Dimethyl fumarate – USA

On June 18, 2020, District Court of West Virginia found method of use patent covering Tecfidera® invalid for lack of written description support.

Background:

Biogen is the owner of US 8,399,514 patent entitled, “treatment for multiple sclerosis” expiring in Feb. 2028. This patent is listed in Orange Book for the product, Tecfidera® (Dimethyl fumarate) DR capsules. Biogen is the NDA holder & markets this product in USA.  Mylan sought approval of generic version & thus filed ANDA containing P-IV certification with USFDA to US’514 patent. Biogen sued Mylan within statutory period. Mylan also filed IPR in PTAB against same patent in Jul. 2018. PTAB issued final written decision in Feb. 2020 finding challenged claims not obvious over cited prior arts. Therefore, Mylan dropped obviousness challenge in district court & focused on lack of written description support under 35 U.S.C 112.

The independent claim 1 reads:

1. A method of treating a subject in need of treatment for multiple sclerosis comprising orally administering to the subject in need thereof a pharmaceutical composition consisting essentially of (a) a therapeutically effective amount of dimethyl fumarate, monomethyl fumarate, or a combination thereof, and (b) one or more pharmaceutically acceptable excipients, wherein the therapeutically effective amount of dimethyl fumarate, monomethyl fumarate, or a combination thereof is about 480 mg per day.

Court’s analysis:

Mylan argued that the ’514 Patent is invalid for lack of written description because the specification described in 2007 (priority date) bears no resemblance to the invention claimed in 2011. Specifically, at the time of filing POSA would not have expected the claimed invention——a 480mg/day dose of DMF (BID)——to effectively treat MS  and secondly when viewed as an integrated whole, the combination of selectively-plucked disclosures in the specification of the ’514 Patent fails to sufficiently describe the claimed invention. According to Mylan, it is only after Phase III trial in 2011 Biogen came to know the effectiveness of 480[mg/day] dose. Before the priority date of patent, only phase II results were known & that disclosed 720[mg/day] dose as effective dose to treat MS.

Court agreed with Mylan based on the facts, expert testimony & held that specification does not demonstrate that the Inventors “Possessed” the claimed invention at the time of filing of application. Court said that in order to satisfy the written description requirement of § 112, the inventor must “‘convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention, and demonstrate that by disclosure in the specification of the patent.’” Nuvo Pharm., 923 F.3d at 1376 (cleaned up) (citation omitted). Significantly, “actual ‘possession’ or reduction to practice outside of the specification is not enough.” Ariad Pharm. Inc., 598 F.3d at 1352. “[I]t is the specification itself that must demonstrate possession.” Court said that the specification of the ’514 Patent begins with a general discussion of MS but quickly turns to a discussion of how “the Nrf2 pathway may be activated in neurodegenerative and neuroinflammatory diseases as an endogenous protective mechanism.” The specification then provides five methods for screening of the compounds. Biogen argued that, “the ’514 Patent links through Method 4 each of the three recited elements of the asserted claims: (1) a method of treating MS with (2) DMF and/or MMF (3) at a dose of 480 mg per day.” But court said that Method 4 is limited in scope and makes no mention of treating MS with a 480mg/day dose of DMF (BID). Bioge then pointed out following paragraph from specification & argued that it provides support for the 480mg/day dose:

“For example, an effective dose of DMF or MMR to be administered to a subject orally can be from about 0.1 g to 1 g per pay [sic], 200 mg to about 800 mg per day (e.g., from about 240 mg to about 720 mg per day; or from about 480 mg to about 720 mg per day; or about 720 mg per day). For example, the 720 mg per day may be administered in separate administrations of 2, 3, 4, or 6 equal doses”.

Court said that this passage, however, neither “links” this “effective dose” to the treatment of MS, nor to a 480mg/day dose of DMF (BID). 480mg dosing is mentioned only once in this paragraph. Moreover, based on the results of Biogen’s Phase II study, as of the claimed priority date of February 8, 2007, a POSA would have known that 720mg/day of DMF (TID) is a therapeutically effective dose for treating MS, and that lower doses, such as 360mg/day of DMF (TID) and 120mg/day of DMF (QD), are not. Thus, on reading the specification, a POSA would be drawn to the 720mg/day dose of DMF because of its specific disclosure & not to 480mg dose. Moreover, this paragraph only discloses DMF & its dose. It does not discloses treatment of MS. Specification provides an exhaustive list of diseases that can be treated. Therefore, the method 4 can be used for a plethora of neurological diseases, and there are no “blaze marks” that would lead a POSA specifically to MS. Moreover, Biogen’s expert, Dr. Wynn, conceded on cross examination. Based on his reading of the ’514 Patent, he testified that he would not know which dose provided in this paragraph would be most effective for treating MS.

Biogen’s reliance on Example 3 fares no better which is an Experimental Autoimmune Encephalomyelitis (“EAE”) animal model used for MS. Dr. Wynn never explained how this experiment teaches a method of treating MS (in humans, not mice) with a therapeutically effective amount of DMF, i.e., 480 mg/day (BID). On the contrary, Dr. Lukashev credibly testified that the three examples in the ’514 Patent were part of his research, which “was separate from preclinical development” and unrelated to the clinical application of DMF in MS. Indeed, the results of Example 3 “provided evidence of [MMF] and [DMF] activation of NRF2 in vivo.”

Moreover, extrinsic evidence confirms the lack of written description. After getting the surprising results from phase III in 2011, Biogen filed different patent application (US 14/119,373) specifically covering the methods of treating Multiple Sclerosis with 480 mg/day dose. The specification provided and discussed in detail a wealth of data generated during Biogen’s Phase III study.  In contrast, the specification in the ’514 Patent included none of this data or information. But because of priority of May 2011, US’373 application would have faced strong invalidity challenges because of the ample availability of prior arts. Therefore, Biogen amended its title and claims of the US 12/526,296 application (parent of US’514 patent, now abandoned) without amending specification so that it can claim priority date of Feb. 2007. This strategy came with a cost, however, since Biogen was left with a specification written in 2007 that bore no resemblance to the ’514 Patent’s title and claimed invention——a method of treating MS with a therapeutically effective amount of DMF, i.e., 480mg/day —an invention that no one knew would work until April 2011 when Biogen received the results of its Phase III study.

Court said that, in sum, Biogen has attempted to satisfy the written description requirement of § 112 by selectively plucking specific words from the specification that correspond to each element of the claimed invention. The Federal Circuit has squarely rejected this approach. [Nuvo Pharm., 923 F.3d at 1380]. The ’514 Patent thus must be viewed as an integrated whole rather than a sum of its parts. As of February 8, 2007, inventors did not “possess” the claimed invention——a method of treating MS with a therapeutically effective amount of DMF, i.e., 480mg/day (BID) & thus Mylan has established by clear and convincing evidence that the asserted claims of the ’514 Patent are invalid for lack of written description.