Case Name: Endo Pharm., Inc. v. Actavis LLC, No. 2018-1054, 2019 U.S. App. LEXIS 13348 (Fed. Cir. May 3, 2019) (Circuit Judges Wallach, Clevenger, and Stoll presiding; Opinion by Wallach; Dissent by Stoll) (Appeal from D. Del., Andrews, J.) 

Drug Product and Patent(s)-in-Suit: Opana® ER; U.S. Patent No. 8,871,779 (“the ’779 patent)

Nature of Case and Issue(s) Presented: Plaintiffs Endo and Mallinckrodt sued Actavis alleging infringement of the ’779 patent, which Endo licenses from Mallinckrodt. The district court held that Actavis failed to prove that any claims were invalid as obvious or anticipated and entered final judgment of infringement based on a stipulation by the parties. Actavis appealed, contending that the district court erred by misconstruing a claim term and finding claims 1-6 were not obvious in light of prior art. The Federal Circuit, in a majority opinion, affirmed the district court.

The ‘779 patent relates to morphinan alkaloid compounds, such as oxymorphone, which have “great medical importance” and “are used extensively for pain relief.” Id. at *2. Pharmaceutically desirable morphinan compounds often have a ketone group and a single (saturated) bond between two carbon atoms positioned α and β to the ketone group (“morphinan-6-one compounds”). Morphinan-6-one compounds are produced using various processes, many of which involve some form of catalytic hydrogenation of α,β-unsaturated ketone intermediate compounds (“ABUKs”). The relevant ABUKs in this case were 14-hydroxymorphinones, or oxymorphone ABUKs, which are ABUK impurities in oxymorphone that are also considered a precursor to oxymorphone because they can be converted into oxymorphone. Catalytic hydrogenation of oxymorphone ABUKs converts the double (unsaturated) bond to a single (saturated) bond by adding a hydrogen atom. However, this process can result in ABUKs persisting as impurities in the final product and can undesirably reduce ketone, which is a key functional part of oxymorphone.

The ‘779 patent discloses processes for producing oxymorphone that has relatively low concentrations of ABUK impurities. These processes reduce ABUK impurities by treating a reaction mixture including oxymorphone and an ABUK with a sulfur–containing compound. This treatment can reduce ABUK concentrations to levels less than 0.001% by weight or 10 parts per million (“ppm”) with minimal side reactions, ketone reduction, or other undesirable effects.

The 0.001% oxymorphone ABUK concentration level stemmed from FDA communications with Mallinckrodt that outlined the FDA’s processes for addressing the problem of mutagenic oxymorphone impurities. Specifically, the communications disclosed that an ABUK concentration of 0.001% in oxymorphone was required to satisfy FDA approval guidelines.

Why Endo Prevailed: The Federal Circuit first addressed the issue of claim construction. The district court found that a POSA would understand the 14‑hydroxymorphinone, an α, β unsaturated ketone, or “ABUK,” limitations stated in claims 1, 2, and 5 to mean “14-hydroxymorphinone hydrochloride.” Actavis argued that the term did not need to be construed because of its plain meaning and the undisputed chemical difference between 14‑hydroxymorphinone and its hydrochloride salt. The Federal Circuit disagreed. The asserted claims only claimed 14-hydroxymorphinone as part of the salt or hydrochloride form of the claimed compounds, not as a separate non-salt or hydrochloride component, which indicated that 14-hydroxymorphinone as used in the claims meant 14‑hydroxymorphinone hydrochloride. This was confirmed by both parties’ experts.

Next, the Federal Circuit addressed the obviousness issue. Three references constituted prior art. “Weiss” disclosed the use of catalytic hydrogenation to convert oxymorphone ABUK to oxymorphone, specifically, employing palladium charcoal as a catalyst to obtain oxymorphone. “Chapman” disclosed processes that employ catalytic hydrogenation to purify oxycodone ABUK into the salt form of oxycodone. Chapman recites processes that convert oxycodone ABUK to oxycodone diol, a precursor to oxycodone ABUK, which can frustrate purification by reverting to oxycodone ABUK through the compound’s conversion to salt form. Chapman provides a reaction that can remove oxycodone diol from a sample before purification is complete to prevent its reversion to oxycodone ABUK. Finally, “Rapoport” discloses a process to convert oxycodone ABUK to oxycodone by adding bisulfite to separate oxycodone from oxycodone ABUK.

The Federal Circuit agreed with the district court that a POSA would not have a reasonable expectation of success in combining the prior art references. First, a POSA would not have a reasonable expectation of success employing Weiss’s catalytic hydrogenation process for oxymorphone with Chapman’s process for removing diol hydrogenation. While Weiss disclosed a method of purifying oxymorphone ABUK through catalytic hydrogenation, it was missing the following: (i) key reaction conditions, such as the time the reaction is run, the amount and composition of the catalyst, and the pressure of hydrogen gas; (ii) any level of achieved purification of oxymorphone let alone purification to the degree claimed by the ‘779 patent; and (iii) a disclosure that catalytic hydrogenation of oxymorphone ABUK produces oxymorphone diol much more readily than oxycodone ABUK and is thus much less effective on oxymorphone ABUK because oxymorphone diol hinders purification by reverting to oxymorphone ABUK. Similarly, Chapman disclosed a process to hydrogenate oxycodone ABUK that creates oxycodone diol, which can hinder purification by reverting to ABUK after an attempted purification. The Chapman process also likely does not achieve the same purity as the process claimed by the ‘779 patent. The only example provided in Chapman reduced the oxycodone diol content of an oxycodone sample to 400 ppm, well above the 10 ppm limit claimed by the ‘779 patent. The example also had a long reaction time of approximately 20 hours, which is undesirable because the longer a hydrogenation reactions runs, the less diol is removed and the more side reactions that introduce other materials occur. More side reactions result in less of the desired product, ketone, in the final product.

Second, Rapoport’s sulfur addition and separation process did not confer a reasonable expectation of success to remove oxymorphone impurities because: (i) Rapoport does not state that any of its disclosed compounds have the purity levels claimed by the ‘779 patent; and (ii) the processes also resulted in a large loss of the desired compound, ketone.

Third, the teaching of Weiss, Chapman, and Rapoport in view of the FDA communications would not provide a POSA with a reasonable expectation of successfully achieving the oxymorphone purity levels claimed by the ‘779 patent. The FDA mandated a 0.001% or 10 ppm ABUK content in oxymorphone, which incentivized purifying oxymorphone to the level claimed by the ‘779 patent, but did not teach how the mandate could be attained. Accordingly, the FDA communications conveyed nothing that would have led a POSA to believe that the sulfur process described in Rapoport might be more effective on oxymorphone ABUK. Therefore, the FDA communications would not have been enough to overcome the disclosures of Weiss, Chapman, and Rapoport, which indicated that a POSA would not reasonably believe their disclosed methods were fruitful avenues to achieve the FDA-mandated oxymorphone purity level.

Finally, the Federal Circuit held that the district court did not err as a matter of law by imposing a heightened standard for the reasonable expectation test. Actavis argued that the district court’s statement that a POSA would not find a “definitive solution” to the diol problem in Chapman improperly heightened the standard for the reasonable expectation test. However, this was not sufficient to find legal error because the statement was “isolated” and “stripped from its context.”

Judge Stoll’s Dissent: Judge Stoll’s dissent finds three errors in the district court’s opinion. First, the district court erred by not equating the FDA’s mandate to achieve 10 ppm purity with a motivation to combine. According to Judge Stoll, the FDA’s mandate discloses “every limitation of claim 1 and is the only references that expressly disclose the limitation of oxymorphone ABUK content less than 0.001%.” Second, the district court erred by elevating the reasonable expectation of success standard to require “that the prior art provide a definitive solution to the problem and proof of actual success.” This standard is greater than the “reasonable expectation of success” standard. Third, the district court erred by conflating the requirements of reasonable expectation of success and motivation to combine. According to the dissent, the district court conflated those requirements by holding that the FDA communications must teach how to achieve the claimed invention in order to provide a motivation to combine. This was because whether a reference teaches how to achieve the claimed invention “speaks to enablement or reasonable expectation of success,” which are “entirely separate inquiries from motivation to combine.” In light of these errors, the district court’s decision should have been vacated and remanded to allow it to apply the correct test for obviousness and “properly consider the role of the FDA mandate—the sole reasons for the ‘779 patent’s existence—in the obviousness analysis.”