Merck Sharp & Dohme LLC v. Halozyme Inc

1. Case Identification

• Case #: PGR2025-00050
• Patent #: 12,077,791
• Filed: May 7, 2025
• Petitioner(s): Merck Sharp & Dohme LLC
• Patent Owner(s): Halozyme Inc.
• Challenged Claims: 1-10

2. Patent Overview

• Title: Modified Human PH20 Polypeptides
• Brief Description: The ’791 patent relates to modified human PH20 hyaluronidase polypeptides that exhibit increased hyaluronidase activity compared to an unmodified reference protein. The claims define a genus of these modified proteins by sequence identity, a mandatory substitution at one position, and the allowance of numerous additional substitutions.

3. Grounds for Unpatentability

Ground 1: Claims 1-10 are unpatentable under 35 U.S.C. § 112 for Lacking Written Description

• Prior Art Relied Upon: This ground relies on the specification of the ’791 patent and its priority applications, arguing they fail to describe the claimed invention.
• Core Argument:
  • Immense and Undescribed Genus: Petitioner argued that the claims cover an astronomically large and diverse genus of modified PH20 polypeptides, ranging from 10^49 to 10^60 distinct sequences. Claim 1 requires a substitution at position 309 and at least 95% sequence identity to a 433-residue reference sequence (SEQ ID NO: 35), permitting up to 20 additional modifications.
  • Lack of Representative Examples: The specification’s working examples were asserted to be non-representative of the claimed genus. All examples were based on a different, 447-residue reference sequence (SEQ ID NO: 3) and involved only a single amino acid substitution. Petitioner contended there are zero examples of the claimed multiply-modified polypeptides based on the required 433-residue sequence, leaving the vast majority of the claimed genus unexplored and undescribed.
  • No Common Structural Features: The petition argued that the specification fails to identify any common structural features or a structure-function relationship that would allow a person of ordinary skill in the art (POSA) to distinguish the active polypeptides from the inactive ones within the vast claimed genus. Simply requiring a substitution at position 309 was argued to be insufficient to confer activity across billions of otherwise different multiply-modified sequences.
  • Disparate Disclosures: Petitioner asserted the claims improperly stitch together disparate and generic disclosures from the specification. For example, the specification allegedly makes only a "passing reference" to the 433-residue sequence (SEQ ID NO: 35) required by the claims, while all experimental data is based on a different sequence, thus failing to show possession of the specific claimed subgenus.
  • Inclusion of Inadvisable Mutations: The petition argued the claims are unpatentable because their broad scope captures polypeptides with mutations that the specification itself instructs should be avoided to retain hyaluronidase activity, such as substitutions known to render the enzyme inactive or significant C-terminal truncations.

Ground 2: Claims 1-10 are unpatentable under 35 U.S.C. § 112 for Lacking Enablement

• Prior Art Relied Upon: This ground relies on the specification of the ’791 patent, arguing it fails to enable a POSA to practice the full scope of the invention without undue experimentation.
• Core Argument:
  • Undue Experimentation and Impossible Scope: Petitioner argued that the immense scope of the claims (10^49+ polypeptides) makes it impossible for a POSA to practice the full claimed invention. To determine which of the countless possible protein sequences possess the claimed increased activity, a POSA would have to engage in a massive "make-and-test" campaign, which constitutes undue experimentation.
  • Prophetic Research Plan: The specification was characterized as providing only a prophetic, "iterative" research plan for discovering active mutants, rather than enabling a POSA to make and use them. This plan allegedly involves randomly generating mutants and screening them, which Petitioner, citing Amgen, argued is a "roadmap for research" and not sufficient for enablement.
  • Unpredictability in the Art: The petition contended that the field of protein engineering was highly unpredictable at the time of filing, particularly regarding the effects of multiple concurrent mutations on a protein's structure and function. The cumulative effects of up to 21 substitutions could not be reliably predicted, and the specification provides no guidance to navigate this unpredictability.
  • Lack of Guidance and Working Examples: The specification was argued to provide no working examples of multiply-modified PH20 polypeptides, let alone any based on the 433-residue reference sequence. Without such examples or credible guidance, a POSA is left to iterative, trial-and-error discovery across an impossibly large search space. The data provided on singly-substituted mutants was deemed insufficient to enable the distinct and unpredictable multiply-substituted claimed genus.

4. Key Claim Construction Positions

• Functional Genus: While not proposing formal constructions for specific terms, the petition’s entire argument rested on interpreting the claims as defining an extraordinarily broad functional genus. The claims are defined by a combination of structural features (sequence identity, specific substitutions) and a functional outcome ("exhibits increased hyaluronidase activity"). The vast number of sequences meeting the structural limitations, combined with the uncertainty of which ones would meet the functional limitation, was central to both the written description and enablement challenges.

5. Key Technical Contentions

• Unpredictability of Multiple Mutations: A core technical contention was that making multiple concurrent changes to a protein’s amino acid sequence has unpredictable effects on its folding, stability, and enzymatic activity. Petitioner argued that the structural and functional effects of a single substitution cannot be extrapolated to predict the effects of combining that substitution with up to 20 others, making the claimed genus highly unpredictable and non-enabled.

6. Relief Requested

• Petitioner requests institution of post-grant review and cancellation of claims 1-10 of the ’791 patent as unpatentable under 35 U.S.C. § 112.