Merck Sharp & Dohme LLC v. Halozyme, Inc.

1. Case Identification

• Case #: PGR2025-00053
• Patent #: 12,195,773
• Filed: June 6, 2025
• Petitioner(s): Merck Sharp & Dohme LLC
• Patent Owner(s): Halozyme Inc.
• Challenged Claims: 1-15

2. Patent Overview

• Title: Modified Soluble Human Hyaluronidase Polypeptides
• Brief Description: The ’773 patent relates to structurally altered, soluble forms of the human PH20 hyaluronidase enzyme that retain enzymatic activity. The claims are directed to a modified human PH20 polypeptide that must contain a specific amino acid replacement at position 320 and may contain 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: Petitioner argued that the claims fail the written description requirement because the specification does not demonstrate that the inventor was in possession of the claimed invention. The claims cover an immense and functionally-defined genus of approximately 10^57 distinct polypeptides, defined by a mandatory substitution at position 320 and up to 19 optional modifications at any of 446 other positions. Petitioner contended that the specification fails to provide a representative number of species or identify a common structural feature shared by the members of this vast genus.
  • The disclosure’s working examples were described as being limited to a narrow set of singly-modified polypeptides, which are not representative of the claimed multiply-modified species.
  • Petitioner asserted that the specification offers only a prophetic “make-and-test” research plan, which is insufficient to describe the unknown contours of the claimed genus and lacks the “blaze marks” necessary to guide a person of ordinary skill in the art (POSITA). The empirical data for single substitutions was argued to provide no predictive guidance for the structure or function of the claimed multiply-modified polypeptides.

Ground 2: Claims 1-15 Lack Enablement under 35 U.S.C. §112

• Core Argument: Petitioner argued the claims are not enabled because practicing their full scope would require undue experimentation. A POSITA would need to perform an impossible quantity of trial-and-error experiments—synthesizing and testing up to 10^57 distinct polypeptides—to identify which species are both soluble and enzymatically active.
  • This experimentation was asserted to be necessary because the specification provides no guidance to predict these properties for multiply-modified proteins, a task known to be highly unpredictable in the field of protein engineering.
  • The petition further argued that the claims are not enabled because they encompass a significant number of inoperative embodiments. This includes an unknown number of "inactive mutants," for which the sole stated utility (contraception) is not scientifically credible, and mutants that cannot be made or will not fold into a soluble protein. Identifying the few operative embodiments from the vast number of inoperative ones would require an undue, if not impossible, research project.

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

• Prior Art Relied Upon: The Patentee's '429 Patent (EX1005) and Chao (a 2007 publication on hyaluronidase structure, EX1006).
• Core Argument for this Ground:
  • Prior Art Mapping: Petitioner argued the claims are obvious because they encompass at least one specific, obvious single-substitution mutant: D320K PH20(1-447). The ’429 patent taught making single amino acid substitutions in “non-essential regions” of the PH20(1-447) polypeptide to create functionally equivalent variants. Chao provided the structural information and analysis that would have allowed a POSITA to identify position 320 as being within such a non-essential region. A multiple sequence alignment (MSA) of homologous proteins—a standard tool for a POSITA—revealed that lysine (K) is the most prevalent amino acid at the position corresponding to 320, making it an obvious choice for substitution.
  • Motivation to Combine: A POSITA, motivated by the ’429 patent to create functionally equivalent PH20 variants, would have naturally consulted the prior art, including Chao and publicly available sequence data, to identify non-essential regions and select a suitable, evolutionarily-tolerated amino acid for substitution.
  • Expectation of Success: A POSITA would have had a reasonable expectation of success. The ’429 patent itself stated that such substitutions would not substantially alter biological activity. The high prevalence of lysine at this position in other hyaluronidases indicated evolutionary tolerance. Petitioner also presented expert testimony and a structural model showing that the D320K substitution would be structurally tolerated and stabilizing, thus preserving the required solubility and enzymatic activity.

4. Key Claim Construction Positions

• Petitioner argued that the term “soluble human PH20 polypeptide” is a functional limitation that requires experimental testing for verification. This property cannot be predicted from the amino acid sequence alone, especially for multiply-modified proteins.
• Petitioner construed the phrase “up to 19 additional modifications” to mean up to 20 total modifications relative to the reference sequence (SEQ ID NO:3). This construction was presented as crucial for establishing the immense breadth of the claimed genus (~10^57 polypeptides), which formed the foundation of the §112 written description and enablement challenges.

5. Key Technical Contentions (Beyond Claim Construction)

• A central technical contention was that the field of protein engineering is highly unpredictable, particularly concerning the cumulative effects of multiple amino acid substitutions on a protein's structure, folding, solubility, and function.
• Petitioner argued that the effects of single substitutions, as disclosed in the specification, are not predictive for multiply-substituted variants. This unpredictability means that discovering the claimed soluble, active, multiply-modified PH20 polypeptides requires an exhaustive, and therefore undue, “make-and-test” experimental campaign, rendering the claims non-enabled.

6. Relief Requested

• Petitioner requested the institution of a post-grant review and the cancellation of claims 1-15 of Patent 12,195,773 as unpatentable under 35 U.S.C. §112 and §103.