Almost four years ago, in a relatively rare occurrence based on there being an insufficient factual record to permit proper appellate review, the Federal Circuit vacated a District Court decision rendering invalid the claims in five patents asserted by Tris Pharma, Inc. against Teva Laboratories FL, Inc. and remanded. The Court has had the opportunity to review the District Court's decision on remand, delayed by the COVID pandemic, and today affirmed the determination that Teva had not shown the claims to be invalid by clear and convincing evidence.
To recap, the case arose in ANDA litigation regarding Quillivant XR®, an extended release, liquid methylphenidate (MPH) formulation for the treatment of Attention Deficit Hyperactive Disorder (ADHD). The District Court found the asserted claims of U.S. Patent Nos. 8,465,765 ('765 patent), 8,563,033 ('033 patent), 8,778,390 ('390 patent), 8,956,649 ('649 patent), and 9,040,083 ('083 patent) were invalid as being obvious under 35 U.S.C. § 103. As explained in the earlier opinion, MPH is a widely used psychostimulant that has been used for treating ADHD since the 1950's. Both immediate-release (IR) and extended-release (ER) formulations of the drug were also known in the art, and sustained-release (SR) formulations were later developed to overcome drawbacks of both IR and ER formulations. Unfortunately, prior art SR formulations were disadvantageous for having slow onset action properties. The claimed invention was a combination formulation comprising an IR component and an SR component that showed "a 45-minute therapeutic onset and 12 hours of therapeutic effect."
Asserted claim 6 (dependent on claim 1) was at issue in the litigation and was deemed to be representative:
1. A methylphenidate aqueous extended release oral suspension comprising (1) an immediate release methylphenidate component, (2) a sustained release methylphenidate component comprising a water-insoluble, water-permeable, pH-independent, barrier coated methylphenidate-ion exchange resin complex, and (3) water, wherein said suspension has a pH of about 3.5 to about 5 and said suspension provides a single mean average plasma concentration peak for methylphenidate and a therapeutically effective plasma profile for methylphenidate for about 12 hours.
6. The suspension according to claim 1, wherein the suspension has a pharmacokinetic profile in which the single mean plasma concentration peak for d-methylphenidate has an area under the curve (AUC)0-∞of about 114 ng-hr/mL to about 180 ng-hr/mL, Cmax of about 11 ng/mL to about 17 ng/mL, Tmax of about 4 hours to about 5.25 hours and T1/2 of about 5 hours to about 7 hours following a single oral administration of an aqueous suspension at a dose equivalent to 60 mg racemic methylphenidate HCl in adults.
The prior art considered by the District Court in the earlier case included several commercially available, extended-release MPH formulations (Concerta®, Daytrana®, Focalin XR®, Metadate CD®, and Ritalin LA®), U.S. Patent Application Publication No. 2010/0260844, and certain scientific publications. The commercial products all exhibited various pharmacokinetic and pharmacodynamics properties regarding a single or multiple PK peak profile, initial onset time and total duration. The '844 patent publication disclosed "a formulation of MPH that provides a rapid onset of action within 1 to 1.5 hours, a single Tmax of 5.5 to 7.5 hours, and a therapeutic duration of about 12 to 14 hours." Actavis relied on the '844 application in combination with Concerta®, Daytrana®, and Metadate CD® as teaching "a single mean peak PK profile, exhibiting an early onset of action, and exhibiting an extended duration of effect" that would have suggested to the skilled worker the early onset and extended duration formulation in the asserted claims. Tris Pharma argued to the contrary that the prior art taught combinations of IR and ER MPH formulations that resulted in a bimodal PK profile. This feature of combined IR and ER MPH formulations was designed to "mimic the peaks and valleys of multiple immediate release dosing regimens" which was not a feature of the claimed invention. In addition, the commercially available formulations showed a later Tmax that was important to achieve the longer duration.
The District Court found the claims to be obvious and the Federal Circuit disagreed, vacating and remanded, in an opinion by Judge Chen, joined by Judges Newman and O'Malley. The opinion was based on Fed. R. Civ. P. 52(a)(1), which states that "[i]n an action tried on the facts without a jury or with an advisory jury, the court must find the facts specially and state its conclusions of law separately." Citing Gechter v. Davidson, 116 F.3d 1454, 1457 (Fed. Cir. 1997), the Federal Circuit stated that "[w]hen the opinion explaining the decision lacks adequate fact-findings, meaningful review is not possible, frustrating the very purpose of appellate review as well as this court's compliance with its statutory mandate." Such considerations were important in this case because the paucity of the District Court's fact-finding made it impossible for the panel to properly assess the correctness of its legal conclusion of obviousness.
On remand, the District Court considered dependent claim 10 of the '033 patent to be exemplary:
1. A methylphenidate aqueous extended release oral suspension comprising (1) an immediate release methylphenidate component, (2) a sustained release methylphenidate component, and (3) water, said suspension having a pH of about 3.5 to about 5, wherein said suspension provides a single mean average plasma concentration peak and a therapeutically effective plasma profile for about 12 hours for methylphenidate, and wherein the suspension has a pharmacokinetic profile in which the single mean plasma concentration peak for methylphenidate has an area under the curve (AUC)0 ® ∞ of about 114 to about 180 ng-hr/mL, Cmax of about 11 to about 17 ng/mL, Tmax of about 4 to about 5.25 hours, and T1/2 of about 5 to about 7 hours following a single oral administration of said suspension at a dose equivalent to 60 mg racemic methylphenidate HCl in adults.
9. A method for treating a patient having a condition susceptible to treatment with methylphenidate, the method comprising administering to the patient the suspension according to claim 1, wherein said suspension provides a therapeutically effective amount of methylphenidate within 45 minutes after administering of said suspension and a single average plasma concentration peak.
10. The method according to claim 9, wherein the suspension which has a pH from about 4 to about 4.5.
(In a footnote the opinion notes that claims 6 and 20 of the '765 patent, claims 4 and 10 of the '033 patent, and claims 15, 16, and 20 of the '390 patent were under consideration on appeal.) The opinion set forth the claim limitations relevant to the issues on appeal to be:
• "aqueous,"
• "therapeutically effective plasma profile . . . for about 12 hours" (12-hour duration, relevant to extended-release formulations),
• "therapeutically effective amount of methylphenidate within 45 minutes" (45-minute onset),
• "Tmax of about 4 to about 5.25 hours" (early Tmax range), and
• "single mean plasma concentration peak" (single mean peak).
All of the claims before the Court recited "a liquid MPH formulation with a 12-hour duration and single mean peak," and claim 6 of the '765 patent, claim 4 of the '033 patent, and claims 15,16, and 20 of the '390 patent recited the early Tmax range. Claim 10 was considered representative because it was the only claim that recited all these features.
On remand, Actavis relied upon the same factual evidence it adduced in the earlier trial, relating to five commercially available prior art MPH formulations, prior art patent publication 2010/0260844 and scientific articles. According to the panel opinion "no single reference disclose[d] all of the limitations in any given claim" (although some references disclosed "various subsets of the claim limitations"). Having considered "the trial record, post-trial record, and the parties' post-remand briefing" the District Court found Actavis failed to show the asserted claims were invalid for obviousness by clear and convincing evidence, and this appeal followed.
The Federal Circuit affirmed this time around, in an opinion by Judge Chen joined by Chief Judge Moore and Judge Hughes. Considering the asserted claims seriatim, the Court affirmed the District Court's determination that Actavis failed to prove that "an artisan of ordinary skill would have been motivated to combine with a reasonable expectation of success a liquid MPH formulation with a single mean peak, 12-hour duration, and 45-minute onset" with regard to claim 20 of the '765 patent. In particular, Actavis did not adduce evidence that "a skilled artisan would have pursued a single mean peak concentration profile," instead merely showing that single or bimodal peaks were potential options and the art taught away from a single mean peak. These determinations were supported, according to the Court, by objective indicia of non-obviousness, specifically unexpected results, and the existence of a long-felt need for the claimed formulations.
For claim 6 of the '765 patent, claim 4 of the '033 patent, and claims 15, 16, and 20 of the '390 patent, the Federal Circuit affirmed the District Court's decision that Actavis had not established that "an artisan of ordinary skill would have been motivated to combine with a reasonable expectation of success a liquid MPH formulation with a single mean peak, 12-hour duration, and the claimed Tmax range." Specifically, the District Court held (and the Federal Circuit agreed) that while one of the references disclosed these features the prior art formulations were not liquid ones, which was required by the asserted claims. And the District Court found that Actavis failed to establish that claim 10 of the '033 patent was invalid for obviousness because of a failure in showing a motivation to combine these references.
On appeal, the panel rejected Actavis's arguments that the District Court erred in finding no motivation to combine the asserted references and no reasonable expectation of success. In the Court's opinion, the lower court's findings were supported by the evidence of record as supplemented by additional evidence required by the Federal Circuit in its remand decision. The District Court held that Actavis had not met this burden on remand.
Specifically with regard to the 45-min onset claims, the Federal Circuit held that the District Court properly found Actavis produced insufficient evidence for motivation to combine the single mean peak profile with "a liquid formulation with a 12-hour duration and 45-minute onset" as required in claim 20 of the '765 patent (what evidence there was being "at best, inconsistent"). The Federal Circuit agreed with the District Court's determination that the prior art taught away from "a liquid formulation with a single peak, 12-hour duration, and 45-minute onset," based on expert testimony inter alia that "[t]o achieve both an early onset and longer duration, a formulator would seek a concentration profile with two separate (bimodal) peaks" rather than the single mean peak profile recited in the asserted claims. And the panel found that the District Court properly did not find the asserted claims obvious over the asserted prior art patent application disclosure because expert testimony characterized these teachings as "aspirational" and "hypothetical."
Also unpersuasive was Actavis's assertion of U.S. Patent Pub. No. 2007/215511 (Mehta) for teaching "an artisan of ordinary skill how to develop a liquid formulation of MPH with a single mean peak [pharmacokinetic] profile, 12-hour duration, and 45-minute onset." The District Court found these teachings to be at "too high a level of generality" to supply the requisite motivation to combine and reasonable expectation of success. Finally, the panel agreed with the District Court's determination that there were secondary indicia factors that supported the District Court's non-obvious determination.
Regarding claims that recited the "early Tmax" limitation, the District Court found and the Federal Circuit affirmed that the '844 published patent application "presented only a hypothetical formulation without any data or explanation for why or how a formulation with the claimed limitations could be accomplished." Accordingly, the District Court did not err in finding that claim 6 of the '765 patent, claim 4 of the '033 patent, and claims 15, 16, and 20 of the '390 patent were not obvious because Actavis did not show by clear and convincing evidence a motivation to combine and reasonable expectation of success.
On this record, the Federal Circuit affirmed.
Tris Pharma, Inc. v. Actavis Laboratories FL, Inc. (Fed. Cir. 2022)
Nonprecedential disposition
Panel: Chief Judge Moore and Circuit Judges Chen and Hughes
Opinion by Circuit Judge Chen
