Decision: Persion Pharms. LLC v. Alvogen Malta Operations Ltd., No. 2018-2361 (Fed. Cir. Dec. 27, 2019) (REYNA, O’Malley, Chen)

Holding: The District Court of Delaware held Persion’s claims invalid for obviousness and lack of written description. The Federal Circuit affirmed the obviousness determination, recognizing the proper application of inherent disclosure in an obviousness determination, and did not reach the written description issue.

Background: Persion owns U.S. Patent Nos. 9,265,760 (“the ʼ760 patent”) and 9,339,499 (“the ʼ499 patent) directed to treating pain associated with renal or hepatic impairment using hydrocodone-only formulations. The patents cover the commercial product Zohydro ER and share a common written description and priority date. When the FDA evaluated Zohydro ER, it required a clinical study that is described in Example 8. The results of this study led researchers to file patent applications that eventually issued as the ’760 and ʼ499 patents. The claims, however, are not limited to the use of the Zohydro ER formulation, rather they cover any extended release formulation with hydrocodone bitartrate as the only active ingredient. Claims 1 and 12 of the ’760 patent are representative:

ʼ760 patent claim 1. A method of treating pain in a patient having mild or moderate hepatic impairment, the method comprising:

administering to the patient having mild or moderate hepatic impairment a starting dose of an oral dosage unit having hydrocodone bitartrate as the only active ingredient, wherein the dosage unit comprises an extended release formulation of hydrocodone bitartrate, and wherein the starting dose is not adjusted relative to a patient without hepatic impairment.

ʼ760 patent claim 12. A method of treating pain in a patient having mild or moderate hepatic impairment, the method comprising:

administering to the patient having mild or moderate hepatic impairment an oral dosage unit having hydrocodone bitartrate as the only active ingredient, wherein the dosage unit comprises an extended release formulation of hydrocodone bitartrate,

wherein the dosage unit provides a release profile of hydrocodone that:

(1) does not increase average hydrocodone AUC0–inf in subjects suffering from mild hepatic impairment relative to subjects not suffering from renal or hepatic impairment in an amount of more than 14%;

(2) does not increase average hydrocodone AUC0–inf in subjects suffering from moderate hepatic impairment relative to subjects not suffering from renal or hepatic impairment in an amount of more than 30%;

(3) does not increase average hydrocodone Cmax in subjects suffering from mild hepatic impairment relative to subjects not suffering from renal or hepatic impairment in an amount of more than 9%; and

(4) does not increase average hydrocodone Cmax in subjects suffering from moderate hepatic impairment relative to subjects not suffering from renal or hepatic impairment in an amount of more than 14%.

The prior art disclosed (1) the Zohydro ER formulation itself and an in vivo study of the formulation for treating pain (“Devane”), (2) that pharmacokinetic parameters for hydrocodone did not vary much between normal subjects and subjects with mild and moderate hepatic impairment (“Jain”), and (3) safety and use instructions from drug labels that do not mention restrictions for patients with mild or moderate hepatic impairment.

Persion sued Alvogen after Alvogen filed an ANDA seeking to market a generic version of Zohydro ER. The district court held that Alvogen would indirectly infringe the asserted claims because its product label would induce doctors and patients to administer Alvogen’s product in an infringing manner. The district court also concluded that the asserted claims were not invalid as anticipated but were invalid for obviousness. A POSITA would have been motivated to administer the extended-release hydrocodone bitartrate formulation disclosed in Devane to patients with mild or moderate hepatic impairment at an unadjusted dose and would have had a reasonable expectation of success in so doing. Furthermore, the district court found that the “pharmacokinetic limitations in the pharmacokinetic claims are ‘inherent in any obviousness combination that contains the Devane formulation’ because the recited pharmacokinetic parameters were ‘necessarily present’ in the Zohydro ER formulation described in both Devane and the asserted patents.” Persion at *8. The district court also held the claims invalid for lack of written description support because the claims are broader than the only formulation disclosed, that in Example 8.

Federal Circuit Decision

The Federal Circuit, in a decision authored by Judge Reyna, affirmed the obviousness holding but did not reach the written description issue.

Although a high bar exists for its use in obviousness cases, the Court found that inherency was properly applied and supplied “‘a missing claim limitation in an obviousness analysis’ where the limitation at issue is ‘the natural result of the combination of prior art elements.’” Id. at *12–13 (emphasis in original). According to the Federal Circuit, there was “no dispute that the Devane formulation, which was identical to the Zohydro ER formulation described in the patents in suit, necessarily exhibited the claimed parameters” and that a POSITA “would have been motivated, with reasonable expectation of success, to administer an unadjusted dose of the Devane formulation to hepatically impaired patients.” Id. at 13.

Persion also argued the district court improperly relied upon the submission of safety data relating to an immediate-release combination product to the FDA that the FDA found insufficient. But the district court dismissed this argument by noting that the patentability standard of motivation to combine is far below that of safety and efficacy to the FDA. Objective evidence of patentability was also found insufficient. The Federal Circuit agreed.

Persion additionally argued that the district court’s obviousness decision was inconsistent with its finding of a lack of written description support. The Federal Circuit rejected this position, noting that the district court’s finding that there was no guidance as to “which of the broadly claimed formulations would work and which would not, with the exception of the single embodiment described in Example 8” was not inconsistent with the finding that the “embodiment described in Example 8 of the common written description of the ’760 and ’499 patents is the Devane formulation, which formed the basis for the district court’s obviousness findings.” Id. at *19. “[T]he district court found that the prior art provided adequate guidance with respect to the sole formulation described in Example 8: the Devane formulation.” Id. at *19–20.

Lessons Learned

The patentee’s main problem appears to be claiming too broadly. The FDA requires ANDA filers to copy the label of the approved product. Due to the identical labels, the district court found Alvogen liable for induced infringement. The cases of Sanofi v. Watson, 875 F.3d 636 (Fed. Cir. 2017) and Vanda Pharm., Inc. v. West-Ward Pharm. Int’l Ltd., 887 F. 3d 1117 (Fed. Cir. 2018), demonstrate a strategic approach is to craft claims to the successful results of the Phase III clinical trials and the approved method of treatment. And lest one has concerns about 505(b)(2) filers, it is good to try the virtues of 35 U.S.C. §112(f) using the active ingredient as the “means for,” with very tight linking tables in the file history of the patent.

It also appears that the patentee should not have waited to file the application until after the successful formulation of the Phase III clinical trials had become prior art. Without that formulation as prior art, the court may not have applicability of inherent disclosure in its obviousness determination.