Amgen Inc v. Bristol Myers Squibb Co

1. Case Identification

• Case #: IPR2025-00603
• Patent #: 11,332,529
• Filed: February 28, 2025
• Petitioner(s): Amgen Inc.
• Patent Owner(s): Bristol-Myers Squibb Company
• Challenged Claims: 1-18

2. Patent Overview

• Title: Methods of Treating MSI-H Colorectal Cancer with Combination Immunotherapy
• Brief Description: The ’529 patent discloses methods for treating colorectal cancer by administering a combination of an anti-PD-1 antibody and an anti-CTLA-4 antibody to a subject whose tumor exhibits a high degree of microsatellite instability (MSI-H).

3. Grounds for Unpatentability

Ground 1A: Anticipation of Claims 1 and 4-14 by NCT-188

• Prior Art Relied Upon: NCT-188 (a clinical trial protocol publicly posted on ClinicalTrials.gov on February 11, 2014).
• Core Argument for this Ground:
  • Prior Art Mapping: Petitioner argued that NCT-188, a study sponsored by the Patent Owner, disclosed every limitation of claims 1 and 4-14 more than two years before the patent’s earliest effective filing date. The protocol explicitly described a method of treating patients with recurrent and metastatic MSI-H colon cancer by administering nivolumab (an anti-PD-1 antibody) in combination with ipilimumab (an anti-CTLA-4 antibody). Petitioner asserted that specific treatment arms in NCT-188, such as “Dose Level 2b” (3 mg/kg nivolumab with 1 mg/kg ipilimumab every 3 weeks for 4 doses), directly mapped to the specific dosage and duration limitations of dependent claims like claim 11.
  • Key Aspects: Petitioner contended that the absence of clinical results in the NCT-188 protocol was irrelevant to anticipation because independent claim 1 only requires a method of "treating," which does not necessitate proof of efficacy. Even for claim 4, which recites a survival outcome, Petitioner argued the outcome is an inherent result of practicing the disclosed method steps.

Ground 1B: Obviousness of Claims 2-3 over NCT-188 in view of Zhang

• Prior Art Relied Upon: NCT-188 (a Feb. 2014 clinical trial protocol) and Zhang (a 2013 journal article on MSI testing).
• Core Argument for this Ground:
  • Prior Art Mapping: Claims 2-3 add limitations defining MSI-H status, including the characteristic that "at least one protein encoded by DNA MMR genes is not detected in the tumor." NCT-188 required screening for MSI-H status as an inclusion criterion. Zhang taught that a primary method for detecting MSI status in colorectal cancer was indirect detection via immunohistochemical staining (IHC) to demonstrate the "absence of expression of MMR proteins."
  • Motivation to Combine: A POSITA implementing the NCT-188 protocol would need a method to identify eligible MSI-H patients. Petitioner argued a POSITA would combine NCT-188 with Zhang's teaching because Zhang described a well-known, reliable, and readily implemented IHC methodology for determining the exact MSI-H characteristic recited in the claims.
  • Expectation of Success: A POSITA would have a high expectation of success, as IHC staining for MMR protein loss was a standard and reliable technique for identifying MSI-H colorectal cancer tumors at the time.

Ground 3A: Obviousness of Claims 1 and 4-14 over Le, Xiao, and Hammers

• Prior Art Relied Upon: Le (a May 2015 journal article), Xiao (a January 2015 journal article), and Hammers (a May 2015 poster abstract).

• Core Argument for this Ground:

  • Prior Art Mapping: Le disclosed favorable clinical results for treating MSI-H colorectal cancer with anti-PD-1 monotherapy (pembrolizumab), establishing that this specific patient population was highly responsive to checkpoint blockade. Xiao reviewed the biology of MSI-H tumors, noted their upregulation of multiple immune checkpoints including PD-1 and CTLA-4, and explicitly predicted that combinations with anti-CTLA-4 therapies would "likely follow" the initial anti-PD-1 studies. Hammers provided a specific, successful protocol for combining nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4) to treat metastatic renal cell carcinoma, demonstrating a working and effective combination regimen.
  • Motivation to Combine: Petitioner argued a POSITA, armed with Le's proof-of-concept for anti-PD-1 efficacy in MSI-H colorectal cancer, would be directly motivated by Xiao's rationale and explicit suggestion to pursue a combination therapy with an anti-CTLA-4 antibody to improve outcomes. This motivation would lead the POSITA directly to a known, successful combination protocol like that disclosed in Hammers to find specific, effective dosages and schedules for the nivolumab/ipilimumab combination.
  • Expectation of Success: The expectation of success was argued to be high based on the demonstrated efficacy of anti-PD-1 monotherapy in the target population (Le), the strong biological rationale for adding an anti-CTLA-4 inhibitor (Xiao), and the proven safety and efficacy of a specific anti-PD-1/anti-CTLA-4 combination regimen in another responsive cancer type (Hammers).

• Additional Grounds: Petitioner asserted further obviousness grounds, including combinations of NCT-188 with NCT-109 (a clinical trial protocol disclosing flat-dosing of nivolumab) for claims 15-18. Other grounds added Postow and Xiao to the NCT-188 combinations to provide further evidence of efficacy and expectation of success. Finally, grounds combining Le/Xiao/Hammers with Zhang and NCT-109 were asserted against claims 2-3 and 15-18, respectively.

4. Arguments Regarding Discretionary Denial

• Petitioner argued against discretionary denial under 35 U.S.C. §325(d), contending that the petition advanced art and arguments not previously considered by the USPTO. Key references, including Zhang, NCT-109, Postow, Hammers, and Xiao, were never cited during prosecution. While NCT-188 and Le were of record, they were never applied or substantively analyzed in a rejection. Petitioner argued the Examiner erred materially by allowing the claims without any art-based rejections, especially when the record was silent on the Examiner’s consideration of highly relevant prior art that disclosed or suggested the claimed invention.

5. Relief Requested

• Petitioner requests the institution of an inter partes review and cancellation of claims 1-18 of Patent 11,332,529 as unpatentable.