Biogen Int'l GmbH v. Mylan Pharmaceuticals Inc. (Fed. Cir. 2021)

McDonnell Boehnen Hulbert & Berghoff LLP

McDonnell Boehnen Hulbert & Berghoff LLP

As is well-known, Congress established the Federal Circuit as a circuit court of appeals to harmonize U.S. patent law in an environment where regional Circuit Courts had developed their own judicial interpretations of the patent statute.  As a consequence, it was often to a party's benefit to choose to litigate in a Circuit where the law was favorable to their case.  The resulting disharmony was occasionally and variably corrected by the Supreme Court, but Congress perceived the High Court's capacity or concentration on patent law to be insufficient to the country's needs for consistent application in this area of the law.  For a generation, the Federal Circuit was able, with little interference from the Supreme Court, to create the harmony Congress mandated, assisted by judges who understood the law and the precedential roots thereof (as well as understanding Congress's mandate and the need to doctrinal consistency).  Recently, however, the Court seems to have morphed (along with the composition of the judges) into a soi-disant court of equity, more concerned with doing what at least two judges on any particular panel have been convinced to believe is "the right thing" (for the parties or the law) than with ruling consistently with the Court's precedent.  And that tendency (which could be termed "equity creep") explains in part the Court majority's decision in Biogen Int'l GmbH v. Mylan Pharmaceuticals Inc. and Judge O'Malley's vigorous and cogent dissent.

To briefly recapitulate proceedings before the District Court, 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.

(Wherein the italicized limitation was the entirety of the basis for the District Court's decision and the Federal Circuit majority's affirmance.)

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 the District 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 specification 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, Dr. Lukashev, 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].'"  Dr. Lukashev was the only named inventor on the earliest 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.  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 in doing so, which permitted it to rely on a February 8, 2007 earliest priority date.

Mylan's position 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."

The District Court held that the '514 specification failed to satisfy the written description requirement because it did not show that the inventors possessed the invention on its earliest claimed priority date.  The Court noted that in the '514 specification only the first of its 30 columns focused on MS and that only one of the five methods expressly disclosed in the '514 specification was directed to treating a neurological disease by administering to the subject in need thereof at least one compound that is partially structurally similar to DMF (or a closely related compound, monomethylfumate).  The District Court understood even 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 District Court cited "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 to the contrary in this regard.  The Court focused on the fact that the specification mentioned the 480 mg/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.  And 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 was clearly persuaded by Mylan's expert.

From the evidence presented at trial, the District Court found that "[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 stated that "the Federal Circuit has clearly rejected" the approach Biogen has taken.  Biogen appealed.

The Federal Circuit affirmed, in an opinion by Judge Reyna joined by Judge Hughes, with Judge O'Malley (the only Federal Circuit judge who had also been a district court judge) dissenting.  A good portion of the majority opinion is devoted to an explication of the scientific background of MS, the procedural mechanics of Hatch-Waxman litigation, and a primer on the Court's written description jurisprudence.  The majority is cognizant (and applies partly in justification) of the high burden Biogen has to show clear error by the District Court over the factual issues underlying its determination that the '514 patent does not satisfy the written description requirement.  But in explicating its reasons for affirmance, the majority indicates it believes that Biogen did what the District Court determined, "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."

In this vein, the opinion states that the specification "casts a wide net for a myriad of neurological disorders, including neuro-degenerative diseases such as amyotrophic lateral sclerosis (ALS), Parkinson's disease, Alzheimer's disease, and Huntington's disease; demyelinating neurological diseases, such as various forms of MS and at least twenty-eight other disorders related to demyelination; polyneuritis; and mitochondrial disorders with demyelination" (Judge O'Malley terms this type of disclosure "laundry list").  The Court further enunciates a repeated enumeration of how many times the specification mentions MS, DMF, and the 480 mg/day dose (tellingly, exactly once, where once for the majority is clearly not enough), saying "consistent with the disclosure's original title concerning Nrf2 screening, the totality of the specification focuses primarily on drug discovery," the majority noting in conjunction with this statement that "[i]ndeed, the invention's title was only amended to "Treatment for Multiple Sclerosis" in 2011 after Biogen acquired Phase III clinical data for the use of DMF480 in treating MS."

Focusing on Example 4 (which the majority and dissent, as well as the District Court, recognized is the portion of the specification most closely related to using DMF to treat MS), the majority opinion sets forth the one paragraph of the specification that "teach[es] potential dosage levels for DMF monotherapy":

Effective doses will also vary, as recognized by those skilled in the art, dependent on route of administration, excipient usage, and the possibility of co-usage with other therapeutic treatments including use of other therapeutic agents.  For example, an effective dose of DMF or MM[F] to be administered to a subject orally can be from about 0.1 g to 1 g per pay, 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 [emphasis in opinion].

In this context the panel majority further recognizes "two crucial aspects of the invention":

First, the above paragraph features the one and only reference to DMF480 in the entire specification, which puts the DMF480 dose that the '514 Patent claims at the bottom end of the spectrum of a DMF 480–720 mg/day range.  Second, the specification defines the term "effective" within a therapeutic, rather than drug-discovery, context.  Thus, according to the specification, the terms "'therapeutically effective dose' and 'therapeutically effective amount' refer to that amount of a compound which results in at least one of prevention or delay of onset or amelioration of symptoms of a neurological disorder in a subject or an attainment of a desired biological outcome, such as reduced neurodegeneration (e.g., de-myelination, axonal loss, and neuronal death) or reduced inflammation of the cells of the CNS" [emphasis in opinion].

(The second aspect the majority finds "crucial" is an important, factual source of Judge O'Malley's disagreement with her brethren and the District Court.)

The majority opinion is replete with instances showing the influence of the history of the development of the claimed invention (and their implied suspicions about its origins) had on their opinion (including, inter alia, mention of Biogen adding as an inventor the clinical scientist who advocated for the 480 mg/day dose and his exclusion in the application originally filed in favor of a laboratory, not clinical, scientist who was involved in developing methods for identifying compounds that acted on biological basis for MS, the Nrf2 pathway).  Also important for the majority are the facts that by naming this scientist as an inventor they were able to "claim a priority date of February 8, 2007, despite filing wholly new claims alongside the [inventorship] amendments."

On the law, the majority is willing to concede that "assuming that a skilled artisan would understand the disclosure to be unambiguously focused on MS despite its inclusion among approximately three-dozen neurological disorders—a determination we need not reach in this case—the specification may arguably provide adequate information to convey to a skilled artisan that the invention supports method-of-treatment claims directed to MS and, perhaps, that the use of DMF may be therapeutically linked to MS treatment" (although in a footnote the majority note that the only method directed to the claimed invention "is devoid of any specific reference to MS").

But the apparently important point for the majority is the disclosure in the specification of dosage amount.  Here, the majority agrees with the District Court (or is unwilling to find clear error in its determination) that "[t]he DMF480 dose is listed only once in the entire specification."  From this (and the more extensive disclosure of ranges of DNF dosages and 720 mg/day dosage in particular) the majority opine that "the specification's focus on basic research and broad DMF-dosage ranges show that the inventors did not possess a therapeutically effective DMF480 dose at the time of filing in 2007."  This assessment was supported, according to the majority, by Dr. Lukashev's testimony regarding the extent to which (i.e., none) his research could be used to arrive at the 480 mg/day dose (despite the majority's recognition that Dr. Lukashev was not a clinical scientist).

According to the majority, "[w]hat matters for purposes of the inquiry in this case is whether, at the time of filing the disclosure—well before the Phase III study 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."

As set forth above, it is a fact that the application resulting in the '514 patent was filed before the clinical trials that established that the 480 mg/day dose was clinically effective at ameliorating the symptoms of MS.  It is also the case that the original focus of the claims was not directed to this dose (indeed, those claims were directed to methods for finding a therapeutically effective dose), and this temporal disjunction inter alia (vide infra) created the impression at the District Court and perhaps for the majority that Biogen was not entitled to claims reciting this dose.

At the end of the opinion the majority broaches the issue upon which Judge O'Malley bases her dissent:

Based on the record, including at least the specification's definition of a "therapeutically effective dose" and the witness and expert testimony, the district court did not find it necessary to distinguish between therapeutic effects and clinical efficacy with respect to its patentability determination, instead electing to consider both under the specification's definition of "therapeutically effective dose."  We determine that such a finding was not clearly erroneous.

This is where Judge O'Malley believes the majority and the District Court got off on the wrong foot as a "threshold error" that the majority dismisses in error.  The District Court's error (an "original sin" in the dissent) was its decision to hold Biogen judicially estopped from making a distinction between clinical efficacy and therapeutic effects, based on positions that party took in the inter partes review instituted by Mylan on obviousness (where Biogen prevailed; in a companion, nonprecedential opinion the Court affirmed the PTAB decision without analysis in view of their precedential decision here) regarding whether a POSA would have had a reasonable expectation of success in achieving the claimed invention.

The basis for that error was, according to Judge O'Malley, not appreciating that:

Clinical efficacy involves the type of scientific rigor associated with Phase III clinical trials: the investigative DMF480 dose must produce superior clinical endpoints to the standard of care for MS, Rebif®. Therapeutic effects, by contrast, "do not require efficacy on clinical endpoints or superior efficacy to existing drugs."  Id.  It, instead, "refer[s] to the amount of [DMF480] which results in . . . prevention or delay of onset or amelioration of symptoms of a neurological disorder" like MS [citations to the record omitted].

This distinction is important because failing to appreciate it, by the District Court and the majority, was the basis, in Judge O'Malley's view, of the determination that "the '514 patent lacked written description support because 'a person of ordinary skill in the art would not have a reasonable expectation that the 480 mg/day [DMF] dose would provide statistically significant and clinically meaningful effectiveness for treating MS.'"  But this is the case, as Biogen argued and Judge O'Malley agreed, only if the "claims required clinical efficacy" when instead they only covered therapeutic effects," i.e., a different albeit related property.  In addition to imposing judicial estopped in these circumstances being an abuse of discretion by the trial court under 4th Circuit law (in a two-sentence footnote in its opinion), Judge O'Malley takes recourse in Biogen's post-trial briefing for the nature of this error as a matter of fact.  For her dissent, Judge O'Malley argues that this error led to the District Court's next error, finding that the '514 patent claims were not supported by an adequate written description.  Because, according to Judge O'Malley, "the district court's refusal to acknowledge the difference between therapeutic and clinical effects evinces a fundamental misunderstanding of what is claimed" (emphasis in dissenting opinion).  Judge O'Malley supports her view with an explication of what the '514 specification says and how the specification uses the term "therapeutic efficacy," and how this definition is tied to just the type of "research" applications that seems to have disquieted the majority.  But both Biogen and Judge O'Malley have a point:  the written description begins and ends with the question, "a written description of what"? and that "what" is the claimed invention as the invention is claimed, i.e., the claim language (which, Judge O'Malley reminds us and the majority defines an invention as a "bedrock principle of patent law," citing Phillips v. AWH Corp., 415 F.3d 1303, 1312 (Fed. Cir. 2005) (en banc)).

According to Judge O'Malley, this conflation of therapeutic and clinical efficacy led the District Court, and the Federal Circuit majority, to improperly apply the Court's Nuvo Pharms. (Ireland) Designated Activity Co. v. Dr. Reddy's Lab'ys Inc., 923 F.3d 1368, 1377, 1381 (Fed. Cir. 2019), precedent.  Judge O'Malley states that "[t]he district court's reliance on Nuvo to conclude that Mylan could use Biogen's own obviousness defenses against it in the written description context is, therefore, legally erroneous" and this erroneous reading of Federal Circuit precedent was not something on which the Court needed to defer, its review of the District Court in this regard being de novo.

Judge O'Malley reaches a critical issue (otherwise unmentioned) when she discusses the question of whether Biogen provided sufficient "blaze marks" in its specification regarding the specific 480 mg/day dosage (which the District Court and the majority determined it did not), using the colorful imagery from In re Ruschig, 379 F.2d 990, 994–995 (C.C.P.A. 1967).  But this analytical tool "is not used in every case concerning written description," Judge O'Malley reminds us, but " instead[] provides a useful framework to analyze whether written description has been met in cases involving patents containing laundry list disclosures," citing Fujikawa v. Wattanasin, 93 F.3d 1559, 1571 (Fed. Cir. 1996).  Judge O'Malley's identification of the majority's error is relegated to a footnote (no. 4):

The majority's decision affirming the district court partially rests on the fact that the '514 patent only mentions the claimed DMF480 dose once.  . . .  But the majority cites no case law (and I know of none) for the proposition that the written description requirement demands that a patentee recite a claim element repeatedly to pass written description muster.  The majority does not, and cannot, deny that the claimed DMF480 dose is expressly disclosed.  To the extent the majority's opinion may be read to establish a requirement that a claim element must be disclosed multiple times, I dissent from that holding as well.

This is not a case where blaze marks are needed, according to Judge O'Malley, who states "[the specification] does not provide a laundry list disclosure of therapeutically effective doses" but rather provides "one range with the exact DMF 480 dose that is claimed" (emphasis in dissenting opinion) and thus blaze marks should not be required or an issue in deciding satisfaction of the written description requirement.

This portion of Judge O'Malley's dissent raises the issue in a way not otherwise addressed expressly in either opinion, but one that seems relevant to the Court's precedent and consideration of it in this case.  It has long been the case that claims must not need in haec verba support in the specification.  See, e.g., Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1352 (Fed. Cir. 2010) (en banc).  This decision, for the first time, may be one where claims that unambiguously have in haec verba support have been found not to satisfy the written description requirement.  As with many of the Court's precedents, the current Court seems to show in its opinions a slow, disquieting tendency to have them spread from the doctrinal boundaries to encompass more and more circumstances that, in past precedent would have been inconceivable.  This is an embodiment of a specialized patent court that it is not easy to appreciate Congress did not intend to create.

Biogen Int'l GmbH v. Mylan Pharmaceuticals Inc. (Fed. Cir. 2021)
Panel: Circuit Judges O'Malley, Reyna, and Hughes
Opinion by Circuit Judge Reyna; dissenting opinion by Circuit Judge O'Malley

Mylan Pharmaceuticals Inc. v. Biogen MA Inc. (Fed Cir. 2021)
Nonprecedential disposition
Panel: Circuit Judges O'Malley, Reyna, and Hughes
Opinion by Circuit Judge Reyna

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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