Methylphenidate - USA

On Sep 05, 2017, District court of Delaware issued its decision in Quillivant XR (methylphenidate ER suspension) case & found asserted claims of the patent-in-suit are invalid as obvious under 35 U.S.C. § 103.

In this Hatch-Waxman patent infringement action, plaintiff Tris Pharma, Inc. ("Tris") alleges patent infringement by defendant Actavis Laboratories FL, Inc. ("Actavis"). Plaintiff alleges that, by filing Abbreviated New Drug Applications ("AND As") seeking approval to market generic versions of Quillivant XR®, Defendant infringed U.S. Patent Nos. 8,46,765 ("the '765 patent"), 8,563,033 ("the '033 patent"), 8,778,390 ("the '390 patent"), 8,956,649 ("the '649 patent"), 9,040,083 ("the '083 patent"). The court held a five-day bench trial in this matter beginning on February 6, 2017.

Actavis challenged the validity of the asserted claims of the '765, '033, '390, '649, and '083 patents, arguing that a POSA would have found it obvious in light of the prior art to synthesize Qullivant XR® as an improved ADHD treatment. At the outset, the parties agreed that at the time of the invention, a POSA would have been motivated to make an extended release liquid methylphenidate product with an early onset of action and extended duration of effect. Actavis therefore contended that a POSA would have had both a motivation and more than a reasonable expectation of success in achieving that goal.

Aqueous MPH Formulation:  

Actavis argues that the prior art taught how to make stable liquid methylphenidate formulations having the pharmacokinetic characteristics and formulation details of the asserted claims. Specifically, Actavis relies on the combination of the Mehta, Ansel, and Connors references.  The Mehta reference discloses the use of ion exchange resin technology to make extended release formulations, including aqueous suspensions that identify methylphenidate as an active ingredient. Further Actavis relied on both the Ansel's and Connors prior art references to support its position that MPH at the claimed pH would have been obvious.

Despite Tris' arguments, for several reasons, the court was persuaded that there was a motivation to combine the teachings of the prior art references to achieve the MPH formulation, and that the skilled artisan would have had a reasonable expectation of success in doing so. In sum, the court was not convinced that the asserted claims include pH range limitations (pH of about 4 to about 4.5) that are critical to the claimed suspension's stability. Accordingly, the court concluded that Actavis has shown by clear and convincing evidence that a POSA would have been motivated to and have had a reasonable expectation of success combining MPH with water, at the claimed pH, in an ion-exchange resin to achieve the claimed liquid MPH product.

Pharmacokinetic Features & Clinical Effects:

The court next considered whether it would have been obvious to obtain the pharmacokinetic features and clinical effects of Quillivant XR®. Actavis contended that, despite the number of peaks being of little relevance to a POSA, the prior art disclosed Single Peak profiles with early onset of action and long duration of effect.

In response, Tris contended that the claimed PK features and clinical effects were not obvious. Specifically, Tris asserted that Actavis did not show why a POSA would have a reasonable expectation of success, be motivated, or have a reason to design a product with the clinical and PK features (such as Single Peak plasma profile) as claimed in a patent. In contrast, Tris further argued that, after the failure of Ritalin-SR®, the second generation of extended release solid oral MPH product-Concerta®, Metadate CD®, Ritalin® LA, and Focalin®-were developed using two components, IR and ER, to provide two peak (bimodal) profiles. Tris also contended that the state of the art second generation oral MPH products used bimodal profiles and delayed Tmax to extend effect.

While the court believed Tris' evidence regarding the second generation products is persuasive, it is not dispositive on the obviousness inquiry. Importantly, the Scicinski reference described the purpose of its invention as providing an oral dosage form of methylphenidate that has a long duration of action and rapid onset. Actavis' expert, Dr. Staller, testified that Scicinski Figure 7 discloses a target plasma profile for his methylphenidate product that has a Single Peak and a 12-hour duration of action.

Finally, although Tris' expert, Dr. McGough, testified that a POSA would not have expected a formulation with a single peak to achieve both early onset and extended duration of action, he admitted that he would "defer completely to a formulator in terms of what sort of curve could be achieved”.  As a result, the court finds the testimony of Actavis' formulator is more compelling. Accepting as credible Dr. Moreton's testimony that a formulator would have had no trouble achieving early onset of action and extended duration of effect with a Single Peak profile as of the priority date, the court finds Tris' arguments unpersuasive.