Merck Sharp & Dohme LLC v. Halozyme Inc

1. Case Identification

• Case #: PGR2025-00033
• Patent #: 12,049,652
• Filed: March 7, 2025
• Petitioner(s): Merck Sharp & Dohme LLC
• Patent Owner(s): Halozyme Inc.
• Challenged Claims: 1-40

2. Patent Overview

• Title: Modified Human PH20 Hyaluronidase Polypeptides
• Brief Description: The ’652 patent relates to modified human PH20 hyaluronidase enzyme polypeptides that contain specific amino acid substitutions. The modified polypeptides are intended to retain or exhibit altered enzymatic activity compared to the unmodified protein.

3. Grounds for Unpatentability

Ground 1: Lack of Written Description - Claims 1-40 are unpatentable under 35 U.S.C. §112

• Core Argument for this Ground: Petitioner argued that the challenged claims lack adequate written description because they cover an immense and diverse genus of modified PH20 polypeptides while the specification provides only a narrow set of working examples. The claims require one amino acid replacement at position 320 but permit up to 41 additional modifications, capturing a genus of between 10^59 and 10^112 distinct polypeptides. The disclosure, however, only describes singly-modified polypeptides and a prophetic, iterative "make-and-test" research plan to discover multiply-modified ones. Petitioner contended this fails to demonstrate that the inventor was in possession of the claimed genus, as the disclosure provides no common structural features or "blaze marks" to guide a person of ordinary skill in the art (POSA) through the vast, unexplored scope of the claims. The provided examples of single-replacement mutants were argued to be non-representative of the claimed multiply-substituted proteins, which are structurally and functionally distinct.

Ground 2: Lack of Enablement - Claims 1-40 are unpatentable under 35 U.S.C. §112

• Core Argument for this Ground: Petitioner argued that practicing the full scope of the claims would require undue experimentation. Given the unpredictability of making multiple concurrent changes to a protein's structure and function, a POSA could not have predicted which of the trillions of possible multiply-modified PH20 polypeptides would be enzymatically active. The specification’s only guidance was a prophetic research plan requiring iterative rounds of randomized mutations and screening. Petitioner asserted that making and testing the immense number of polypeptides covered by the claims to determine which ones meet the functional limitations is an impossible task, far exceeding the threshold for undue experimentation. The limited working examples, all involving single substitutions, were argued to provide no credible guidance for creating the claimed multiply-substituted polypeptides, leaving a POSA with only a "trial-and-error" path to discover the claimed invention.

Ground 3: Obviousness over the ’429 Patent and Chao - Claims 1-2 and 5-40 are obvious over the ’429 patent in view of Chao

• Prior Art Relied Upon: Patentee's own prior '429 patent (Patent 7,767,429) and Chao (a 2007 publication in Biochemistry).
• Core Argument for this Ground:
  • Prior Art Mapping: Petitioner argued that each challenged claim encompasses at least one obvious variant of the PH20 polypeptide, specifically a single-replacement D320K or D320S mutant. The ’429 patent, owned by the Patent Owner, described soluble, enzymatically active PH20 polypeptides (termed sHASEGPs) and taught that single amino acid substitutions in "non-essential regions" do not substantially alter biological activity. Chao, a paper on human hyaluronidase structures, provided the tools for a POSA to identify position 320 as being within a non-essential region of PH20. A multiple-sequence alignment based on Chao and other publicly available data showed that lysine (K) and serine (S) are frequently found at the position corresponding to 320 in homologous proteins, making them obvious amino acids to substitute for the native aspartic acid (D).
  • Motivation to Combine: A POSA would combine the teachings of the ’429 patent and Chao to engineer equivalent PH20 polypeptides. The ’429 patent explicitly motivated a POSA to make single amino acid substitutions in non-essential regions to produce variants with substantially unaltered activity and utility. A POSA would have looked to subsequent publications like Chao for detailed structural insights to implement the ’429 patent’s general guidance.
  • Expectation of Success: A POSA would have reasonably expected that substituting lysine or serine at position 320 would result in an enzymatically active protein. This expectation was based on the express statements in the ’429 patent that such modifications in non-essential regions are tolerated, combined with Chao’s structural data and sequence alignments showing that these amino acids naturally occur at that position in other active hyaluronidases.

4. Key Technical Contentions (Beyond Claim Construction)

• Unpredictability of Multiple Protein Mutations: A central technical contention was that in 2011, the effects of multiple, concurrent amino acid substitutions on a protein’s structure, stability, and function were highly unpredictable. While a POSA could reasonably assess the impact of a single substitution in a non-essential region, predicting the cumulative and interactive effects of two or more substitutions (up to 42 as claimed) was beyond the capacity of available computational models and rational design techniques. This unpredictability underpinned the arguments that the specification fails to enable the full scope of the claims and that the provided single-mutant examples are not representative for written description purposes.

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 ’652 patent was pending, making discretionary denial based on Fintiv factors unwarranted. Furthermore, Petitioner contended that denial was inappropriate because the obviousness grounds rely on the Chao reference, which was not cited or considered during examination. The petition also argued that the examiner erred by not rejecting the claims for lack of written description and enablement, providing a further basis for institution.

6. Relief Requested

• Petitioner requests institution of post grant review (PGR) and cancellation of claims 1-40 of the ’652 patent as unpatentable.