Finding a new salt form of a composition obvious in view of the prior art, the U.S. Court of Appeals for the Federal Circuit held that a motivation to combine references can be gleaned not only from the prior art as a whole, but also from the nature of the problem to be solved. Pfizer Inc. v. Apotex, Inc., Case No. 06-1261 (Fed. Cir., Mar. 22, 2007,) (Michel, C.J.).
Pfizer owns U.S. Patent No. 4,879,303 (the ’303 patent), which relates to amlodipine besylate, marketed as Norvasc® for treatment of hypertension and angina. Pfizer was previously awarded U.S. Patent No. 4,572,909 (the ’909 patent), which claims certain dihydropyridine compounds and their pharmaceutically acceptable acid addition salts. The ’909 patent discloses 10 pharmaceutically acceptable acid addition salts of amlodipine and describes maleate as the preferred salt. Pfizer scientists subsequently encountered two problems with the amlodipine maleate tablet formulation: chemical instability and stickiness. After testing seven other acid addition salts of amlodipine, Pfizer settled on amlodipine besylate and filed a further U.S. patent application that matured into the ’303 patent. During prosecution, the examiner initially rejected the claims as obvious over the ’909 patent in view of secondary references, including a scientific journal article. Pfizer overcame the rejection by filing 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."
Apotex filed an Abbreviated New Drug Application (ANDA) with the FDA for generic amlodipine besylate tablets and Pfizer filed suit. Following a bench trial, the district court determined, inter alia, that Apotex failed to meet its burden of proving invalidity.
On appeal, in support of the district court decision, Pfizer argued that the earlier ’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 like besylate. Pfizer also argued that even if the ’909 patent were combined with the cited scientific journal article, the skilled artisan would not have been motivated to make amlodipine besylate because the publication shows that besylate was a very rarely used anion in the pharmaceutical industry. Echoing the string of obviousness decisions preceding oral argument in the (still pending) KSR v. Teleflex Supreme Court appeal, (See IP Update, Vol. 9, No. 12) the Court rejected this argument, stating that "a suggestion, teaching, or motivation to combine the relevant prior art teachings to achieve the claimed invention 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 fact that some of the prior art references relied upon by Apotex disclosed besylate salts in pharmaceuticals unrelated to amlodipine was considered irrelevant because disclosed characteristics such as enhanced stability and solubility are universally useful. The Court noted 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," and pointed to Pfizer’s supplemental FDA filing, which indicated that the besylate salt of amlodipine would work for its intended purpose. The Court also rejected Pfizer’s assertion that amlodipine besylate would have been, at most, obvious to try, noting that only one parameter needed to be varied via routine testing and that the prior art taught a specific approach to the problem rather than only a "general approach that seemed to be a promising field of experimentation." The Court further rejected the district court’s finding of unexpected results because the record showed no evidence of what it was the skilled artisan would have found to expected. Summarizing its findings, the Court concluded that "[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. "
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