93%). 

X = 1 and Rl' RJ' RJ and R) are each H , maonaloc- The product wa recystallized .by dislving in boilthylenediamine platium (II), metbylmalonatoc- ing or nea boiling water. Thc above yield (20.5g) rethylened!am!oepI31!nUm (II) and el ylmilonatoc- quired about lilers of boilng waler Cor complele diss

Ibylcn a.tn tmum 01);. and .wbere!o x = 2 and 10 lution. Milonic acid IgI was dislved io the waler to

each R6" H. e., m lonat tammmeplatinum (II). me- suppresi any hydrolysis.- The fJtered solution was

thylmalol1tod meplatmUD 01) an ethyl- colcd -to. .0' C to give while fluffy neees

milonalodtamrmneplatmum (II). . (18.1511-83%). 

The prdctTcd Pt OV) compounds arc those wbcrem 'U.V JVla ,pertlo! and conduclivi.y .,udi.. havc show. .ha. hydrlysi.

X = 2, eacb R6 is H and y = 2, ie., bismalonato (or IS is nCllip"btc. 

bismelbylmalonaloorbis:tbylmalonato)di:mineplat- The: crysub decompose between 185' 190' C. The um (IV). structure of the: product was verfied cia an ir. spThe cordination compounds of Ibe: invention lUy be tru Solubility of the prouct i, low in cold water, i.e..

prepared by one ofa varidy of well-mown methods. A 20 mg/IOO mls at 20' C. and 43 mgllOO mls al 37' c.,

gene:ral method of preparation of the: Pt OI) cordina- 20 but higher in near boiling water (90' - 100' C)- 65g1100

tion compounds is as follows: Staing compounds hav- mi.

ing the formula cis-(Pt A(Hal)zl whcrein Hil is I, Cl or 

The empirca composition was verified y elemental

Br and A is one bidentate or two monodenta:e amine anilysis:

Iig:mds (prepared by the method of S. C.Dba India Malonatodmicplatinwn(I (P(Nil(CJ

J. Cbcm., V91 S, p. 193 (1970)) are react with silver 2S Caculated for C HaNl Pt.C: 10.88; -H: 2.43; N:

nitrte to form the diaquo eomplcx. 

lattr is then ' 8.46: Pt 58.9; Found C: 10.67; H: 2.35; N: 8.54; PI 58.

reacted with Ihe milonate ion to form the cordintion

compounds of the invention. Th method is replt- EXMPLE 2

seted by the foUoy..ing rcacdon scheme: (PI (en) (C. (j4)) (en = H2N(CH NHJ; C.I0,

cilPt AOJJ + lAgNOJ + 1HzO) - a..(P 30 - =OJ . CH(CH)) cOt -

A(H20) JJetmJh + 2,,&a Silver ;Utrate (3.64g) wa dislved in 20 ml ofwalcr

and adde:d to :z(CH:zCL21 (3..g) supended iD

a..(P A(HzO)zjOJh +. 1t2C-iCOh .. IPI water (30 cl) in a conica ()!51c. The miture was ,fued

A(OOHii + 1KOJ - + 2H on a war hOI plate for 5::10 miutC$ unti all the yd-

.

JS low platinum complex Iw dilved to give a yenow

wherem A!s o e b.dentate ame hgand or two mouo- liquor plus a copious white siver. choride precpitte.

dentate amIDe. hgands.

. . .

The mitue was ftt.red hrough a lie pore fiter and :

The followmg non-hmJtl

g 

exple: are iJustraUve the precipitate washed lwie with small volumes of hot 

?f the mvenUon. . melhods for prepag the compounds of the water. The clea fttl1tc plus wasgs was added to an

40 aqueou solution of mcthylnonic acid (2g in 20mb)

EXAMPLE 1 which had ben adj!l!i. to pH 5-6. The miture wa -

heated 10 aboul SO' C for five miutcs and then cooled M2.onalodiacplaUnlim(II) to 0: c. The shny white crysta whicb .formed were 

(P1(NJMC 04)) fillcred and """ahCd with colif water and actone (Yeld

45 2.65g). The mothe:r liquor plus aqu. washis wa

reduce 10 about half its origi Volume (-30 mI) to

yield a second crop on coing to. O' C. (Yield 0. 85g).

Tota Crude: yi.c1d (88%). The complex

. . 

was recf)"Stalized from :a inum volum of boiling

(PJh:O)z(NoPz + C, O.z- water (arund 250 mJs) with falr:tiori Ihrougb a fine

(Pt(NHJh(c)1tJ 1 + 2N0, - +1H10. tI pore mtcr prior to eooling.to ct c. 

Yield of shiy whit leaets 2.96g (74%).

ilvcr trte (21;558 sligbtl les tha the StOI- CacuJatCd for C:19.41 H 3.26 N:7.sS;

omelne 3;0oot m. order to aVOId silver coola- Found C:19.U H 3.61 N:7.89. -

;

tion) was dISlved. m watc: (SO ) and 2/dc to'5 A second crop (0.33g':8%) viis obtaed by reducing

(Pt(N' J)zOzl (2OS) m ' 2 mJ. comca k. P' e co the bulk of tbe mother liquor. "

eo were wae O\ OD a pia e WI rap '

stig unil the siver chloride precpitatioD wa com. EXPLE 3

plcte and. the mother liqoor wa alost c:Jor1 The I--'.ro IV

,y 

silver cbloride wa fJtercd offusg a fie pore sitcred 60 .

. - J ,-m 

glas fiter and the precipitate wa washed seve ties Silver nitr (5.45g) wa dilved in water (J mJ

with bot water to give a tota6lrrate volume of 100200 mi. and added to tr (Pt(NJna.. (3g) suspcdcd in

Witer (30 ml) cotag_conCetrted nitrc acd (3

loblonic acid (13g - a twofold exces) wa dilved ml), The. cootets were waed on a hot plate (70'-8. 

in water (30 ml.) and neutred wilh a solution of 65 C.) an stired Cor.at leat ot: hour- The mixture 

KOH (- 13g in 30 mi.) 10 pH 5-6. The: resuJt.g pota- fttered through a fine pore sintere glas fiter to re-

. sium maJor-ate solution wa added to the: platinum eoo- move the silver chloride:. The precpilate wa washe

wning fttrate and the mixture was cacCully warmed t..ice v.;tb n smal volume of hot wat r. e dea fI.

Reactions:

(PtJhOzJ + 1AI 0, + 2Hl0) 

(PI(NHY1(Hl0)zClO,) + lA,a
140 707

trJle plus WJsbir:gs was tested wilh a drop of 1M KCI following standard protocols for Ibis tesling as set by

sclutions to detennin if excess silver chloride was pres- the National Cancer Institute. (Cancer Chemotherapy

ent. (If Ihe test is posilive. surtdent KCI is added drop- Rep.. 25(1962)). 

wise to th: bul;c solution until no silver chloride is pre- For thes tests an SJ80 tumor taken from a sacrifice

cipilaled.) The solution \I':S refiltered and the filtrate S mouse was disected free of superfluous tissue and cut

reduced to 20-:!0 mls in volume and cooled to O' C. to under sterile conditions into approxitely 10 miJiyield plate yellow crytals (presumably trans gram size 'pieces These lisue pieces were then im-

(PI(NH3)z(NOJ)')). These were washed with a liule planted by Irocr in the left axlar region. subcutaeco!d water and then acetone (Yield 1.8g). A ponion of ously, in new mice.-The mice were, on the average.

this)' ield (lg)wasdisslvedinnminimumofhotweter 10 approximately fouf wecks old and weighed 18-20

to which sodium. nitrate (0.2g) bad bccn added. This grams. Takng day 0 as the day of implat. the anmas

solution was filtered iulO zn aqueous solution of malonic were sacrificed on day JO. The tumors were excisd and

acid (0.5g - a slight excess) which had bccn adjusted to weighed and the ratio of the weights of the tumors in

pH 5-6 with sodium hydro"idc. Wbitc nucro-ryslals of mice in the: treated animals to the control set of anma

the complex quickly form on cooling. These were fi. IS was obtained. This ralio, multiplied by 100, is given as

tered ocr and washed with cold waler and acetone. the TIC ratio in Table I, 

(Yidd 0.7g - 30-%). For the flIt set of tests the coordination compound

C:Iculatec! for 20aPt C:16.63 H 2.33 N:6A7; was freshly dislved in stenle distiled water and inFound C:IU H 2.64 N:6.80. jected intraperiton ally on day I into each of the tet

GENERAL STUCTRE CONFORM TJON 20 mice. The volume of the injecton wa usually I mI.

The malonate g,roup is shown to be coordinzted to some cases. in order to get an active dose into the aniplatinum by the o rved change in the electronic 'mal where the chemical was not soluble in th amount

spectra on soicg from Ih aquo to Ihe malonate speces of solvent, a fine dispersion was prepared of the dose .

Thus, structures such as-(Pt(NH)Jz(H20)zJzH2C)O,)) Deeed for the tes Thus so e of our test rcsults w~re

3n ruled out confirming the analyt!;al data Simiarly, 25 obtamcd oil -animal where a sluny of ,the co pound .

zero.time conductivit). m asuremenrs support a neuual was injected. These are so noted in Table I below. In

compound. The i.r. specua show the presence of coor- adilition, for some of the compounds, there wa injcctl:

di:tated carboxyl ,groups (16001650 cm I and 140 about I m1 of sol uti an, either in one single injection. or

with no COzH sroups (which would show at in 2 injecuons given a few hours apart of I m1 each.

1700-1750 cm). Finally Ihe cerboxyl group vibrations 30 These injections were initilly given in 4 iferent dose

are compalible: ",ith a ehelated strulure as compared to levels for eacb Dew compound with 6 mice in each dose

ulate complexes of known struclures. leveL The tess covered a dose rage from a low mefThe comtJunds of the invention were tcsted for fective dose, to en upper dose level which prodlJd

anti-tuDor a::livily using our standard screening tumor, some: death within the tie period of the experiment.

solid szrcorua I SO tume: in female: Swiss white: mice, 35 The results are 3d forth in Table I. 

TABLE I

TOb of ADtit.",or Activity or Malo..lo aDd Substituted MaI..to

Cordinat:oa Coplex or Plarm""

Tw:or-S..cor.. ISO ADal.Fcme Swi while mice

Si. e injectia 00 day. Doled iatupcritoc.

Coordinalion Comptcl.

M2!O:tJ.todi1.cctncpbt:\:D1

(II) (.Iurry in HID) .

Day oK

I'lCCioD

(solution ia HP) D.ily ror

dlY' 1-

Methylml!o..todiaminef'atinam(ll) (Slution in H

malonlOdhylcasruir.c

pbtlnum (II)

clhylmalon'lo:thytencdminplariD" (U

","10..0.\. propylen::i.:nin..

platinum (II)

No. of 

Dose Let TIC D..1h

10 mEls

J5 rnEls

20 ..(le

25 rnEle )0 rn&/ 1/6

40 ..eI!: 6/6

50 rn 5/6 Ii mes 6/6

4 rnsle

5 lDe 6 rn&

1 ..eI&

30 ..eI!:

40 "'ele '0 "'sis

eo "'Slg

10 "'els 124 3/6

50 ..&:!: 616

138

100

120

100

110

120
,;;

140 707

-continued

CoorC:in an Co:rp1cs

Doy of t:o.of

lnje-lion Dox LcvcJ TIC !)Ibs

r.:Jo:c:o-t.3 s:r",, I:l;clil k.c.

rlal,nu;: (tl)

cch)-1m3!o:o:cc:h!tcDt 30m

I!:amir!:aliu:n (II)

(sclurioa r. H C( mg/r;

50 mglr; II mgr;

70 mglr;

90 mglg

clh)':""lor. w=\r JO Ins/g

pb.in=(11)

(..I"lion in HPI 40 mg/g

Ing/1

70 mglg

20 mg/jJ

maJoDa:oct!ylc3ei:.a-i:C'

10 mglg

pb.icuIR (II)

(..:uc:n i., 8; JO mV\1 '" mglg

45 mg/g

50 mglE

55 ",elg

mV\1 3/6

10 m;Va 3/6

1.c)'"looulo,,-.i: 1 yb,: 10 mglg

lUm::":cpb.i' :1 (II) 40 mglg

60 mV\c

10 mgr;

100 lIg/c

no mg/c

160 "'&11

l:!or..I J:elt:).br:ne) 10 mBlke

F1zlin '" (\0 100 ..ile

110 melc

140 mg/c

160 IIg/r; 180 mg8

In a.dilion to th day 1 injections descrbed above. in 35

a nu;nl: r oC C2 inj tions were delayed until day g 

tUIor growth. In thes cas the tumor was usU3ly at

least brg=r than 1 g:. as estimated by palpatioD. Tbe

a.s wue thOt inject and observed Cor a period 

approxia:ely 60 days. Activity was measured by tbe 40

number oC aniraI whos tumon had regresd to the

aoi:ng PO:Dt. whik stilllliowing the anl to sur-

"ive for this time period. Such test results are descrbed

in TABLE II below.

TABLE II

Tcs of Luge SL-Co: I!O .. b)' MaC21O

C1 Coplescs cC Plaw"...

T=o'. aI:: 110 Ar.!.Fame S..u. while mic:

Si...ilc injeODS "0

Day' irav.cac:)' iI H.O solU1o

Tou! Nu:nbcr

Ccordiurion Comp!cr. Doo of Repesons Oall

rr.t!c:ut ,.i.c.. U mgllB

p:"ti.,=(II)

16 IDg/g

II mglg

::.2tcutoe!hyICDC"

10 IDi:B

di=crhliu:(l1)

40 mr;l

4' lDg/g

'" IDaI&:

60 mal.

Th Jesuits dcsn"b in Tabl s I and Jl indicate Imt ro

the compouDds of the invention are very potent anlituDor agents againsl the S 180 tumor in Swi white mice

Confirmatory tests of anlitumor activity agait the

Walker 256 Circiosacoma in rats. and the ADJIPC6A tu"1or in tnc= were conducted. The initial test 

resuI:s 2re shown in Table III and confinn the potent

act:on of the C3mI=oc.nds of the invenlion against these

o:her tUtor s)"Slern. 

TABLE II 

CODfirmtory Test5 or Aftdrumor Aclivity

MoIO""loda..mi..cpla.inum(tl)

TVtr: W.1icr 2'6 CacC: 0Srcoma .. Aairn. R:at

Sinele injccacn In)' 1 in Oil. Do Inmpen.onc.lly

,. Inhibiuoo 10 lDg/g tOO 10 mtlB 100 40 milB 100

11 lDelS 

MoIo..rDelb)"cncdWnin.pbtinull(U

TI:r: Walker J56 Carcnosacoma. ADim. . Rat

SiDa!e injcc.ion Do)' Iln Do Oi lotnperilonc:ally 10 ,. IDllibitD Dea 10 40 100 15 IIi all

Tumor: ADJIPC6,\ . ""IDol - Mouo

Single injeioo Da)' Do.. 15 in Oil. IntraperioDuUy

,. Inhibition

100 20 100

Dotll

Death

Samles of tbe malonato die and maonato

ethylene diarno complexes of phtinum(Il) wae submitted to the Drg Rcsn: and Development Brach

oftbe Natiott Cancer Inslitute for scrg for mUtumor actvity against Ihe LI110 tumor in mi The rcsalts obtaind on th tumor system arc shown in Table

IV. They confirm the actty of the compounds of the

inVcnIiOD.

- TABLE IV 

CoDr"".,o,y Tests of Anrilumoc Activity atlb

NoEioa1 Cancer Institute. Tumor: Ll110 Animal - Mia

Daily injcclons D )'s 1-. In"apcrilon..lIy
TABLE IV-continued

707

ConrirrrINY Tnti or Anti1u or Aclivit7 It Ihe

btion31 Cancer Institute.

Cnonln..:a. Compteo

M.IoNl,xD::micepb.i.um(II)

" IDeu:

in Life,po"

163

13)

II)

Dose

50 malg U malg

12-' m&lg

50 mglg

mglg

12-' mglg (..;ot In:1 )1-' mVkg

Tumor: LlltO Animl- Mice

D3ity inj lons Da)' s 1-9. Inu3palolu~.JII,

tolatanOlocth)'l:nediOl:ncpbtiwo(ll)

Coo, .,t:c. Camp!:..

101

160

1)1

121

V. JnC1C'

in U'::pa

196

160

141

Dos

25 mglg

16-' milg

II mglg

The malonatoplatinum cordination compounds 

the inv::nlion are preferably disslved or suspended in 20

waler or other pharmaceulically acceptable carrier

liquids, . The p:ucnleral1y adminislcnble composition

should preferably conlain from about O.Smg to about

IOmg per mL, it being undersoo at the amount may

vary greatly depeding .upon the parular cO!Dpound 2S

emplo)' cd and Ihe anima to be !reatm.

The platinum coordination compounds or the invenlion.are preferably adminitered parenteraly 10. an ani.

m3J affected with a malignant Iwnor. The durtion or

treatmenl and the dos level, r cours, will depnd in 30

each c upon the size of the hot anim, natue and

size oflhe lumor. etc. Gcneraly, however, a dose level

or rroJ: about 20 to about 200 mg/g or boy weight

per day will be suffcienL It is 10 be undersloo. however, th:!1 tbe plalinum coordination compounds eom- 3S

pounded 'wilh a suitable pharaceulical carner in the

S3me proportions as rected a.bove may also be administered orally al the s.e dosage leVels.

We claim:

1. Plalinum coordiD3lion compounds havig the formula:

(PI(II)At(OOz-CRR

wherein: -

x-=lor2;

Rand R, arc selected from the group consistig oCH.

lower alyl, arl, aralkyl. aIcnyl. cycloalkyl, cycloakenyl, alkoxy, OH. or combine with the carbon atom 10 form a cycloalkyl or cycloalkenyl

group;

when x = I, A is HR N-CHR)- NR5H

and when x = 2, A is H2 or an amino acid

wherein R . R3. R. and Rs are the same or different

and arc selecled Crom the group consisting oC 

CH), CzH" hydroxy aDd lower aJkoxy, provided

Ihat Rz and Rs may al be aryl or aralkyl and each

R6 is the sae or diffcrenl and is selected from the

group consting oC H. lower aJyl, aryl. aral.

hydroxy lower alkyl, hydroxyl- and alkoxylamincs.

and alkoxyl aJkyl amines.

2. The: compowid oCctaim t"having Ihe Connula:

(PI(lI)A ((OOCHz))

wherein

:I = I, and

R2' R and R) arc each H3. The compound oC clai 1 having the formula:

(PI(lI)'" t(OOCK z)l

wherein:

x = 2, and each is H.

4. Malonalo diamine platinum (0,
. .

REEXAATION CERTIFICATE (1173rd)

United States Patent (19) (II) Bl 4 140 707

(4S) Certcate Issued De. 19, 1989

Oeae et 

(S4) l\1ANAYo PU'1'UM ANTI-TUOR

COMP'U

(7S) Inventors: Mkhsc J. Oc James D. Hcecr Ba Lo L Vm CaP, al or i:t

Lag. Micl

(73) A5 : Res CorU TlthDol

lA TUcn. 

a Reque

No. 90101.716, Feb. 14, 1989

t1OC Cecs ror. .

Patct No. 4.140707 b.uc: Feb 20 199

Appl. No. 77,,55 Fdcd: Ma. 18, 

(63)

. Relarrd U.s. AppUodoD Ibis

Conrinuation of $cr. o. 160.919. JUD 3. 1912. abon

doned

(S I) IDt. a." --.-_u_--..----...-..-.- C1 15/0

(S1) U.s. a. -....-..-.--.....-.-.-- 556/137; 5412

556/17

8) Fldd of Sc --._u.--'- S46n; ' 6/I1, 137

(S6) Rdcr ate

PUBLICATIONS

On the Srcreohrn!r or Pla:o S.u (I". authored

by A. A. Gruberg 00 Jan. 8. 1931 2.d pub cd OD

May 2. 455-72. 193 I in Hclvcrica Cbi Acta xrv at pp.

Prmary bDmilltr-A. McFarlane

(57). ABCT

MaJonato platium coOrd D co poUDds and '1 .

method or tr tig uWgnt ncOD compriiDg th

parentera adtntiOD to an afcc an of 1

solutin or die compoUDd.
B14. 14O 707

(P.((octJl

AS A REULT OF REATION. IT HAS

EEN DETD TIT:

wherein:

%=1 or 2;

5 R :ad R 1 UC sd tcd from 1Ie group c:nsistig of It

lower ilyl. arl, anl, alcuyl, cyc1oayl. cy.

cloalkenyl, aloxy, OR, or combine with the cabon :al0m Us CRRt to form .. cycloalkyl or cycloalftenyl grup;

when x= 1. A is HRIN-CHR)-CKR-NR,H and

whco x=2. A is H2N'or aD amo:ad, wherein

RI. RJ. 1U and R, arc the sme or dierent and arc

selecte (ro:n the grup constig of It CH).

C1H" hydroxy and lower aloJ;, provided tht

Rl u: R, (ImY al be) c:re als scl dfrm 

poup conr..ng 'of arl or anl an c.h 14 is the

sae or dicrct an is seec fr the grup

co03g of R, lower all, arl. anyJ; hydrol:Y

lower all, hydroxyl. o. aloxy1ao, Cl 1 is detc to be patetable as amended. 20 .noxyl alyl acinC1 prori&J rMl whclI JC=l and A

uHvVR,anJ R,isH.rf.mR GnJRIlUnDrbachH. Cl 2; depdent 00 an amended c!,uCl is delAr- 5. Tic compond af claim 1 '..urcu. R 13M Ri tcUII

cicd 10 be patentale. rogclu, ..ilh ru carbll to k1s rhey an aru!rcd form 

. . . .  

C)doal1cl grp. 

New cWr S, 6, and 7 ar added LDd detcn:ed to 25 6. 11e compond of claim ..!rcreill R OM Rlltun be patctale. rogtrhtr wirk l!re coban alom ro ..1ah rhey an Imai:hed

form a CJloblran

7. 1. cylotrar:t tficrba;r!clt c!i4mrint pla:illum

(ll)

REATION CERTICATE

ISS ER 35 U. C. 307

TIrE PATE IS HEBY AMNDED 

JNICAlCD BELOW.

MJlttu c.clos In hCA1' brackets () a.pa In thc

patu but h. b1n deleted and is DO lODger. pa or the 10

patet; _tt pritc. In ItAcs 1nca adtions 

to the palat.

CW 3 JId 4 are caccUcd

L Pbtium cordilico compounds hAvig the formuh
J:-

UNITED STATES PATENT AND TRDEM OFFICE

CERTIFICATE EXTENDING PATENT TERM

UNDER 35 U. C. 156

Patent No. 140 707

Da ted February 20, 1979

Inventor (s) Michael J. Cleare et al

Patent Owner Research corporation Technologies, Inc.

This is to certify that there has been presented to the

COMMISSIONER OF PATENTS AND TRADEMAS

an application under 35 U. C. 156 for an extension of the

patent term. since it appears that the requirements of the law

have been met , this certificate extends the term of the patent

for the period of

916 DAYS

with all rights pertaining thereto as provided by 35

USC 156 (b).

' . J. II) ,/ .

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I have caused the seal of the Patent

and Trademark Office to be affixed

this 25th day of January 1990.

;L 

Jeffrey H. Samuels

Acting commissioner of

pa tents and Trademarks