Merck Sharp & Dohme LLC v. Halozyme Inc

1. Case Identification

• Case #: PGR2025-00003
• Patent #: 11,952,600
• Filed: November 12, 2024
• Petitioner(s): Merck Sharp & Dohme LLC
• Patent Owner(s): Halozyme Inc.
• Challenged Claims: 1-21

2. Patent Overview

• Title: Modified PH20 Polypeptides
• Brief Description: The ’600 patent relates to structurally altered forms of the human PH20 hyaluronidase enzyme. The claims are directed to genera of modified PH20 polypeptides containing specific amino acid substitutions that purportedly retain or exhibit hyaluronidase activity.

3. Grounds for Unpatentability

Ground 1: Claims 1-21 are unpatentable under 35 U.S.C. § 112 for Lack of Written Description

• Prior Art Relied Upon: Not applicable (challenge based on patent’s own disclosure).
• Core Argument for this Ground:
  • Prior Art Mapping: Petitioner argued that the claims define an immense and structurally diverse genus of modified PH20 polypeptides, encompassing between 10⁴⁹ and 10⁶⁵ distinct molecules. These claims require one specific amino acid replacement at position 320 but then permit up to 22 additional modifications anywhere in the sequence. The specification, however, fails to provide a representative number of species, disclosing only data for singly-modified PH20 polypeptides.
  • Key Aspects: Petitioner contended these singly-modified examples are not representative of the claimed, vastly larger group of multiply-modified polypeptides. The disclosure allegedly fails to identify any common structural features shared by members of the claimed genus that would distinguish active mutants. Instead, it provides only a prophetic "make-and-test" research plan, which is insufficient to demonstrate possession of the claimed invention.

Ground 2: Claims 1-21 are unpatentable under 35 U.S.C. § 112 for Lack of Enablement

• Prior Art Relied Upon: Not applicable (challenge based on patent’s own disclosure).
• Core Argument for this Ground:
  • Prior Art Mapping: Petitioner asserted that practicing the full scope of the claims would require undue experimentation. A person of ordinary skill in the art (POSA) would need to create and test trillions of polypeptide combinations to determine which ones exhibit the claimed hyaluronidase activity. This "make-and-test" methodology for an astronomically large and diverse genus is impossible, not merely undue.
  • Key Aspects: The petition emphasized that, at the time of invention, the effects of making multiple concurrent amino acid changes on a protein’s structure and function were highly unpredictable. The specification provides no guidance to navigate this unpredictability, offering only an iterative research plan that requires screening an immense number of mutants without any reasonable expectation of success for any given combination.

Ground 3: Claims 1-4 and 7-21 are obvious over the ’429 Patent in view of Chao

• Prior Art Relied Upon: Patent 7,767,429 (’429 patent) and Chao (a 2007 biochemistry journal article).
• Core Argument for this Ground:
  • Prior Art Mapping: Petitioner argued that the broad genus claims encompass at least one specific, obvious species: the PH20 protein with a single D320K substitution (aspartic acid to lysine at position 320). The ’429 patent, also owned by Halozyme, explicitly teaches making single amino acid substitutions in "non-essential regions" of the PH20 protein to create equivalents that retain biological activity.
  • Motivation to Combine: A POSA, motivated by the ’429 patent to create modified PH20, would consult contemporary scientific literature like Chao for structural information. Chao provided a multiple-sequence alignment of human hyaluronidases that would have allowed a POSA to readily identify position 320 as being within a non-essential region.
  • Expectation of Success: The ’429 patent created an expectation of success by stating that single substitutions in non-essential regions generally do not alter biological activity. Furthermore, Chao’s alignment and other known homologous sequences showed that lysine (K) is the most prevalent amino acid at the position corresponding to 320, suggesting this substitution is well-tolerated by evolution and would likely result in a stable, active enzyme.

4. Key Claim Construction Positions

• "Active mutants": Petitioner argued that the specification describes two mutually exclusive categories of modified polypeptides: "active mutants" (possessing hyaluronidase activity) and "inactive mutants" (lacking activity). Petitioner asserted that the claim language, including the required substitutions at position 320 (which were all disclosed as "active") and the functional requirements of dependent claims 5 and 6, restricts the scope of all challenged claims to only the "active mutant" embodiment.

5. Key Technical Contentions (Beyond Claim Construction)

• Unpredictability of Multiple Mutations: A central technical premise of the §112 arguments was that while a POSA in 2011 could reasonably predict the effect of a single amino acid substitution in certain contexts, predicting the cumulative and interactive effects of multiple concurrent substitutions on protein folding, stability, and function was not possible. This unpredictability rendered the patent's prophetic "make-and-test" plan for discovering multiply-modified proteins insufficient for enablement.

6. Arguments Regarding Discretionary Denial

• Petitioner argued that discretionary denial under §324(a) or §325(d) would be inappropriate. There is no parallel litigation, so Fintiv factors do not favor denial. Further, the substantive grounds relied on prior art (Chao) and arguments (scope of the genus under §112) that were not before the Examiner during prosecution, meaning the Board would be considering the issues for the first time.

7. Relief Requested

• Petitioner requests institution of Post Grant Review and cancellation of claims 1-21 of the ’600 patent as unpatentable.