In ANDA litigation between branded drug maker Alcon Research and generic drugmaker Barr Laboratories, the Federal Circuit affirmed a District Court finding of non-infringement and reversed a finding of invalidity for failure to satisfy either the enablement or written description requirements of 35 U.S.C. §112(a).
The case involved BARR's filing of an ANDA (as the second filer) for a generic version of "Alcon's glaucoma and ocular hypertension drug Travatan Z®, which contains travoprost [a type PGF2a prostaglandin analog], the synthetic prostaglandin fluprostenol isopropyl ester." The claims at issue were directed to methods for producing chemically stabilized prostaglandin formulations, as claimed in U.S. Patent No. 5,631,287 (the "'287 patent") and U.S. Patent No. 6,011,062 (the "'062 patent"); claims 1 and 12 of the '287 patent are representative:
1. A method of enhancing the chemical stability of an aqueous composition comprising a therapeutically-effective amount of a prostaglandin, wherein the method comprises adding a chemically-stabilizing amount of a polyethoxylated castor oil [("PECO")] to the composition.
12. The method of claim 1 wherein the composition is a topically administrable ophthalmic composition.
There are a number of curiosities regarding Alcon's patents and how they were asserted in this case. For example, the '287 patent and the '062 patent, which were the subject of this litigation are not listed in the Orange Book, and Barr stipulated to infringement of claims from two Orange Book listed patents (U.S. Patent Nos. 6,503,497 and 6,849,253) and that those claims were not invalid. Two other Alcon patents (U.S. Patent Nos. 5,510,383 (the "'383 patent") and 5,889,052 (the "'052 patent") were not asserted and the District Court denied Barr's post-judgment motion to enter judgment as a matter of law ("JMOL") of non-infringement as to these patents (which procedural ruling the Federal Circuit affirmed under Third Circuit law).
The District Court based its non-infringement determination on its finding that Alcon did not test Barr's product and thus did not show that Barr added a "chemically stabilizing amount of PECO" to its generic formulations. The District Court also found that Barr had shown by clear and convincing evidence that Alcon's claims were overbroad, supported by a too-limited disclosure and that the art of stabilizing prostaglandin formulations was unpredictable, and thus that the '287 and '062 specifications did not satisfy either the enablement or written description requirements.
The Federal Circuit affirmed-in-part (as to non-infringement) and reversed-in-part (as to invalidity), in an opinion by Judge Lourie joined by Judges Newman and Bryson. With regard to non-infringement, the Federal Circuit agreed with the District Court, stating that in an ANDA case, infringement is predicated on a comparison of the claims to "'the product that is likely to be sold following ANDA approval,'" citing Abbott Labs. v. Tor- Pharm, Inc., 300 F.3d 1367, 1373 (Fed. Cir. 2002). The District Court determined, and the Federal Circuit agreed, that the results of Alcon's own stability of its branded product could not be extrapolated to Barr's proposed generic product because "the composition of the generic product proposed in Barr's ANDA is significantly different from the compositions tested in Alcon's study," specifically having a significantly lower pH, slightly less travoprost, and a different mixture of buffering agents. Alcon itself admitted that these differences could "have a substantial impact on the chemical stability of a prostaglandin in an ophthalmic formulation" and thus the Federal Circuit held that there was substantial evidence supporting the District Court's finding of non-infringement.
Regarding invalidity, the Federal Circuit, citing In re Wands, held that Barr failed to make a "threshold showing" that any experimentation (much less undue experimentation) was necessary. Specifically:
The claimed methods comprise only a single step -- adding a chemically-stabilizing amount of PECO to the prostaglandin composition -- that Barr's own expert testified was "routine." The claims as a whole merely require that the addition of PECO to the composition provide some increase in chemical stability, but do not require a particular level of stability or a particular magnitude of increase. Moreover, the patents disclose exemplary compositions within the scope of the claims, detail how those example compositions are prepared from commercially-available ingredients, and provide step-by-step procedures for adding PECO to a prostaglandin composition in a way that embodies the claimed invention. The patents also identify the various prostaglandins and PECOs that can be used and a range of suitable concentrations for both components, including narrow preferred embodiments.
[citations to the record omitted]
The Federal Circuit rejected what it termed "conclusory statements" by Barr with respect to a putatively large number of variables in the formulation that could affect stability; while "[a]djusting variables may be relevant to optimizing the stability of a given prostaglandin composition, . . . Barr proffered no evidence that any experimentation, let alone undue experimentation, with those variables would be necessary in order to practice the claimed invention" (emphasis in opinion). This left the District Court's enablement without any foundation according to the Federal Circuit.
In a section of the Court's opinion that read broadly its precedent regarding what is needed to satisfy the enablement requirement, the Court further noted that actual reduction to practice, working examples in the specification, knowledge by the inventor that the invention actually works, nor any guarantee of operability must be provided, making "irrelevant" the lack of any data "proving" that adding PECOs to a prostaglandin formulation enhances its chemical stability. What Barr needed to show, and did not according to the panel, was that at least some of the claimed embodiments were in fact inoperable and that the ordinarily skilled worker would need to resort to undue experimentation to practice the invention. The deficiencies in Barr's showing resulted in a lack of clear and convincing evidence and the Federal Circuit thus reversed.
Turning to the written description question, the panel found that the '287 patent "details the claimed invention and provides a step-by-step description of how a person of ordinary skill in the art may use it," specifically that "the use of . . . polyethoxylated castor oils in [pharmaceutical] compositions," especially those "topically applied to the eye," "enhances the chemical stability of prostaglandins." (The disclosure of the '062 patent was substantially similar.) The specification discloses "exemplary formulations" that recite "every ingredient," "data generated by the inventor  showing the effect of PECO and prostaglandin concentration on stability," "various classes of prostaglandins" that could be used with the disclosed formulations (including "thirty-two specifically preferred examples of those prostaglandins"), varying types of PECOs and their concentrations, and the "various formulation parameters, including osmolality and pH, that may be selected when practicing the invention," according to the Court. This was enough to demonstrate that the inventors had possession of the claimed invention:
In summary, the '287 and '062 patent disclosures demonstrate that the inventors possessed the claimed invention: they conceived of and described their invention at the time the respective original patent applications were filed, including the idea that adding PECO would enhance the chemical stability of prostaglandins across a range of various formulation parameters as cited by the district court. . . . That is all that the written description requirement demands.
Alcon Research Ltd. v. Barr Laboratories Inc. (Fed. Cir. 2014)
Panel: Circuit Judges Newman, Lourie, and Bryson
Opinion by Circuit Judge Lourie