The written description requirement has had a twenty-five year renaissance, particularly in the chemical and biotechnology arts as a way of restricting claim scope to what an inventor has actually invented (see Regents of the University of California v. Eli Lilly & Co. and "Ariad Pharmaceuticals Inc. v. Eli Lilly & Co."). In view of the unpredictability of these arts (compared with the mechanical arts; but see Tronzo v. Bionet and Gentry Gallery, Inc. v. Berkline Corp.), the same evidence that supports non-obviousness (due to the skilled worker not having the requisite reasonable expectation of success) can also restrict the scope of what has been described (because there can be much less reliance and supplementation of what the person of ordinary skill would know for disclosures that fail to satisfy the possession test of written description due to that unpredictability). These conflicting rubrics were part of the District Court's decision last week that Biogen failed to provide adequate written description in ANDA litigation styled Biogen Int'l GmBH v. Mylan Pharmaceuticals Inc.
The case arose over Mylan's attempt to get regulatory approval and come to market with a generic equivalent of Biogen's Tecfidera® (dimethyl/monomethyl fumarate) multiple sclerosis drug. Biogen asserted Orange Book-listed U.S. Patent Nos. 6,509,376; 7,320,999; 7,619,001; 7,803,840; 8,399,514; and 8,759,393, but the parties dismissed their causes of action on all patents except the '514 patent, where Biogen asserted claims 1-4, 6, 8-13, and 15-16; claim 1 is representative:
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.
While this litigation was proceeding, Mylan successfully petitioned the Patent Trial and Appeal Board to institute an inter partes review proceeding, on the grounds that the asserted claims of the '514 patent were obvious. The Board issued a Final Written Decision that Mylan had not shown obviousness by a preponderance of the evidence, and the District Court held that Mylan was collaterally estopped from asserting obviousness as a basis for invalidating the '514 patent in this litigation. Accordingly, the only ground Mylan pursued before this Court was that the specification of the '514 patent did not satisfy the written description requirement of 35 U.S.C. § 112(a).
Mylan's arguments on its written description defense were grounded on certain characteristics of the '514 specification and its prosecution history. The '514 patent reflected Biogen's more general research goal of finding treatments for neurological disorders, including but not limited to multiple sclerosis (MS). Mylan noted that the original named inventor was not a clinician but rather a research scientist investigating the mechanism of action of the claimed compound. Specifically, the research underlying the '514 patent disclosure showed that DMF could activate a particular metabolic pathway (the Nrf2 pathway). One important consequence of this inventor's testimony is that he "denied that his research could be extrapolated to a clinical dose of DMF; it 'was never the focus of [his] work to inform the clinical dosing of [DMF].'" This inventor, Dr. Lukashev, was the only named inventor on the earliest priority applications from which the '514 patent claimed priority.
As originally filed, the claims of the application that matured into the '514 patent did not recite methods of treatment but rather were drawn to methods for identifying compounds that affected the Nrf2 pathway. However, in April 2011, Biogen received the results of a Phase III clinical study showing that a 480mg/day dose of DMF was effective in treating MS (specifically). Apparently in response, Biogen replaced the then-pending claims with claims that eventually issued, changed the title of the application, and added as an inventor the scientist who posited that this dosage would be particularly effective as an MS treatment; significantly to the written description calculus Biogen did not supplement its specification which permitted it to rely on a February 8, 2007 earliest priority date. In addition, Biogen filed a stand-alone provisional application expressly directed to MS treatment with 480mg/day of DMF. Biogen subsequently abandoned this application when the '514 patent was allowed.
Mylan's argument was simple: the invention described in the specification filed in 2007 "bears no resemblance to the invention claimed in 2011." Mylan supported this assertion with two arguments. First, Mylan argued that "a POSA [person of skill in the art] would not have expected the claimed invention—a 480mg/day dose of DMF (BID)—to effectively treat MS" and "that nothing in the specification of the '514 Patent teaches otherwise." Second, Mylan argued that "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—a method of treating MS with a therapeutically effective amount of DMF, i.e., 480mg/day of DMF (BID)." According to Mylan, the reason for this situation is that "Biogen grafted the '514 claims onto a specification written to cover an entirely different set of inventions, conceived of by an entirely different inventor, and filed more than four years before Biogen's 2011 Phase III trial results demonstrated the effectiveness of the 480[mg/day] dose."
Biogen, for its part, asserted that Mylan was relying on arguments it had asserted for obviousness, and that the '514 specification contained express disclosure -- in Method 4 provided in an Example -- that linked each of these three recited elements of the claims ("(1) a method of treating MS with (2) DMF and/or MMF (3) at a dose of 480 mg per day") in a way sufficient to satisfy the written description requirement.[1]
The District Court held that the '514 specification did not show that the inventors possessed the invention on its earliest claimed priority date. The Court noted that, although the '514 specification "[s]pan[s] 30 columns," with the first column focusing on MS, the specification is then directed to disclosure of "how 'the Nrf2 pathway may be activated in neurodegenerative and neuroinflammatory diseases as an endogenous protective mechanism,' and how '[e]merging evidence suggests that [plant-derived] compounds may exert their neuroprotective effects by activating cellular stress-response pathways, including the Nrf2 pathway, resulting in the upregulation of neuroprotective genes." As set forth in the Court's opinion, the '514 specification discloses five methods:
1) methods of screening for at least one new candidate compound for treating a neurological disease;
2) methods of evaluating neuroprotective properties of at least one drug candidate for treating a neurological disease;
3) methods of comparing (e.g., for bioequivalence) at least two pharmaceutical compositions which comprise fumaric acid derivatives;
4) methods of treating a neurological disease by administering to the subject in need thereof at least one compound that is partially structurally similar to DMF or MMF; and
5) methods of treating a neurological disease by a combination therapy that comprises administration of at least one first compound that upregulates the Nrf2 pathway and at least one second compound that does not upregulate the Nrf2pathway.
Even Biogen conceded that Methods 1-3 were directed to screening drug methods and not therapeutic methods, and Method 5 was limited to combination therapies using DMF and other drugs having different activities. The only disclosure relating to the claimed methods was Method 4, which Biogen contended provided the linkage between the elements of the asserted claims. The opinion is blunt: it says plainly "[t]his simply is not so." The Court understands this method to "broadly describe[] treating neurological diseases with a therapeutically effective amount of DMF; MS is merely one such disease 'among a slew of competing possibilities,'" citing Novozymes A/S v. DuPont Nutrition Biosciences APS by analogy in support of the inadequacy of the '514 patent disclosure. As further indicia of the lack of necessary specificity of the '514 patent disclosure, the Court cites "an exhaustive list of 'diseases suitable for the [five] methods described' in the '514 Patent." In view of this listing of a "plethora of neurological diseases," the Court held that there were no blaze marks that would teach the skilled worker to treat MS with DMF at this dosage. The Court particularly rejected Biogen's contention that the specification would teach the POSA that the '480 mg/day dosage was the preferred dosage, crediting Mylan's expert Dr. Greenberg's testimony in this regard. The Court particularly focused on the fact that the specification mentions the 480mg/day dosage only once, as part of a preferred range ("from about 480 to about 720mg/day"). The Court found "neither credible no persuasive" Biogen's argument that a POSA would understand that using the lowest effective dose of the narrowest range was preferred. The Court found it more consistent with what was known at the time the application was filed that dosages of 720 mg/day were effective in treating MS, and 120 and 360 mg/day were ineffective. In this context, the Court found that a POSA would understand from the '514 patent specification that 720mg/day was effective, to the extent that this was the upper range of every effective dosage range disclosed in the '514 patent.
In the "battle of the experts" the Court was unpersuaded by Biogen's expert (whose credibility Mylan impeached on cross-examination, according to the Court) and clearly persuaded by Mylan's expert.*
The Court also was convinced that the reason for this failure to describe the invention claimed in the '514 patent was that the specification contained predominantly the work and inventions of one inventor (Dr. Lukashev) directed to methods for identifying drugs for treating neurological disorders, while the claims were directed to the other inventor's (Dr. O'Neill) work on developing an effective therapeutic agent for treating MS:
From the evidence presented at trial, Dr. Lukashev's research regarding the activation of the Nrf2 pathway and screening drug compounds had nothing to do with the clinical development of Tecfidera®. That task fell to Dr. O'Neill and later Dr. Dawson. Notably, Dr. O'Neill's hypothesis, that a 480mg/day dose of DMF (BID) would be efficacious in treating MS, evolved from his review of Fumapharm's confidential studies of Fumaderm® [an early Biogen acquisition target], not Dr. Lukashev's unrelated research regarding the mechanism of action [citations to the record omitted].
From the evidence presented at trial, the District Court identified the following deficiencies in Biogen's failure to satisfy the written description requirement: "[i]n 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." Citing Nuvo Pharm. (Ir.) Designated Activity Co. v. Dr. Reddy's Labs. Inc., Enzo Biochem, Inc. v. Gen–Probe Inc., and Novozymes A/S v. DuPont Nutrition Biosciences APS, the Court states that "the Federal Circuit has clearly rejected" the approach Biogen has taken. Precluded from prevailing on these arguments, the Court found that Biogen must rely on inventor O'Neill's testimony that he invented the claimed invention, which the Court found insufficient under Nuvo Pharm. ("inventor testimony cannot establish written description support where none exists in the four corners of the specification").
The Court also considered "extrinsic" evidence (including the disclosure of the abandoned Biogen application filed immediately after Biogen received the Phase III clinical trial results). The comparison, wherein this application "provided and discussed in detail a wealth of data generated during Biogen's Phase III study" showed in stark relief the inadequacies of the '514 patent specification.
Finally, the Court took note of the fact that:
At every stage of this case and the related IPR proceeding, Biogen defended against Mylan's obviousness challenge by insisting that a POSA would not have expected a 480mg/day dose of DMF to be efficacious in treating MS. . . . This statement only underscores the failure of the specification to teach a POSA, who would expect otherwise, that a 480mg/day dose of DMF (BID) is efficacious in treating MS.
The District Court found the facts and circumstances of this case most analogous to the Nuvo Pharm. case, wherein the patent at issue was invalidated on written description grounds. The Court summarized its findings as follows:
Mylan has established by clear and convincing evidence that the asserted claims of the '514 Patent are invalid for lack of written description. First, the text of the specification does not reasonably convey to a POSA that Dr. Lukashev and Dr. O'Neill "actually invented" a method of treating MS with a therapeutically effective amount of DMF, i.e., 480mg/day BID, as of February 8, 2007. This reading of the text is confirmed by the testimony of Dr. Greenberg, Dr. Lukashev, Dr. O'Neill, and Dr. Wynn. Second, the context of the '514 Patent's prosecution history and the significant omissions from the specification further underscore the failure to adequately describe the claimed invention. Biogen's attempt to avoid this conclusion by combining a few selectively plucked disclosures from the specification of the '514 Patent has been squarely rejected by the Federal Circuit.
Satisfaction of the written description requirement is a question of fact reviewed for clear error from a bench trial. In addition, the District Court cited trial testimony from inventors and experts, and the Federal Circuit give substantial deference to the fact-finder for decisions based on the trial court's ability to assess witness credibility and demeanor. Finally, the Federal Circuit has recently increased the stringency with which is assesses satisfaction of the written description requirement (see "Amgen Inc. v. Sanofi"). These factors suggest that Biogen will face quite a challenge in getting the Federal Circuit to reverse the District Court's judgment on appeal.
* In a footnote, the Court illustrated how an expert witness can inform a fact finder regarding complex scientific concepts using commonplace relationships to illustrate the underlying principles:
As described by Mylan's expert witness, Benjamin M. Greenberg, M.D., autoimmune diseases such as MS are much like a confused house cat that mistakes a curtain, or other house-hold objects, for an invading mouse. Instead of attacking the mouse, the confused cat attacks a portion of the house it is meant to protect. The cat's breed, and the type of friendly object it attacks, will help identify which autoimmune disease is causing the confusion. For example, a Siamese cat (i.e., multiple sclerosis) may be confused and attack one part of the house (i.e., the central nervous system), and a Tabby cat (i.e., psoriasis) may be confused and attack another part of the house (i.e., the skin).
[1] Biogen also asserted that Mylan was under a heightened burden of proof because the Patent Office had addressed the written description requirement during prosecution and issued the '514 patent when Biogen successfully overcame this ground of rejection. This argument was particularly unavailing: the District Court rejected it out of hand.
