Pfizer, Inc. v. Apotex, Inc., No. 2006-1261.

• Court: United States Courts of Appeals. United States Court of Appeals for the Federal Circuit
• Writing for the Court: Michel
• Citation: 480 F.3d 1348
• Parties: PFIZER, INC., Plaintiff-Appellee, v. APOTEX, INC. (formerly known as TorPharm, Inc.), Defendant-Appellant.
• Docket Number: No. 2006-1261.
• Decision Date: 22 March 2007

480 F.3d 1348 PFIZER, INC., Plaintiff-Appellee,
v.
APOTEX, INC. (formerly known as TorPharm, Inc.), Defendant-Appellant. No. 2006-1261. United States Court of Appeals, Federal Circuit. March 22, 2007.

[480 F.3d 1351]

Richard G. Greco, Kay Scholer LLP, of New York, NY, argued for plaintiff-appellee.

[480 F.3d 1352]

With him on the brief were Milton Sherman, Betty A. Ryberg, and Regina O. Kent.

Robert B. Breisblatt, Welsh & Katz, Ltd., of Chicago, IL, argued for defendant-appellant. With him on the brief were A. Sidney Katz, Steven E. Feldman, and Philip D. Segrest, Jr.

Before MICHEL, Chief Judge, MAYER, and LINN, Circuit Judges.

MICHEL, Chief Judge.

Pfizer Inc. filed suit against Apotex, Inc. (formerly known as TorPharm, Inc.) in the United States District Court for the Northern District of Illinois on July 30, 2003, alleging that, pursuant to 21 U.S.C. § 355(j)(5)(B)(iii), Apotex's filing with the United States Food and Drug Administration ("FDA") of its Abbreviated New Drug Application ("ANDA") No. 76-719 seeking approval to commercially sell amlodipine besylate tablets (2.5 mg, 5 mg, and 10 mg strengths) before the expiration of the term of U.S. Patent No. 4,879,303 ("the '303 patent") to Pfizer, infringed claims 1-3 of the '303 patent. The ANDA product sought to be approved by Apotex is a generic version of Pfizer's amlodipine besylate drug product, which is commercially sold in tablet form in the United States under the trademark Norvasc®. Norvasc® is approved by the FDA for treating hypertension and chronic stable and vasospastic angina. The '303 patent, entitled "Pharmaceutically Acceptable Salts," is listed in the FDA's Approved Drug Products with Therapeutic Equivalence Evaluations ("Orange Book") with respect to the Norvasc® drug product in accordance with 21 U.S.C. § 355(b)(1). Apotex certified in ANDA No. 76-719 that it believed the '303 patent was invalid and unenforceable, and sought approval to market and sell its amlodipine besylate tablets before September 25, 2007 (i.e., the expiration date of the '303 patent plus an additional six months of pediatric exclusivity) pursuant to 21 C.F.R. § 314.94(a)(12)(i)(A)(4).

In its answer to Pfizer's complaint, Apotex denied infringement and counterclaimed for declaratory judgments that the claims of the '303 patent are invalid for anticipation and obviousness, and that the '303 patent is unenforceable due to Pfizer's alleged inequitable conduct before the United States Patent and Trademark Office ("USPTO"). Prior to trial, however, Apotex stipulated that its ANDA product contains each limitation of claims 1-3 of the '303 patent, and that if the '303 patent were upheld as valid and enforceable, its ANDA product would literally infringe those claims.

Following a bench trial, the district court entered a final judgment on January 29, 2006 for Pfizer and against Apotex on Apotex's request for declaratory judgments that the claims of the '303 patent are invalid or unenforceable. Based on the stipulation, the trial court found infringement. The district court then ordered that the effective date of any approval of Apotex's ANDA No. 76-719 shall not be earlier than September 25, 2007, and enjoined Apotex from making, using, offering to sell, selling, or importing into the United States any product comprising amlodipine besylate covered by (or the use of which is covered by) the claims of the '303 patent until September 25, 2007. Pfizer Inc. v. Apotex, Inc., No. 03C 5289 (N.D.Ill. Jan. 29, 2006).

Pfizer dismissed its claim of willful infringement against Apotex by a Stipulation and Order dated January 23, 2006. Apotex now appeals from the district court's final judgment, challenging the rulings as to validity and enforceability. Because the district court erred in holding that the subject matter of claims 1-3 of the '303

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patent would not have been obvious, we reverse. We therefore do not address Apotex's assertion that it had proven that Pfizer engaged in inequitable conduct before the USPTO during prosecution of the '303 patent.

I. BACKGROUND A.

Norvasc® contains amlodipine besylate. The active ingredient found in Norvasc® is 2-[ (2 -aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxy-carbonyl-6-methyl-1,4-dihydropyridine, commonly referred to as amlodipine. Amlodipine is a member of a class of compounds referred to as dihydropyridines. Active drug molecules, such as amlodipine, are frequently made into pharmaceutically-acceptable acid addition salts to improve their bioavailability. Amlodipine besylate¹ is an acid addition salt form of amlodipine, formed from the reaction of amlodipine, a weak base, and benzene sulphonic acid.

Pfizer's Discovery Chemistry group, located in Sandwich, England, invented amlodipine and discovered its anti-hypertensive and anti-ischemic pharmacological properties prior to 1982. Pfizer filed a patent application in the United Kingdom on March 11, 1982 specifically claiming amlodipine. A U.S. counterpart application claiming priority from the U.K. application issued as U.S. Patent No. 4,572,909 ("the '909 patent") on February 25, 1986.² The '909 patent claims certain dihydropyridine compounds and their pharmaceutically-acceptable acid addition salts. The '909 patent discloses that the pharmaceutically-acceptable acid addition salts of amlodipine "are those formed from acids which form non-toxic acid addition salts containing pharmaceutically acceptable anions, such as hydrochloride, hydrobromide, sulphate, phosphate or acid phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate and gluconate salts," and that the preferred salt is maleate.³ '909 patent col.2 ll.3-10.

Meanwhile, on or about July 14, 1982, the Discovery Chemistry group recommended that amlodipine be developed as a commercial drug product. By this time, Pfizer had made several acid addition salts of amlodipine, including the maleate, fumarate, salicylate, hydrochloride, and methane sulphonate forms. The Discovery Chemistry group designated amlodipine maleate as the drug substance for development.

On or about August 11, 1982, the project of formulating a commercial drug product was assigned to Dr. James Wells, a manager in Pfizer's Pharmaceutical Research and Development Department, who was assisted by Mr. Edward Davison, a member of the same group. By April 24, 1984, Dr. Wells identified a formulation for amlodipine maleate that produced "excellent capsules." In attempting to produce a direct compression tablet product of an amlodipine maleate formulation, however, Dr. Wells encountered two problems: (1)

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chemical instability of the amlodipine maleate, and (2) stickiness of the tablet blend of amlodipine maleate. Chemical stability refers to the resistance of a drug compound to chemical breakdown, while stickiness refers to the adherence of the drug substance, in formulation, to manufacturing equipment, such as the punch faces of a tablet-making press.

To solve the problems of the tablet form of amlodipine maleate, Dr. Wells suggested that other amlodipine salts be made and tested. In a memo dated April 24, 1984, Dr. Wells acknowledged the difficulty in stickiness and stability he was experiencing in attempting to make a tablet formulation of amlodipine maleate and stated that, by changing from the maleate salt to the free base of amlodipine or another acid addition salt, "many of the stability problems would disappear." Dr. Wells identified six alternative anions, i.e., hydrochloride, methane sulphonate, benzene sulphonate, lactate, succinate, and acetate, as potential anions with which to create acid addition salt forms of amlodipine. He also eventually added the tosylate anion to this group. Dr. Wells testified at trial that he selected these candidates based on their differing structures and properties, but could not explain why three of the seven alternative anions were members of the same class of sulphonic acids.

Mr. Davison testified at trial that he tested these amlodipine acid addition salt forms as well as amlodipine maleate and the free base for solubility, pH, hygroscopicity, and stickiness. Another researcher, Dr. Robin Platt, an analytical chemist at Sandwich, was brought in to test the stability of the amlodipine acid addition salts. Dr. Platt subjected the maleate, acetate, succinate, besylate, mesylate, and eventually the tosylate, salicylate, and hydrochloride salt forms of amlodipine to thin-layer chromatography to determine the number and amount of degradants found in the various amlodipine salts, and compiled a ranking thereof based upon the stability of each salt formulation.

Dr. Platt's findings were communicated to Dr. Wells via memorandum on or about October 9, 1984, wherein Dr. Platt reported that the besylate salt "showed a much improved stability profile over the maleate in all cases." On October 11, 1984, Dr. Wells recommended via memorandum to Dr. J.R. Davidson, a deputy of Pfizer's Pharmaceutical Research and Development Department, that the amlodipine maleate salt be replaced with amlodipine besylate for the commercial amlodipine tablet product based on Dr. Platt's memo and Mr. Davison's test results.

By April 30, 1985, both amlodipine maleate and amlodipine besylate were undergoing human testing in clinical trials. Pfizer scientists predicted that the capsule form of amlodipine maleate would have a shelf life of three years, but that "poor stability of amlodipine maleate tablet formulations" precluded commercialization. On the other hand, the scientists noted that amlodipine besylate tablet formulations exhibited "clear superiority" in their processing characteristics, particularly non-stickiness, and in stability. Capsule formulations of amlodipine besylate had not yet been produced, but work on this project was "expected to be straightforward."

On April 4, 1986, Pfizer filed a patent application to amlodipine besylate in the U.K., which eventually...