PTAB

PGR2025-00042

Merck Sharp & Dohme LLC v. Halozyme Inc

Log In
Key Events
Petition
petition

1. Case Identification

2. Patent Overview

  • Title: Modified Human PH20 Polypeptides
  • Brief Description: The ’618 patent relates to modified human PH20 hyaluronidase polypeptides. The claims define a genus of polypeptides that must contain an amino acid substitution at position 309 and may contain numerous additional modifications, provided the resulting polypeptide retains a specified minimum sequence identity to a reference sequence.

3. Grounds for Unpatentability

Ground 1: Claims 1-40 Lack Written Description Under 35 U.S.C. § 112

  • Core Argument: Petitioner argued the challenged claims encompass a functionally-defined genus of modified PH20 polypeptides of immense scope, calculated to capture between 10^60 and 10^113 distinct sequences, for which the specification fails to demonstrate possession. The patent’s disclosure was characterized as meager, providing only examples of singly-substituted mutants and a prophetic "make-and-test" research plan for discovering multiply-substituted ones. Petitioner contended this fails the written description requirement by not describing a representative number of species or identifying common structural features that would allow a person of ordinary skill in the art (POSA) to visualize and distinguish active members of the genus. The argument highlighted that the disclosed single-substitution examples are not structurally representative of the claimed polypeptides having up to 42 substitutions. Moreover, the claims impermissibly capture mutants with features the disclosure suggests avoiding, such as substitutions known to render the protein inactive or significant C-terminal truncations that eliminate activity, without teaching how activity might be restored.

Ground 2: Claims 1-40 Are Not Enabled Under 35 U.S.C. § 112

  • Core Argument: Petitioner asserted that practicing the full scope of the claims would require undue, if not impossible, experimentation. To identify the subgenus of "active mutants" within the astronomical number of claimed polypeptides, a POSA would be forced to follow the patent's "iterative, trial-and-error process" of making and testing a virtually infinite number of candidates. The field of protein engineering was described as highly unpredictable, especially regarding the cumulative and interactive effects of multiple concurrent substitutions on protein folding and function. Petitioner argued the specification provides no credible guidance to bypass this undue experimentation, as its working examples are limited to single substitutions and do not inform the properties of multiply-substituted variants. This forces a POSA to navigate a vast and unpredictable landscape of unknowable properties to practice the invention.

Ground 3: Claims 1-2, 4-5, 7-22, and 24-40 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:
    • Prior Art Mapping: Petitioner argued that the challenged claims encompass a specific, obvious mutant: I309N PH20(1-447), which involves substituting asparagine (N) for isoleucine (I) at position 309. The ’429 patent, owned by the Patent Owner, explicitly teaches making single amino acid substitutions in "non-essential regions" of the PH20 protein to create functional equivalents. The Chao reference, which provides an experimentally determined structure for the homologous human HYAL1 enzyme and an alignment of human hyaluronidases, would have enabled a POSA in 2011 to identify position 309 of PH20 as being within such a non-essential region, situated between two conserved essential residues.
    • Motivation to Combine: A POSA, motivated by the ’429 patent's explicit suggestion to create modified PH20 polypeptides, would combine its teachings with publicly available structural information like Chao to identify suitable locations and substitutions. By performing a multiple-sequence alignment of homologous proteins—a standard technique informed by Chao—a POSA would have identified not only that position 309 was non-essential but also that asparagine (N) appears with high frequency (~9%) at the homologous position across different species. This evolutionary data provided a strong motivation to select asparagine as a viable substitution.
    • Expectation of Success: The ’429 patent created an expectation of success by stating that single substitutions in non-essential regions generally do not substantially alter biological activity. This was strongly reinforced by the evolutionary data from the sequence alignment, which showed that nature has repeatedly selected for and tolerated asparagine at this position. Petitioner's expert also used structural modeling—a tool available in 2011—to confirm that the I309N substitution would be structurally tolerated and would not disrupt the protein's function, further solidifying the expectation of success.

4. Arguments Regarding Discretionary Denial

  • Petitioner argued that discretionary denial under § 324(a) or § 325(d) is unwarranted. No parallel litigation involving the ’618 patent is pending, making denial under the Fintiv factors inapplicable. Furthermore, the obviousness grounds rely on the Chao reference, which was not cited or considered during prosecution, and are supported by new expert testimony not previously before the examiner, weighing against discretionary denial.

5. Relief Requested

  • Petitioner requests institution of post-grant review and cancellation of claims 1-40 of the ’618 patent as unpatentable.