Merck Sharp & Dohme LLC v. Halozyme Inc

1. Case Identification

• Case #: PGR2025-00017
• Patent #: 12,110,520
• Filed: January 17, 2025
• Petitioner(s): Merck Sharp & Dohme LLC
• Patent Owner(s): Halozyme Inc.
• Challenged Claims: 1-35

2. Patent Overview

• Title: Modified Hyaluronidase Polypeptides
• Brief Description: The ’520 patent relates to modified human hyaluronidase (PH20) polypeptides that have at least one amino acid substitution at position 324 and retain enzymatic activity. The claims encompass vast genera of such modified proteins defined by sequence identity to reference sequences.

3. Grounds for Unpatentability

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

• Core Argument for this Ground: Petitioner argued the common disclosure of the ’520 patent fails to provide adequate written description for the immensely broad and diverse genera of modified PH20 polypeptides claimed. The claims capture genera of between 10^59 and 10^112 distinct species, requiring a mandatory substitution at position 324 while permitting up to 41 additional modifications anywhere in the sequence.
  • Immense Genus vs. Meager Disclosure: Petitioner contended that to support this vast scope, the specification provides only a narrow set of working examples, all of which are limited to a single type of change (a single amino acid replacement) in only one specific PH20 sequence (PH201-447). These singly-modified examples were argued to be structurally and functionally non-representative of the claimed multiply-modified polypeptides of varying lengths.
  • Lack of Common Features: The petition asserted the disclosure fails to identify any common structural features shared among the members of the claimed genera that would distinguish active mutants from inactive ones. Instead, the disclosure was characterized as a mere "research plan" that proposes a prophetic, iterative "make-and-test" methodology to discover multiply-modified mutants, which fails to demonstrate possession of the claimed invention.
  • Inconsistent Guidance: Petitioner further argued the claims improperly capture polypeptides that the disclosure instructs a POSITA to avoid, such as combinations of substitutions the specification explicitly states "not to make" and mutants containing substitutions that individually rendered the protein inactive.

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

• Core Argument for this Ground: Petitioner argued the full scope of the challenged claims is not enabled because it would require undue experimentation to practice. The argument centered on the extreme scope of the claims, the unpredictability of the art, and the lack of guidance in the disclosure.
  • Undue Experimentation: The petition asserted that a POSITA could not practice the full scope of the claims without engaging in an iterative, trial-and-error process for each of the trillions of claimed polypeptides. The disclosure's only guidance was a prophetic research plan requiring iterative rounds of randomized mutations and screening to discover active mutants, a process Petitioner described as impossible to complete.
  • Unpredictable Art: Petitioner contended that in 2011, the effect of making multiple concurrent amino acid substitutions on a protein's structure and function was highly unpredictable. While a POSITA could reasonably assess single substitutions, predicting the complex, cumulative effects of 2 to 42 substitutions was beyond the capacity of available computational tools and rational design techniques.
  • Limited Working Examples: The disclosure’s examples, limited to single-replacement mutants, were argued to provide no credible guidance for making and using the claimed multiply-modified and/or truncated polypeptides. The specification provides no data for any polypeptide with two or more substitutions.

Ground 3: Obviousness over the ’429 patent and Chao - Claims 1-2 and 5-35 are obvious over Patent 7,767,429 in view of Chao (2007)

• Prior Art Relied Upon: Patent 7,767,429 (“’429 patent”) and Chao et al., "Structure of Human Hyaluronidase-1..." Biochemistry (2007) (“Chao”).
• Core Argument for this Ground:
  • Prior Art Mapping: Petitioner argued the challenged claims encompass, at a minimum, three specific single-replacement mutants of the PH201-447 polypeptide: E324D, E324N, and E324R. These specific, obvious species were alleged to render the broader claims unpatentable. Arguments for dependent claims were based on additional teachings in the ’429 patent regarding solubility, glycosylation, and formulation with therapeutic agents.
  • Motivation to Combine: The ’429 patent, also owned by Patent Owner, was argued to have expressly motivated a POSITA to make "single amino acid substitutions in non-essential regions" of the PH201-447 polypeptide to create "equivalent" proteins that do not substantially alter biological activity. A POSITA, implementing this teaching, would have looked to the state of the art for structural information. This would have led them to Chao, a 2007 publication detailing the structure of a homologous human hyaluronidase (HYAL1). The collective teachings would have guided a POSITA to identify position 324 as being in a non-essential region and view aspartic acid (D), asparagine (N), and arginine (R) as obvious substitutions, as these residues are frequently found at the corresponding position in other homologous, active hyaluronidases.
  • Expectation of Success: A POSITA would have reasonably expected these single-point mutations to be tolerated and yield enzymatically active proteins. This expectation was based on the ’429 patent’s own assertion that such substitutions in non-essential regions generally do not alter activity, the fact that these specific amino acids are naturally tolerated by evolution in homologous proteins, and structural modeling confirming the substitutions would be compatible with the local protein environment.

4. Arguments Regarding Discretionary Denial

• Petitioner argued that discretionary denial under § 324(a) or § 325(d) is unwarranted.
• No parallel litigation involving the ’520 patent is pending, making denial under Fintiv factors inapplicable.
• The obviousness ground relies on Chao, a prior art reference that was not cited or considered by the Examiner during prosecution. The petition also relies on expert testimony not previously available to the USPTO.

5. Relief Requested

• Petitioner requests institution of Post Grant Review and cancellation of claims 1-35 of Patent 12,110,520 as unpatentable.