Last week, the Federal Circuit affirmed a District Court decision (by Circuit Judge Bryson, sitting by designation) in an ANDA litigation, finding obvious claims asserted for treating patients having mild to moderate hepatic impairment with extended release opioid formulations, in Persion Pharmaceuticals LLC v. Alvogen Malta Operations Ltd. In reaching this obviousness determination, Judge Bryson made recourse to the concept of inherent disclosure in questions of obviousness, which while limited in scope, the Federal Circuit found their colleague properly applied.
The case involved infringement under 35 U.S.C. § 271(e)(2) of Orange Book-listed U.S. Patent Nos. 9,265,760 and 9,339,499, which claimed extended release hydrocodone formulations for treating patients with hepatic impairment, who were known in the prior art to be at greater risk for opioid overdose; Persion's drug product was marketed as Zohydro ER. Claims 1 and 12 of the '760 patent are representative:
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.
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 dos- age unit having hydrocodone bitartrate as the only active ingredient, wherein the dos- age 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 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%.
Defendant Alvogen asserted an obviousness defense over two prior art patent references: U.S. Patent Publication No. 2006/0240105 (Devane), that disclosed the Zohydro ER formulation itself and an in vivo study in which the formulation is used to treat pain; and U.S. Patent Publication No. 2010/0010030 (Jain), which disclosed Vicodin CR, a mixture of hydrocodone and acetaminophen, and that pharmacokinetic parameters for hydrocodone "were similar in normal subjects and subjects with mild and moderate hepatic impairment." The District Court also considered the contents of the Vicodin and Lortab labels (Lortab is a related hydrocodone prior art formulation).
The District Court held that Alvogen's ANDA formulation would infringe Persion's asserted patent claims but that these claims were invalid as obvious over the combination of Devane and Jain and the Vicodin and Lortab labels; the Federal Circuit's opinion provided a succinct synopsis of the District Court's reasoning:
Specifically, the district court found that in light of the teachings of Jain and the Vicodin and Lortab labels, a person of ordinary skill in the art 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. The district court further 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. Finally, the district court found that the objective factors of unexpected results, long-felt but unmet need, and failure of others did not weigh in favor of finding nonobviousness.
The District Court also held that Persion's asserted claims (which were broader in scope than the Zohydro ER formulation) did not satisfy the written description requirement of 35 U.S.C. § 112(a), because the specification common to the two asserted patents only specifically described Zohydro ER.
The Federal Circuit affirmed, in an opinion by Judge Reyna, joined by Judges O'Malley and Chen. The opinion was based on the Federal Circuit finding no clear error in the District Court's factual bases for its obviousness determination, as required under Supreme Court precedent (the opinion specifically citing Zenith Radio Corp. v. Hazeltine Research, Inc., 395 U.S. 100, 123 (1969), quoting United States v. U.S. Gypsum Co., 333 U.S. 364, 395 (1948)).
On appeal, Persion raised four grounds of asserted error. First, Persion argued that the District Court improperly relied on inherency to determine that Devane disclosure inherently disclosed the pharmacokinetic limitations recited in claim 12 and related asserted claims. Persion also argued that it was improper for the District Court to rely on pharmacokinetic profiles from drugs that were not extended-release single-active-ingredient hydrocodone formulations, and from patients without hepatic impairment in reaching its obviousness conclusion. Persion also contended that the District Court did not properly consider its evidence of the objective indicia factors of non-obviousness. Finally, Persion contended that the District Court's holding of obviousness and inadequate written description was inconsistent with each other.
(The opinion notes, in a footnote, that Persion argued many of these points as legal issues, but the panel believes that they are based on factual determinations by the District Court, which has the more deferential "clear error" standard of review.)
With regard to inherency, the opinion cites Supreme Court precedent for the proposition that "[i]t is not invention to perceive that the product which others had discovered had qualities they failed to detect," specifically Gen. Elec. Co. v. Jewel Incandescent Lamp Co., 326 U.S. 242, 249 (1945). The panel further cited multiple instances of the Court's own (and CCPA) precedent, for the principle that merely discovering a new property of a prior art compound is not sufficient to defeat obviousness, including Santarus, Inc. v. Par Pharm., Inc., 694 F.3d 1344, 1354 (Fed. Cir. 2012); In re Kao, 639 F.3d 1057, 1070 (Fed. Cir. 2011); In re Kubin, 561 F.3d 1351, 1357 (Fed. Cir. 2009); and In re Wiseman, 596 F.2d 1019, 1023 (C.C.P.A. 1979). On the other hand, the opinion notes that inherency is "carefully circumscribed" in the obviousness context, to require that an inherent property is consistently present and is not a matter of probabilities. To Persion's generic challenge to the District Court's use of inherency to support its obviousness determination the panel stated:
To the extent Persion contends that inherency can only satisfy a claim limitation when all other limitations are taught in a single reference, that position is contrary to our prior recognition that "inherency may supply a missing claim limitation in an obviousness analysis" where the limitation at issue is "the natural result of the combination of prior art elements." PAR Pharm., Inc. v. TWI Pharm., Inc., 773 F.3d 1186, 1194-95 (Fed. Cir. 2014) (emphasis added, internal quotations omitted).
Further, Persion argued that "Devane does not teach administering its hydrocodone-only formulation to patients with mild or moderate hepatic impairment" and that this deficiency negates inherency (an argument more fitting for rebutting invalidity for lack of novelty), and the opinion response was as follows:
The district court found that a person of ordinary skill in the art would have been motivated, with reasonable expectation of success, to administer an unadjusted dose of the Devane formulation to hepatically impaired patients. There was also 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 under these conditions [italics added].
The panel also rejected Persion's arguments directed to various aspects of the pharmacokinetic evidence and claims, which were what was inherent in the prior art Zohydro ER formulation. The District Court's consideration of evidence for FDA requirements for combination products was also not error, according to the panel, because the FDA standard is more rigorous than the obviousness standard, and the art (Jain) supported the conclusion that single drug formulations (or at least not combinations with acetaminophen) were preferred for patients with hepatic injury. Jain also provided evidence that the panel held the District Court properly considered in concluding that the reference suggested no difference in pharmacokinetics of hydrocodone between normal and hepatically impaired individuals. Not surprisingly, the panel also found no clear error in the District Court relying on expert testimony regarding the relevance of pharmacokinetic comparisons between normal and hepatically impaired individuals. And the panel found ample evidence related the existence of motivation to combine the teachings of these references by one of ordinary skill in the art. The opinion states:
In sum, after reviewing the entire evidentiary record, we are not left with any conviction that the district court has made a mistake. See Zenith, 395 U.S. at 123. We therefore reject Persion's challenge to the district court's factual findings, which are not clearly erroneous.
Regarding the District Court's treatment of the objective indicia, the opinion stated:
[T]he substance of the court's analysis makes clear that it properly considered the totality of the obviousness evidence in reaching its conclusion and did not treat the objective indicia as a mere "afterthought" relegated to "rebut[ting]" a prima facie case. Leo Pharm. Prods., Ltd. v. Rea, 726 F.3d 1346, 1357–58 (Fed. Cir. 2013); In re Cyclobenzaprine Hydrochloride Extended-Release Capsule Patent Litigation, 676 F.3d 1063, 1075 (Fed. Cir. 2012).
The Federal Circuit did not reach the District Court's decision on the written description issue, but noted that the decisions were not inconsistent based on the differences in scope that the District Court considered in invalidating the asserted claims on § 103 and § 112 grounds.
Application of inherency to obviousness determinations here was facilitated by the description in the prior art of Persion's extended release formulation, and the patentee's reliance on the pharmacokinetic properties of this formulation to distinguish their claimed method from how these drugs were administered (and to whom) in the prior art. It was those very properties that were inherent and thus could not be used to distinguish the prior art on the obviousness question. Also, the negative limitation, "and wherein the starting dose is not adjusted relative to a patient without hepatic impairment," was directly related to the absence of any in vivo difference between effectiveness or toxicity (i.e., risk of overdose) between patients with hepatic impairment and those with normal liver function. Under these facts, and in view of the deferential standard of review the Court must give to a district court's factual determinations, Federal Circuit affirmance of the District Court's decision was not particularly remarkable.
Persion Pharmaceuticals LLC v. Alvogen Malta Operations Ltd. (Fed. Cir. 2019)
Panel: Circuit Judges O'Malley, Reyna, and Chen
Opinion by Circuit Judge Reyna
