Merck Sharp & Dohme LLC v. Halozyme Inc

1. Case Identification

• Case #: PGR2025-00046
• Patent #: 12,091,692
• Filed: April 29, 2025
• Petitioner(s): Merck Sharp & Dohme LLC
• Patent Owner(s): Halozyme Inc.
• Challenged Claims: 1-40

2. Patent Overview

• Title: Modified Human PH20 Polypeptides
• Brief Description: The ’692 patent relates to modified human PH20 hyaluronidase enzymes. The claims define modified PH20 polypeptides that have at least one amino acid substitution at position 313 and may have numerous additional substitutions, insertions, or deletions, while retaining a specified minimum sequence identity to reference sequences.

3. Grounds for Unpatentability

Ground 1: Claims 1-40 Lack Written Description under §112

• Core Argument for this Ground:
  • Prior Art Mapping: Petitioner argued that all challenged claims lack adequate written description because they claim an immense genus of modified PH20 polypeptides while the specification fails to demonstrate possession of the invention. The claims, defined by sequence identity parameters, capture a staggering number of distinct polypeptides (between 10^60 and 10^113). The specification’s disclosure, however, is limited to experimental data for only singly-modified polypeptides and a prophetic research plan for discovering multiply-modified mutants.
  • Key Aspects: Petitioner contended the specification does not disclose a representative number of species across the full scope of the claims, nor does it identify common structural features that would allow a person of ordinary skill in the art (POSITA) to distinguish which of the vast number of claimed polypeptides are enzymatically active. The provided examples of single-substitution mutants were argued to be qualitatively different and not representative of the claimed multiply-substituted polypeptides, which could have between 2 and 42 additional changes. The specification’s guidance was characterized as merely "drawing a fence" around a purported genus without describing the members within it.

Ground 2: Claims 1-40 Are Not Enabled under §112

• Core Argument for this Ground:
  • Prior Art Mapping: Petitioner argued that practicing the full scope of the claims would require undue experimentation. To identify the operative species ("active mutants") from the inoperative ones within the immense genus claimed would require a POSITA to make and test an impossible number of polypeptides (at least ~10^60). The patent’s only guidance is a prophetic, iterative "make-and-test" research plan.
  • Key Aspects: The petition emphasized the unpredictability in the field of protein engineering, particularly concerning the effects of multiple concurrent amino acid substitutions. The cumulative effects of many changes on protein structure and function could not be reliably predicted by a POSITA at the time of the invention. The specification provided no guidance to bypass this trial-and-error discovery process, offering only a narrow set of working examples (single-substitution mutants) that are not predictive for the claimed multiply-substituted mutants. This, Petitioner argued, is a textbook case of non-enablement under the reasoning of Amgen Inc. v. Sanofi.

Ground 3: Claims 1-2, 4-5, 7-26, and 29-40 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 et al., “Structure of Human Hyaluronidase-1…” (2007) (Chao).
• Core Argument for this Ground:
  • Prior Art Mapping: Petitioner asserted that the claims encompass at least one specific, obvious mutant: a PH201-447 polypeptide with a methionine-to-lysine substitution at position 313 (M313K). The ’429 patent taught making single amino acid substitutions in non-essential regions of the PH201-447 polypeptide to create equivalents that do not substantially alter biological activity. Chao, which described the structure of a related human hyaluronidase, provided the tools for a POSITA to identify position 313 as being in a non-essential region of PH20.
  • Motivation to Combine: A POSITA, guided by the ’429 patent’s suggestion to create modified PH20 polypeptides, would have been motivated to consult the state of the art, including Chao, to identify suitable non-essential regions for modification. A multi-sequence alignment of homologous proteins, informed by Chao, would have revealed that lysine is the most prevalent amino acid at the position corresponding to 313, making it an obvious choice for substitution.
  • Expectation of Success: A POSITA would have reasonably expected the M313K mutant to retain enzymatic activity. The ’429 patent itself stated that single substitutions in non-essential regions generally do not alter biological activity. Furthermore, the high prevalence of lysine at this position across numerous homologous, naturally occurring hyaluronidases indicated that this substitution was well-tolerated by evolution, providing a strong expectation of success.

4. Key Technical Contentions (Beyond Claim Construction)

• Extreme Claim Breadth vs. Unpredictable Art: A central technical contention underpinning the §112 grounds was the massive disconnect between the scope of the claims and the nature of the technology. Petitioner argued that the claims functionally claim an astronomical number of possible protein sequences (up to 10^113). In the unpredictable field of protein engineering, the effects of combining multiple amino acid substitutions on a protein's structure and activity were not foreseeable. Therefore, identifying the small subset of functional "active mutants" from this vast space was not possible without an iterative, trial-and-error process tantamount to a research project, not routine experimentation.

5. Arguments Regarding Discretionary Denial

• Petitioner argued that the Board should not exercise its discretion to deny institution under §324(a) or §325(d). The obviousness grounds rely on the Chao reference, which was not cited or considered during prosecution. The petition was also supported by new expert testimony not available to the examiner. Petitioner further contended that a recently-filed infringement complaint by the Patent Owner does not warrant denial under the Fintiv factors.

6. Relief Requested

• Petitioner requested institution of post-grant review and cancellation of claims 1-40 of the ’692 patent as unpatentable.