In Endo Pharmaceuticals Solutions, Inc. v. Custopharm Inc., the Federal Circuit affirmed the district court's finding that two patents listed in the Orange Book for Aveed® had not been shown to be obvious. Although prior art disclosed clinical studies that used the formulation, the Federal Circuit agreed the disclosures were not sufficient for inherency-based invalidity. This decision provides an illustrative reminder of the difference between prior art challenges based on a prior art publication versus a prior use.

The Aveed® Patents at Issue

The Aveed® patents at issue were Bayer’s U.S. 7,718,640 and U.S. 8,338,395. (Endo Pharmaceuticals Solutions holds the approved NDA for Aveed®). Aveed® is a long-acting testosterone replacement therapy for physiologically low levels of testosterone, known as hypogonadism. The patented formulation is said to require only five injections a year, work for nearly all hypogonadism patients, and avoid testosterone fluctuations associated with previous injectable testosterone therapies.

Claim 2 of the '640 patent was asserted in the litigation. Claims 1 and 2 recite:

1. A composition formulated for intramuscular injection in a form for single injection which contains 250 mg/ml testosterone undecanoate in a vehicle containing a mixture of castor oil and benzyl benzoate wherein the vehicle contains castor oil in a concentration of 40 to 42 vol %.

2. A composition formulated for intramuscular injection in a form for single injection according to claim 1, which contains 750 mg testosterone undecanoate.

Claim 18 of the '395 patent also was asserted. Claims 14 and 18 recites:

14. A method of treating a disease or symptom associated with deficient endogenous levels of testosterone in a man, comprising administering by intramuscular injection a composition comprising testosterone undecanoate (TU) and a vehicle consisting essentially of castor oil and a cosolvent, the castor oil being present in the vehicle at a concentration of 42 percent or less by volume, the method further comprising:

(i) an initial phase comprising 2 initial intramuscular injections of a dose of TU at an interval of 4 weeks between injections, each dose including 500 mg to 1000 mg of TU, followed by,

(ii) a maintenance phase comprising subsequent intramuscular injections of a dose of TU at an interval of 10 weeks between injections, each dose including 500 mg to 1000 mg of TU.

18. The method of claim 14, in which each dose contains 750 mg of TU.

The District Court Proceeding

Endo and Bayer brought an infringement action against Custopharm in response to the latter's submission of an ANDA to the FDA for approval to market a generic version of Aveed®, which included a Paragraph IV certification. In the district court, Custopharm stipulated to infringement, and Endo and Bayer limited their asserted claims to claim 2 of the '640 patent and claim 18 of the '395 patent. The resulting bench trial concerned invalidity of those claims. The district court concluded that Custopharm had not proven invalidity under § 103.

The Federal Circuit Decision

The Federal Circuit decision was authored by Judge Chen and joined by Judges Moore and Linn.

A key issue on appeal was the district court's finding that the vehicle formulation—40% castor oil and 60% benzyl benzoate—was not inherently described in prior art articles describing the clinical studies. Custopharm had argued that this formulation was "necessarily present" in the prior art because, as later revealed, the authors—one of whom overlapped with the inventorship of the patent at issue—had actually used it in their studies. The Federal Circuit disagreed.

In particular, Custopharm argued that the vehicle formulation was inherently disclosed through the detailed pharmacokinetic data reported in the articles, from which—according to Custopharm—”a skilled artisan could derive that the vehicle consisted of 40% castor oil and 60% benzyl benzoate.” The district court had determined that information was not enough "to establish that the Articles barred the possibility of an alternative vehicle being used in the prior art compositions," as required to “meet the rigorous standard of inherency.”

The Federal Circuit agreed that Custopharm had not demonstrated that a skilled artisan could extrapolate the vehicle formulation from the pharmacokinetic data, and noted that Custopharm had improperly tried to shift the burden to the patent owner on this point:

Custopharm's own opening brief does not argue that the pharmacokinetic performance reported in the Articles can only be attributed to the claimed vehicle formulation. Moreover, Custopharm's brief incorrectly shifts the burden of proof to Endo and Bayer. Custopharm argues that . . . Endo and Bayer's pharmacokinetic expert, failed to provide any evidence to support his view that "it was possible to have the same pharmacokinetic profile with two different formulations." But, it is Custopharm's burden to present clear and convincing evidence that the Articles necessarily disclosed the vehicle formulation to one of skill in the art.

The Federal Circuit also observed that a skilled artisan would not have necessarily recognized that the study authors had used benzyl benzoate as a cosolvent, given the abundance of other potential cosolvents:

Endo and Bayer's expert testified that, based on the Articles' disclosures, a skilled artisan would not have recognized that a co-solvent was necessary. And even if a skilled artisan concluded that a co-solvent was necessary, there were any number of available co-solvents, including, for example, benzyl alcohol, ethanol, cottonseed oil, sesame oil, peanut oil, corn oil, fractionated coconut oil, ethyl lactate, ethyl oleate, and isopropyl myristate. Moreover, Custopharm's expert conceded that even knowing the identity of the cosolvent would not necessarily lead a skilled artisan to the particular ratio claimed in the '650 and '395 patents.

The Federal Circuit distinguished this case from inherency cases where the prior art had described a known product:

Importantly, Crish and Omeprazole were about inherently present properties or characteristics for a "known" prior art product. But here, the TU injection composition recounted in the Articles cannot be said to be "known" in the same way; the Articles failed to disclose that the composition's vehicle formulation included another, key ingredient, benzyl benzoate, let alone the ratio of benzyl benzoate to castor oil. And there was no evidence in the record that a skilled artisan could determine the non-disclosed vehicle formulation based on the reported pharmacokinetic performance profile, or that the non-disclosed vehicle formulation was necessarily a feature of the TU injection studied in the Articles.

The Federal Circuit concluded:

[T]he incomplete description of the TU injection composition elements denied skilled artisans from having access to that composition, thereby precluding use of the inherency doctrine to fill in disclosure about the product missing from the Articles.

Inherency and "Necessarily Present" Limitations

While the "necessarily present" requirement of the inherency doctrine is well-settled, this decision highlights important factors in an inherency analysis. First, this case illustrates that when the product at issue is not known in the prior art, there must be evidence that the non-disclosed features would necessarily be present. Second, this case provides a reminder of the difference between invoking the doctrine with reference to a prior art publication, where the inquiry focuses on what was disclosed, and invoking the doctrine with reference to prior art public use, where the inquiry would concern what actually was used.

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