Pharmaceutical patents frequently claim treatment methods that utilize a range of amounts or concentrations for the active ingredient or excipients included in the formulation. Given the prevalence of such patents, there is surprisingly little practical guidance in the case law regarding the circumstances under which prior art references that disclose treatments with ranges that overlap with those claimed in the patent will or will not anticipate or obviate the claimed invention. The Patent Trial and Appeal Board’s (“PTAB”) recent final decision in Koios Pharmaceuticals LLC v. Medac Gesellschaft Für Klinische Spezialpräparate, Case IPR2016-01370 (Paper 54, February 7, 2018), provides an example of how that issue will be evaluated, which pharmaceutical companies can use to guide their efforts to withstand challenges to the patentability of their method of treatment patents.
PTAB Decision – Koios Pharmaceuticals
The patent at issue claimed a method for treating inflammatory autoimmune diseases comprising subcutaneously administering methotrexate at a concentration of more than 30 mg/ml.
The prior art Grint patent disclosed the use of methotrexate to treat inflammatory autoimmune diseases (among other ailments), teaching that the methotrexate is present “from about 0.1 to about 40 mg/ml of carrier” and that subcutaneous injection is a suitable route of administration. Despite the express teachings of both subcutaneous administration and methotrexate concentrations that overlap with the claimed range, the PTAB found Grint insufficient to invalidate the claimed invention. It held that the Petitioner was required to demonstrate that the portion of Grint’s disclosed methotrexate concentration range that overlapped with the claimed range would have been understood by those of ordinary skill in the art to be applicable to subcutaneous administration in particular. It rejected the Petitioner’s expert’s testimony that skilled artisans would have envisaged subcutaneously administering 35 mg/ml of methotrexate by preparing a 35 mg dose (which was within the “preferred” dosage range) using a 1 ml solution common for such injections, which he opined was consistent with Grint’s teaching that the formulation should be “compounded for convenient and effective administration in effective amounts.” The PTAB credited, instead, the Patent Owner’s expert’s testimony (among other things) that Grint disclosed at least eighteen different modes of parenteral administration, that it was known that different modes of administration have different concentration limits, and that Grint did not correlate any particular concentration with any particular mode of administration.
For similar reasons, the PTAB also rejected the Petitioner’s arguments based on Wyeth’s 2004 label for Methotrexate Sodium, which disclosed 20 mg and 1 gram vials of lyophilized methotrexate for injection in treating various conditions, including juvenile rheumatoid arthritis. The Wyeth label teaches that the 20 mg vial should be reconstituted to a concentration no greater than 25 mg/ml, but that the 1 gram vial is to be reconstituted to a concentration of 50 mg/ml. Although one of the two vial products is to be reconstituted to a methotrexate concentration within the range claimed in the patent, the PTAB held that the Wyeth label did not anticipate the claimed invention or render it obvious because Petitioner failed to establish a link between the label’s disclosure of subcutaneously administering methotrexate to treat inflammatory autoimmune disease and its disclosure of the 1 gram vial in particular, and thereby failed to demonstrate that a person of ordinary skill in the art would have envisioned performing the claimed method based on that label.
Koios Pharmaceuticals provides practical instruction to pharmaceutical companies as to the types of proofs they will need to adduce in defending the validity of their method of treatment patents against prior art references that disclose treatment regimens using ranges for the active ingredient and/or excipients that overlap with those claimed in the patent. Thoughtful practitioners can use that instruction during patent prosecution and subsequent enforcement proceedings and IPRs to guide their thinking from the outset of the matter, so that they can muster the expert evidence needed to sustain their validity arguments.