The Federal Circuit issued three decisions on Monday relating to Eli Lilly & Co's. challenge in separate inter partes review proceedings on obviousness grounds of nine patents licensed by Teva Pharmaceuticals Int'l, with disparate results.
The patents were related to humanized monoclonal antibodies immunologically specific for calcitonin gene-related peptide (CGRP), for treatment of "all forms of vascular headache, including migraines"; each party marketed a product for this purpose (Teva's AJOVY® and Lilly's Emgality®). The appeals clustered separate but related IPR proceedings that the Board had combined for oral argument. In the first of these (as considered here), Eli Lilly & Co. v. Teva Pharmaceuticals Int'l GmbH, Lilly appealed the Board's decision that it had failed to show that challenged claims 1, 3, 4, 8–17, 19, 20, and 24–31 of U.S. Patent No. 8,586,045, claims 1–18 of U.S. Patent No. 9,884,907, and claims 1–18 of U.S. Patent No. 9,884,908 were obvious. Representative claims from each patent are:
The '045 patent:
1. A method for reducing incidence of or treating at least one vasomotor symptom in an individual, comprising administering to the individual an effective amount of an anti-CGRP antagonist anti-body, wherein said anti-CGRP antagonist antibody is a human monoclonal antibody or a humanized monoclonal antibody.
The '907 patent:
1. A method for treating headache in an individual, comprising:
administering to the individual an effective amount of a humanized monoclonal anti-Calcitonin Gene-Related Peptide (CGRP) antagonist antibody, comprising:
two human IgG heavy chains, each heavy chain comprising three complementarity determining regions (CDRs) and four framework regions, wherein portions of the two heavy chains together form an Fc region; and
two light chains, each light chain comprising three CDRs and four framework regions;
wherein the CDRs impart to the antibody specific binding to a CGRP consisting of amino acid residues 1 to 37 of SEQ ID NO:15 or SEQ ID NO:43.
The '908 patent:
1. A method for treating headache in an individual, comprising:
administering to the individual an effective amount of a humanized monoclonal anti-Calcitonin Gene-Related Peptide (CGRP) antagonist antibody, comprising:
two human IgG heavy chains, each heavy chain comprising three complementarity determining regions (CDRs) and four framework regions, wherein portions of the two heavy chains together form an Fc region; and
two light chains, each light chain comprising three CDRs and four framework regions;
wherein the CDRs impart to the antibody specific binding to a CGRP consisting of amino acid residues 1 to 37 of SEQ ID NO:15 or SEQ ID NO: 43, and wherein the antibody binds to the CGRP with a binding affinity (KD) of about 10 nM or less as measured by surface plasmon resonance at 37o C.
Lilly asserted three prior art references in support of its obviousness challenge:
• Olesen et al., "Calcitonin Gene-Related Peptide Receptor Antagonist BIBN 4096 BS for the Acute Treatment of Migraine," N. ENG. J. MED. 350: 1104–10 (2004), which taught treatment of migraine with CGRP receptor antagonist.
• Tan et al., "Calcitonin gene-related peptide as an endogenous vasodilator: immunoblockade studies in vivo with an anti-calcitonin gene-related peptide monoclonal antibody and its Fab' fragment," 89 CLINICAL SCI. 6: 565–73 (1995), which taught using full-length anti-CGRP mAb to block CGRP binding to its receptor in rats.
• U.S. Patent No. 6,180,370, which is a general reference teaching use of "recombinant DNA and monoclonal antibody technologies for developing novel therapeutic agents."
The Board rendered its decision that Lilly failed to show the challenged claims were obvious over this art. This decision depended in part of its claim construction wherein the preambles of each of the challenged claims constituted a "statement of intended purpose" and were limiting to that extent, which thus raised in Lilly the burden of showing that the skilled worker would have had a reasonable expectation of success in achieving this intended purpose. In a bit of circular reasoning, the Board construed the claim term "effective amount" to be the amount that would achieve this preamble purpose of a beneficial result but not a clinical result (i.e., of treating migraine).
The Board found the cited art taught each and every one of the limitations recited in the claims, and the skilled artisan would have been motivated to combine the teachings in the cited art and that safety concerns would not have deterred, discouraged, or taught away from pursuing" the invention. But Lilly failed to show a reasonable expectation of success in the Board's opinion, including that the blood-brain barrier "raised uncertainty, unpredictability, and skepticism in using full-length anti-CGRP antibodies" therapeutically. This was enough to defeat obviousness for these method claims, which the panel stated was consistent with Honeywell International Inc. v. Mexichem Amanco Holdings S.A. DE C.V., 865 F.3d 1348, 1356 (Fed. Cir. 2017), and were analogous to Novartis Pharmaceuticals Corp. v. West-Ward Pharmaceuticals International Ltd., 923 F.3d 1051 (Fed. Cir. 2019).
The Federal Circuit affirmed in a decision (as all three decisions were) by Judge Lourie joined by Judges Bryson and O'Malley. On appeal, Lilly raised two arguments. First, that the Board's claim construction was in error for interpreting the preambles to require a beneficial result that was related to the construction of "effective amount." Second, Lilly argued the Board's standard for reasonable expectation of success was improperly high.
With regard to claim construction, the panel agreed with Teva that the Board properly construed the preambles to be limiting. Specific to the facts in each case, as it must be under Storage Tech. Corp. v. Cisco Sys., Inc., 329 F.3d 823, 831 (Fed. Cir. 2003), here the panel held that in this case, the claims were directed to methods for achieving a particular purpose, i.e., "treating or reducing the incidence of vasomotor symptoms, and the method comprises a single step of administering an effective amount of a composition, namely, a humanized anti-CGRP antagonist antibody." The panel recognized the contrast between method claims such as these and composition of matter or apparatus claims, which are directed to what the claimed invention is rather than what it does, citing Hewlett-Packard Co. v. Bausch & Lomb Inc., 909 F.2d 1464, 1468 (Fed. Cir 1990); Cochlear Bone Anchored Solutions AB v. Oticon Med. AB, 958 F.3d 1348, 1355 (Fed. Cir. 2020); Boehringer Ingelheim Vetmedica, Inc. v. Schering-Plough Corp., 320 F.3d 1339, 1345 (Fed. Cir. 2003); and Jansen v. Rexall Sundown, Inc., 342 F.3d 1329, 1333 (Fed. Cir. 2003). The Board's construction with regard to the limiting nature of the preambles satisfied the "essence of the claimed invention" requirement and thus was proper. Recitation of the affirmative limitation of an "effective amount" raised the question of an "effective amount" to do what according to the opinion, which is to achieve the purpose recited in the preamble (the opinion calls this "the only metric by which one practicing the claim could determine whether the amount administered is an 'effective amount'"). The specification defined this amount to be "an amount sufficient to effect beneficial or desired results" and further the specification contained "extensive discussions of such treatment in every section of the patent[]," according to the opinion. Under these circumstances the panel held that the preamble thus gives "life and meaning" to the claimed methods and is thus properly construed to be limiting. And the panel further recognized that the preamble also provides antecedent basis for reciting "an individual" in the affirmative limitations recited in the claim, distinguishing Cochlear because that was an apparatus claim and method claims were at issue here.
Turning to reasonable expectation of success, the panel pointed out that the Board's finding of sufficient motivation to combine does not necessarily satisfy the reasonable expectation of success standard, citing Procter & Gamble Co. v. Teva Pharms. USA, Inc., 566 F.3d 989, 994 (Fed. Cir. 2009), and in particular Novartis Pharmaceuticals Corp. v. West-Ward Pharmaceuticals International Ltd., 923 F.3d 1051 (Fed. Cir. 2019). The Court found the claims here to be analogous to those in WestWard, where despite there being motivation to combine, the biology involved was sufficiently uncertain and unpredictable for there to be no reasonable expectation of success. Because the limitations in the preamble were properly construed by the Board to require successful methods of treatment, these limitations informed the expectation of success argument as to what is expected and what constitutes success according to the Court.
This understanding by the Board as supported by definition in specification according to the opinion:
As is understood by those skilled in the art, individuals may vary in terms of their response to treatment, and, as such, for example, a "method of reducing incidence of headache in an individual" reflects administering the anti-CGRP antagonist antibody based on a reasonable expectation that such administration may likely cause such a reduction in incidence in that particular individual.
The expectation was not based on a requirement for clinical data (which Lilly argued) and not supported by "isolated, out-of-context statements plucked from dozens of pages of the Board's factual findings" by Lilly. As in the Court's decision in Sanofi v. Watson Labs. Inc., 875 F.3d 636, 647 (Fed. Cir. 2017), the panel "decline[d] to infer a demand for data from the Board's observation that references did not include those data." The substantial evidence standard merited the panel's deference to the Board's conclusion that Lilly had not shown a reasonable expectation of success for the challenged method claims.
The Court also rejected Lilly's challenge of error based on considerations of the blood-brain barrier and whether uncertainty regarding the capacity for the claimed antibodies to traverse this natural barrier. Lilly argued that the prior art showed some evidence for migraine relief in the absence of crossing the blood-brain barrier, and thus that any basis by the Board for finding no reasonable expectation of success of this basis as error. The Court focused on the uncertainty of whether the antibody therapeutic used in the claimed method would actually cross the blood-brain barrier or would need to do so to provide a beneficial effect. The Court held that Lilly bore the burden of establishing a reasonable expectation of success which under the facts considered by the Board it did not do.
The second appeal, Teva Pharmaceuticals Int'l GmbH v. Eli Lilly & Co., was directed to the Board's finding that claims to anti-CGRP monoclonal antibodies were obvious. The claims challenged by Lilly in these IPRs were claims 1–7 and 15–20 of U.S. Patent No. 9,340,614, claims 1–6 and 14–19 of U.S. Patent No. 9,266,951, and claims 1–5 of U.S. Patent No. 9,890,210. The following claims are representative:
The '614 patent:
1. A human or humanized monoclonal anti-CGRP antagonist antibody that preferentially binds to human α-CGRP as compared to amylin.
The '951 patent:
1. A human or humanized monoclonal anti-CGRP antagonist antibody that (1) binds human α-CGRP and (2) inhibits cyclic adenosine monophosphate (cAMP) activation in cells.
The '210 patent:
1. A humanized monoclonal anti-Calcitonin Gene-Related Peptide (CGRP) antagonist anti-body, comprising:
two human IgG heavy chains, each heavy chain comprising three complementarity determining regions (CDRs) and four framework regions, wherein portions of the two heavy chains together form an Fc region; and
two light chains, each light chain comprising three CDRs and four framework regions;
wherein the CDRs impart to the antibody specific binding to a CGRP consisting of amino acid residues 1 to 37 of SEQ ID NO:15 or SEQ ID NO:43.
Lilly asserted these prior art references in support of its obviousness challenge in these IPRs:
• Tan et al., "Calcitonin gene-related peptide as an endogenous vasodilator: immunoblockade studies in vivo with an anti-calcitonin gene-related peptide monoclonal antibody and its Fab' fragment," 89 CLINICAL SCI. 6: 565–73 (1995), which taught using full-length anti-CGRP mAb to block CGRP binding to its receptor in rats.
• Wimalawansa, "Calcitonin Gene-Related Pep-tide and its Receptors: Molecular Genetics, Physiology, Pathophysiology, and Therapeutic Potentials," 17 ENDOCRINE REVIEWS 5: 533–85 (1996), which is a review article regarding CGRP, its structure and effects, as well as possible uses for agonists and antagonists.
• U.S. Patent No. 6,180,370, which is a general reference teaching use of "recombinant DNA and monoclonal antibody technologies for developing novel therapeutic agents."
The Board found the skilled worker would have both a reason to combine these teachings to achieve the claimed invention and have had a reasonable expectation of success in finding the claims obvious. The Board based its decision on the existence of anti-CGRP mAbs from other species, which would have provided sufficient motivation for the skilled worker to make humanized counterparts, and for the reasonable expectation of success that the claims recited no limitations regarding safety or efficacy for any intended purpose (in this way differing from the method claims the Board found not to be obvious over the same or related art as discusses above). On this basis, the Board rejected Teva's argument that Lilly had a burden of establishing a reasonable expectation from the cited art for treating any disease or condition.
(In a side note, Teva had challenged the Board's decision based on the purported unconstitutionality of the APJs under the Court's decision in Arthrex, Inc. v. Smith & Nephew, Inc., 941 F.3d 1320 (Fed. Cir. 2019). After the Supreme Court's decision in United States v. Arthrex, Inc., 141 S. Ct. 1970 (2021), during the pendency of this appeal, the panel gave Teva the choice of a hearing on the merits of the appeal or request for an immediate remand to the Board for resolution of the Arthrex question. Teva chose this appeal on the merits, and the Federal Circuit's opinion followed.)
The Federal Circuit affirmed, in an opinion by Judge Lourie joined by Judges Bryson and O'Malley. The panel rejected Teva's argument that the Board erred in finding a motivation and basis for the skilled worker to combine the cited art that differed from what Lilly had argued in this regard. The difference, Teva maintained, was that under Lilly's purported argument there would need to be a therapeutic aim implicating safety and efficacy for the claimed anti-CGRP antibodies while in the Board's consideration did not. The Federal Circuit agreed with the Board that this was not a case where the Board "deviate[d] from the grounds in the petition and raise its own obviousness theory," citing Sirona Dental Sys. GmbH v. Institut Straumann AG, 892 F.3d 1349, 1356 (Fed. Cir. 2018). In a nuanced argument, the panel found that the Board's appreciation of the motivation to make the claimed antibodies was to make humanized antibodies for treating human disease, based on "[c]ommon sense and scientific reality." But the needed motivation was to make the antibodies not to use the antibodies to treat disease. For the panel, "the relevant inquiry—which the Board extensively analyzed—is whether those [safety and efficacy] concerns would have dissuaded a skilled artisan from making the claimed antibodies to study their therapeutic potential in the first place." That not being the case, the panel held that the Board had properly considered and was convinced by Lilly's evidence for a motivation to combine sufficient to support the Board's obviousness determination. The panel noted that the Board had not disregarded Teva's arguments regarding safety and efficacy, according to the opinion; rather, it had considered the evidence in making a factual finding supported by substantial evidence to which the Court was obligated to defer.
Teva also argued more specifically that the Board had relied upon "unsupported interpretations of isolated statements in the prior art to find a motivation to study or use humanized anti-CGRP antibodies." The panel noted that Lilly provided evidence, including expert testimony, to the contrary. But the basis for the Court's rejection of Teva's arguments is that "[b]ut what a piece of prior art teaches presents a question of fact that is reviewed for substantial evidence," citing In re Warsaw Orthopedic, Inc., 832 F.3d 1327, 1332 (Fed. Cir. 2016), and In re Gartside, 203 F.3d 1305, 1316 (Fed. Cir. 2000). Under this deferential review, the panel held that the Board did not err in finding a reasoned basis for the skilled worker to combine the references.
The panel also considered and rejected Teva's arguments that the Board's determination that Teva's evidence for secondary considerations (or objective indicia) of non-obviousness failed due to a lack of nexus between the evidence and the claimed invention. This evidence was related to both Teva's own (AJOVY®) and Lilly's (Emgality®) anti-CGRP mAb products with regard to "industry-wide acclaim, satisfied a long-felt need, achieved unexpected results, faced industry skepticism, and achieved commercial success" (i.e., almost all the secondary considerations), as well as licenses with third parties for its products falling within the scope of the claims. With regard to the Board's lack-of-nexus determination, the panel acknowledged the presumption that a nexus exists if tied to a specific product "that is the invention disclosed and claimed," under Fox Factory, Inc. v. SRAM, LLC, 944 F.3d 1366 (Fed. Cir. 2019). However, under certain circumstances there can be unclaimed features of such a commercial product along a continuum that can affect the nexus determination under this precedent. Although the Court found that the "rule" the Board distilled from the Court's precedent was flawed and error, the panel held that the Board nevertheless conducted the proper nexus assessment in finding Teva was not entitled to the nexus presumption that can attach to a successful commercial product and that its error was thus harmless. That assessment was consistent with the Court's rubrics set forth in Immunex Corp. v. Sandoz Inc., 964 F.3d 1049, 1067–68 (Fed. Cir. 2020), in the distinctions the panel appreciates between this invention and the one in Immunex. In that case, the antibodies were disclosed and claimed based on structure whereas here they are claimed with regard to their function. The Court cited its decision in Amgen Inc. v. Sanofi, 987 F.3d 1080, 1087 (Fed. Cir. 2021) (acknowledging in a footnote that the Amgen decision was rooted in Section 112 considerations), that antibodies claimed by function can be broad (or overbroad) because they do not define antibodies falling within the scope of the claims by structural limitations. As a result, the panel opined that "[a] claim to 'anything that works' hardly has a nexus to any particular product." Once again, the panel found that the Board's factual determinations were sufficient to support by substantial evidence its determination that there was a lack of nexus here between the parties' commercial products and the claimed invention.
The panel also rejected Teva's arguments that the third party licenses were sufficient to show the required nexus. This decision rested on those licenses encompassing 188 patents (including the ones at issue here) and that the royalty obligations did not depend on whether these patents were invalidated or not.
The final decision, Teva Pharmaceuticals Int'l GmbH v. Eli Lilly & Co., was the only non-precedential decision and was directed to the Board's determination that the challenged claims of Teva's U.S. Patents 9,346,881, 9,890,211, and 8,597,649 were obvious. In a summary opinion by Judge Lourie joined by Judges Bryson and O'Malley, the Court affirmed the Board's obviousness determination, substituting any detailed explication of the Board's decision and the panel's own rationale by stating:
In the two consolidated appeals, the parties made substantively identical arguments, mostly copied and pasted verbatim from one case to the other. Teva included the following footnote in its opening brief:
In a second decision issued the same day, the Board also held unpatentable the challenged claims of three related composition patents. That decision, which is materially identical in reasoning, is the subject of Teva's companion appeal no. 20-1747. Teva's arguments in the two appeals are the same . . . [emphasis in opinion].
Lilly, not disagreeing with this sentiment, the panel asserted that "[d]uring the combined oral argument in the two consolidated appeals, neither party argued that any one of the six appeals should be decided differently from the others." Accordingly, the Court based this opinion on its opinion affirming the Board's obviousness determination in Teva's other appeal of rejection of its monoclonal antibody claims.
Teva Pharmaceuticals Int'l GmbH v. Eli Lilly & Co. (Fed. Cir. 2021)
Panel: Circuit Judges Lourie, Bryson, and O'Malley
Opinion by Circuit Judge Lourie
Eli Lilly & Co. v. Teva Pharmaceuticals Int'l GmbH (Fed. Cir. 2021)
Panel: Circuit Judges Lourie, Bryson, and O'Malley
Opinion by Circuit Judge Lourie
Teva Pharmaceuticals Int'l GmbH v. Eli Lilly & Co. (Fed. Cir. 2021)
Panel: Circuit Judges Lourie, Bryson, and O'Malley
Opinion by Circuit Judge Lourie
