Biogen Int’l Gmbh V. Mylan Pharms. Inc. Tecfidera® (Dimethyl Fumarate)

Robins Kaplan LLP

Case Name: Biogen Int’l GMBH v. Mylan Pharms. Inc., 18 F.4th 1333 (Fed. Cir. 2021) (Circuit Judges O’Malley, Reyna, and Hughes presiding; Opinion by Reyna; Dissent by O’Malley) (Appeal from N.D.W.V., Keeley, J.)

Drug Product and Patent(s)-in-Suit: Tecfidera® (dimethyl fumarate) (“DMF”); U.S. Patent No. 8,399,514 (“the ’514 patent”)

Nature of Case and Issue(s) Presented: Biogen uses DMF at a specific dose of 480 mg/day (called “DMF480”) and markets that use under the brand name Tecfidera. Between 2004 and 2006, Biogen conducted a Phase II, clinical, dose-ranging study to test the efficacy of DMF at 120, 360, and 720 mg/day concentrations (DMF120, DMF360, and DMF720, respectively). The results showed that DMF720 was efficacious in treating MS, and DMF120 and DMF360 were not. The FDA then recommended that Biogen add a DMF480 dosing regimen in the Phase III study because the lower dose might limit adverse effects. The Phase III results showed efficacy for both DMF480 and DMF720. Based on the 2006 Phase II results—and before starting the Phase III trial to test the DMF480 dose—Biogen filed a provisional application (to which the ’514 patent claims priority) on February 8, 2007. The ’514 patent issued in 2011 and claims a method for treating MS using 480 mg/day of DMF. In 2017, Mylan filed an ANDA seeking FDA approval to market a generic DMF product for treating MS before the expiration of the ’514 patent. Biogen subsequently filed a lawsuit against Mylan alleging patent infringement. Mylan counterclaimed for declaratory judgment that the ’514 patent was invalid and not infringed.

Following a bench trial, the district court determined that the asserted claims of the ’514 patent were invalid for lack of written description. The district court found that the specification of the ’514 patent does not focus exclusively on MS, but instead discusses myriad neurological disorders that might be targets for DMF treatments. Then, because the claims at issue concern methods to treat MS, the district court looked to methods of treatment disclosed the specification. One disclosure describes only “methods of treating a neurological disease by administering to the subject in need thereof at least one compound that is at least partially structurally similar to DMF,” as well as “a method of treating a mammal who has or is at risk for a neurological disease ... [by] administering to the mammal a therapeutically effective amount of at least one neuroprotective compound” such as DMF, and “a method of slowing or preventing neurodegeneration.” The district court also noted that, save for one paragraph in the specification, the disclosure does not teach potential dosage levels for DMF monotherapy as treatment for MS. The sole DMF-dosage paragraph is not linked to treatment of any specific disease but states that “an effective dose of DMF … to be administered to a subject orally can be … from about 480 mg to about 720 mg per day…. The reference to DMF480 appears at the end of one range among a series of ranges, including DMF concentrations of 100-1,000, 200-800, 240-720, and 480-720 mg/day. Further, when confronted at trial with the lack of a specific, independent reference to DMF480 in the ’514 patent, Biogen and its expert argued that a skilled artisan would be “drawn to” the DMF480 dose because it was “anchored” to the DMF720 dose, which was known to be effective to Biogen scientists at the time of Phase II trials when the specification was drafted. But the district court found that the very same sentence in the specification that discloses the DMF 480-720 mg/day range also “anchors” DMF240 (a known ineffective dose) to DMF720. Likewise, the district court credited Mylan’s expert testimony at trial that the paragraph containing the DMF480 reference fails to specifically link an effective dose of DMF to the treatment of MS. Biogen appealed, and the Federal Circuit affirmed.

Why Mylan Prevailed: Biogen argued that the district court erred by incorrectly applying the written-description analysis, and raised several “ancillary” arguments. Whether a claim meets the written-description requirement is a question of fact, which the Federal Circuit reviews for clear error on appeal from a bench trial. The Federal Circuit found that the district court began by properly noting that “it is the specification itself that must demonstrate possession.” Then, after hearing live testimony from the parties’ experts at trial, the district court found that the Biogen expert’s opinion that a skilled artisan would be drawn to a DMF480 dose from the disclosures in the specification was “neither credible nor persuasive.” More specifically, the district court did not clearly err in finding that a skilled artisan would not have recognized, based on the single passing reference to a DMF480 dose in the disclosure, that DMF480 would have been efficacious in the treatment of MS, particularly because the specification’s only reference to DMF480 was part of a wide DMF-dosage range and not listed as an independent therapeutically efficacious dose for the disease.

Biogen also argued, Judge O’Malley’s dissent agreed, that the district court erred in its legal analysis by conflating the meanings of “therapeutic” and “clinical” efficacy. But the district court found, and the majority agreed, that the specification’s own definition of a “therapeutically effective dose” made it unnecessary to distinguish between therapeutic effects and clinical efficacy with respect to any patentability determination. For example, the specification defines a “therapeutically effective dose” as an “amount of a compound” that results in the “prevention or delay of onset or amelioration of symptoms of a neurological disorder in a subject.” This, per the majority, was a definition of “therapeutically effective dose” that generally aligned with “clinical insignia.” The specification further expanded its definition of “therapeutically effective dose” to include “an attainment of a desired biological outcome, such as reduced neurodegeneration (e.g., demyelination, axonal loss, and neuronal death) or reduced inflammation of the cells of the CNS,” which constitute “therapeutic insignia.” The Federal Circuit concluded that the distinction between “therapeutic” and “clinical” efficacy, when viewed through the lens of the ’514 patent, was not a legal issue, but a factual one. The district court, as the finder of fact, did not find it necessary or appropriate to distinguish between therapeutic effects and clinical efficacy based on the specification’s definition of “therapeutically effective dose” because both clinical and therapeutic effects were encompassed but the specification’s definition. Such a determination was not clearly erroneous.

The majority also noted that Biogen’s later establishment the therapeutic efficacy of DMF480 was of no import to the written-description analysis done by the district court. Instead, what mattered for purposes of the inquiry in this case was whether, at the time of filing the disclosure—well before the Phase III study using DMF480 even commenced—a skilled artisan could deduce simply from reading the specification that DMF480 would be a therapeutically effective treatment for MS. As to this point, the specification’s focus on drug discovery and basic research further buttresses the district court's conclusion that the specification lacks an adequate written description to support the DMF480 claims.

Finally, as a backstop, the district court concluded that Biogen was judicially estopped from pointing out the distinction between clinical and therapeutic efficacy in its post-trial briefing, because Biogen was changing “positions according to the exigencies of the moment.” The Dissent found the district court’s treatment of the estoppel issue (a two-sentence footnote) to be reversible legal error because it failed to apply a multi-factor test established by the Fourth Circuit. The majority held that its conclusion that the district court did not clearly err in finding the ’514 patent invalid for lack of written description under § 112 rendered other arguments by Biogen superfluous.

DISCLAIMER: Because of the generality of this update, the information provided herein may not be applicable in all situations and should not be acted upon without specific legal advice based on particular situations.

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