On February 14, 2019, the PTAB issued final written decisions in two separate IPRs filed by Sanofi-Aventis, Genzyme Corp., and Regeneron Pharmaceuticals (collectively “Sanofi”) against U.S. Patent No. 8,679,487 (“the ʼ487 patent”) assigned to Immunex Corporation (“Immunex”). Claim 1 of the ʼ487 patent is the only independent claim, and it is directed to “an isolated human antibody that competes with a reference antibody for binding to human IL-4 interleukin-4 (IL-4) receptor.” The claim also requires that the reference antibody heavy and light chains comprise particular amino acid sequences.

As we previously reported, Immunex filed suit in the Central District of California alleging that Sanofi’s Dupixent® dupilumab product infringed the ʼ487 patent. Dupilumab is a monoclonal antibody intended to inhibit signaling of interleukin-4 and interleukin-13 (IL-13) by binding to the IL-4 receptor (IL-4R). Dupilumab is indicated for the treatment of adult patients with moderate-to-severe atopic dermatitis and as an add-on maintenance treatment in patients aged 12 years old and older with moderate-to-severe asthma with an eosinophilic phenotype or oral corticosteroid dependent asthma.

In IPR2017-01884, the PTAB determined that Sanofi sustained its burden of showing claims 1-17 of the ʼ487 patent were unpatentable by a preponderance of the evidence. Central to the PTAB’s decision was its determination that the claim term “human antibody” encompassed both partially human and fully human antibodies. In reaching this conclusion, the PTAB principally relied on the disclosures of the specification, and in particular a paragraph stating that “[a] method for producing an antibody comprises immunizing…with an IL-4R polypeptide, whereby antibodies directed against the IL-4R polypeptide…Procedures have been developed for generating human antibodies in non-human antibodies. The antibodies may be partially human, or preferably completely human.” (emphasis added). According to the PTAB, this passage clearly teaches that the term “human antibody” as used in the ʼ487 patent includes both partially human and completely human antibodies.

Immunex argued that the (bolded) sentence the PTAB relied on actually modifies antibodies against IL-4R, which are referred to in the first quoted sentence, and not the human antibodies referred to in the second sentence, because the bolded sentence does not use the term “human antibodies.” However, the PTAB did not find this argument compelling in view of the specification as a whole. In particular, the PTAB pointed to instances where the specification clarified that some human antibodies are “fully human,” and explained that if a person of ordinary skill in the art (“POSA”) would have equated human with fully human, then there would have been no need for the specification to make that clarification. The PTAB also noted that the specification explained that the invention included partially human antibodies.

Immunex pointed to certain portions of the prosecution history in support for its argument that “human antibody” excludes partially human antibodies. Specifically, Immunex asserted that the term “human” was added to claim 1 to overcome an anticipation rejection, and a dependent claim reciting “human, partially human, humanized, or chimeric antibody” was canceled. According to Immunex, this combination of amendments demonstrated that “human antibodies” are distinct from “partially human, humanized, or chimeric antibodies.” However, the PTAB did not accept this reasoning because the specification does not identify partially human, humanized, or chimeric antibodies as distinct classes of antibodies, and in fact indicates that the terms overlap. Thus, the PTAB concluded that it is reasonable to interpret human and partially human as similarly overlapping terms. The PTAB also pointed out that anticipation rejection during prosecution was based on art that was directed to murine antibodies, and so it did not suggest the Applicant was limiting the claims to only fully human antibodies. According to the PTAB, the Examiner’s treatment of the claims during the remainder of prosecution is consistent with the PTAB’s understanding.

Interestingly, the district court reached a different conclusion in construing the same term. In the litigation, the district court found that human antibody was limited to fully human antibodies. The PTAB explained that it reached a different conclusion based on its use of the broadest reasonable interpretation standard, which was the claim construction standard in place when the IPR petition was filed. As a result, this IPR is a prime example illustrating the potential for inconsistency in parallel IPR and district court claim construction proceedings. The PTAB’s adoption of the Phillips standard for IPR petitions filed after November 13, 2018 (you can read more in a post on our PTAB blog here), should eliminate the potential for inconsistency based solely on the differing standards. However, it is not inconceivable that the PTAB and the district court could reach two different interpretations of a claim term even when using the same claim construction standard, and neither the PTAB nor a district court are bound by each other’s claim construction rulings.

Based on its interpretation of the term “human antibody,” the PTAB found all of the ʼ487 patent claims obvious in view of two references referred to as Hart and Schering-Plough. The Hart reference describes the use of a murine anti-hIL-4 antibody that acts as “a neutralizing antibody to IL-4Rα,” and inhibits IL-4 and IL-13 signaling. The antibody was commercially obtained. The Schereing-Plough reference explains that antibodies specific for the IL-4 receptor could be useful as therapeutic entities, and further recognizes that non-human monoclonal antibodies could be humanized and used as such therapeutic entities. Schering-Plough also describes techniques for making humanized versions of mouse anti-hIL-4R antibodies. Sanofi asserted that the Hart reference taught every limitation of claim 1 except that the antibody is murine instead of human; however, according to Sanofi, Schering-Plough supplies this limitation by teaching techniques for humanizing murine antibodies for use as human therapeutics.

Sanofi alleged that a POSA would have had reason to combine the references because it was well-known in the art that humanization of a non-human antibody would decrease its immunogenicity while maintaining its antigen binding specificity and affinity. Sanofi further alleged that a POSA would have had a reasonable expectation of success in combining the references because humanization techniques were well-developed as of the ʼ487 patent priority date.

The PTAB agreed with Sanofi’s reasoning, and found the claims unpatentable as obvious. In doing so, the PTAB addressed Immunex’s argument that Sanofi did not consider the full scope and content of the prior art by pointing out that the law requires only that the motivation to combine present a suitable option, and not necessarily the best option. Thus, the fact that other strategies for inhibiting IL-4R signaling may have existed did not alter the PTAB’s analysis. The PTAB also explained in response to Immunex’s contention that the prior art did not demonstrate a reasonable expectation of success in developing a therapeutic antibody from the Hart reference that the relevant question is whether a POSA could have arrived at the claimed invention, and not whether that antibody would be therapeutically effective. Of note, the claims here do not require therapeutic efficacy. Moreover, the PTAB explained that the law does not require absolute certainty of success, and here Sanofi’s expert testified without contradiction by Immunex that humanizing an antibody was well-within the ability of a POSA.

In contrast to its determination in IPR-01884, the PTAB found the claims not unpatentable in IPR2017-01879 in a decision that issued the same day. IPR2017-01879 was instituted on a single ground of anticipation under § 102(e) based on a reference referred to as the ʼ132 publication. The ʼ132 publication is in the priority chain of applications leading to the ʼ487 patent; however, Immunex disclaimed priority to the ʼ132 publication and earlier applications during prosecution. Immunex sought to remove the ʼ132 publication as a prior art reference to the ʼ487 patent by demonstrating that the portions of the ʼ132 publication that Sanofi relied on was the work of the ʼ487 patent inventors, and thus was not the work of another as required by the statute. The PTAB found Immunex’s evidence on this point sufficient to establish that the ʼ132 publication was not prior art. Consequently, the PTAB determined that the challenged claims were not unpatentable.

As suggested by the title of this post, the two IPRs described above are the second and third IPR challenges filed by Sanofi against the ʼ487 patent. The first challenge was in IPR2017-01129. However, the PTAB denied institution of that IPR by concluding that the cited prior art reference was not prior art.  As explained here, Immunex attempted to persuade the PTAB to exercise its discretion to deny the follow-on petitions described above, but the PTAB declined to do so.

We will continue to keep you updated on further developments.