By Donald Zuhn ---
In an appeal from a District Court judgment of validity, enforceability, and infringement, the Federal Circuit reversed the District Court's finding of validity, holding that U.S. Patent No. 4,879,303 (the '303 patent) was rendered obvious by, inter alia, U.S. Patent No. 4,572,909 (the '909 patent) and Berge, 1977, "Pharmaceutical Salts," J. Pharm. Sci., 66:1-19 (Berge).
Plaintiff-Appellee Pfizer, Inc. owns the '303 patent, which relates to amlodipine besylate (sold under the trademark Norvasc®), which is approved for treating hypertension and chronic stable and vasospastic angina. The active ingredient in Norvasc® is 2-[(2-aminoethoxy)methyl]-
dihydropyridine, which is a commonly referred to as amlodipine, and which is a member of a class of compounds known as dihyrdopyridines. Like many active drugs, amlodipine is made into a pharmaceutically-acceptable acid addition salt (i.e., amlodipine besylate) to improve its bioavailability. Amlodipine besylate is an acid addition salt of amlodipine formed by reacting amlodipine with benzene sulphonic acid.
More than twenty-five years ago, Pfizer discovered the active ingredient in Norvasc® and identified that compound's anti-hypertensive and anti-ischemic pharmacological properties. In February of 1986, Pfizer was awarded the '909 patent, which claims certain dihydropyridine compounds and their pharmaceutically-acceptable acid addition salts. The '909 patent discloses ten pharmaceutically-acceptable acid addition salts of amlodipine, and describes the preferred salt as being maleate.
Shortly after the U.K. counterpart to the '909 patent issued in March of 1982, Pfizer began the process of formulating a commercial drug product from amlodipine maleate. Pfizer scientists, however, encountered two problems with the amlodipine maleate formulation: its chemical instability and stickiness in tablet form. To solve these problems, Pfizer scientists tested seven other acid addition salts of amlodipine, settling on amlodipine besylate.
In March of 1987, Pfizer filed a U.S. patent application claiming amlodipine besylate. During prosecution of this application, the examiner initially rejected the claims as obvious over the '909 patent in view of U.S. Patent Nos. 3,816,612 (the '612 patent) and 4,032,637 (the '637 patent). The examiner observed that the '612 patent discloses that besylate acid salts are superior to maleate acid salts, and that the '637 patent discloses a pharmaceutical composition in which the besylate form is the preferred embodiment. The examiner subsequently cited Berge as disclosing 53 FDA-approved anions for making pharmaceutically-acceptable salts, including the anion - benzene sulphonate - used to make amlodipine besylate. To overcome the obviousness rejection, Pfizer filed a Rule 1.132 Declaration from one of its scientists stating that "each salt imparts unique properties to the parent compound," and therefore, "the besylate salt of amlodipine is a unique compound and not an obvious one." The examiner allowed the application, which issued as the '303 patent in November of 1989.
Seeking approval to market generic amlodipine besylate tablets, Defendant-Appellant Apotex, Inc. filed an Abbreviated New Drug Application (ANDA) with the FDA. In response, Pfizer filed suit against Apotex, alleging that the filing of the ANDA infringed claims 1-3 of the '303 patent. Apotex counterclaimed for declaratory judgments that the '303 patent was invalid for anticipation and obviousness and unenforceable due to inequitable conduct.
Following a bench trial, the District Court determined that Apotex failed to meet its burden of proving invalidity or inequitable conduct by clear and convincing evidence. With respect to its finding of nonobviousness, the District Court concluded that Berge did not direct the skilled artisan to make amlodipine besylate because Berge discloses that benzene sulphonate is used for making pharmaceutically-acceptable salts only 0.25% of the time. The District Court also concluded that "[t]here is no reliable way of predicting the influence of a particular salt species on the behavior of a parent compound." Finally, the District Court determined that amlodipine besylate "clearly and unexpectedly illustrates a superior combination of properties when compared to the preferred preparation [i.e., amlodipine maleate, the preferred embodiment of the '909 patent]." Apotex appealed the District Court's determinations of validity and no inequitable conduct.
On the issue of obviousness, the Federal Circuit determined that the "evidence of record easily satisfies us that a reasonable fact-finder could only conclude that Apotex has shown by clear and convincing evidence that the skilled artisan would indeed have been so motivated to combine the prior art to produce the besylate salt of amlodipine." The Court also concluded that "[t]he record also satisfies us that . . . a reasonable fact-finder could only conclude that the skilled artisan would have had a reasonable expectation of success with the besylate salt form of amlodipine."
With respect to the motivation to combine the prior art, Pfizer contended that (1) the '909 patent did not suggest the besylate salt of amlodipine, (2) Berge shows that the besylate salt was rarely used in the pharmaceutical industry, and (3) the besylate salts disclosed in other prior art references (such as the '612 and '637 patents) were unrelated to amlodipine. The Federal Circuit rejected Pfizer's first argument, noting that "a suggestion, teaching, or motivation to combine the relevant prior art . . . does not have to be found explicitly in the prior art references sought to be combined, but rather 'may be found in any number of sources, including common knowledge, the prior art as a whole, or the nature of the problem itself.'" The Court also rejected Pfizer's second argument, observing that of the 53 anions disclosed by Berge, 40 were used in less than 1% of drugs, and 23 were used in 0.25% or less of drugs. Finally, the Court rejected Pfizer's third argument, finding that "the besylate acid addition salt form was described in these prior art references as useful in promoting stability and solubility, as well as improving other physicochemical characteristics," and therefore, the fact that none of these references discloses a medication for treating hypertension or angina was "unimportant, if not actually irrelevant."
After addressing the motivation to combine prong, the Federal Circuit next examined the District Court's determination that a skilled artisan would not have had a reasonable expectation of success in making amlodipine besylate. In finding that the District Court had erred in reaching this determination, the Federal Circuit noted that "the '909 patent contained a strong suggestion that any and all pharmaceutically-acceptable anions would form non-toxic acid addition salts and would work for their intended purpose - that is, to improve bioavailability of the active ingredient amlodipine and to improve handling and storage of amlodipine." In addition, the Court noted that Pfizer's supplemental FDA filing also indicates that the besylate salt of amlodipine would work for its intended purpose, the FDA filing stating that "the change in salt form [from maleate to besylate] is justified since benzenesulfonate is a commercially acceptable salt, as exemplified by the tranquilizer mesoridazine (Serentil)."
Determining that a reasonable fact-finder could find evidence of both a motivation to combine the prior art and a reasonable expectation of success in making amlodipine besylate, the Federal Circuit next addressed Pfizer's assertion that amlodipine besylate would be, at the most, "obvious to try." In response to Pfizer's argument, the Court stated that "the prior art provided not only the means of creating acid addition salts but also predicted the results, which Pfizer merely had to verify through routine testing," and therefore, that Pfizer's experimentation with amlodipine besylate was "not equivalent to the trial and error procedures often employed to discover a new compound where the prior art gave no motivation or suggestion to make the new compound nor a reasonable expectation of success." The Court then analogized Pfizer's work to the optimization of a range or other variable, "hold[ing] that the optimization of the acid addition salt formulation for an active pharmaceutical ingredient would have been obvious where as here the acid addition salt formulation has no effect on the therapeutic effectiveness of the active ingredient and the prior art heavily suggests the particular anion used to form the salt."
The Federal Circuit concluded its analysis by examining the District Court's findings with respect to secondary considerations of nonobviousness. In particular, the District Court determined, inter alia, that amlodipine besylate "clearly and unexpectedly illustrates a superior combination of properties when compared to the preferred preparation [i.e., amlodipine maleate]." The Federal Circuit, however, noted that "[a]nother defect in the district court's reasoning is its failure to recognize that by definition, any superior property must be unexpected to be considered as evidence of non-obviousness." While refusing to "simply presume that the skilled artisan would have expected that amlodipine besylate would have the same characteristics as amlodipine maleate," the Federal Circuit did determine that "Pfizer has simply failed to prove that the results are unexpected." In summarizing its findings, the Court concluded: "[a]t most, then, Pfizer engaged in routine, verification testing to optimize selection of one of several known and clearly suggested pharmaceutically-acceptable salts to ease its commercial manufacturing and marketing of the tablet form of the therapeutic amlodipine."
Pfizer, Inc. v. Apotex, Inc. (Fed. Cir. 2007)
Panel: Chief Judge Michel and Circuit Judges Mayer and Linn
Opinion by Chief Judge Michel; Circuit Judge Linn concurring in result