Methylphenidate – USA

On Nov 20, 2018, Federal Circuit vacated invalidity decision of Delaware court as it was based on inadequate fact-findings & remanded the case for further considerations.

Tris Pharma markets Quillivant XR®, an extended release methylphenidate (MPH) formulation for the treatment of Attention Deficit Hyperactive Disorder (ADHD). When Actavis submitted ANDA to USFDA, Tris sued Actavis for infringement of U.S. Patent Nos. 8,465,765, 8,563,033, 8,778,390, 8,956,649, and 9,040,083. Patent claims are directed to pharmacokinetic (PK) and pharmacodynamic (PD) properties of the Quillivant XR® extended release formulation. These properties include: (1) an extended duration of action of about 12 hours; (2) a single mean peak PK profile; (3) a Tmax of about 4 to 5.25 hours (early Tmax); and (4) a 45-minute onset of action/therapeutic effects. After a five-day bench trial, the district court found all asserted claims of the patents-in-suit invalid under 35 U.S.C. § 103. The prior art consists of a number of commercially available, second-generation, extended release formulations of MPH including Concerta®, Daytrana®, Focalin XR®, Metadate CD®, and Ritalin LA®;2 scientific articles; and U.S. Patent Application Publication No. 2010/0260844 (Scicinski). Specifically, district court credited Actavis’s expert’s testimony that a skilled artisan would have no trouble achieving early onset of action and extended duration of effect with a single mean peak PK profile based on disclosures in prior arts. District court also considered secondary indicia of non-obviousness but found unpersuasive. Tris then appealed.

Tris raised three primary issues on appeal:

1. Tris argued that a skilled artisan would not have reasonably expected to successfully combine the claimed single mean peak PK profile with the claimed 45-minute onset of action and 12-hour duration of effect (PD characteristics) because the PK-PD relationship was unknown.

2. Tris contended that the district court failed to address why the combination of an early Tmax and 12-hour duration of effect would have been obvious.

3. Tris claimed that the district court mistakenly disregarded Tris’s evidence of unexpected results based on a belief that Tris’s experts did not compare the claimed invention to the closest prior art.

Federal circuit said that district court failed to make adequate findings of fact to support their holding. First, while the district court found that one would have expected from the prior art that a single mean peak PK profile could provide for rapid onset of action and extended duration of effect,  it never articulated which prior art references do so and how. Specifically, the district court never made explicit findings that Daytrana®, Concerta®, Metadate CD®, and/or Scicinski also teach a 45-minute onset of action or 12-hour duration of effect. With respect to the 45-minute onset of action limitation, the district court cited a concession by Tris’s expert that second-generation MPH formulations could have an onset of action in as early as 30 minutes, but it did not explain the significance of this concession. As for the 12-hour duration of effect limitation, the district court’s opinion is vague as to whether any of the prior art formulations actually teach the 12-hour duration of effect limitation. Throughout its analysis, the district court imprecisely states that certain prior art discloses “efficacy that last[s] throughout the day,” a “long duration of effect,” or an “extended duration of action.” It is unclear, however, whether the district court intended this language to equate to the claimed 12-hour duration of effect.

Second, and importantly, the district court does not address a fundamental aspect of the obviousness inquiry—i.e. why a skilled artisan would have been motivated to use a single mean peak PK profile to achieve a formulation with a 45-minute onset of action and/or 12- hour duration of effect with a reasonable expectation of success. Tris argued on appeal that the acute tolerance theory as well as the prior art taught away from using a single mean peak PK profile to achieve a 45-minute onset and 12-hour duration of effect. Actavis argued that the acute tolerance theory is irrelevant to whether a drug has a single or bimodal peak PK profile, attempts to discredit the theory, and asserts that skilled artisans did not regard the number of peaks as important when formulating a drug. But the district court made none of these findings. It is thus unclear whether the district court found that (1) the theory is not applicable because it does not affect the shape of the plasma concentration curve; (2) the theory is unreliable; or (3) the theory is applicable, but even acknowledging it, a skilled artisan would have a reasonable expectation of success to combine a single mean peak curve with a 45-minute onset of action and a 12-hour duration of effect. Without the requisite factual findings and adequate explanation, federal circuit declined to affirm the district court’s conclusion of obviousness & remanded for further consideration.

Federal circuit further said that district court’s analysis with respect to early Tmax and 12-Hour Duration of Effect is very cursory. The entirety of the district court’s discussion of Tmax appears amounts to a mere recitation of Actavis’s experts’ testimony. And, yet again, the district court fails to articulate whether it credited this testimony or explain why and how the testimony supports its conclusion. The district court’s opinion lacks any response to Tris’s argument that formulations with an early Tmax (such as Metadate CD® and Ritalin LA®) did not achieve 12 hours of effect while those with 12 hours of effect (Concerta® and Focalin XR®) had later Tmax values. Therefore, federal circuit remanded the obviousness of the combination of an early Tmax with 12-hour duration of effect to the district court for further consideration.

Federal circuit agreed with the Tris on the issue of secondary considerations such as unexpected results & long-felt need. Federal circuit said that with respect to unexpected results district court’s analysis is deficient because it addresses the single mean peak PK limitation. The district court does not explain why—separately, and more importantly together with the single mean peak PK profile limitation—the Tmax, 45-minute onset, and 12 hour duration of effect limitations were not unexpected. With respect to long-felt need district court opinion identified various prior art products that meet each of the three individual needs above, but never identified a prior art product that contains all three properties. Thus in view of these errors federal circuit asked district court to reconsider all the evidence of objective indicia in its overall determination of obviousness.