PTAB

PGR2025-00053

Merck Sharp & Dohme LLC v. Halozyme Inc

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Key Events
Petition
petition

1. Case Identification

2. Patent Overview

  • Title: Soluble Human PH20 Polypeptides
  • Brief Description: The ’773 patent concerns structurally altered, soluble forms of the human PH20 hyaluronidase enzyme that are modified to retain or alter enzymatic activity. The claims cover polypeptides with a mandatory amino acid replacement at position 320 and up to 19 additional modifications.

3. Grounds for Unpatentability

Ground 1: Claims 1-15 Lack Written Description Under 35 U.S.C. § 112

  • Core Argument for this Ground:
    • Prior Art Mapping: Petitioner argued that the ’773 patent fails to provide an adequate written description for the claimed genus of soluble human PH20 polypeptides. The claims, which require one substitution at position 320 and permit up to 19 additional modifications, encompass an immense genus of approximately 10^57 distinct polypeptides. The specification, however, only discloses examples of singly-modified polypeptides and provides no data for any multiply-modified species.
    • Petitioner contended that the specification does not disclose a representative number of species or identify common structural features that would allow a person of ordinary skill in the art (POSITA) to visualize or recognize the members of the claimed genus. The disclosure provided only a prophetic "make-and-test" research plan, which amounts to an invitation to discover the claimed invention rather than a description of what was actually possessed. The limited examples of single-substitution mutants were argued to be not representative of the structurally and functionally diverse multiply-modified polypeptides claimed, especially given the unpredictable effects of multiple concurrent mutations on protein structure and solubility.

Ground 2: Claims 1-15 Are Not Enabled Under 35 U.S.C. § 112

  • Core Argument for this Ground:
    • Prior Art Mapping: Building on the written description arguments, Petitioner asserted that practicing the full scope of the claims would require undue experimentation. The sheer scope of the claims (~10^57 polypeptides) makes it impossible for a POSITA to make and test all, or even a substantial number, of the claimed species to determine which are soluble and enzymatically active as required by the claims.
    • The specification provided no guidance beyond a prophetic, iterative research plan of random mutagenesis and screening. Petitioner argued this "trial-and-error" approach is insufficient for enablement, particularly in the unpredictable field of protein engineering where multiple amino acid changes can have unforeseen effects on folding, stability, solubility, and activity. The specification did not disclose any actual multiply-modified polypeptides, nor did it provide any method to predict which combinations of up to 20 modifications would result in a soluble, active protein. This necessitates an impossible level of experimentation to practice the invention.

Ground 3: Claims 1-2 and 5-15 are obvious over the ’429 Patent in view of Chao

  • Prior Art Relied Upon: Patentee’s own Patent 7,767,429 (’429 patent) and Chao (a 2007 publication on the structure of human hyaluronidase).
  • Core Argument for this Ground:
    • Prior Art Mapping: Petitioner argued that the claims encompass at least one obvious single-substitution mutant: a D320K variant of the PH201-447 polypeptide. The ’429 patent, owned by the Patent Owner, taught that single amino acid substitutions in non-essential regions of a PH20 polypeptide generally do not substantially alter biological activity. Chao provided an experimentally determined structure of a related human hyaluronidase (HYAL1) and an alignment of human hyaluronidases, which a POSITA would use to identify essential and non-essential regions of the PH20 protein.
    • Motivation to Combine: A POSITA, motivated by the ’429 patent’s teaching to create functionally equivalent variants of PH20 through single amino acid substitutions, would have looked to prior art like Chao for structural guidance. Chao’s structural alignment would have identified the region around position 320 as non-essential.
    • Expectation of Success: The combination of the ’429 patent and Chao would have led a POSITA to identify position 320 as a suitable target for modification. A multiple sequence alignment of known hyaluronidases revealed that lysine (K) is the most prevalent amino acid at the position corresponding to 320, appearing in nearly 60% of homologous enzymes. This high frequency of natural occurrence, combined with the ’429 patent’s assurance that such substitutions are well-tolerated, would have given a POSITA a reasonable expectation of success that substituting aspartic acid (D) with lysine (K) at position 320 would result in a soluble, enzymatically active PH20 polypeptide. Because this obvious mutant falls within the scope of claims 1-2 and 5-15, those claims were argued to be unpatentable under §103.

4. Relief Requested

  • Petitioner requests institution of post-grant review and cancellation of claims 1-15 of the ’773 patent as unpatentable.