By Kevin E. Noonan –

Last month, the Federal Circuit rendered a decision in Amgen Inc. v. Sanofi that brought clarity to how the Court (and U.S. Patent and Trademark Office) should apply the written description requirement in 35 U.S.C. § 112(a) to properly circumscribe the scope of claims to monoclonal antibodies.  As a bonus, the panel opined on the relationship between the various requirements for a court to grant a permanent injunction when the infringing article comprises a medicine or other therapeutic agent.

Prior to the Supreme Court's recent focus on patent law questions (and the uncertainty and jurisprudential chaos that has arisen as a consequence), the Federal Circuit spent almost a decade refining the application of the written description requirement to biotechnology patent claims.  Arguably beginning with Amgen v. Chugai and Fiers v. Revel, the Court spoke most clearly in University of California v. Eli Lilly & Co.; this jurisprudence matured in University of Rochester v. G.D. Searle and Enzo Biochem v. GenProbe, culminating in the Court's Ariad v. Eli Lilly en banc decision that the written description and enablement requirements of 35 U.S.C. § 112, first paragraph (now, 35 U.S.C. § 112(a)), were separate and distinct and could be differentially satisfied on the same disclosure (i.e., enablement could be satisfied even though the written description requirement was not).

These cases arose from the complexities of assessing the sufficiency of disclosure for claims to isolated nucleic acids (including cDNA molecules that remain patent-eligible after AMP v. Myriad Genetics).  Another complex class of important biomolecules, antibodies and, in particular, monoclonal antibodies, have had a more murky course through § 112 jurisprudence; the issue in the few decided cases related to the requirements for producing humanized and ultimately human antibodies from (typically) mouse monoclonal progenitors rather than the scope of antibody claims as they relate to antigenic specificity.  The Federal Circuit's decision in this case provides some clarity in this regard.

The case arose when Amgen sued Sanofi over its sales of Praluent® (alirocumab) in competition with Amgen's Repatha™ (evolocumab); Amgen's asserted patents, U.S. Patent Nos. 8,829,165 ("'165 patent") and 8,859,741 ("'741 patent"), claim a genus of antibodies that encompass Sanofi's Praluent® product.  As background, blood plasma contains low-density lipoproteins that bind cholesterol and are associated with atherosclerotic plaque formation.  Liver cells express receptors for LDL (LDL-R) wherein binding thereto reduces the amount of LDL cholesterol in blood and reduces the risk of plaque formation and cardiovascular disease.  PCSK9 (proprotein convertase subtilisin kexin type 9) is a molecule that binds to and causes liver cell LDL-R to be destroyed, thus reducing the capacity and effectiveness of the liver cell's ability to reduce serum LDL-cholesterol.  The antibodies at issue in this suit bind to PCSK9 and prevent PCSK9 from binding to LDL-R, causing their destruction.

Claim 1 of the '165 patent is representative:

An isolated monoclonal antibody, wherein, when bound to PCSK9, the monoclonal antibody binds to at least one of the following residues: S153, I154, P155, R194, D238, A239, I369, S372, D374, C375, T377, C378, F379, V380, or S381 of SEQ ID NO:3, and wherein the monoclonal antibody blocks binding of PCSK9 to LDL[-]R.

It is important to note that, while reciting the structure of the residues on PCSK9 that are bound by the claimed antibody, the claim does not recite any structural limitations of the antibody.  The only antibody characteristic recited as a limitation is a functional one, i.e., the ability to bind (and not even specifically bind) to at least one of the recited PCSK9 residues.

Evidence at trial showed that Amgen had produced a plurality of anti-PCSK9 antibodies and screened them for the ability to inhibit PCSK9 binding to LDL-R in liver.  This screening was done using a "trial and error" process that reduced 3,000 human monoclonal antibodies down to 85 antibodies that "blocked interaction between the PCSK9 . . . and the LDLR [at] greater than 90%," of which the specification illustrated the three-dimensional binding arrangement for two (one of which became the Repatha™ antibody) by x-ray crystallography.  The specification of the Amgen patents in suit disclose amino acid sequence information for twenty-two human anti-PCSK9 antibodies able to compete for PCSK9 binding with these two more fully characterized antibodies.  Regeneron's patents (not at issue here) recited antibody-specific amino acid sequences for its claimed anti-PCSK9 antibodies.

The jury found Amgen's patents not to be invalid; Sanofi stipulated to infringement.  The District Court excluded Sanofi evidence relating to written description and enablement based on Praluent® and other post-priority-date antibodies (i.e., that were produced after Amgen's earliest priority date).  The District Court, relying on Noelle v. Lederman as precedent, instructed the jury that an applicant can be entitled to claim scope encompassing generically described antibodies (as was the case for Amgen's claims) provided that the applicant provided a full characterized, novel antigen:

In the case of a claim to antibodies, the correlation between structure and function may also be satisfied by the disclosure of a newly characterized antigen by its structure, formula, chemical name, or physical properties if you find that the level of skill and knowledge in the art of antibodies at the time of filing was such that production of antibodies against such an antigen was conventional or routine.

The District Court denied Sanofi's post-trial motion for judgment as a matter of law (JMOL) that Amgen's claims were invalid for failing the written description and enablement requirements of 35 U.S.C. § 112(a), and granted Amgen's motion for JMOL that the claims were non-obvious.  On this record, the District Court also granted Amgen a permanent injunction preventing Sanofi from selling Praluent® (which was stayed pending Sanofi's appeal).

The Federal Circuit reversed in part, affirmed in part, vacated in part, and remanded, in an opinion by Chief Judge Prost, joined by Judges Taranto and Hughes.  The opinion distinguishes two bases for a court to consider post-priority date evidence of failure to satisfy the written description requirement, and finds that the District Court misapplied the law in excluding Sanofi's evidence.  The first basis for considering evidence regarding written description is when the evidence is proffered to show whether there was sufficient disclosure in the specification as filed and for this purpose the panel states that post-priority date evidence is improper.  Here, Sanofi's evidence was proffered under the second basis, which is whether the specification discloses a representative number of species in a claimed genus.  For such purposes, the opinion held that post-priority evidence is admissible, because such evidence can show that the genus is sufficiently diverse that the number of species disclosed in the specification is not representative.  As set forth in Ariad, an adequate written description of a genus requires the specification to disclose "a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can 'visualize or recognize' the members of the genus."  The panel distinguished prior precedent cited by Amgen, including In re Koller, 613 F.2d 819, 825 (CCPA 1980), and In re Hogan, 559 F.2d 595, 605 (CCPA 1977), because those cases were directed to the first basis for evaluating whether a specification satisfies the written description requirement.  (Another reason is that the second basis recognized by the opinion is arguably a creation of the Federal Circuit's more recent written description jurisprudence.)

The opinion acknowledges that the Court has not directly addressed this application of the law to date, but finds it to be consistent with the Court's earlier decision in AbbVie Deutschland GmbH & Co. v. Janssen Biotech, Inc., 759 F.3d 1285 (Fed. Cir. 2014).  In AbbVie, the accused infringer used evidence from its own, later-developed antibodies to show that patentee AbbVie's claims were not supported by an adequate written description of a representative number of species within the claimed antibody genus (although, as the opinion admits, defendant's antibody "was a basis for the unrepresentativeness ruling without regard to whether it postdated the patent's priority date").  With regard to the Hogan precedent (which is binding on Federal Circuit panel opinions unless overturned by the en banc Court), the opinion states that "Appellees misread In re Hogan by conflating the difference between post-priority-date evidence proffered to illuminate the post-priority-date state of the art, which is improper, with post-priority-date evidence proffered to show that a patent fails to disclose a representative number of species.  In re Hogan prohibits the former but is silent with respect to the latter."  Hogan was based on the USPTO requiring an applicant to disclose at an application's filing date species that did not exist at that time.  The panel understood that not to be analogous to the case before it, and stated that as a consequence, the District Court's exclusion of Sanofi's evidence relating to whether Amgen's specification disclosed a representative number of species was error.  The Court remanded the matter to the District Court for a new trial on this issue.

The Court also found it to be error for the District Court to have excluded evidence regarding enablement on the same grounds.  This evidence related to the "lengthy and potentially undue experimentation" Amgen needed to employ to arrive at its antibodies that fell within the scope of the claims of the '165 and '741 patents.  This was relevant evidence not barred by its post-priority date origins, and the panel remanded for a new trial on enablement in light of this evidence.

Perhaps the most significant portion of the opinion involves the jury instructions, which relied on Noelle v. Lederman for the proposition that characterizing a new antigen was sufficient to satisfy the statute for claims encompassing a broad genus of antibodies that could bind to the new antigen.  The panel found that this instruction "is not legally sound and [] not based on any binding precedent" and then provided its legal analysis of Enzo Biochem, Inc. v. Gen-Probe Inc., 323 F.3d 956 (Fed. Cir. 2002), Noelle v. Lederman, 355 F.3d 1343 (Fed. Cir. 2004), and Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341 (Fed. Cir. 2011) in support of its conclusion.

The basis for the instruction, according to the opinion, is in Guidelines from the USPTO discussed by the Court in the Enzo opinion.  There, the Court noted (in dicta, as characterized in this opinion), that the PTO would find claims to an antibody in compliance with Section 112 "notwithstanding the functional definition of the antibody, in light of the well-defined structural characteristics for the five classes of antibody, the functional characteristics of antibody binding, and the fact that the antibody technology is well developed and mature."  The decision in Noelle was actually contrary (the claims were not entitled to priority to an earlier application because that application did not disclose "the structural elements of the antibody or antigen") but (again in dicta) stated that "as long as an applicant has disclosed a 'fully characterized antigen,' either by its structure, formula, chemical name, or physical properties, or by depositing the protein in a public depository, the applicant can then claim an antibody by its binding affinity to that described antigen" based on the Court's Enzo decision.  Finally, in Centocor, the Court questioned the interpretation of its precedent that, as Amgen did here, an applicant was entitled to a broad claim based solely on functional properties (e.g., binding affinity or specificity) provided that the applicant provided a fully characterized, novel antigen.  As expressed in Centocor, one basis for skepticism over the "fully characterized antigen" test advocated there and here (by Amgen) was that instead of "analogizing the antibody-antigen relationship to a 'key in a lock,' it was more apt to analogize it to a lock and 'a ring with a million keys on it" (italics in opinion).  The panel emphasized that because the written description requirement is a question of fact, the value of these cases as precedent is "extremely limited."

The panel held this instruction to be improper because it effectively eliminated the written description requirement from the statute in favor of enablement, contrary to the Court's en banc Ariad decision, stating that "[b]y permitting a finding of adequate written description merely from a finding of ability to make and use, the challenged sentence of the jury instruction in this case ran afoul of what is perhaps the core ruling of Ariad."  And the panel found that whether the relationship between the structure of the antigen, no matter how fully characterized, and any of its cognate antibodies is (here and hitherto) "hotly contested" which precluded the Court from making any definitive finding.  The panel recited its abrogation of the "fully characterized antigen" test more directly:

Further, the "newly characterized antigen" test flouts basic legal principles of the written description requirement.  Section 112 requires a "written description of the invention."  But this test allows patentees to claim antibodies by describing something that is not the invention, i.e., the antigen.  The test thus contradicts the statutory "quid pro quo" of the patent system where "one describes an invention, and, if the law's other requirements are met, one obtains a patent."  Indeed, we have generally eschewed judicial exceptions to the written description requirement based on the subject matter of the claims [citations omitted].

For the same reasons the opinion affirmed the District Court's denial of JMOL that Amgen's claims lack written description and enablement, in favor of those questions being decided on remand based on the facts properly permitted to be considered by the jury.

Turning to the grounds for granting Amgen a permanent injunction, the panel found error in how the District Court applied the standards enunciated by the Supreme Court in eBay, Inc. v. MercExchange, L.L.C., 547 U.S. 388 (2006):

[A] plaintiff seeking a permanent injunction must satisfy a four-factor test before a court may grant such relief.  A plaintiff must demonstrate: (1) that it has suffered an irreparable injury; (2) that remedies available at law, such as monetary damages, are inadequate to compensate for that injury; (3) that, considering the balance of hardships between the plaintiff and defendant, a remedy in equity is warranted; and (4) that the public interest would not be disserved by a permanent injunction.  Id. at 391 (emphases added).

Here, the District Court granted the injunction despite finding that an injunction would "disserve" the public interest in the absence of plaintiff Amgen refuting this conclusion.  The panel's plain reading of the Supreme Court's mandate held this to be error.  In addition, the panel held to be error the District Court's finding that the public interest would be disserved because the effect of the injunction would be to ""tak[e] an independently developed, helpful drug off the market."  According to the opinion, using this standard a court would never be able to enjoin an infringing drug product because that would always involve taking a helpful drug off the market, contrary to both eBay and 35 U.S.C. § 271(e)(4)(B), citing WBIP, LLC v. Kohler Co., 829 F.3d 1317 (Fed. Cir. 2016).

This case is the latest application of the Federal Circuit's written description doctrine, which is one of the few areas that the Supreme Court has not found it fit to question the Court's application of U.S. patent law.  On the one hand this is curious, because written description is perhaps the preeminent example of the Federal Circuit exercising its special expertise and Congressional mandate to provide a harmonized interpretation of patent law.  On the other hand, how the Federal Circuit has developed this area of the law has (generally) limited the scope of biotechnology patent claims, consistent with the Supreme Court's penchant for treating the patent grant parsimoniously.  In any case, this decision makes the application of the written description requirement as applied to antibody claims more consistent with how the Court has applied § 112 to other biotechnological inventions and thus is in keeping with past twenty years of the Court's jurisprudence.  It is also more congruent with how the technology has developed since monoclonal antibodies were first disclosed (but not patented) by Kohler and Milstein in 1973.  If such consistency is the proper role of the Federal Circuit, then this decision is an exemplar of it fulfilling that role.

Amgen Inc. v. Sanofi (Fed. Cir. 2017)
Panel:  Chief Judge Prost and Circuit Judges Taranto and Hughes
Opinion by Chief Judge Prost