Merck Sharp & Dohme LLC v. Halozyme Inc

1. Case Identification

• Case #: PGR2025-00052
• Patent #: 12,264,345
• Filed: June 27, 2025
• Petitioner(s): Merck Sharp & Dohme LLC
• Patent Owner(s): Halozyme Inc.
• Challenged Claims: 1-17

2. Patent Overview

• Title: Modified PH20 Polypeptides
• Brief Description: The ’345 patent relates to modified human hyaluronidase PH20 polypeptides. The claims define a modified "hyaluronidase domain" with a required amino acid substitution at position 313 and up to 19 additional optional modifications within that domain, which must retain enzymatic activity.

3. Grounds for Unpatentability

Ground 1: Claims 1-17 Lack Written Description and Enablement under 35 U.S.C. §112(a)

• Core Argument: Petitioner argued that the challenged claims are invalid because the specification fails to provide adequate written description and enabling disclosure for the immense scope of the claimed subject matter. The claims encompass an astronomical number of structurally distinct modified PH20 polypeptides—ranging from 10⁴³ to 10⁵⁶ species—yet the disclosure provides no working examples of any multiply-modified polypeptide. Instead, the specification only describes singly-modified mutants and offers a prophetic "make-and-test" research plan, which Petitioner contended is insufficient to demonstrate possession of the claimed genera.
  • Written Description Deficiencies: Petitioner asserted that the specification lacks the "blaze marks" necessary to guide a person of ordinary skill in the art (POSITA) to the claimed invention. It argued the claims improperly combine disparate concepts from the disclosure: the prior art concept of a "hyaluronidase domain" and the idea of making multiple modifications, which are never linked in the specification. The disclosure provides no common structural features for the claimed genus and fails to describe a representative number of species. The ~2,500 disclosed "active" single-substitution mutants were argued to be non-representative of the claimed multiply-modified polypeptides. Furthermore, Petitioner argued the claims improperly capture polypeptides with sequences outside the hyaluronidase domain that were unknown or undiscoverable at the time of filing.
  • Enablement Deficiencies: Petitioner argued that practicing the full scope of the claims would require undue experimentation. To identify the "active mutants" within the claimed genera, a POSITA would need to follow the patent's trial-and-error methodology to create and test at least 10⁴³ different mutants, an impossible task. The field of protein engineering was described as unpredictable, particularly concerning the cumulative effects of multiple mutations on protein folding and function. The disclosure was said to offer no meaningful guidance beyond this iterative research plan, providing no data for any multiply-modified proteins and no way to predict which of the countless combinations would result in a stable, active enzyme.

Ground 2: Claims 1-7 and 15-17 are obvious over the ’429 Patent in view of Chao under 35 U.S.C. §103

• 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 all challenged claims encompass at least one specific, obvious mutant: a PH20₁₋₄₄₇ polypeptide with a single substitution of methionine (M) with lysine (K) at position 313 (the "M313K mutant"). The ’429 patent, owned by the Patentee, taught that single amino acid substitutions in non-essential regions of the PH20 protein do not substantially alter biological activity and explicitly identified lysine as a suitable conservative substitution for methionine. Chao, which reported the first experimentally determined structure for a human hyaluronidase, provided a multi-sequence alignment and structural insights that would have allowed a POSITA to readily identify position 313 as being located within a non-essential region of the PH20 protein.
  • Motivation to Combine: A POSITA would be motivated to produce modified versions of the PH20₁₋₄₄₇ polypeptide because the ’429 patent taught its therapeutic utility and expressly motivated the creation of equivalents through single amino acid substitutions. A POSITA would combine the teachings of the ’429 patent with Chao because Chao provided the structural and sequence information necessary to rationally implement the ’429 patent’s general guidance—specifically, to identify non-essential regions where substitutions could be made without disrupting function.
  • Expectation of Success: Petitioner asserted a POSITA would have had a high expectation of success. The ’429 patent itself assured that single substitutions in non-essential regions would likely retain activity. This expectation was reinforced by Chao's data showing that lysine is prevalent at the corresponding position in other homologous hyaluronidases. Furthermore, structural modeling confirmed that a lysine substitution at position 313 would be well-tolerated and potentially stabilizing.

• Additional Grounds: Petitioner asserted that claims 1-17 are also unpatentable as indefinite under 35 U.S.C. §112(b) because they only define a portion of the claimed polypeptide (the "hyaluronidase domain"), leaving the remainder of the sequence undefined and rendering the scope of the claims unascertainable.

4. Relief Requested

• Petitioner requests institution of Post Grant Review and cancellation of claims 1-17 of Patent 12,264,345 as unpatentable.