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A Prima Facie Case of Obviousness Was Found over the Same Prior Art References Considered by the Examiner During the Prosecution

March 22, 2007
Wang, Ningling

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Last Month at the Federal Circuit - April 2007

Judges: Michel (author), Mayer, Linn (concurring)

[Appealed from: N.D. Ill., Judge Rosenbaum]

In Pfizer, Inc. v. Apotex, Inc., No. 06-1261 (Fed. Cir. Mar. 22, 2007), the Federal Circuit reversed the district court’s holding of validity and infringement, and held claims 1-3 of U.S. Patent No. 4,879,303 (“the ’303 patent”) invalid for obviousness.

Claim 1 of the ’303 patent is directed to “[t]he besylate salt of amlodipine.” Claims 2 and 3 are directed, respectively, to a pharmaceutical composition and a tablet formulation comprising the besylate salt of amlodipine of claim 1. Amlodipine besylate (or amlodipine benzene sulphonate) is an acid addition salt form of amlodipine formed from the reaction of amlodipine, a weak base, and benzene sulphonic acid. Pfizer, Inc. (“Pfizer”) sells an amlodipine besylate drug product in tablet form under the tradename Norvasc®.

Pfizer’s scientists discovered amlodipine and its antihypertensive and anti-ischemic pharmacological properties before 1982. Pfizer obtained U.S. Patent No. 4,572,909 (“the ’909 patent”), claiming certain dihydropyridine compounds and their pharmaceutically acceptable acid addition salts. The ’909 patent discloses pharmaceutically acceptable acid addition salts of amlodipine, which do not specifically include besylate, and that the preferred salt is maleate. However, Pfizer’s scientists later found that amlodipine maleate is chemically unstable and sticks to manufacturing equipment. To solve these problems, Pfizer’s scientists identified seven alternative anions, including besylate, and found that amlodipine besylate tablet formulations exhibited “clear superiority” in stability and in their processing characteristics, particularly nonstickiness.

Pfizer filed a U.S. patent application directed to amlodipine besylate. During the prosecution, the examiner initially rejected all of the claims as obvious over the ’909 patent in view of two prior art references, Spiegel and Schmidt. Schmidt discloses that aryl sulphonic acid salts, which include besylate, are superior to the preferred maleate of the ’909 patent. Spiegel provides an example of a pharmaceutical compound wherein the besylate form is specifically identified as the preferred embodiment. The examiner further maintained the rejection and cited another prior art reference, Berge, which shows fifty-three FDA-approved, commercially marketed anions, including besylate, that are useful for making pharmaceutically acceptable salts. To overcome the obviousness rejection, Pfizer filed a Rule 132 declaration by one of its scientists, which stated that the besylate salt of amlodipine was “found to possess a highly desirable combination of physicochemical properties,” including good solubility, stability, nonhygroscopicity, and processability, which are “unpredictable both individually and collectively.” Consequently, the examiner allowed the pending claims, which issued as the ’303 patent.

Pfizer filed a suit against Apotex, Inc. (“Apotex”), alleging that Apotex’s filing of its ANDA seeking approval to commercially sell amlodipine besylate tablets, i.e., Norvasc®, before the expiration of the term of the ’303 patent infringed claims 1-3 of that patent. Apotex denied infringement and counterclaimed for DJ 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. Apotex admitted, however, that if the ’303 patent were held valid and enforceable, its ANDA product would literally infringe claims 1-3 of the ’303 patent. After a bench trial, the district court entered judgment for Pfizer, holding the ’303 patent valid, enforceable, and infringed. Apotex appealed.

Relying on the same prior art references that were considered by the examiner during the prosecution of the application that issued as the ’303 patent, the Federal Circuit reversed the district court’s holding of validity. Initially, the Court noted that the district court improperly held that the examiner’s interim finding of prima facie obviousness renders the issued claims prima facie obvious. Specifically, the Federal Circuit stated that “a court is never bound by an examiner’s finding in an ex parte patent application proceeding” and that “deference to the decisions of the PTO takes the form of the presumption of validity under 35 U.S.C. § 282.” Slip op. at 15-16. The Federal Circuit further stated that “[t]he basis (as opposed to the mere existence) of an examiner’s initial finding of prima facie obviousness of an issued patent is therefore, at most only one factual consideration that the trial court must consider in context of the totality of the evidence ‘in determining whether the party asserting invalidity has met its statutory burden by clear and convincing evidence.’” Id. at 17 (emphasis in original) (citation omitted).

The Federal Circuit then moved on to the obviousness analysis. While Pfizer argued that the ’909 patent does not suggest or motivate the skilled artisan to make amlodipine besylate because none of the anions listed in the ’909 patent have a cyclic structure as does besylate, the Court disagreed. The Court explained that a suggestion, teaching, or motivation to combine the prior art teachings to achieve the claimed invention does not have to be found explicitly in the prior art references, but rather, it may be found in other sources, including common knowledge, the prior art as a whole, or the nature of the problem itself. The Federal Circuit held that clear and convincing evidence established that, out of the list of fifty-three anions disclosed in Berge, one of ordinary skill in the art, facing the problems of the maleate tablet form, would have been motivated to use besylate, because of its known acid strength, solubility, and other known chemical properties disclosed in the prior art references and to combine it with the teachings of the ’909 patent to produce the besylate salt of amlodipine.

With regard to the district court’s finding of no expectation of success in making amlodipine besylate, the Federal Circuit explained that “obviousness cannot be avoided simply by a showing of some degree of unpredictability in the art so long as there was a reasonable probability of success.” Id. at 24.

Pfizer also argued that amlodipine in its besylate salt form would at most be obvious to try, but the Federal Circuit disagreed. The Court held that what Pfizer had done in selecting the besylate salt was routine testing because the prior art provided not only the means of creating acid addition salts but also predicted the results. The Federal Circuit further held that Pfizer’s showing of superior results of amlodipine besylate were not sufficiently unexpected to rebut Apotex’s showing of a prima facie case of obviousness.

Because the Federal Circuit reversed the district court’s nonobviousness judgment, it did not determine whether the ’303 patent is unenforceable due to Pfizer’s alleged inequitable conduct before the PTO. Judge Linn concurred in the Court’s decision without a separate opinion.