Merck Sharp & Dohme LLC v. Halozyme Inc

1. Case Identification

• Case #: PGR2025-00039
• Patent #: 12,104,185
• Filed: March 28, 2025
• Petitioner(s): Merck Sharp & Dohme LLC
• Patent Owner(s): Halozyme Inc.
• Challenged Claims: 1-11

2. Patent Overview

• Title: Methods of Increasing Delivery of Therapeutic Agents
• Brief Description: The ’185 patent relates to methods for increasing the delivery of a therapeutic agent by co-administering it with a modified, enzymatically active PH20 hyaluronidase polypeptide. The claimed polypeptides must contain a specific amino acid substitution at position 320 and maintain at least 95% sequence identity to one of several reference sequences.

3. Grounds for Unpatentability

Ground 1: Obviousness over the ’429 Patent in view of Chao - Claims 1-11 are obvious over Patent 7,767,429 in view of Chao (2007)

• Prior Art Relied Upon: Patentee's Patent 7,767,429 (’429 patent) and Chao (a 2007 publication in Biochemistry).
• Core Argument for this Ground:
  • Prior Art Mapping: Petitioner argued that the challenged claims are unpatentable because they encompass at least one obvious species: a PH20 polypeptide with a single D320K substitution (aspartic acid to lysine at position 320) used in a method to increase therapeutic agent delivery. The ’429 patent, owned by Patentee, taught using modified PH20 polypeptides—including single amino acid substitution mutants in non-essential regions—as "spreading" agents to enhance the delivery of other drugs. Chao provided detailed structural analysis and sequence alignments of human hyaluronidases, which a person of ordinary skill in the art (POSITA) would use to guide such modifications.
  • Motivation to Combine: A POSITA, motivated by the ’429 patent's explicit suggestion to create single-substitution mutants in non-essential regions of PH20, would consult the state of the art, including publications like Chao, for structural and comparative sequence information. This combination would provide a roadmap for identifying suitable non-essential regions for modification and selecting a tolerated amino acid for substitution to create an enzymatically active variant.
  • Expectation of Success: The ’429 patent explicitly stated that "single amino acid substitutions in non-essential regions of a polypeptide do not substantially alter biological activity." A POSITA using the teachings of Chao and publicly available sequence data would identify position 320 as being within a non-essential region of PH20. Further, a multi-sequence alignment of homologous proteins would reveal that lysine (K) is a highly prevalent and thus evolutionarily tolerated residue at the position corresponding to 320. This provided a strong and reasonable expectation that substituting the native aspartic acid (D) with lysine (K) would be well-tolerated and would result in a mutant that retained the necessary enzymatic activity for the method taught in the ’429 patent.
• Additional Grounds: Petitioner asserted that claims 1-11 are also unpatentable under 35 U.S.C. §112 for lacking adequate written description and enablement. The basis for these challenges was the vast disparity between the immense scope of the claims, which cover functionally defined genera encompassing trillions of potential polypeptide sequences, and the narrow disclosure, which provides only a small number of non-representative, single-substitution examples and a prophetic "make-and-test" research plan.

4. Key Technical Contentions (Beyond Claim Construction)

• Claims Require Enzymatically Active PH20: Petitioner contended that a proper interpretation of the claims, informed by the specification, requires the modified PH20 polypeptide to be enzymatically active. The patent’s disclosure unequivocally attributes the "spreading" and "increased delivery" function to the ability of PH20 to hydrolyze hyaluronic acid in the extracellular matrix. Therefore, hyaluronidase activity is a prerequisite for performing the claimed method, and the claims are limited to using "active" mutants.
• Disparity Between Claim Scope and Disclosure: A central technical argument was that the claims are fatally broad relative to the disclosure. Petitioner argued the claims, defined by percent sequence identity, encompass an astronomical number of multiply-modified polypeptides (estimated between 10⁴⁹ and 10⁶⁶). In contrast, the specification's working examples are limited to a small number of singly-modified polypeptides. Petitioner asserted these examples are not structurally or functionally representative of the vast, unexplored genus of multiply-substituted mutants, and that the disclosure’s prophetic research plan fails to enable a POSITA to practice the full scope of the claims without undue—and practically impossible—experimentation.

5. Arguments Regarding Discretionary Denial

• Petitioner argued that discretionary denial under 35 U.S.C. §325(d) is unwarranted. The obviousness ground relies on the Chao reference, which was not cited or considered by the Examiner during prosecution. The petition is also supported by new evidence in the form of expert testimony that was not before the Examiner. As no parallel district court litigation involving the ’185 patent is pending, denial under the Fintiv factors is inappropriate.

6. Relief Requested

• Petitioner requests institution of post-grant review (PGR) and cancellation of claims 1-11 of Patent 12,104,185 as unpatentable.