Merck Sharp & Dohme LLC v. Halozyme Inc

1. Case Identification

• Case #: PGR2025-00009
• Patent #: 12,123,035
• Filed: December 27, 2024
• Petitioner(s): Merck Sharp & Dohme LLC
• Patent Owner(s): Halozyme Inc.
• Challenged Claims: 1-34

2. Patent Overview

• Title: Modified PH20 Polypeptides
• Brief Description: The ’035 patent relates to modified human hyaluronidase (PH20) polypeptides that contain one or more amino acid substitutions compared to a reference sequence but retain enzymatic activity. The technology is aimed at creating altered forms of the PH20 enzyme for therapeutic use.

3. Grounds for Unpatentability

Ground 1: Claims 1-34 Lack Written Description under 35 U.S.C. § 112

• Core Argument for this Ground:
  • Prior Art Mapping: Petitioner argued that all challenged claims are unpatentable because the specification failed to provide an adequate written description for the immensely broad genus of claimed polypeptides. The claims, through sequence identity limitations, encompassed a staggering number of potential mutants (between 10^59 and 10^112), including those with up to 42 amino acid substitutions. However, the specification’s disclosure was limited to a narrow set of examples of singly-modified PH20 polypeptides.
  • Key Aspects: Petitioner contended these few examples were not representative of the vast and structurally diverse genus of multiply-modified proteins being claimed. The disclosure provided no common structural features to identify members of the genus and instead offered only a prophetic “make-and-test” research plan to discover other qualifying mutants. Petitioner argued this amounted to merely “drawing a fence around a purported genus” without demonstrating possession of the invention. The disclosure also failed to provide guidance for sub-genera of the claims, such as polypeptides with C-terminal truncations or those incorporating substitutions the specification itself suggested avoiding.

Ground 2: Claims 1-34 Are Not Enabled under 35 U.S.C. § 112

• Core Argument for this Ground:
  • Prior Art Mapping: Petitioner asserted that practicing the full scope of the claims would require undue experimentation, rendering them not enabled. The argument centered on the immense scope of the claims combined with the unpredictability of the art of protein engineering. A person of ordinary skill in the art (POSA) could not have predicted the effects of multiple concurrent amino acid substitutions on the structure and function of the PH20 protein.
  • Key Aspects: The specification provided no guidance beyond a prophetic, iterative "trial-and-error" process. To identify the active mutants within the claimed scope, a POSA would have to synthesize and test an impossible number of candidates. Petitioner argued this extensive, unpredictable research effort far exceeded routine experimentation, making it an undue burden to practice the invention across its full claimed scope.

Ground 3: Claims 1-2, 5-34 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 claims were obvious because they each encompassed at least one of two specific, obvious single-replacement mutants: S312T (serine to threonine at position 312) and S312N (serine to asparagine at position 312) in the PH20(1-447) polypeptide. The ’429 patent taught making single amino acid substitutions in “non-essential regions” of PH20 polypeptides to create equivalents. Chao, which described the structure of a human hyaluronidase homologous to PH20, provided the tools for a POSA to identify position 312 as being in such a non-essential region.
  • Motivation to Combine: A POSA would combine the teachings to implement the ’429 patent’s suggestion to create improved or equivalent PH20 variants. The ’429 patent motivated the goal (single substitutions in non-essential regions), and Chao provided the structural insights to achieve it by identifying suitable target locations like position 312. Analysis of homologous proteins, as taught by the art, showed that threonine and asparagine were the most prevalent natural substitutions for serine at that position, making them obvious choices.
  • Expectation of Success: A POSA would have had a reasonable expectation of success. The ’429 patent itself stated that “single amino acid substitutions in non-essential regions of a polypeptide do not substantially alter biological activity.” Furthermore, structural modeling and the natural occurrence of these amino acids at the corresponding position in other hyaluronidases confirmed that the S312T and S312N substitutions would be tolerated without significant disruption to the protein's structure or enzymatic activity.

4. Key Technical Contentions (Beyond Claim Construction)

• Claim Scope Limited to "Active Mutants": Petitioner argued that the specification distinguished between "active mutants" (exhibiting at least 40% activity) and "inactive mutants." Based on the claim language and the specification’s focus, Petitioner contended the claims were limited to the "active mutant" embodiment. This interpretation defined the scope of the invention that must be described and enabled, highlighting the failure to support the vast genus of active multiply-substituted proteins.
• Unpredictability of Multiple Substitutions: A central technical premise was that while the effect of a single amino acid substitution in a non-essential region could be reasonably predicted, the cumulative effects of multiple concurrent substitutions were highly unpredictable in 2011. Introducing multiple changes could disrupt protein folding and function in complex ways that were beyond the predictive capacity of the tools available to a POSA.

5. Arguments Regarding Discretionary Denial

• Petitioner argued that the Board should not exercise its discretion to deny institution under §324(a) or §325(d). No parallel litigation involving the ’035 patent was pending, making discretionary denial under Fintiv inapplicable. Furthermore, the obviousness grounds relied on the Chao reference, which was not cited or considered by the Examiner during prosecution, presenting new arguments and evidence for the Board’s consideration.

6. Relief Requested

• Petitioner requests institution of a post-grant review and cancellation of claims 1-34 of the ’035 patent as unpatentable.