PTAB

IPR2018-01403

Mylan Pharmaceuticals Inc v. Biogen Ma Inc

Key Events

Petition

petition

Title: Treatment for Multiple Sclerosis
Brief Description: The ’514 patent relates to a method for treating multiple sclerosis (MS) by orally administering a pharmaceutical composition containing a therapeutically effective amount of about 480 mg per day of dimethyl fumarate (DMF).

Prior Art Relied Upon: January 2006 Biogen Press Release (a 2006 press release), Schimrigk 2004 Abstract (a 2004 clinical study abstract).
Core Argument for this Ground:
- Prior Art Mapping: Petitioner argued the Biogen Press Release confirmed that DMF monotherapy was an effective MS treatment, as it announced a Phase II study (the "Kappos study") met its primary endpoint of reducing brain lesions. The Schimrigk 2004 Abstract taught that Fumaderm®, a composition whose most active ingredient was known to be DMF, was effective in treating MS at doses containing 360 mg/day and 720 mg/day of DMF. Petitioner contended that these references established a known effective range for DMF in treating MS, rendering the selection of an intermediate dose of 480 mg/day obvious.
- Motivation to Combine: A POSITA would combine the teachings to optimize a known therapy. Knowing that DMF was effective but had dose-dependent side effects (e.g., flushing, gastrointestinal issues), a POSITA would have been motivated to explore doses between the known effective 360 mg/day and 720 mg/day points to find an optimal balance of efficacy and tolerability.
- Expectation of Success: A POSITA would have a high expectation of success because Schimrigk established efficacy at both 360 mg/day and 720 mg/day. This success was further supported by prior art showing that 480 mg/day of DMF was an effective dose for treating psoriasis, an analogous autoimmune disease.

Prior Art Relied Upon: Kappos 2006 (a 2006 clinical study abstract), Schimrigk 2004 Abstract (a 2004 clinical study abstract).
Core Argument for this Ground:
- Prior Art Mapping: Petitioner asserted that Kappos 2006 explicitly disclosed that 720 mg/day of DMF monotherapy significantly reduced brain lesion activity in a "dose-dependent manner." This established the high end of an effective range. As in Ground 1, Schimrigk 2004 provided the low end of the effective range (360 mg/day). The combination brackets the claimed 480 mg/day dose.
- Motivation to Combine: The motivation was identical to Ground 1: routine dose optimization. The express teaching in Kappos 2006 of a "dose-dependent" effect would have strongly encouraged a POSITA to investigate intermediate doses like 480 mg/day to improve the side-effect profile while maintaining efficacy.
- Expectation of Success: The expectation of success was clear. With two known effective data points and the knowledge of a dose-dependent response, a POSITA would reasonably expect an intermediate dose to also be effective, particularly one already proven effective in a related disease.

Prior Art Relied Upon: Kappos 2006 (a 2006 clinical study abstract), WO '342 (International Publication No. WO 2006/0037342).
Core Argument for this Ground:
- Prior Art Mapping: Kappos 2006 established that 720 mg/day of DMF was an effective treatment for MS. WO '342 taught using pharmaceutical compositions of DMF to treat MS and explicitly disclosed a daily dosage range of "480 to 600 mg of active substance." Petitioner argued this combination directly taught all elements of the independent claims.
- Motivation to Combine: A POSITA, aware from Kappos 2006 that DMF was an effective MS therapy, would have been motivated to consult other art like WO '342 for formulation and dosing information. WO '342 provided an explicit roadmap, suggesting a 480 mg to 600 mg daily dose for treating MS.
- Expectation of Success: The expectation of success would be exceedingly high, as WO '342 explicitly taught administering the claimed 480 mg dose of DMF for the exact purpose of treating MS.
Additional Grounds: Petitioner asserted an additional obviousness challenge (Ground 4) based on Kappos 2006, Clinical Trials, Joshi '999, and ICH. This ground was previously reviewed by the Board in a prior IPR, but Petitioner argued it was presenting new evidence to rebut the Patent Owner's prior arguments on unexpected results.

Rebuttal of Unexpected Results: A central contention was that the Patent Owner’s argument of unexpected results was based on a flawed premise. The Patent Owner had previously argued that the 480 mg/day dose was surprisingly effective because the next lowest tested dose, 360 mg/day, was statistically ineffective. Petitioner presented evidence, including the Kappos 2006 slide presentation, showing the 360 mg/day patient group in that study had a significantly higher baseline disease activity than other groups. Petitioner argued that when this baseline imbalance is corrected, the 360 mg/day dose was, in fact, effective. This correction reveals a predictable dose-response curve, making the efficacy of the 480 mg/day dose entirely expected and not surprising.

Petitioner argued that the Board should not exercise its discretion to deny institution under 35 U.S.C. § 325(d). The petition asserted it presented new arguments and evidence not previously before the Board or the Patent Office. Key reasons included:
- The petition provided significant new evidence to rebut the Patent Owner's "unexpected results" argument, an issue on which a previous petitioner had failed to submit any rebuttal evidence, leading to the patent being upheld.
- The petition presented new prior art combinations not previously considered by the Board, specifically the combinations of Kappos 2006 with either Schimrigk 2004 or WO '342.
- The petition provided new arguments and expert declarations explaining why the Examiner erred during prosecution by not considering evidence showing DMF was the most active component of Fumaderm® in the Schimrigk reference.

Petitioner requested institution of an inter partes review and cancellation of claims 1-20 of the ’514 patent as unpatentable.