Sanofi-Synthelabo v. Apotex, Inc.

• Citation: 550 F.3d 1075
• Decision Date: 12 December 2008
• Docket Number: No. 2007-1438.,2007-1438.
• Parties: SANOFI-SYNTHELABO, Sanofi-Synthelabo, Inc., and Bristol-Myers Squibb Sanofi Pharmaceuticals Holding Partnership, Plaintiffs-Appellees, v. APOTEX, INC. and Apotex Corp., Defendants-Appellants.
• Court: U.S. Court of Appeals — Federal Circuit

550 F.3d 1075

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

No. 2007-1438.

United States Court of Appeals, Federal Circuit.

December 12, 2008.

Evan R. Chesler, Cravath, Swaine & Moore LLP, of New York, NY, argued for plaintiffs-appellees. With him on the brief were Richard J. Stark and David Greenwald. Of counsel on the brief were Robert L. Baechtold, John D. Murnane, and William E. Solander, Fitzpatrick, Cella, Harper & Scinto, of New York, NY.

Robert B. Breisblatt, Welsh & Katz, Ltd., of Chicago, IL, argued for defendants-appellants. With him on the brief were Steven E. Feldman, Philip D. Segrest, Jr., and Sherry L. Rollo. Of counsel on the brief were Robert S. Silver, Manny D. Pokotilow, Bruce J. Chasan, and Mona Gupta, Caesar, Rivise, Bernstein, Cohen & Pokotilow, Ltd., of Philadelphia, PA.

Before NEWMAN, LOURIE, and BRYSON, Circuit Judges.

NEWMAN, Circuit Judge.

This suit arose in accordance with the provisions of the Hatch-Waxman Act, codified at 35 U.S.C. § 271(e) and 21 U.S.C. § 355(j). The patent at issue is United States Patent No. 4,847,265 (the '265 patent), owned by Sanofi-Synthelabo and related companies (collectively "Sanofi"), and covers the pharmaceutical product having the common name clopidogrel bisulfate and the brand name Plavix®. The product has the property of inhibiting the aggregation of blood platelets, and is used to treat or prevent blood-thrombotic events such as heart attacks and strokes. We affirm the district court's ruling sustaining patent validity.

BACKGROUND

Clopidogrel is the common name of the dextrorotatory isomer of the chemical compound named methyl alpha-5(4,5,6,7-tetrahydro(3,2-c)thienopyridyl)(2-chlorophenyl) -acetate. Claim 3 of the patent is in suit:

3. Hydrogen sulfate of the dextro-rotatory isomer of methyl alpha-5(4,5,6,7-tetrahydro(3,2-c)thienopyridyl)(2-chlorophenyl)-acetate substantially separated from the levo-rotatory isomer.

The '265 patent was issued on July 11, 1989, with priority from an application first filed in France in 1987. Approval of the product by the United States Food and Drug Administration (FDA) was received in 1998.

Apotex, Inc. filed an Abbreviated New Drug Application (ANDA)¹ in November 2001 for FDA approval to sell clopidogrel bisulfate, stating, pursuant to 21 U.S.C. § 355(j)(2)(A)(vii)(IV), that it believed the '265 patent to be invalid. Such "paragraph IV certification" is defined as an act of infringement for litigation purposes, 35 U.S.C. § 271(e), in order to facilitate pre-marketing legal challenge by the producer of a generic form of a patented pharmaceutical product. In accordance with the statutory procedures Sanofi duly filed suit for infringement, and Apotex counterclaimed that the '265 patent is invalid on several grounds and unenforceable. The suit initiated a thirty-month stay of FDA approval of Apotex's ANDA, as provided by 21 U.S.C. §355(j)(5)(B)(iii). A proposed settlement was not achieved, the statutory stay expired, the FDA approved the Apotex ANDA, and Apotex commenced sale of its generic clopidogrel bisulfate product on August 8, 2006. Sanofi then moved in the district court for a preliminary injunction, asking that Apotex be enjoined from marketing its infringing product while the litigation was pending, noting that infringement was conceded by Apotex.

The district court found that Sanofi was likely to succeed on the merits of the validity and enforceability of the '265 patent, and that the equitable factors of the balance of harms, the probability of irreparable harm, and the various public interests, favored granting the injunction. Sanofi-Synthelabo v. Apotex Inc., 488 F.Supp.2d 317, 350 (S.D.N.Y.2006) ("Sanofi I"). This court affirmed the district court's rulings, while explaining that the record on the substantive issues was necessarily incomplete and that the district court could review all aspects at trial. See Sanofi-Synthelabo v. Apotex Inc., 470 F.3d 1368, 1374-84 (Fed.Cir.2006) ("Sanofi II") (holding that the patentee was likely to succeed on the merits, and that the balance of hardships and public interest supported the injunction). A bench trial was held from January 22 to February 15, 2007, following which the district court ruled that the '265 patent is valid and enforceable. Sanofi-Synthelabo v. Apotex Inc., 492 F.Supp.2d 353, 397 (S.D.N.Y. 2007) ("Sanofi III").

This appeal is focused on the question of patentability of this dextrorotatory isomer in view of its known racemate described in earlier Sanofi patents, specifically, Sanofi's United States Patent No. 4,529,596 (the '596 patent) and Canadian Patent No. 1,194,875 (the '875 patent). Both reference patents are derived from the same French priority filing and are prior art against the '265 patent.

The activities that led to the product in suit are discussed in the earlier opinions, and are summarized as relevant herein: In 1972 Sanofi scientists were seeking products that might have improved anti-inflammatory properties, and in the course of this work discovered that certain compounds of the class known as thienopyridines (compounds having a thiene ring fused to a pyridine ring) have the property of inhibiting blood platelet aggregation. Sanofi scientists, led by Dr. Jean-Pierre Maffrand, pursued this direction of research. The record states that they initially synthesized and evaluated several hundred chemical modifications and derivatives of thienopyridines, seeking optimum anti-platelet aggregation properties with minimal undesirable effects. They eventually selected for development the compound having the following structural formula:

NOTE: OPINION CONTAINING TABLE OR OTHER DATA THAT IS NOT VIEWABLE

Sanofi gave this compound the common name "ticlopidine." After lengthy development, including animal and human trials, in 1991 ticlopidine was approved in the United States for use as an anti-thrombotic agent. This approval, however, was accompanied by required warnings concerning possible adverse effects, for reports had been received of rarely occurring but serious blood disorders, neutropenia and thrombotic thrombocytopenic purpura, associated with prolonged usage of ticlopidine. Thus Sanofi continued its search for a product that would have the therapeutic benefits of ticlopidine but without the adverse properties.

Sanofi synthesized and evaluated several hundred additional thienopyridine derivatives, including a class of compounds having the following general structure, wherein one of the hydrogen atoms on the bridge carbon atom (marked with an asterisk), is replaced with an ester, carboxylic acid, or amide group. This class is the subject of the '596 patent (and the counterpart Canadian '875 patent), and is shown as follows:

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X and Y can be any of a number of substituents, as identified in the patents; the district court found that there are thirty-seven possibilities for X and 1710 choices for Y. The patents state that compounds of this class exhibit good anti-platelet aggregation properties and are well tolerated. Focusing on the '596 patent, the specification includes twenty-one examples of specific compounds, including a compound designated as PCR 4099, which Sanofi synthesized in July 1980. In PCR 4099 the substituent attached to the bridge carbon is the methyl ester group (-COOCH₃), and X is chlorine in the 2-position, as follows:

NOTE: OPINION CONTAINING TABLE OR OTHER DATA THAT IS NOT VIEWABLE

This compound has the chemical name methyl alpha-5(4,5,6,7-tetrahydro(3,2-c)thieno pyridyl)(2-chlorophenyl)-acetate, with the acronym MATTPCA. PCR 4099 as the hydrochloride salt was selected for commercial development as a potential replacement for ticlopidine in light of its improved platelet inhibition and toxicity profile.

However, PCR 4099 still raised toxicity concerns, for at very high doses it caused convulsions in laboratory animals. Thus the research efforts continued, concurrently with the clinical and commercial development of PCR 4099. Sanofi states that about 1500 compounds in this general class were synthesized, of which about 600, including PCR 4099, were chiral thienopyridines. "Chiral" is defined as "describ[ing] asymmetric molecules that are mirror images of each other, i.e., they are related like right and left hands. Such molecules are also called enantiomers and are characterized by optical activity." Richard J. Lewis, Sr., Hawley's Condensed Chemical Dictionary 270 (15th ed.2007).

Enantiomers are spatial isomers, also called stereoisomers, wherein the isomeric compounds have the same chemical formula and the same chemical structure, but differ in their orientation in three-dimensional space. Such stereoisomers can exist for all molecules that contain an asymmetric carbon atom. An "asymmetric carbon" is a carbon atom to which four different substituents are attached, whereby, due to the tetrahedral structure of carbon bonds in three dimensions, the spatial orientation of substituents attached to a carbon atom varies. When there is only one asymmetric carbon atom in the molecule and thus only two stereoisomers, these isomers are called enantiomers.

Enantiomers are identified and distinguished by their optical characteristics when a purified solution of the separated isomers is exposed to plane-polarized light. One enantiomer will rotate plane-polarized light to the right (and thus is called the dextrorotatory or d- or (+) isomer), and the other rotates plane-polarized light to the left (called the levorotatory or l- or (-) isomer). For the compounds here at issue, the asymmetric carbon is at the bridge between the thienopyridine and the benzene components of the molecule, as marked with an asterisk in the drawings shown ante. Enantiomers generally are formed in equal amounts, to produce...