Merck Sharp & Dohme LLC v. Johns Hopkins University

1. Case Identification

• Case #: IPR2024-00648
• Patent #: 11,643,462
• Filed: March 13, 2024
• Petitioner(s): Merck Sharp & Dohme LLC
• Patent Owner(s): The Johns Hopkins University
• Challenged Claims: 1-30

2. Patent Overview

• Title: Treatment of Cancer with Mismatch Repair Deficiency
• Brief Description: The ’462 patent claims methods of treating patients having solid tumors with microsatellite instability-high (MSI-H) or DNA mismatch repair deficiency (dMMR) by administering the anti-PD-1 antibody pembrolizumab.

3. Grounds for Unpatentability

Ground 1: Anticipation of Claims 1-2, 4-7, 9-12, 14-17, and 19-30 under §102

• Prior Art Relied Upon: MSI-H Study Record (a clinical trial protocol, NCT01876511, published on ClinicalTrials.gov on June 10, 2013).
• Core Argument for this Ground:
  • Prior Art Mapping: Petitioner argued that the MSI-H Study Record, a publicly available clinical trial protocol published more than a year before the patent’s priority date, disclosed every limitation of the challenged claims. The study protocol described a method of treating patients with MSI-H non-colorectal cancer using a specific dose of pembrolizumab (10 mg/kg every 14 days), which is the same dose described in the ’462 patent. Petitioner asserted the study’s inclusion criteria for a Phase II trial inherently required patients with solid tumors that had progressed after prior treatment. The protocol’s requirement to enroll patients with “MSI positive” cancer was argued to directly teach the limitation of testing for and treating patients with MSI-H or dMMR status, as these terms are biologically synonymous.
  • Key Aspects: Petitioner contended that any claimed efficacy is an inherent result of practicing the method disclosed in the prior art study protocol. Citing Federal Circuit precedent like In re Montgomery, Petitioner argued that a prior art disclosure of a planned clinical study anticipates a method of treatment claim, even if the treatment had not yet been practiced or its results published, because the claimed efficacy is inherent in carrying out the disclosed steps.

Ground 2: Obviousness of Claims 1-2, 4-7, 9-12, 14-17, and 19-30 under §103

• Prior Art Relied Upon: MSI-H Study Record, Brown (a 2014 journal article on neo-antigens and patient survival), Duval (a 2004 journal article on the mutator pathway), and Benson (2014 clinical practice guidelines for colon cancer).

• Core Argument for this Ground:

  • Prior Art Mapping: As an alternative to anticipation, Petitioner argued that even if the MSI-H Study Record did not explicitly disclose every limitation, the claimed methods were obvious. The MSI-H Study Record provided the foundational method of treating MSI-H cancer with pembrolizumab. Brown and Duval provided the scientific rationale for why this method would work, teaching that PD-1 inhibitors are more effective against tumors with many mutations (like MSI-H tumors) that are easily recognized by the immune system. Benson was cited to supplement the MSI-H Study Record by teaching the standard characteristics of patients in oncology clinical trials, namely that they typically have metastatic disease that has progressed after at least one prior standard-of-care treatment.
  • Motivation to Combine: A POSITA would combine the MSI-H Study Record with Brown and Duval because the latter references explained the underlying biological mechanism making MSI-H tumors particularly susceptible to PD-1 inhibitors, thus providing a strong scientific motivation to pursue the treatment outlined in the study protocol. A POSITA would look to Benson to understand the standard patient population for a Phase II oncology trial like the one described in the MSI-H Study Record, making it obvious that the trial would enroll patients with progressive, metastatic disease.
  • Expectation of Success: A POSITA would have a reasonable expectation of success because the prior art established a clear link between the MSI-H condition and heightened immunogenicity, which was known to be the target mechanism for PD-1 inhibitors like pembrolizumab. The combination of the known biological rationale (from Brown and Duval) and the existence of a formal clinical protocol (the MSI-H Study Record) would provide a strong expectation that the treatment would be effective.

• Additional Grounds: Petitioner asserted additional obviousness challenges based on the MSI-H Study Record in combination with other references. These grounds added specific prior art to address particular dependent claims, such as Koh (for uterine cancer), Ajani (for gastric cancer), Chapelle (for specific MSI-H testing markers), Steinert (for using body fluid as a sample), and Hamid (for intravenous administration).

4. Arguments Regarding Discretionary Denial

• Discretionary Denial under Fintiv: Petitioner argued against discretionary denial, asserting that the co-pending district court litigation is in a very early stage and that a stay will be sought upon institution, minimizing any overlap. Petitioner contended the strong merits of the petition, particularly the anticipation ground based on legal precedent the Examiner did not consider, weigh heavily in favor of institution to serve the public interest against leaving potentially invalid patents enforceable.
• Discretionary Denial under §325(d): Petitioner argued denial under §325(d) is inappropriate for three reasons. First, the Examiner for the ’462 patent never considered the MSI-H Study Record. Second, while the Examiner in a related case (’356 patent) did consider the study record, the Examiner committed legal error by failing to properly apply the law of inherent anticipation. Third, the Examiner did not consider the numerous obviousness combinations and arguments presented in this petition.

5. Relief Requested

• Petitioner requests institution of inter partes review and cancellation of claims 1-30 of the ’462 patent as unpatentable.