Plavix Patent

Issue
 Group No 4
Members
Gaurav Rawal(17)
Sayli Vaidya(55)
Sagar More(40)
Laxmikant Shimpi(45)
Vaibhav Patil(34)
Neha More(61)
PLAVIX

GENERIC NAME: Clopidogrel bisulfate

BRAND NAME: Plavix

 What is Plavix?

 Anti-platelet medication approved by the U.S. Food

and Drug Administration to reduce the risk:
› Heart attack
› Stroke
› Vascular death in patients with established
peripheral arterial disease
 When taken daily can help reduce risk of having a
future heart attack or stroke
 Used by 48 million Americans
 MECHANISM OF ACTION

ADP
clopidogrel bisulfate

ADP P2Y12

SCH 530348
ADP
E 5555
cAMP

Activation Thrombin
GP IIb/IIIa
(fibrinogen COX-1
receptor)
TXA2
aspirin

adapted from Schafer AI. Am J Med. 1996;101:199-209.

 MARKETING

 Plavix is marketed worldwide in nearly 110 countries

 Sales of US$6.6 billion in 2009
 Global sales of $5.9 billion
 Second best selling drug in the world
 Marketed through a partnership with Bristol-Myers
and Sanofi-Aventis
 Sanofi Aventis

 Headquartered in Paris
 World’s third largest Pharmaceutical (#1 in Europe
 Sales = 27 billion euros
 R&D = 4 billion euros

Bristol-Myers Squibb
• Bristol-Myers Squibb 2005 revenue was $19.2b.
Plavix sales represent about 30% of total revenues
• U.S. sales of $3.8b in 2005, up 15% from 2004
 Apotex

 Largest Canadian-owned pharmaceutical company

 Main business is making and selling generic pharmaceuticals
 2005 sales of $740 million (Canadian)
 Received FDA approval for generic Plavix in early 2006
 The issue
UNITED STATES DISTRICT COURT
SOUTHERN DISTRICT OF NEW YORK
SANOFI-SYNTHELABO;
SANOFI-SYNTHELABO, INC. and APOTEX INC. and
Vs
BRISTOL-MYERS SQUIBB SANOFI APOTEX CORP.,
PHARMACEUTICALS
HOLDING PARTNERSHIP

Plaintiffs Defendants

SIDNEY H. STEIN, U.S. District Judge

 History of Plavix Case
Sanofi

The ‘596 patent The ‘265 patent

U.S. Patent No. 4,529,596 U.S. Patent No. 4,847,265

Issued in 1985 Expired in 2003 Issued in1989 Expires in2011

 The ‘596 patent
The ‘596 patent covers a genus of chemical
compounds called thienopyridines, within which
clopidogrel bisulfate falls

The ‘596 patent discloses only the free base of

clopidogrel, and does not expressly describe the
dextrorotatory and levorotatory enantiomers or
any salt
 The ‘265 patent
July 11, 1989: Sanofi obtained a patent claiming
clopidogrel bisulphate.
Sanofi employees Alain Badorc and Daniel Fréhel as
inventors.

Claims: clopidogrel bisulfate by its chemical name in Claim 3:

“Hydrogen sulfate of the dextro-rotatory isomer of methyl
alpha-5(4,5,6,7-tetrahydro(3,2-c)thieno pyridyl)(2-
chlorophenyl)-acetate substantially separated from the
levo-rotatory isomer.”
Source: (‘265 patent at col. 12, ll. 37-41.)
• November 1997: Plavix approved for sale in US by
FDA.

• The ‘265 patent is exclusively licensed to Bristol-

Myers Squibb Sanofi Pharmaceuticals Holding
Partnership.
 
Launch of Generic Clopidogrel by
Apotex
 ANDA Application
Nov 2001:
• Filed ANDA with the FDA
• Sought approval from the FDA to manufacture and
sell clopidogrel bisulfate tablets
before the expiration of the ‘265 patent.
• Apotex was the first to file an ANDA for clopidogrel
bisulfate

• Thus, secured the right to 180 days of market

exclusivity provided by the Hatch-Waxman Act

• August 8, 2006: Apotex initiated an at-risk launch of

its generic clopidogrel bisulphate product.
 Hatch-Waxman Act
• Abbreviated New Drug Applications (ANDAs) to seek
FDA approval of the generic

• Paragraph IV
allows 180 day exclusivity to companies that are the
"first-to-file" an ANDA against holders of patents for
branded counterparts.
Sanofi’s Action
 Infringement of ‘265 patent
SANOFI-AVENTIS
March 21, 2002:
• Filed litigation against Apotex and asserted that Apotex’s filing
of the ANDA constituted infringement of the ‘265 patent,
specifically Claim 3.

• Claim 3 of the '265 patent : Hydrogen sulphate of

dextro-clopidogrel seperated from levo-clopidogrel.
 What is Infringement??
• A person infringes a patent by making, using, offering
to sell, selling, or importing into the country any
patented invention, without authority, during the
term of the patent.
 Preliminary Injunction
• Sanofi moved for a preliminary injunction prohibiting
Apotex from distributing its generic product.

• It is a court order prior to a final determination of the

merits of a legal case whereby a party is required to
do, or to refrain from doing, certain acts.
 Apotex Defends……
1) Apotex alleges that the ‘265 patent is anticipated
pursuant to 35 U.S.C. § 102(b) by an earlier patent
held by Sanofi that covered a genus of chemical
compounds called thienopyridines, within which
clopidogrel bisulfate falls.
 Apotex’s Defends….
2) Apotex contends pursuant to 35 U.S.C. § 103 that the
subject matter claimed in the ‘265 patent would have
been obvious to a person of ordinary skill in the art at
the time the invention was made.

3) Apotex contends that the patent is invalid under the

judicial doctrine of obviousness-type double
patenting.
 Other Claims Made by Apotex
Finally, Apotex also asserts that the ‘265 patent is
unenforceable on the basis of Sanofi’s alleged
inequitable conduct before the U.S. Patent and
Trademark Office (“PTO”).
 Result
After trial on the merits, this Court finds that

• Apotex have failed to prove by clear and

convincing evidence that the ‘265 Patent is invalid
or unenforceable on any of the grounds asserted.

• Accordingly, Sanofi are entitled to permanent

injunctive relief and, as shall be determined by
the Court in a future proceeding, damages.
 District Court Judgement
• District court however, believed that "it is not enough for Apotex to
have shown that the [elements] found in Claim 3 of the ’265 patent
would have been “obvious to try”.

• District court reasoned that "evidence of the fact that any property
of clopidogrel bisulfate is unexpected as compared to PCR4099 or
anything else in the prior art rebuts the presumption that
clopidogrel bisulfate is obvious in view of its racemate”

• Two enantiomers as compared with each other and the racemate

could not have been "predict[ed] with a reasonable expectation of
success”.
 Federal Circuit Decision
• It agreed with the district court that clopidogrel bisulfate was
nonobvious regardless of whether the compound was "obvious to try”

• The Federal Circuit also thought that rendering clopidogrel as the

bisulfate salt was not obvious because the scientific literature listed
many acids "as candidates for forming salts with basic drug
compounds," and the parties’ experts agreed that it was
"unpredictable" whether any "particular acid-base combination"
would yield a pharmaceutically suitable salt

• The Federal Circuit denied Apotex’s petition for rehearing.

 Conclusion

Obviousness to try doesn't mean that

experiment and its results are obvious