Must a "Human Antibody" Be Entirely Human? Or May It Also Be "Partially Human?"

October 16, 2020 – Article

This is a consolidated appeal from two Patent Trial and Appeal Board (“Board”) decisions in inter partes reviews (“IPRs”) of U.S. Patent 8,679,487 (“the ’487 patent”), owned by Immunex Corp. (“Immunex”). Sanofi-Aventis U.S. LLC, Genzyme Corp., and Regeneron Pharmaceuti-cals, Inc. (“Sanofi”) challenged the ’487 patent. The Board invalidated all challenged claims in IPR 2017-01884. Immunex appealed, contesting the construction of the claim term “human antibodies.” The Court of Appeals for the Federal Circuit (“the Court”) agreed with the Board’s claim construction and affirmed the invalidity decision.

The ’487 patent is directed to antibodies that bind to the human interleukin-4 (“IL-4”) receptor. The inhibition of the receptor is important for treating various inflammatory disorders, such as arthritis, dermatitis, and asthma. Claim 1 reads:

An isolated human antibody that competes with a reference antibody for binding to human IL-4 inter-leukin-4 (IL-4) receptor, wherein the light chain of said reference antibody comprises the amino acid sequence of SEQ ID NO:10 and the heavy chain of said reference antibody comprises the amino acid sequence of SEQ ID NO:12.

Central to the appeal was the parties’ dispute over the construction of the term “human antibody”, i.e. “in the context of this patent, must a “human antibody” be entirely human? Or may it also be ‘partially human,’ including ‘humanized’?”

Claim Construction Standard Dispute

The Court reviewed the Board’s claim construction under the broadest reasonable interpretation (BRI) standard. Specifically, at the Board after appellate briefing was complete, Immunex filed a terminal disclaimer with the USPTO, which was accepted and the patent expired on May 26, 2020, over two months before oral argument. Immunex requested to change the applicable claim construction standard to the Phillips standard. On appeal, the Court noted that today, in all newly filed IPRs, the Board applies the Phillips claim construction standard. Phillips v. AWH Corp., 415 F.3d 1303 (Fed. Cir. 2005) (en banc). When Sanofi filed its IPRs, the Board applied this standard only to expired patents (including when a patent expired on appeal and the patent’s term expired as expected and was not cut short by a litigant’s terminal disclaimer). The Court reminded that it shall review the decision from which an appeal is taken on the record before the PTO and noted that the Board refused to consider terminal disclaimers filed after the Board’s decision (“where the patentee shortened the term abruptly after the parties had already fully briefed claim construction under the BRI standard”) and applied the BRI standard. “In this situation, we do the same.”

Claim Interpretation Dispute under BRI

In “chimeric” antibodies, the constant regions tend to be human in origin, and the variable regions, including the CDRs, tend to be nonhuman, making the antibodies’ amino acid sequences mostly human in origin. In “humanized” antibodies, only the CDRs are nonhuman, where the antibodies’ amino acid sequences, including the portions responsible for immune reaction, are almost entirely human in origin.  Fully human antibodies can be made in which even the CDRs are human in origin. In the ‘487 patent, some of the disclosed embodiments are “partially human” and some are “completely human.” Among “partially human”, the specification specifically includes humanized and chimeric antibodies.

Immunex contended that the Board erred by construing the term “human antibody” to encompass not only “fully human” but also “partially human” antibodies. Claim 1 of the ’487 patent recites a “human antibody.” The Board determined that the BRI of “human antibody” “includes both fully human and partially human antibodies.” The Board’s construction included “humanized” antibodies. According to Immunex, however, “humanized” is not “human.” The Court disagreed with Immunex and agreed with the Board’s interpretation.

First, the Court turned to the intrinsic record and agreed that the intrinsic evidence support the correctness of the Board’s construction. The Court looked at the language of the claim itself and found that “nothing in the claim’s language restricts ‘human antibodies’ to those that are fully human.” The Court concluded that “[t]his is not surprising: antibodies, amid a rapidly evolving scientific background, are a frequent subject of claim-construction disputes that stretch beyond plain meaning. Nor is the claim context helpful, as the dependent claims provide no further guidance.” The Court consulted the rest of the intrinsic record and found no express definition of the contested term in the specification and that the usage of “human” throughout the specification confirmed its breadth. “The specification contrasts ‘partially human’ with ‘fully’ or ‘completely human.’” The Court reviewed various passages in the specification, e.g. “[a]ntibodies of the invention include, but are not limited to, partially human (preferably fully human) monoclonal antibodies” and “[t]he desired anti-bodies are at least partially human, and preferably fully human” and agreed that the specification makes clear that “human antibodies” is a broad category and includes both partially and completely human antibodies. “The specification also repeatedly clarifies that some ‘human’ antibodies are ‘fully human’” and this usage confirmed that a reader would take “human monoclonal antibodies” to be broader. “Consistent with this usage, the abstract and the summary each simply refer to ‘human’ antibodies.” The Court agreed that the language of the specification confirms a broadest reasonable interpretation of “human antibodies” “that includes those that are partially human—including ‘humanized’ antibodies.”

The Court next turned to the prosecution history, which is “relevant and informative”, and agreed that it supported the Board’s construction. Immunex used both “fully human” and “human” within the same claim set in another patent application in the same family. “[T]he prosecution of related patents may be relevant to the construction of a given claim term.” Immunex provided no convincing explanation for its simultaneous use of the two terms “beyond what is apparent: they are not interchangeable.” The Court reminded that “there is a strong presumption against a claim construction that excludes a disclosed embodiment.” Nobel Biocare Servs. AG v. Instradent USA, Inc., 903 F.3d 1365, 1381 (Fed. Cir. 2018) (quoting In re Katz Call Processing Pat. Litig., 639 F.3d 1303, 1324 (Fed. Cir. 2011)). The Court noted that the specification’s embodiments included partially human antibodies, humanized and chimeric. “And the prosecution history here illustrates why the presumption against their exclusion from the claims is not overcome.”

The Court further pointed out that originally filed claim 1 recited “an isolated antibody” and that the word “human” was added later, at the same time that dependent claim 11, which recited “a human, partially human, humanized, or chimeric antibody,” was canceled.  Immunex suggested that the amendment surrounded the partially human embodiments. The Court disagreed. As the Board noted, “human” was added to overcome an anticipating reference “that disclosed nonhuman murine antibodies—a far cry from ‘humanized’ antibodies.’” The Court agreed with the Board that “nothing indicates that Immunex added ‘human’ to limit the scope to fully human. There was no apparent need to do so in light of the rejection, and no evidence that anyone understood Immunex to be casting aside subject matter that was not at issue.”

Immunex further pointed out that the examiner subsequently issued a new obviousness rejection, combining Mosley with Jakobovits’s “fully human” antibodies and argued that “the examiner must have understood human antibodies to mean only ‘fully human’ antibodies because the examiner ‘repeatedly referred to ‘fully human’ antibodies while describing Jakobovits.’” The Court disagreed, as “this argument shows only that ‘fully human’ antibodies are ‘human’ which is undisputed” and noted that there was no support for Immunex’s argument that the claim is limited “to fully human antibodies just because the particular combination of prior art used to reject it included antibodies that were fully human.” Also, in “a post-amendment office action, the examiner expressly wrote that the amended ‘human’ antibodies encompassed ‘humanized’ antibodies.”

The Court then addressed the role of extrinsic evidence in the Board’s construction. Immunex argued that the Board “failed to establish how a person of ordinary skill in the art would have understood the term ‘human antibody.’” Immunex contended that the Board did not adequately consult extrinsic evidence, experts’ testimony, product catalogs, and a selection of journal articles, to establish whether “human antibody” had an established meaning to a person of ordinary skill in the art, independent of the specification. The Court disagreed with Immunex and pointed out that “we seek the meaning of claim terms from the perspective of the person of ordinary skill in the art. The key, however, is that we look to how that person would have understood a term in view of the specification. While extrinsic evidence may sometimes illuminate a well-understood technical meaning . . . that does not mean that litigants can introduce ambiguity in a way that disregards language usage in the patent itself.” The Court reminded that the patent drafter “controls the content of the specification, writes the claims, and responds to office actions. The drafter, then, is in the best position to anticipate ambiguity or questions of scope and to write the patent accordingly. Indeed, we give the intrinsic evidence ‘priority.’”

The Court explained that the Board cited and considered the extrinsic evidence, but “found nothing credible to call its interpretation into question. To the contrary, it credited a prior art reference and expert testimony that were squarely consistent with ‘humanized’ being understood as a subset of ‘human.’” The Board “credited this evidence, and therefore necessarily rejected Immunex’s conflicting evidence, we owe it deference.” The Court found that the intrinsic evidence “here decides the issue” and that extrinsic evidence “may be of assistance if the intrinsic record is equivocal, leaving us looking for further guidance.” However, the Court stated that “the meaning of ‘human antibody’ as discerned from the intrinsic evidence squarely conflicts with the meaning that Immunex would distill from its selected extrinsic evidence.” The Court held that “the intrinsic record trumps” and affirmed the invalidity decision.

In litigation that prompted this IPR, a district court construed “human” to mean “fully human” only, which is different from the Board’s interpretation. Contrary to Immunex’s allegation, the Court concluded that the Board did not err by reaching a different claim construction. The Court also disagreed with Immunex that the Board had to provide a detailed explanation of why the Board’s claim interpretation was different noting that the Board “is not generally bound by a previous judicial construction” and that “the Board’s opinion was sufficiently detailed to permit meaningful appellate review.”

Immunex Corp. v. Sanofi-Aventis U.S. LLC, No. 2019-1749, 2019-1777 (Fed. Cir. October 13, 2020)

http://www.cafc.uscourts.gov/sites/default/files/opinions-orders/19-1749.OPINION.10-13-2020_1667763.pdf