Patent Baristas

The CAFC finally shot down Pfizer’s Norvasc® patent after it filed suit against Apotex alleging infringement stemming from Apotex’s filing an Abbreviated New Drug Application (“ANDA”) seeking approval to commercially sell amlodipine besylate tablets before the expiration of the term of U.S. Patent No. 4,879,303. Pfizer, Inc. v. Apotex, Inc. (f/k/a Torpharm) (2006-1261; Decided March 22, 2007).  Pfizer won in three earlier district court cases. 

The ANDA product is a generic version of Pfizer’s amlodipine besylate drug product, approved by the FDA for treating hypertension and chronic stable and vasospastic angina.  Norvasc® contains amlodipine besylate. The active ingredient found in Norvasc® is 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine, commonly referred to as amlodipine. Amlodipine is a member of a class of compounds referred to as dihydropyridines.

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®.  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).

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”).

Earlier, the district court entered a judgment for Pfizer and 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 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.

On appeal, the CAFC has now reversed and has held that the district court erred in holding that the subject matter of claims 1-3 of the ’303 patent would not have been obvious. By statute, a claimed invention is unpatentable if the differences between it and the prior art “are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art.”

Here, the CAFC felt that evidence of record easily satisfied 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 held 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.

Pfizer argued that (1) 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 as does besylate, and (2) even if the ’909 patent were combined with the cited Berge refernce, the skilled artisan would not have been motivated to make amlodipine besylate because Berge shows that besylate was actually one of the most rarely used anions in the pharmaceutical industry, as only 0.25% of approved drugs as of 1974 were besylate salts. Finally, Pfizer asserts that other prior art references relied upon by Apotex are not relevant because the examples of besylate salts disclosed in these references are limited to pharmaceuticals unrelated to amlodipine.

The Court rejected this argment 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.”

While the district court found that the skilled artisan would have had no expectation of success in making a besylate salt of amlodipine because there was no reliable way to predict the influence of a particular salt species on the active part of the compound, the CAFC held 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.

Many often complain that holdings of obviousness were based on the impermissible “obvious to try” standard. The question becomes then, when the skilled artisan must test, how far does that need for testing go toward supporting a conclusion of non-obviousness?

Citing DyStar, 464 F.3d at 1367, the court held that:

Obviousness is a complicated subject requiring sophisticated analysis, and no single case lays out all facets of the legal test. [There is] danger inherent in focusing on isolated dicta rather than gleaning the law of a particular area from careful reading of the full text of a group of related precedents for all they say that is dispositive and for what they hold. When parties . . . do not engage in such careful, candid, and complete legal analysis, much confusion about the law arises and, through time, can be compounded.

Pfizer argued that an obvious rejection would negate its “discovery” because it was obtained through the use of trial and error procedures. The CAFC differentiated this case stating that:

We find this case analogous to the optimization of a range or other variable within the claims that flows from the “normal desire of scientists or artisans to improve upon what is already generally known.” In re Peterson, 315 F.3d 1325, 1330 (Fed. Cir. 2003) (determining where in a disclosed set of percentage ranges the optimum combination of percentages lies is prima facie obvious). In In re Aller, 220 F.2d 454, 456 (C.C.P.A. 1955), our predecessor court set forth the rule that the discovery of an optimum value of a variable in a known process is usually obvious.

Thus, while patentability of an invention is not negated by the manner in which it was made, “the converse is equally true: patentability is not imparted where ‘the prior art would have suggested to one of ordinary skill in the art that this process should be carried out and would have a reasonable likelihood of success.’” Merck, 874 F.2d at 809 (quoting In re Dow Chem. Co., 837 F.2d 469, 473 (Fed. Cir. 1988)). For these reasons, we hold that Apotex introduced clear and convincing evidence that a skilled artisan would have had a reasonable expectation of success with the besylate salt form of amlodipine at the time the invention was made. Accordingly, we agree with the district court that a prima facie case of obviousness was established with regard to the claims of the ’303 patent, albeit for different reasons.