IPR Final Written Decision Finds Pembrolizumab Patent Claims Unpatentable

On June 9, 2025, the Patent Trial and Appeal Board (“Board”) issued a Final Written Decision (“FWD”) in Merck’s IPR2024-00240 against The Johns Hopkins University’s (“JHU”) U.S. Patent No. 11,591,393 (“the ’393 patent”), finding method of treatment claims 1-2, 4-7, 11-12, 14-15, 17-20, 24-25, 27-42 unpatentable as anticipated, and claims 1-42 unpatentable as obvious.  The ’393 patent is directed to anti-cancer therapies that block immune system checkpoints, including the PD-1 receptor, in colorectal cancer patients.  In particular, the ’393 patent is directed to treating cancer patients with high mutational burdens, such as found in microsatellite instable (“MSI”) and mismatch repair deficient (“dMMR”) cancer, with anti-PD-1 antibodies including pembrolizumab.  Merck sells anti-PD-1 antibody Keytruda^® (pembrolizumab), which is FDA-approved for patients with microsatellite instability-high (“MSI-H”) and dMMR colorectal cancer.

The main prior art reference cited by Merck was a record of a Phase 2 clinical trial “Study of [Pembrolizumab] in Patients With Microsatellite Unstable (MSI) Tumors (Cohorts A, B and C)” (“MSR”) completed by JHU.  Information about the study was published on a government website more than two years before the priority date of the ’393 patent.  While Petitioner and Patent Owner disputed the timing of when the patients were tested to determine if they had MSI-H colorectal cancer, the Board agreed with Petitioner that patients would have been tested prior to enrollment in the study to ensure they qualified for the study and to determine which arm they would be put into.  This timing was consistent with the claims requiring treatment with an effective amount of pembrolizumab in response to determining the patient’s colorectal cancer was MSI-H.

While the Patent Owner argued that patients with MSI-stable colorectal cancer were also treated with pembrolizumab, the Board did not construe the claims to exclude treating other patients because the claims did not recite any steps or limitations other than testing a biological sample from a patient having colorectal cancer to determine if the cancer is MSI-H or dMMR and, in response to a determination that the colorectal cancer is MSI-H or dMMR, treating the patient with a therapeutically effective amount of pembrolizumab.

The Board also agreed with Petitioner that the MSR’s planned trial was sufficient to inherently anticipate the claims despite being an initial submission for an experimental trial that had not yet begun, because it taught the steps of independent claim 1 and the result of the drug treatment inherently follows its administration.

The Board disagreed with the Patent Owner’s argument that the MSR discloses an experimental use that does not qualify as prior art, particularly in a highly unpredictable field such as cancer treatment, because it was not persuaded that the Patent Owner could not have filed an earlier application to secure a priority date before the MSR was publicly available.

Based on these conclusions, the Board found the independent claims anticipated.  It also found the dependent claims, which added limitations requiring cancer progression on prior therapies, and for patients to have metastatic disease, to be anticipated by the MSR’s requirement that the enrolled patients have “measurable disease” based on Petitioner’s more persuasive evidence of what a person of ordinary skill would have understood from the MSR.  For independent claims directed to the therapeutic effects of treating patients with pembrolizumab, the Board agreed with Petitioner that the claims were anticipated, finding that because the MSR teaches treating patients with MSI-H colorectal cancer with 10 mg/kg of pembrolizumab every 14 days, it is inherently effective in achieving the results in the dependent claims even though the results were not yet reported.

As to obviousness, the Board only analyzed the additional claims that it did not already find anticipated, noting that anticipated claims are also obvious.  It found the Petitioner’s arguments persuasive that the prior art disclosed the additional claim elements and there was a motivation to combine the references with a reasonable expectation of success, and it disagreed with the Patent Owner’s arguments, which were limited to the Petitioner using the wrong legal standard for a reasonable expectation of success.  The Board also found the Patent Owner’s objective evidence of non-obviousness lacked a nexus to the dependent claims that were not found to be anticipated.

JHU’s Request for Director Review

On June 26, 2025, JHU requested Director Review of the FWD issued in IPR2024-00240 asserting that the conduct of the case presents an important policy issue.  JHU alleged that Merck had exploited a declaratory judgment (“DJ”) loophole in the American Invents Act (“AIA”) that allows petitioners to file DJ actions for non-infringement, but not invalidity, in the district court, avoiding estoppel and forcing patent owners to defend their patents in two forums.  JHU also alleges that Merck caused delay and unnecessary expense by waiting until the PGR filing window was closed to file this IPR, and subsequently eight additional IPRs on other patents that were part of the litigation (Case No. 1:22-cv-03059 (D. Md.)).  JHU also notes that Merck did not file a Sotera stipulation that would prevent duplication of arguments between the PTAB and district court.  While JHU acknowledged that none of Merck’s actions were in violation of the language of the AIA, it urged the Director to rectify the situation that “cannot be reconciled with the clear congressional intent that the IPR serve as a ‘substitute’ for district court litigation” by vacating the FWD and terminating the other eight ongoing IPRs.  The district court action is currently stayed, and has been since institution of IPR2024-00240.

Merck reported $29.5B in worldwide Keytruda^® sales in 2024.

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The author would like to thank April Breyer Menon for her contributions to this article.