Amgen Inc v. Bristol Myers Squibb Co

1. Case Identification

• Case #: IPR2025-00602
• Patent #: 10,174,113
• Filed: February 28, 2025
• Petitioner(s): Amgen Inc.
• Patent Owner(s): Bristol-Myers Squibb Company
• Challenged Claims: 1-20

2. Patent Overview

• Title: Method of Treating Melanoma with Combination Immunotherapy
• Brief Description: The ’113 patent relates to methods of treating melanoma using a combination of anti-PD-1 (nivolumab) and anti-CTLA-4 (ipilimumab) antibodies. The claimed method involves an initial combination therapy phase followed by a monotherapy phase using a flat dose of the anti-PD-1 antibody.

3. Grounds for Unpatentability

Ground 1: Obviousness over NCT-505 and NCT-109 - Claims 1-4, 10-15, and 17-20 are obvious over NCT-505 in view of NCT-109.

• Prior Art Relied Upon: NCT-505 (a clinical trial protocol posted May 2013) and NCT-109 (a clinical trial protocol posted October 2013).
• Core Argument for this Ground:
  • Prior Art Mapping: Petitioner argued that NCT-505 disclosed the core of the claimed invention: a two-stage treatment for melanoma involving co-administration of nivolumab (1 mg/kg) and ipilimumab (3 mg/kg), followed by nivolumab monotherapy. However, NCT-505 taught a weight-based monotherapy dose (3 mg/kg every two weeks). NCT-109, a separate trial protocol for solid tumors including melanoma, disclosed administering a flat dose of 240 mg of nivolumab every two weeks. The combination of these references allegedly taught all elements of the independent claims.
  • Motivation to Combine: A Person of Ordinary Skill in the Art (POSITA) would combine the teachings by modifying the regimen in NCT-505 to use the flat monotherapy dose from NCT-109. The motivation was the known advantages of flat dosing over weight-based dosing for antibodies like nivolumab, which has a wide therapeutic window. These advantages included improved convenience, patient adherence, and reduced risk of dosing error.
  • Expectation of Success: A POSITA would have a reasonable expectation of success because a 240 mg flat dose is the arithmetic equivalent of a 3 mg/kg dose for an average 80 kg melanoma patient. The known linear pharmacokinetics and wide therapeutic window of nivolumab would assure a POSITA that this substitution would be safe and comparably effective. The 480 mg dose every four weeks was argued to be an obvious optimization to reduce dosing frequency.

Ground 2: Obviousness over Postow and NCT-109 - Claims 1-6, 9-10, 13-15, and 19-20 are obvious over Postow in view of NCT-109.

• Prior Art Relied Upon: Postow (a New England Journal of Medicine article published April 2015) and NCT-109.
• Core Argument for this Ground:
  • Prior Art Mapping: Petitioner asserted this ground is analogous to Ground 1, but uses Postow as the primary reference. Postow published the successful clinical trial results for the regimen described in NCT-505, confirming that combination therapy followed by weight-based nivolumab monotherapy resulted in durable responses and longer progression-free survival in melanoma patients, including those with PD-L1-negative tumors. When combined with NCT-109's teaching of a 240 mg flat dose of nivolumab, all limitations were allegedly met.
  • Motivation to Combine: The motivation was identical to Ground 1: a POSITA would be motivated to substitute the known, convenient flat-dosing regimen from NCT-109 into the clinically validated treatment protocol disclosed in Postow.
  • Expectation of Success: The expectation of success was high because Postow provided clinical proof of the underlying regimen's efficacy. A POSITA would reasonably expect that substituting an equivalent flat dose for the weight-based dose would yield comparable clinical results, given nivolumab's known properties.

Ground 3: Obviousness over Postow, NCT-109, and Cogswell - Claims 5-9 and 16 are obvious.

• Prior Art Relied Upon: Postow, NCT-109, and Cogswell (WO 2013/173223).
• Core Argument for this Ground:
  • Prior Art Mapping: This ground built upon Ground 2 to address dependent claims reciting specific PD-L1 measurement techniques and the addition of another anti-cancer agent. While Postow mentioned PD-L1 testing, Cogswell provided the specific, well-known methods, disclosing pre-treatment PD-L1 expression measurement using an IHC assay on FFPE tumor samples with a specific antibody clone (28-8). Cogswell also taught that PD-1/CTLA-4 immunotherapy could be combined with standard cancer treatments like chemotherapy for synergistic effects.
  • Motivation to Combine: A POSITA would be motivated to use the detailed methods in Cogswell to implement the PD-L1 testing strategy of Postow. Furthermore, a POSITA would be motivated to combine the immunotherapy of Postow/NCT-109 with an additional anti-cancer agent as taught by Cogswell to increase efficacy.
  • Expectation of Success: A POSITA would expect Cogswell's detailed PD-L1 testing method to work for the Postow regimen, as Cogswell expressly referenced the NCT-505 trial. A POSITA would also reasonably expect the addition of chemotherapy to be at least additive, if not synergistic, as this was a common and recommended practice.
• Additional Grounds: Petitioner asserted additional obviousness challenges based on variations of the same prior art. Grounds 1C and 3C specifically argued the 480 mg every four weeks dosage was an obvious modification to reduce injection frequency. Ground 4 mirrored the arguments of Ground 3 but used NCT-505 as the primary reference instead of Postow.

4. Key Technical Contentions (Beyond Claim Construction)

• Claims Not Entitled to Priority Date: A central contention was that most challenged claims (1-10, 12-16, 18-20) were not entitled to the April 28, 2015 filing date of the parent '973 provisional application. Petitioner argued the provisional failed to provide adequate written description for the "about 480 mg" flat dose limitation, as this dosage was never disclosed. Because the claims recite alternatives ("240 mg or about 480 mg"), the failure to describe one alternative invalidates the priority claim for the entire Markush group. This pushed the effective filing date to April 28, 2016, making Postow (published April 20, 2015) indisputable prior art.

5. Arguments Regarding Discretionary Denial

• Petitioner argued that discretionary denial under §325(d) would be inappropriate. The core prior art references central to the petition's obviousness grounds—NCT-505, Postow, and NCT-109—were never cited, discussed, or otherwise of record during prosecution. Petitioner asserted the Examiner made only a single anticipation rejection based on a different reference (Wolchok) and never conducted an obviousness analysis, meaning the Office erred materially by overlooking highly pertinent art and arguments.

6. Relief Requested

• Petitioner requested institution of an inter partes review and cancellation of claims 1-20 of the ’113 patent as unpatentable.