Law360, New York (August 21, 2015, 10:23 AM ET) —

The first institution decisions for inter partes review in a biosimilars context were handed down by the Patent Trial and Appeal Board the week of July 13, 2015.[1] Boehringer Ingelheim Pharmaceuticals Inc. had petitioned for IPR of two patents owned by Genentech Inc. (U.S. Pat. Nos. 7,820,161 and 7,976,838)[2] and one owned by Biogen Inc. (U.S. Pat. No. 8,329,172),[3] each of which dealt with Rituxan (rituximab), an antibody that binds to CD20. The PTAB instituted trial on the two Genentech patents, but declined to do so for the Biogen patent. These patent challenges are significant because the challenged patents extend coverage of Rituxan from 2013 to at least 2020. They also represent the first PTAB challenges associated with this biologic.

The challenged patents generally claim: (1) combination therapy using rituximab and methotrexate to treat rheumatoid arthritis, (2) treating RA in certain patients that do not respond to other therapy according to a specific dosing regimen, and (3) treating low grade B-cell non-Hodgkin’s lymphoma using chemotherapy followed by administration of rituximab according to a specific regimen. Importantly, all of these indications are specifically recited on the Rituxan label and ostensibly would thus be infringed by a rituximab biosimilar developer copying the Rituxan label. Boehringer Ingelheim’s biosimilar rituximab (BI 695500) is in Phase III clinical trials[4] and, if these patent challenges are any indication, the clinical data for BI 695500 is likely positive.

PTAB Continues Its Critical Treatment of Therapeutic Dosing Claims

In deciding these Rituxan petitions, the PTAB remained consistent with its previous critical treatment of dosing regimen claims. For example, the PTAB recently held that dosing regimen claims associated with administration of Myozyme were obvious in view of the prior art.[5] With respect to the Genentech ‘161 patent, the claims are directed to an RA combination therapy using rituximab and methotrexate. In petitioning for IPR, Boehringer asserted that the prior art suggested that treating RA with combination therapies, including methotrexate, were gaining recognition as an important approach for treating RA. The board agreed with Boehringer and instituted review,[6] even though Genentech argued that the prior art’s suggestion to treat RA with rituximab was inconsistent with the scientific literature at the time of the invention.

The claims of the ‘838 patent are directed to treating RA patients who experience an inadequate response to a TNFα-inhibitor, using an antibody that binds CD20, and specifies certain benchmarks for efficacy. With respect to the ‘838 patent, Boehringer asserted that the prior art disclosed treating RA using similar doses of rituximab alone and in conjunction with methotrexate and corticosteroids, as well as the therapeutic benchmarks. They also argued that treating RA patients who do not respond to TNFα-inhibitors was expressly disclosed in the prior art. The Board again sided with Boehringer despite Genentech’s arguments that the cited art disclosed using contrary doses and that the dosing regimen displayed unexpected properties.[7]

The Risks of Using Clinical Trial Protocols as Printed Publications

Boehringer was unsuccessful, however, in convincing the board to institute IPR for the Biogen ‘172 patent. The only claim of the ‘172 patent is directed to a method of treating low grade B-cell non-Hodgkin’s lymphoma by administering a specific chemotherapy followed by a specific dosing regimen of rituximab maintenance therapy. Here, Boehringer was not able to demonstrate that their cited art qualified as a publically available printed publication.

In asserting invalidity, Boehringer first contended that the claim of the ‘172 patent was unpatentable over two references — the ECOG 1496 and ECOG 4494 clinical trial protocols. The ECOG is a cooperative group, funded primarily by the National Cancer Institute, composed of a large network of researchers, physicians and health care professionals at public and private institutions around the world which performs multicenter cancer clinical trials. Boehringer contended that, because those trial protocols were designated as active prior to the effective filing date of the ‘172 patent, the ECOG could provide them to member institutions, and physicians at ECOG institutions, and in turn, could discuss the protocols freely, distribute them to other physicians and patients, obtain informed consent from patients, and enroll patients in the clinical trials. They also contended that ECOG 1496 and ECOG 4494 were distributed to all members of the cooperative shortly after activation of the trial and before the ‘172 effective filing date with no confidentiality restrictions.

The board, however, concluded that Boehringer presented no direct evidence from the ECOG, or from anyone directly associated with the ECOG, explaining specifically whether or how ECOG 1496 and ECOG 4494 were distributed, or whether the protocols were under confidentiality restrictions. Nor did Boehringer advance such firsthand evidence to support its contention that the ECOG protocols were actually disseminated to all members of the cooperative without confidentiality restrictions. Particularly problematic for Boehringer was that they did not explain how or where they obtained the ECOG protocols. Instead, they relied extensively on their expert’s declaration for an explanation. The Board contended that Boehringer’s expert did not assert any firsthand knowledge of how the ECOG protocols at issue were distributed. The board then declined to recognize ECOG 1496 and ECOG 4494 as printed publications based merely on expert testimony, even given the expert’s “substantial credentials.”[8]

Boehringer also asserted unpatentability based on another single reference, which did not explicitly disclose all of the claimed limitations, and relied on the general teaching in the art to assert claim 1 of the ‘172 patent was obvious. The board, however, was not persuaded, stating that although Boehringer represented the challenge based on a single reference, they relied on at least eight additional references to explain why claim 1 would have been obvious.

The board’s treatment of the clinical trial protocols as prior art publications is reminiscent of the difficulty of using white papers or manuals in the electronics industry for the same purpose. Since it may be difficult to establish that clinical trial protocols were indexed or somehow cataloged, proving public accessibility may remain a challenge. In this case, since all of the unpatentability contentions were based in part on the ECOG protocols or did not adequately explain why a skilled artisan would have modified the cited references to arrive at the subject matter of the challenged claim, the board denied institution.

Two Out of Three Ain’t Bad?

Boehringer was successful in getting institution in two out of the three patents it challenged. But what does that mean? It is important to remember that these decisions merely represent institution of review and not a final adjudication on the patentability of the challenged claims. Given the standard for institution, however — reasonable likelihood that petitioner will prevail with respect to at least one of the challenged claims — Genentech faces an uphill battle defending its patents. Claims to dosage regimens seem especially vulnerable at the U.S. Patent and Trademark Office. At least in the Myozyme IPR challenges, the PTAB stated that, since a person of ordinary skill in the art would have had a reasonable expectation of success in treating a given condition with the claimed therapeutic, “what [remains is] the execution of human clinical trials, arguably “routine” to a person of ordinary skill in the art, to verify the expectation that a specific dosage (within a previously suggested dosage range) and corresponding dosage regimen would have been safe and effective.”[9]

Moreover, the two patents on which IPR trial was instituted both deal with treatment of RA. But Rituxan is indicated in three additional patient populations including: non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, and granulomatosis with polyangiitis (Wegener’s Granulomatosis) and microscopic polyangiitis in adult patients in combination with glucocorticoids. This leaves open the possibility that biosimilar applicants may be able to “carve out” patented indications.

It is important to note that the Biologics Price Competition and Innovation Act provides that a biosimilar applicant may seek a license for a biosimilar product: (1) for a different formulation than the reference product, (2) for fewer than all routes of administration for which an injectable reference product is licensed; and (3) for fewer than all indications for which the reference product is licensed. Thus, these provisions may develop as a counterpart to the “skinny label” or “carve-out” provision of the Hatch-Waxman Act. Since Boehringer does not have to copy the Rituxan label, they may be able carve-out indications where challenge is unsuccessful. Whether physicians will prescribe off-label use of a biosimilar remains to be seen, however.

Key Takeaways From the Institution Decisions

Even though Boehringer failed to have trial instituted on one of the challenged patents, dosing regimen claims appear to be particularly vulnerable to IPR challenge. However, the use of clinical trial protocols as prior art may be difficult because the PTAB will closely scrutinize whether they qualify as publicly available printed publications. Since biosimilar applicants can forgo the BPCIA’s patent-exchange process[10] — at least for now — biosimilar applicants will increasingly use post-grant challenges at the USPTO to obtain patent certainty. And because there is a possibility to carve out patented indications from a product label, biosimilar applicants may not need to challenge all patented indications. No doubt these lessons are also being learned by reference product sponsors as well in hopes of identifying ways to shore up patent estates covering their blockbuster biologics from future challenges.

—By Paul A. Calvo and Eldora L. Ellison, Sterne Kessler Goldstein & Fox PLLC

Paul Calvo, Ph.D., and Eldora Ellison, Ph.D., are directors at Sterne Kessler in Washington, D.C.

The opinions expressed are those of the author(s) and do not necessarily reflect the views of the firm, its clients, or Portfolio Media Inc., or any of its or their respective affiliates. This article is for general information purposes and is not intended to be and should not be taken as legal advice.

[1] In IPR 2013-00365, Hospira challenged Janssen’s U.S. Pat. No. 6,747,002 related to dosing regimens for erythropoietin. Janssen disclaimed the challenged claims thereby rendering the petition for IPR moot.

[2] IPR2015-00415 and IPR2015-00417, respectively.

[3] IPR2015-00418


[5] IPR2013-00537

[6] IPR2015-00415, Paper No. 13, p. 12-22.

[7] IPR2015-00417, Paper No. 11, p. 14-15.

[8] IPR2015-00418, Paper No. 14, p. 10-11.

[9] IPR2013-00537, Paper No. 79, p.15.

[10] Amgen Inc. v. Sandoz Inc., Fed. Cir. Case No. 2015-1499.

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