Merck Sharp & Dohme LLC v. Halozyme Inc

Prosecution History analysis

Examiner Search analysis

Invalidity Framework analysis

Petition

Petition Analysis

## 1. Case Identification
- Case Number: [PGR2025-00003](https://ai-lab.exparte.com/case/ptab/PGR2025-00003)
- Patent #: [11,952,600](https://ai-lab.exparte.com/patent/11952600)
- Filed: November 12, 2024
- Petitioner(s): [Merck Sharp & Dohme LLC](https://ai-lab.exparte.com/party/merck-sharp-and-dohme-corp)
- Patent Owner(s): [Halozyme Inc](https://ai-lab.exparte.com/party/halozyme-inc).
- Challenged Claims: 1-21

## 2. Patent Overview
- Title: Modified PH20 Polypeptides
- Brief Description: The [’600](https://ai-lab.exparte.com/patent/11952600) patent relates to structurally altered forms of the human PH20 hyaluronidase enzyme. The claims are directed to modified PH20 polypeptides that contain at least one specific amino acid substitution and are further defined by a percentage of sequence identity to various reference sequences.

## 3. Grounds for Unpatentability

#### Ground 1: Lack of Written Description (§ 112) - Claims 1-21 are unpatentable under 35 U.S.C. § 112.
  - **Core Argument for this Ground:** Petitioner argued that the claims fail the written description requirement because they cover an immense and structurally diverse genus of modified PH20 polypeptides, calculated to be between 10⁴⁹ and 10⁶⁶ distinct species. The specification’s disclosure was asserted to be not representative of this vast genus, as its examples are limited almost exclusively to *singly-modified* polypeptides. Petitioner contended that these examples cannot support the claims to *multiply-modified* polypeptides containing up to 22 additional changes. The specification allegedly fails to identify any common structural features shared by the genus members that would confer their function. Instead, it was argued to provide only a prophetic "make-and-test" research plan, which fails to demonstrate that the inventor possessed the full scope of the claimed invention at the time of filing.

#### Ground 2: Lack of Enablement (§ 112) - Claims 1-21 are unpatentable under 35 U.S.C. § 112.
  - **Core Argument for this Ground:** Petitioner argued that the claims are not enabled because practicing their full scope would require undue experimentation. The sheer number of polypeptides encompassed by the claims would force a person of ordinary skill in the art (POSITA) to engage in an impossible "make-and-test" screening campaign to identify which of the trillions of potential combinations result in a functional protein. Petitioner asserted that the field of protein engineering, particularly regarding the cumulative effects of multiple mutations, was highly unpredictable in 2011. The specification was characterized as providing no guidance beyond a prophetic, iterative research plan, which is insufficient to enable a POSITA to practice the invention without undue experimentation.

#### Ground 3: Obviousness over the ’429 patent and Chao - Claims 1-4 and 7-21 are obvious over the ’429 patent in view of Chao.
  - **Prior Art Relied Upon:** Patent 7,767,429 ([’429](https://ai-lab.exparte.com/docs/ptab/PGR2025-00003/1005) patent`), [Chao](https://ai-lab.exparte.com/docs/ptab/PGR2025-00003/1006) et al., *Biochemistry* (2007) ([Chao](https://ai-lab.exparte.com/docs/ptab/PGR2025-00003/1006)).
  - **Core Argument for this Ground:**
    - **Prior Art Mapping:** Petitioner argued that the claims encompass a specific, obvious variant: the D320K single-replacement mutant of the PH20(1-447) polypeptide. The `[’429](https://ai-lab.exparte.com/docs/ptab/PGR2025-00003/1005) patent`, also owned by the Patent Owner, taught making single amino acid substitutions in non-essential regions of the PH20 protein to create "equivalent" proteins that retain biological activity. The `[Chao](https://ai-lab.exparte.com/docs/ptab/PGR2025-00003/1006)` reference provided structural analysis of human hyaluronidases, which a POSITA would use to identify position 320 as being within a non-essential region suitable for such a substitution.
    - **Motivation to Combine:** A POSITA, motivated by the `[’429](https://ai-lab.exparte.com/docs/ptab/PGR2025-00003/1005) patent` to create improved or equivalent PH20 variants, would combine its teachings with subsequent literature like `[Chao](https://ai-lab.exparte.com/docs/ptab/PGR2025-00003/1006)` for structural insights to guide the protein engineering process. This combination would lead a POSITA to make targeted substitutions in non-essential regions, such as the one containing position 320.
    - **Expectation of Success:** The `[’429](https://ai-lab.exparte.com/docs/ptab/PGR2025-00003/1005) patent` itself created an expectation of success by stating that single substitutions in non-essential regions generally do not alter biological activity. Furthermore, an analysis of homologous sequences, as informed by `[Chao](https://ai-lab.exparte.com/docs/ptab/PGR2025-00003/1006)`, revealed that Lysine (K) is the most prevalent amino acid at the position corresponding to 320, strongly suggesting its substitution for Aspartic acid (D) would be well-tolerated and would maintain protein function.

## 4. Key Claim Construction Positions
- Petitioner argued that the claim language, particularly the use of percentage sequence identity (e.g., "at least 95% sequence identity"), defines an astronomically large and diverse genus of polypeptides. This construction is based on the claim's allowance for numerous substitutions, insertions, or deletions at any position along the protein sequence, aside from the single required replacement at position 320. This interpretation of the claim scope is foundational to Petitioner's § 112 arguments, as it establishes the immense size of the genus for which the specification allegedly lacks adequate written description and enabling disclosure.

## 5. Key Technical Contentions (Beyond Claim Construction)
- **Unpredictability of Multiple Mutations:** A central technical contention was that, in 2011, the effect of introducing multiple amino acid substitutions into a protein like PH20 was highly unpredictable. While the effect of a single substitution could sometimes be assessed, Petitioner argued that the cumulative and interactive effects of many changes (up to 22 permitted by the claims) on protein folding, stability, and activity were beyond the predictive capacity of a POSITA.
- **Lack of a Structure-Function Relationship:** Petitioner contended the specification fails to establish any correlation between specific amino acid changes and the resulting biological activity. The provided data on ~2,500 "active" single-replacement mutants was argued to not provide a predictive basis for a POSITA to determine which combinations of these, or other, mutations would result in an active multiply-modified polypeptide.

## 6. Arguments Regarding Discretionary Denial
- Petitioner argued that discretionary denial under § 324(a) or § 325(d) is unwarranted. It asserted that there is no parallel litigation, a key factor weighing against denial under *Fintiv*. Furthermore, Petitioner contended that the Examiner did not consider the core arguments or prior art presented in the petition during prosecution, specifically the `[Chao](https://ai-lab.exparte.com/docs/ptab/PGR2025-00003/1006)` reference and the detailed § 112 arguments regarding the immense scope of the claimed genus.

## 7. Relief Requested
- Petitioner requested institution of post-grant review (PGR) and cancellation of claims 1-21 of Patent [11,952,600](https://ai-lab.exparte.com/patent/11952600) as unpatentable.

Merck challenges Halozyme's PH20 polypeptide patent, arguing all 21 claims lack written description and enablement for an immense genus of molecules.