As we previously reported, Pfizer filed three IPR petitions against Biogen-owned patents claiming methods of treatment with rituximab in April 2017. The three proceedings are: IPR2017-01166, regarding U.S. Patent No. 8,329,172 (“the ’172 patent”); IPR2017-01167, regarding U.S. Patent No. 8,557,244 (“the ’244 patent”); and IPR2017-01168, regarding U.S. Patent No. 8,821,873 (“the ’873 patent”). Institution decisions for all three IPRs have come down within the past three weeks, with institution being denied for the ’172 and ’244 patents, and trial being instituted for the ’873 patent.

In brief review, the three patents cover methods of treating certain types of lymphoma with an anti-CD20 antibody, and all three patents contain at least one claim where that antibody is specifically rituximab. The ’172 patent claims a method for treating low grade B-cell non-Hodgkin’s lymphoma comprising chemotherapy followed by maintenance therapy involving administering four weekly administrations of rituximab at 375 mg/m² every six months over a period of two years. The ’244 patent claims a method for treating diffuse large cell lymphoma in patients over 60 by administering anti-CD20 antibody (or rituximab specifically) and a specific chemotherapy regimen, CHOP (which is cyclophosphamide, hydroxydaunorubicin/doxorubicin, oncovin/vincristine, and prednisone/prednisolone). The treatment claimed in the ʼ244 patent is specific to a patient who is greater than 60 years old, has bulky disease, and has a tumor greater than 10 cm in diameter. The ’873 patent claims treatment of diffuse large cell lymphoma with a similar CHOP regimen, with the additional requirement that the antibody is administered in combination with a stem cell transplantation regimen.

In IPR2017-01168, trial was instituted as to all challenged claims of the ’873 patent on November 6, 2017. In considering Pfizer’s argument, the Board was persuaded by the combination of the primary reference, which was asserted to teach all elements of the claim except for rituximab, with additional references teaching a combination of a CHOP regimen and rituximab to treat patients with diffuse large cell lymphoma as an improvement to CHOP therapy alone.  Further references in the combination support the overall motivation to combine by noting that older patients have issues with the CHOP regimen, and that the combination of CHOP and rituximab could help that population.  In brief, the PTAB adopted all of Pfizer’s arguments relating to the obviousness of the claims. Notably, Biogen elected not to file a preliminary response. Although there are a number of reasons that a Patent Owner may not choose to file a preliminary response, it is interesting to note that the Rituxan® label does not disclose stem cell transplantation as an indicated treatment for diffuse large cell lymphoma as claimed in the ʼ873 patent.

Next, in IPR2017-01167, the PTAB denied institution as to all challenged claims of the ’244 patent on November 6, 2017. In its preliminary response, Biogen largely attacked the asserted art as not actually disclosing the treatment of patients over 60 with diffuse large cell lymphoma and who have bulky disease, as claimed. For example, Biogen attacked a “Shipp” reference, which was part of both combinations asserted by Pfizer, by noting that Shipp did contain certain claimed elements, such as the treatment of patients 60 or older, but that it did not disclose the histology of lymphoma presented in those patients, such as diffuse large cell or other lymphomas. Biogen also attacked a “Link” reference along similar lines. Biogen further attacked at length the motivation to combine the asserted references, as well as attacking the combination for not having a reasonable expectation of success. The Board ultimately agreed with Biogen, including that the Shipp reference did not adequately describe the patient population and whether the older patients had diffuse large cell lymphoma.  This was the second IPR petition denied institution regarding the ’244 patent, as a Celltrion IPR, the filing of which we previously reported, was denied on October 2, 2017. That denial was similar in many ways, including determining that the Link reference did not disclose the claimed patient population.

Finally, in IPR2017-01166, the PTAB denied institution of all challenged claims of the ’172 patent on November 13, 2017. This was the third petition denied institution for this patent, with this denial joining earlier efforts by Boehringer Ingelheim on December 15, 2014, and another by Celltrion, filed March 15, 2017.

Institution on Boehringer Ingelheim’s petition was denied on October 5, 2015. Denial was based in part on the Board finding that certain references were not actually printed publications as required for IPR proceedings. These references were two clinical study protocols from an oncology research organization. The protocols were argued to have been potentially available to physicians at institutions affiliated with the organization based on general practices and a declaration from a doctor who had worked with similar organizations. However, the Board found that no direct evidence had been presented from anyone with firsthand knowledge of these documents or the actual originating organization as to whether they were distributed or otherwise available. Celltrion’s petition, the filing of which we previously reported, again relied on one of the clinical study protocols at issue in Boehringer Ingelheim’s petition—this time accompanied by the declaration of a doctor who had worked with the research organization and who actually took part in the clinical study as a sub-investigator. However, despite Celltrion’s efforts to show the protocol as a printed publication, the Board denied institution on October 6, 2017, determining that Celltrion had not demonstrated that the protocol or related forms were actually “disseminated or otherwise made available” to interested artisans. The Board noted that times of receipt of the documents or any possible distribution were not disclosed in the doctor’s declaration, that the fact that the documents were not confidential was insufficient to show availability, and that the remaining testimony was largely hypothetical and lacking any evidence to suggest that any of these speculative events actually occurred.

The Board additionally determined that a label for Rituxan® relied upon as prior art by Celltrion was not established as a printed publication. The label had similarly been used by Boehringer Ingelheim, although in that case Biogen had not challenged, and the Board did not discuss, it’s availability as a printed publication. The Board determined Celltrion did not introduce evidence as to its availability, including what date it was alleged to be publically accessible or any evidence that the specific label relied upon was disturbed with the drug itself or otherwise made available to the interested artisan.

As such, when Pfizer filed its IPR petition on April 21, 2017, it may have been aware of Boehringer Ingelheim’s issues regarding proving public accessibility of the study protocols but unaware of the arguments facing the Rituxan® label. Instead of attempting to prove the printed publication status of the study protocol as Celltrion did, Pfizer asserted a new primary reference which had been published, distributed, and shelved in libraries. However, Pfizer also relied upon the Rituxan® label. Perhaps wary due to the outcome of the Boehringer Ingelheim IPR, even though the label had not previously been challenged, Pfizer attempted to cover its bases and assert the availability of the label by showing its origin as a label approved in 1997 on the FDA’s website, by showing the availability of a Rituxan® label on Genentech’s website as of January 1998 according to the Internet Archive, by demonstration of the citation to a Rituxan® label in other publications in 1998, by showing that a label with the same information was contained in a Physician’s Desk Reference® available in December 1998, and by showing that much of the information relied upon in the label was contained in a published paper.

Biogen challenged the status as a printed publication of the specific label relied upon by Pfizer in its preliminary response. Noting that the document presented by Pfizer contained handwriting, Biogen argued that even if the document contained information consistent with the Rituxan® label which may have been distributed, that Pfizer had not demonstrated that the actual document relied upon had ever been distributed.  The Board agreed with Biogen, stating that arguments that the same information was available before the priority date did not support the actual version of the label relied upon (“handwriting and all”) as having been made available to interested artisans.

A relatively rare dissenting opinion was also filed with the Board’s decision, noting that additional evidence establishing the label as a printed publication might be found through trial. The dissent discussed the standard for institution of IPRs as a question of deciding whether the petition supported a reasonable likelihood of proving by a preponderance of the evidence that the petitioner would prevail on a challenged claim by the conclusion of the trial and the close of evidence. Whether Pfizer would be able to establish the status of the label as a printed publication by the close of evidence was thus seen as only a factor in deciding that question. The majority opinion, however, treated whether the label was a printed publication as a threshold issue, and held that as the petition did not sufficiently demonstrate the availability of the document, that institution relying on that document would be improper.

As such, IPR2017-01166 and the other IPRs addressing the ’172 patent are yet further examples, as we recently reported, of the growing body of institution decisions involving the Board’s scrutiny of non-patent literature asserted in IPR grounds. These IPRs highlight not only the importance to petitioners of providing adequate support for the printed publication status of any non-patent references, but also of choosing the best version of a reference for which prior art dates and actual distribution can most clearly be established.