Sanofi-Synthelabo v. Apotex Inc.

492 F.Supp.2d 353

SANOFI-SYNTHELABO; Sanofi-Synthelabo, Inc.; and Bristol-Myers Squibb Sanofi Pharmaceuticals Holding Partnership, Plaintiffs, v. APOTEX INC. and Apotex Corp., Defendants.

No. 02 Civ. 2255(SHS).

United States District Court, S.D. New York.

June 19, 2007.

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Evan R. Chesler, Richard J. Stark, David Greenwald, Cravath, Swaine & Moore LLP, New York, NY, for Plaintiffs.

OPINION & ORDER

STEIN, District Judge.

After trial on the merits, this Court finds that Apotex, Inc. and Apotex Corporation (collectively, "Apotex") have failed to prove by clear and convincing evidence that U.S. Patent No. 4,847,265 is invalid or unenforceable on any of the grounds asserted. Accordingly, Sanofi-Aventis, Sanofi-Synthelabo, Inc. and Bristol-Myers Squibb Sanofi Pharmaceuticals Holding Partnership (collectively, "Sanofi") are entitled to permanent injunctive relief and, as shall be determined by the Court in a future proceeding, damages.

This action concerns a patent dispute between Sanofi — which invested in the research and development to patent and bring to market the drug known as Plavi® — and Apotex, which seeks to market the generic equivalent of that drug. On the basis of the record established by the parties and the applicable law, the Court enters the following findings of fact and conclusions of law pursuant to Fed. R.Civ.P. 52(a).

FINDINGS OF FACT¹

I. History of this Action

Plavix®, approved for sale in the United States by the U.S. Food and Drug Administration ("FDA") in November 1997, is prescribed for the reduction of thrombotic events such as heart attacks and strokes for patients who have recently suffered those events or who have arterial disease or acute coronary syndrome. (See Stipulated Statement of Facts ("Fact Stmt."), attached as Exhibit A to Joint Pretrial Order dated May 27, 2005 at ¶ 12.) The active ingredient of Plavix® is clopidogrel bisulfate. (Id.) Sanofi obtained a patent claiming clopidogrel bisulfate on July 11, 1989, naming Sanofi employees Alain Badorc and Daniel Fréhel as inventors. (Id. at ¶¶ 8-9.) That patent, U.S. Patent No. 4,847,265 ("the '265 patent"), claims clopidogrel bisulfate by its chemical name in Claim 3: "Hydrogen sulfate of the dextrorotatory isomer of methyl alpha-5(4,5,6,7tetrahydro(3,2-c)thieno pyridyl) (2-chlorophenyl)-acetate substantially separated from the levo-rotatory isomer." ('265 patent at col. 12, ll. 37-41.) Sanofi-Aventis is the owner of the patent-in-suit, which expires on November 17, 2011. The foreign priority filing date of the '265 patent — the date on which Sanofi filed its earlier application for the corresponding French patent — is February 17, 1987. The '265 patent is exclusively licensed to Bristol-Myers Squibb Sanofi Pharmaceuticals Holding Partnership. (Fact Stmt. at ¶¶ 3, 13.)

Apotex sought approval from the FDA to manufacture and sell clopidogrel bisulfate tablets before the expiration of the '265 patent by filing an Abbreviated New Drug Application ("ANDA") with the FDA in November 2001. (Id. at ¶¶ 14-15.) In the ANDA, Apotex certified pursuant to the requirements of 21 U.S.C. § 355(j) (2)(A)(vii)(IV) that it believed the '265 patent to be invalid. (Id. at ¶ 16; see also Glaxo Group Ltd. v. Apotex, Inc., 376 F.3d 1339, 1344 (Fed.Cir.2004).) Apotex was the first to file an ANDA for clopidogrel bisulfate (Decl. of Dr. Bernard Sherman, dated Aug. 16, 2006 ("Sherman Decl.") at ¶ 17), thereby securing the right to 180 days of market exclusivity provided by the Hatch-Waxman Act to the first ANDA filer to challenge a patent. See 21 U.S.C. § 355(j)(5)(B)(iv); see also In re Tamoxifen Citrate Antitrust Litig., 429 F.3d 370, 376 (2d Cir.2005).

In response to that ANDA filing by Apotex, Sanofi filed this litigation against Apotex on March 21, 2002 pursuant to 35 U.S.C. § 271(e), and asserted that Apotex's filing of the ANDA constituted infringement of the '265 patent, specifically Claim 3. (See Fact Stmt. at ¶ 17.) Apotex counterclaimed, asserting that the '265 patent is both invalid for three separate reasons and unenforceable as well.

First, 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. (See Fourth Amended Answer and Amended Counterclaim ("Answer"), filed Nov. 17, 2006, at 3, 13.) The earlier patent, U.S. Patent No. 4,529,596 ("the '596 patent"), issued in July 1985 and expired in July 2003. (Fact Stmt. at ¶ 28.)

Second, 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. (See Answer at 3, 13.)

Third, Apotex contends that the patent is invalid under the judicial doctrine of obviousness-type double patenting. (Id. at 6, 15.)

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"). The alleged conduct consists of failing to name Dr. Jean-Pierre Maffrand as an inventor, making false statements to the PTO regarding the unexpected pharmacological properties of clopidogrel bisulfate, failing to disclose relevant prior research that Sanofi had conducted on a similar chemical compound, and failing to disclose a journal article that Apotex alleges is a material prior art reference. (Id. at 4-6, 8-15.)

With regard to infringement, the parties have stipulated that Apotex's clopidogrel bisulfate product infringes Claim 3 of the '265 patent. (See May 7, 2004 Stipulation and Order; Fact Stmt. at ¶ 18.) The ensuing procedural history of this action — including an account of the extensive settlement negotiations between the parties and the consequences for this litigation — is described in detail in this Court's Opinion dated August 31, 2006; familiarity with that Opinion is assumed. See Sanofi-Synthelabo v. Apotex Inc., 488 F.Supp.2d 317, 323-26 (S.D.N.Y.2006). In brief, Apotex initiated an at-risk launch of its generic clopidogrel bisulfate product on August 8, 2006. Shortly thereafter, Sanofi moved for a preliminary injunction prohibiting Apotex from distributing its generic product. After an evidentiary hearing was held, the Court granted Sanofi's motion for preliminary injunctive relief on August 31, 2006, but denied its request for a recall of the approximately six-month supply of product that Apotex had already shipped to distributors in the United States. Id. at 347-349.

Apotex then moved to stay the preliminary injunction, but both this Court and the U.S. Court of Appeals for the Federal Circuit denied that motion. Apotex then appealed the order granting the preliminary injunction to the Federal Circuit, which affirmed the grant of the preliminary injunction in an opinion dated December 8, 2006. See Sanofi-Synthelabo v. Apotex, Inc., 470 F.3d 1368 (Fed.Cir.2006), reh'g denied, 2007 U.S.App. LEXIS 2807 (Fed.Cir. Jan. 19, 2007). The parties then tried the merits of this action before this Court without a jury from January 22 through February 15, 2007. That trial — as well as the evidentiary hearing held in August 2006 — adduced the following facts.

II. Sanofi's Efforts to Develop Antiplatelet Aggregation Drugs

A. Ticlopidine

In 1972, Dr. Jean-Pierre Maffrand, then a Sanofi chemist in charge of a small research team, was asked by his supervisor to synthesize compounds structurally similar to tinoridine, a drug with known anti-inflammatory properties, in an effort to discover a superior anti-inflammatory drug. (Maffrand Tr. 1570-74.)² Tinoridine is a member of a class of compounds known as thienopyridines. (Maffrand Tr. 1575-76.). The chemical structure of a thienopyridine is characterized by the fusion of a thiophene ring to a pyridine ring. (Maffrand Tr. 1575-76.)

During 1972 and 1973, Sanofi synthesized a number of thienopyridine compounds. (Maffrand Tr. 1573-74.) Tests on those compounds revealed that unlike tinoricline, they possessed no anti-inflammatory properties. Some of the compounds, however — one of which Sanofi named "ticlopidine" — exhibited antiplatelet aggregation activity. (Maffrand Tr. 1573-75.) Put simply, the compound helped ensure that platelets in the blood would not aggregate together as much as they otherwise would. This was an important discovery. Researchers at Sanofi were convinced that platelets play a major role in events such as myocardial infarction and brain ischemia and Dr. Maffrand and his colleagues were interested to find an antiplatelet aggregation agent that would be "[a] better drug than aspirin." (Maffrand Tr. 1574-75.) In 1977, Sanofi obtained a patent on ticlopidine; that patent expired in 1994.

Ticlopidine was introduced as a drug in France in 1978 and in the United States in 1991, where it was marketed under the brand name "Ticlid." (Maffrand Tr. 1578-79; 1581-82.) Soon after the launch of ticlopidine in France, Sanofi became aware of rare but potentially fatal side effects associated with ticlopidine, specifically blood disorders known as neutropenia and thrombotic thrombocytopenic purpura ("TTP"). (Schneller Tr. 763, 815-16; Maffrand Tr. 1580-81.) As a result, the FDA required Ticlid to carry a "black box" warning that ticlopidine could cause life-threatening blood disorders. (Maffrand Tr. 1581.) The potential for these serious side effects meant that patients taking ticlopidine had to be clinically monitored for signs of blood disorders. (Maffrand Tr. 1581.) The sub-optimal side effect profile of ticlopidine — i.e., the risk of developing serious blood disorders — left open the need in the market for a drug that was as effective or more effective than ticlopidine, but with a lower risk of side effects.

B. PCR 1033

In 1975, Sanofi synthesized a thienopyridine named PCR 1033. That compound is the...