Methylphenidate – USA

 

On Nov. 30, 2020, Delaware court on remand found Quillivant XR® patents valid & infringed by ANDA filer in a Hatch-Waxman suit.

Plaintiff (Tris Pharma) filed suit against defendant (Actavis) for alleged infringement of U.S. Patent Nos. 8,465,765; 8,563,033; 8,778,390; 8,956,649 and 9,040,083. Actavis challenged the validity based on obviousness and obviousness-type double patenting. After a five-day bench trial, the original judge (now retired) found all the asserted claims to be invalid for obviousness under 3 5 U.S. C. § 103. Tris appealed. The Federal Circuit vacated the judgment because [the judge]'s obviousness decision lacked the requisite fact-finding, and because the [judge] erred in rejecting Tris's evidence of objective indicia of non-obviousness." The Federal Circuit thus remanded the obviousness analysis to the district court for further fact-finding.

All asserted claims basically related to methylphenidate aqueous extended release oral suspension & its pharmacokinetic (PK) & pharmacodynamic (PD) aspects. Federal Circuit specifically ordered further fact-finding to address whether a liquid MPH formulation with a single mean PK profile, 12-hour duration of effect, 45-minute onset of action, Tmax range of 4 to 5.25 hours would have been obvious over the prior art. Prior arts cited were disclosing one or more limitations but not all. Most of the prior arts were related to ER solid formulations of methylphenidate. Only one art cited was related to liquid formulation but that disclosed IR composition. The question on remand was whether Actavis has demonstrated by clear and convincing evidence that an artisan of ordinary skill would have been motivated to achieve the combination in question and would have had a reasonable expectation of success in doing so.

Court said that Actavis bears the burden & their arguments are confusing and conflicting. Actavis first submitted that POSA would have been motivated to make a formulation with a single peak profile. Court said that assuming arguendo that this fact were established, it would not by itself constitute clear and convincing evidence that an artisan of ordinary skill would have been motivated to combine a single peak profile with a liquid MPH formulation that has both a 12-hour duration and 45-minute onset. On the contrary, Actavis next states in the opening line of its second argument that its own expert, Dr. Staller, established at trial "that POSA would not have been concerned about the specific shape of the PK curve-[because] clinical effects [i.e., PD characteristics as opposed to PK characteristics] are what matter." Court thus said that, so POSA would have been indifferent (i.e., would have lacked motivation) to use a formulation that produced a single peak profile. Actavis' last affirmative argument with respect to motivation to combine a single peak profile, 12-hour duration, and 45-minute onset in a liquid MPH formulation too, lacks merits. Actavis argued that POSA "would have been motivated to pursue this [combination] because [the combination had] already appeared in the prior art." Court however said that only two of the extended release prior art references disclosed formulations with a single mean peak plasma profile, and neither of those references achieved an onset within 45 minutes. Court also said that there was no reasonable expectation of success because prior art taught away from combining in a liquid MPH formulation a single mean peak, 12-hour duration, and 45-minute onset. Specifically, prior art taught that multiple peaks, achieved by multiple pulses of medication, were required to achieve both a 12-hour duration and 45-minute onset. Thus, the prior art taught away from use of a single peak to achieve that combination of clinical effects.

With respect to secondary consideration, court found unexpected results and long-felt, unmet need in favor of Tris. Court said that combination of single peak profile with a 12-hour duration and 45-minute onset was unexpected as discussed above. Moreover, Tris's evidence of long-felt unmet need as of July 2010 for a liquid methylphenidate formulation with a 12-hour duration and 45-minute onset is especially compelling. Because, children, the primary focus of ADHD treatment, often have difficulty swallowing pills; and it is much easier for patients generally and children in particular to comply with a therapy regimen that is accomplished with a single daily dose as opposed to multiple doses taken throughout the day. The need was long-felt and unmet because even though methylphenidate had been used to treat ADHD since the mid-1950s, the only two formulations available as of July 2010 that allowed for a single daily dose regimen (i.e., 12-hour duration of effect) and an early onset were Concerta® and Focalin®, and both of those formulations required the swallowing of a pill or capsule. The only liquid formulation available at the time, Methylin® OS, was an immediate release product with a duration of effect that lasted only three to four hours.

Court thus concluded that all asserted claims are not invalid and defendants infringed each of the asserted claims.