PTAB

PGR2025-00004

Merck Sharp & Dohme LLC v. Halozyme Inc

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Key Events
Petition
petition

1. Case Identification

2. Patent Overview

  • Title: Structurally Altered Hyaluronidase Enzymes
  • Brief Description: The ’298 patent discloses modified forms of the human hyaluronidase protein PH20. The claims cover vast genera of PH20 polypeptides having at least one specific amino acid substitution and a minimum sequence identity to a reference sequence, which are intended to retain enzymatic activity.

3. Grounds for Unpatentability

Ground 1: Claims 1-22 Lack Written Description under 35 U.S.C. § 112

  • Core Argument for this Ground:
    • Prior Art Mapping: Petitioner argued that the ’298 patent fails the written description requirement because its claims encompass an immense and structurally diverse genus of polypeptides (calculated to be between 10⁴⁹ and 10⁶⁶ distinct molecules) while the specification provides a comparatively meager disclosure. The specification only exemplifies single-replacement PH20 mutants and provides no common structural features that would allow a person of ordinary skill in the art (POSITA) to identify which of the trillions of multiply-modified polypeptides within the claims’ scope would be functional.
    • Key Aspects: The working examples (single amino acid substitutions in one specific PH20 sequence) were asserted to be entirely non-representative of the claimed genus, which permits up to 22 additional substitutions in any of 35 different PH20 sequences of varying lengths. The disclosure was characterized as merely a "research plan" that improperly fences in a genus without demonstrating possession of it.

Ground 2: Claims 1-22 Are Not Enabled under 35 U.S.C. § 112

  • Core Argument for this Ground:
    • Prior Art Mapping: Petitioner contended that practicing the full scope of the claims would require undue experimentation. The specification’s only guidance for creating multiply-modified PH20 mutants is a prophetic, iterative "make-and-test" research plan. A POSITA would have to create and screen a physically impossible number of mutants to identify those that are enzymatically active.
    • Key Aspects: The field of protein engineering for multiple concurrent mutations was highly unpredictable in 2011, and the patent provides no guidance to navigate this unpredictability. The sheer quantity of experimentation—requiring the synthesis and testing of a mass of protein exceeding that of the Earth—was argued to be beyond undue and factually impossible, rendering the claims non-enabled.

Ground 3: Obviousness of Specific Embodiment - Claims 1-4 and 7-22 are obvious over the ’429 Patent in view of Chao

  • Prior Art Relied Upon: Patentee’s ’429 patent (Patent 7,767,429) and Chao (a 2007 Biochemistry journal article).
  • Core Argument for this Ground:
    • Prior Art Mapping: Petitioner argued that the challenged claims encompass at least one specific, obvious mutant: a PH20 polypeptide with a single M313K substitution (methionine to lysine at position 313). The ’429 patent taught making single amino acid substitutions in "non-essential regions" of the PH20 protein to create equivalents that do not substantially alter biological activity. Chao, which described the structure of a homologous human hyaluronidase (HYAL1), provided the tools for a POSITA to identify position 313 as being in a non-essential region of PH20.
    • Motivation to Combine: A POSITA, motivated by the ’429 patent to create modified PH20 polypeptides, would combine its teachings with conventional rational design principles. This would lead the POSITA to consult literature like Chao to identify non-essential regions and suitable amino acid substitutions.
    • Expectation of Success: A POSITA would expect the M313K substitution to be tolerated and retain enzymatic activity. This expectation was based on the ’429 patent's explicit statement that such changes do not substantially alter activity, the fact that lysine is the most prevalent amino acid at the corresponding position in 88 homologous hyaluronidase sequences, and lysine’s known propensity to support the α-helix secondary structure present at that location.

4. Key Technical Contentions (Beyond Claim Construction)

  • Vast Genus vs. Narrow Disclosure: A central technical contention was the astronomical disparity between the claimed scope and the disclosed examples. Petitioner argued that the data from approximately 2,500 single-substitution "active mutants" provided no structurally predictive guidance for the properties of the trillions of claimed multiply-substituted mutants, as the effects of multiple simultaneous mutations on protein structure and function were highly unpredictable.
  • Unreliability of Disclosed Data: Petitioner contended that the empirical data presented in the patent was unreliable and uninformative. For example, stability testing data for single-mutants showed extensive variability in the positive controls, raising doubts about the significance of the results for any individual tested mutant and providing no reliable basis for extrapolation to multiply-modified proteins.

5. Arguments Regarding Discretionary Denial

  • Petitioner argued that discretionary denial under § 324(a) or § 325(d) would be inappropriate. No parallel litigation regarding the ’298 patent exists. Furthermore, the Examiner did not consider the primary obviousness reference, Chao, during prosecution. The Examiner also did not consider the core § 112 arguments regarding the lack of support for the immense genus of claimed polypeptides, as the only § 112 rejections were for unrelated, narrow issues that were subsequently mooted or amended.

6. Relief Requested

  • Petitioner requests institution of post grant review and cancellation of claims 1-22 of the ’298 patent as unpatentable under 35 U.S.C. §§ 112 and 103.