DCT

2:25-cv-03179

Halozyme Inc v. Merck Sharp & Dohme Corp

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 2:25-cv-03179, D.N.J., 04/24/2025
  • Venue Allegations: Venue is asserted as proper in the District of New Jersey because Defendant Merck resides in the district and is subject to the court's personal jurisdiction.
  • Core Dispute: Plaintiff alleges that Defendant’s subcutaneous formulation of its cancer drug KEYTRUDA infringes fifteen patents related to modified hyaluronidase enzymes that facilitate the rapid subcutaneous administration of therapeutic drugs.
  • Technical Context: The technology concerns genetically modifying the human enzyme PH20 hyaluronidase to increase its stability and activity, enabling large-molecule drugs to be administered via simple subcutaneous injection rather than lengthy intravenous infusion.
  • Key Procedural History: The complaint alleges that Defendant Merck was aware of the patents-in-suit and the underlying technology through, among other things, prior collaboration discussions and its own filing of Post-Grant Review (PGR) petitions challenging the validity of several of the asserted patents before the U.S. Patent and Trademark Office.

Case Timeline

Date Event
2011-12-30 Earliest Patent Priority Date ('400, '149, et al.)
2020-12-15 U.S. Patent No. 10,865,400 Issued
2021-06-22 U.S. Patent No. 11,041,149 Issued
2021-07-20 U.S. Patent No. 11,066,656 Issued
2024-04-09 U.S. Patent No. 11,952,600 Issued
2024-06-25 U.S. Patent No. 12,018,298 Issued
2024-07-16 U.S. Patent No. 12,037,618 Issued
2024-07-30 U.S. Patent No. 12,049,652 Issued
2024-08-06 U.S. Patent No. 12,054,758 Issued
2024-09-03 U.S. Patent No. 12,077,791 Issued
2024-09-17 U.S. Patent No. 12,091,692 Issued
2024-09-XX Primary Completion of Phase III Clinical Trial for SC KEYTRUDA
2024-10-01 U.S. Patent No. 12,104,185 Issued
2024-10-08 U.S. Patent No. 12,110,520 Issued
2024-11-26 U.S. Patent No. 12,152,262 Issued
2025-01-14 U.S. Patent No. 12,195,773 Issued
2025-04-01 U.S. Patent No. 12,264,345 Issued
2025-04-24 Complaint Filing Date
2025-10-01 Expected Launch of SC KEYTRUDA

II. Technology and Patent(s)-in-Suit Analysis

U.S. Patent No. 10,865,400 - "PH20 polypeptide variants, formulations and uses thereof"

The Invention Explained

  • Problem Addressed: The patent addresses the challenge of delivering therapeutic drugs subcutaneously (under the skin) (Compl. ¶37). The body's extracellular matrix contains hyaluronan (HA), a carbohydrate that acts as a barrier, preventing large molecules from being absorbed quickly and often causing swelling and discomfort at the injection site (Compl. ¶37; ’400 Patent, col. 2:1-12). While a naturally occurring human enzyme, PH20, can break down HA, its native form is insoluble and not suitable for therapeutic use (Compl. ¶40).
  • The Patented Solution: The invention provides modified versions of the human PH20 enzyme (polypeptides) that have one or more amino acid replacements at specific positions in their sequence ('400 Patent, Abstract). These modifications are designed to result in a PH20 polypeptide that exhibits increased stability and/or increased hyaluronidase activity compared to the unmodified, "wild type" enzyme, making it more effective as a "spreading agent" to improve the dispersion and absorption of co-administered drugs ('400 Patent, col. 2:36-47). The complaint provides a diagram illustrating the amino acid sequence of the wild-type PH20 enzyme that the inventors sought to modify (Compl. p. 11, ¶46).
  • Technical Importance: This technology enables the conversion of drugs that traditionally require time-consuming intravenous (IV) infusions into simple subcutaneous injections, significantly improving patient convenience and quality of life (Compl. ¶42).

Key Claims at a Glance

  • The complaint generally alleges infringement of the '400 patent without specifying claims but focuses on technology covered by independent claim 1 (Compl. ¶¶87-91, 51, 54).
  • Independent Claim 1:
    • A modified PH20 polypeptide, comprising one or more amino acid modifications in an unmodified PH20 polypeptide.
    • The unmodified PH20 polypeptide consists of an amino acid sequence from the group of SEQ ID NOs: 3, 7, and 32-66.
    • The modified PH20 polypeptide exhibits increased hyaluronidase activity compared to the unmodified version.
    • The amino acid replacement(s) that confer the increased activity are at specific positions identified by alignment with SEQ ID NO: 3.
    • The modified polypeptide has at least 95% sequence identity to the group of unmodified sequences.

U.S. Patent No. 11,041,149 - "PH20 polypeptide variants, formulations and uses thereof"

The Invention Explained

  • Problem Addressed: As with the '400 Patent, this patent addresses the need for improved hyaluronidase enzymes to facilitate subcutaneous drug delivery by overcoming the HA barrier in the extracellular matrix (Compl. ¶37; ’149 Patent, col. 2:1-17).
  • The Patented Solution: The invention is a modified human PH20 polypeptide that exhibits increased hyaluronidase activity due to specific amino acid replacements. This patent is directed to modifications at particular positions, including a specific replacement at amino acid residue 313, which corresponds to replacing methionine with lysine in the wild-type sequence ('149 Patent, Claim 3, col. 312:42-49; Compl. ¶52). The complaint includes a diagram showing this specific modification, which allegedly confers a 285% improvement in activity compared to wild-type (Compl. p. 14, ¶52).
  • Technical Importance: The claimed modifications provide a specific means of engineering a more potent hyaluronidase enzyme, enabling more efficient co-formulation with therapeutic agents for subcutaneous delivery (Compl. ¶42).

Key Claims at a Glance

  • The complaint generally alleges infringement of the '149 patent without specifying claims but focuses on technology covered by independent claim 1 (Compl. ¶¶97-101, 52).
  • Independent Claim 1:
    • A modified PH20 polypeptide, comprising one or more amino acid modifications in an unmodified PH20 polypeptide.
    • The unmodified PH20 polypeptide consists of an amino acid sequence from the group of SEQ ID NOs: 3, 7, and 32-66.
    • The modified PH20 polypeptide exhibits increased hyaluronidase activity compared to the unmodified version.
    • The amino acid replacement(s) confer the increased activity.
    • The amino acid replacement is at a position corresponding to residue 313 of SEQ ID NO: 3.

U.S. Patent No. 11,066,656 - "PH20 polypeptide variants, formulations and uses thereof"

  • Technology Synopsis: The patent claims modified human PH20 polypeptides with specific amino acid substitutions that increase the enzyme's hyaluronidase activity. The claims are directed to specific modifications, including a substitution at position 309.
  • Asserted Claims: The complaint does not specify claims but focuses on a modification at residue 309 (Compl. ¶51).
  • Accused Features: The berahyaluronidase alfa (BHA) enzyme in SC KEYTRUDA, which allegedly contains an amino acid modification at residue 309 (Compl. ¶60).

U.S. Patent No. 11,952,600 - "PH20 polypeptide variants, formulations and uses thereof"

  • Technology Synopsis: The patent claims modified human PH20 polypeptides with specific amino acid substitutions that increase the enzyme's hyaluronidase activity. The claims are directed to specific modifications, including a substitution at position 320.
  • Asserted Claims: The complaint does not specify claims but focuses on a modification at residue 320 (Compl. ¶54).
  • Accused Features: The BHA enzyme in SC KEYTRUDA, which allegedly contains an amino acid modification at residue 320 (Compl. ¶63).

U.S. Patent No. 12,018,298 - "PH20 polypeptide variants, formulations and uses thereof"

  • Technology Synopsis: The patent claims modified human PH20 polypeptides with specific amino acid substitutions that increase the enzyme's hyaluronidase activity, as well as methods of administration. The claims are directed to specific modifications, including a substitution at position 313.
  • Asserted Claims: The complaint does not specify claims but focuses on a modification at residue 313 (Compl. ¶52).
  • Accused Features: The BHA enzyme in SC KEYTRUDA and its method of administration (Compl. ¶¶61, 142).

U.S. Patent No. 12,037,618 - "PH20 polypeptide variants, formulations and uses thereof"

  • Technology Synopsis: The patent claims modified human PH20 polypeptides with specific amino acid substitutions that increase the enzyme's hyaluronidase activity, as well as methods of administration. The claims are directed to specific modifications, including a substitution at position 309.
  • Asserted Claims: The complaint does not specify claims but focuses on a modification at residue 309 (Compl. ¶51).
  • Accused Features: The BHA enzyme in SC KEYTRUDA and its method of administration (Compl. ¶¶60, 155).

U.S. Patent No. 12,049,652 - "PH20 polypeptide variants, formulations and uses thereof"

  • Technology Synopsis: The patent claims modified human PH20 polypeptides with specific amino acid substitutions that increase the enzyme's hyaluronidase activity, as well as methods of administration. The claims are directed to specific modifications, including a substitution at position 320.
  • Asserted Claims: The complaint does not specify claims but focuses on a modification at residue 320 (Compl. ¶54).
  • Accused Features: The BHA enzyme in SC KEYTRUDA and its method of administration (Compl. ¶¶63, 168).

U.S. Patent No. 12,054,758 - "PH20 polypeptide variants, formulations and uses thereof"

  • Technology Synopsis: The patent claims modified human PH20 polypeptides with specific amino acid substitutions that increase the enzyme's hyaluronidase activity, as well as methods of administration. The claims are directed to specific modifications, including a substitution at position 317.
  • Asserted Claims: The complaint does not specify claims but focuses on a modification at residue 317 (Compl. ¶53).
  • Accused Features: The BHA enzyme in SC KEYTRUDA and its method of administration (Compl. ¶¶62, 181).

U.S. Patent No. 12,077,791 - "PH20 polypeptide variants, formulations and uses thereof"

  • Technology Synopsis: The patent claims modified human PH20 polypeptides with specific amino acid substitutions that increase the enzyme's hyaluronidase activity. The claims are directed to specific modifications, including a substitution at position 309.
  • Asserted Claims: The complaint does not specify claims but focuses on a modification at residue 309 (Compl. ¶51).
  • Accused Features: The BHA enzyme in SC KEYTRUDA (Compl. ¶60).

U.S. Patent No. 12,091,692 - "PH20 polypeptide variants, formulations and uses thereof"

  • Technology Synopsis: The patent claims modified human PH20 polypeptides with specific amino acid substitutions that increase the enzyme's hyaluronidase activity, as well as methods of administration. The claims are directed to specific modifications, including a substitution at position 313.
  • Asserted Claims: The complaint does not specify claims but focuses on a modification at residue 313 (Compl. ¶52).
  • Accused Features: The BHA enzyme in SC KEYTRUDA and its method of administration (Compl. ¶¶61, 208).

U.S. Patent No. 12,104,185 - "PH20 polypeptide variants, formulations and uses thereof"

  • Technology Synopsis: The patent claims modified human PH20 polypeptides with specific amino acid substitutions that increase the enzyme's hyaluronidase activity, as well as methods of administration. The claims are directed to specific modifications, including a substitution at position 320.
  • Asserted Claims: The complaint does not specify claims but focuses on a modification at residue 320 (Compl. ¶54).
  • Accused Features: The BHA enzyme in SC KEYTRUDA and its method of administration (Compl. ¶¶63, 221).

U.S. Patent No. 12,110,520 - "PH20 polypeptide variants, formulations and uses thereof"

  • Technology Synopsis: The patent claims modified human PH20 polypeptides with specific amino acid substitutions that increase the enzyme's hyaluronidase activity, as well as methods of administration. The claims are directed to specific modifications, including a substitution at position 324.
  • Asserted Claims: The complaint does not specify claims but focuses on a modification at residue 324 (Compl. ¶55).
  • Accused Features: The BHA enzyme in SC KEYTRUDA and its method of administration (Compl. ¶¶64, 234).

U.S. Patent No. 12,152,262 - "PH20 polypeptide variants, formulations and uses thereof"

  • Technology Synopsis: The patent claims modified human PH20 polypeptides with specific amino acid substitutions that increase the enzyme's hyaluronidase activity, as well as methods of administration. The claims are directed to specific modifications, including a substitution at position 317.
  • Asserted Claims: The complaint does not specify claims but focuses on a modification at residue 317 (Compl. ¶53).
  • Accused Features: The BHA enzyme in SC KEYTRUDA and its method of administration (Compl. ¶¶62, 247).

U.S. Patent No. 12,195,773 - "PH20 polypeptide variants, formulations and uses thereof"

  • Technology Synopsis: The patent claims modified human PH20 polypeptides with specific amino acid substitutions that increase the enzyme's hyaluronidase activity, as well as methods of administration. The claims are directed to specific modifications, including a substitution at position 320.
  • Asserted Claims: The complaint does not specify claims but focuses on a modification at residue 320 (Compl. ¶54).
  • Accused Features: The BHA enzyme in SC KEYTRUDA and its method of administration (Compl. ¶¶63, 260).

U.S. Patent No. 12,264,345 - "PH20 polypeptide variants, formulations and uses thereof"

  • Technology Synopsis: The patent claims modified human PH20 polypeptides with specific amino acid substitutions that increase the enzyme's hyaluronidase activity. The claims are directed to specific modifications, including a substitution at position 313.
  • Asserted Claims: The complaint does not specify claims but focuses on a modification at residue 313 (Compl. ¶52).
  • Accused Features: The BHA enzyme in SC KEYTRUDA (Compl. ¶61).

III. The Accused Instrumentality

Product Identification

  • The accused product is Merck's SC KEYTRUDA, a new drug product for the subcutaneous administration of pembrolizumab, which is the active ingredient in Merck's established cancer immunotherapy drug, KEYTRUDA® (Compl. ¶3).

Functionality and Market Context

  • SC KEYTRUDA is co-formulated with berahyaluronidase alfa ("BHA"), which the complaint identifies as a modified PH20 hyaluronidase (Compl. ¶4). The function of BHA is to degrade hyaluronan in the subcutaneous space, enabling the rapid administration and absorption of the large-molecule drug pembrolizumab without the swelling, discomfort, or degradation risk associated with such injections (Compl. ¶66).
  • The complaint alleges that the amino acid sequence of BHA was published in the Global Substance Registration System in September 2024 and confirms that it contains the specific amino acid modifications claimed by the patents-in-suit (Compl. ¶57). An illustration in the complaint explicitly shows the amino acid sequence for the accused BHA product, highlighting the same five modifications that Halozyme alleges are patented (Compl. p. 18, ¶58).
  • The complaint positions SC KEYTRUDA as a commercially critical "successor product" for Merck, intended to convert patients from the intravenous version of its "blockbuster product" KEYTRUDA before the original drug loses patent protection in 2028 (Compl. ¶¶67, 70). This subcutaneous version is alleged to offer significant "quality-of-life benefits" for patients, which Merck anticipates will be "demanded by the field" (Compl. ¶8).

IV. Analysis of Infringement Allegations

U.S. Patent No. 10,865,400 Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A modified PH20 polypeptide, comprising one or more amino acid modifications in an unmodified PH20 polypeptide... The accused SC KEYTRUDA product contains berahyaluronidase alfa (BHA), which is alleged to be a modified PH20 polypeptide. ¶¶4, 57 col. 45:6-14
wherein the unmodified PH20 polypeptide consists of the amino acid sequence selected from the group consisting of SEQ ID NOs: 3, 7, and 32-66... The complaint alleges that the BHA sequence is greater than 91% identical to SEQ ID NO: 3, the reference "wild-type" sequence. ¶65 col. 299:39-43
wherein the modified PH20 polypeptide exhibits increased hyaluronidase activity compared to the unmodified PH20 polypeptide... It is alleged that SC KEYTRUDA's BHA has greater than 120% hyaluronidase activity compared to wild-type PH20. ¶66 col. 48:1-13
wherein the amino acid replacement(s) that confers the increased hyaluronidase activity is at a position corresponding to a position of SEQ ID NO:3... The BHA sequence is alleged to contain modifications at positions 309, 313, 317, 320, and 324, corresponding to SEQ ID NO:3. ¶¶58, 60-64 col. 299:53-65
and wherein the modified PH20 polypeptide has at least 95% sequence identity to the amino acid sequence of the unmodified PH20 polypeptide... The complaint alleges that the BHA sequence is greater than 95% identical to at least SEQ ID NOs: 32-37, which are part of the claimed group. ¶65 col. 299:44-52

U.S. Patent No. 11,041,149 Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A modified PH20 polypeptide, comprising one or more amino acid modifications in an unmodified PH20 polypeptide... The accused SC KEYTRUDA product contains BHA, which is alleged to be a modified PH20 polypeptide. ¶¶4, 57 col. 45:6-14
wherein the unmodified PH20 polypeptide consists of the amino acid sequence selected from the group consisting of SEQ ID NOs: 3, 7, and 32-66... The complaint alleges that the BHA sequence is based on and highly identical to SEQ ID NO: 3. ¶65 col. 312:18-22
wherein the modified PH20 polypeptide exhibits increased hyaluronidase activity... It is alleged that SC KEYTRUDA's BHA has greater than 120% hyaluronidase activity compared to wild-type PH20. ¶66 col. 48:1-13
wherein an amino acid replacement that confers the increased hyaluronidase activity is at a position corresponding to residue 313 of SEQ ID NO: 3. The complaint alleges that the BHA sequence has an amino acid modification at residue 313: a lysine instead of a methionine. ¶61 col. 312:42-49
  • Identified Points of Contention:
    • Scope Questions: A central issue may be whether the accused BHA molecule, with its specific amino acid sequence, falls within the scope of the claimed polypeptides. This analysis may turn on the construction of terms like "at least 95% sequence identity" and whether the comparison must be made to SEQ ID NO: 3 specifically or to any of the dozens of sequences in the claimed group. The complaint's allegation of "greater than 91% identical to SEQ ID NO: 3" (Compl. ¶65) suggests a potential dispute over whether the 95% threshold of certain claims is met.
    • Technical Questions: A key factual question will be whether the accused BHA product actually "exhibits increased hyaluronidase activity" relative to the proper unmodified reference polypeptide and under what experimental conditions this activity must be measured. The complaint alleges an activity level of "greater than 120%" (Compl. ¶66), but this is a technical assertion that Merck may contest, likely requiring competing expert testing and analysis.

V. Key Claim Terms for Construction

  • The Term: "a modified PH20 polypeptide"

    • Context and Importance: This term defines the fundamental subject matter of the invention. The entire infringement analysis depends on whether Merck's BHA is properly characterized as a "modified PH20 polypeptide" as defined and claimed in the patents.
    • Intrinsic Evidence for Interpretation:
      • Evidence for a Broader Interpretation: The specification defines a "modified hyaluron-degrading enzyme" broadly as a polypeptide that has been "altered or modified" from a starting polypeptide and can have "one or more amino acid differences" ('400 Patent, col. 45:20-31). This language may support a broad reading covering a wide range of variants.
      • Evidence for a Narrower Interpretation: The specific embodiments and extensive tables in the patent detail thousands of specific mutations and their resulting activity levels ('400 Patent, Tables 8, 9). A defendant may argue that the term should be understood in the context of these specific disclosed modifications, particularly those that result in a significant, non-obvious improvement in function.

  • The Term: "increased hyaluronidase activity"

    • Context and Importance: This is a functional limitation that is a prerequisite for infringement under the asserted claims of the lead patents. The parties will likely dispute the baseline for comparison (i.e., which "unmodified" polypeptide) and the methodology for measuring the "increase." Practitioners may focus on this term because functional limitations are common areas of dispute in biotechnology patents.
    • Intrinsic Evidence for Interpretation:
      • Evidence for a Broader Interpretation: The specification suggests that an increase can be as low as 110% or 120% compared to the reference and describes various assays for measuring activity ('400 Patent, col. 48:1-13, col. 181:1-67). This may support the patentee's position that any measurable increase above the baseline under a standard assay is sufficient.
      • Evidence for a Narrower Interpretation: The patent highlights certain modifications that result in dramatic increases in activity, such as 311% or 642% (Compl. ¶¶51, 54). A defendant may argue that "increased" should be construed to mean a commercially and therapeutically meaningful increase, rather than any statistically observable but minor change, pointing to the patent's emphasis on these highly improved examples.

VI. Other Allegations

  • Indirect Infringement: The complaint alleges that Merck will induce infringement by actively encouraging its subsidiaries, affiliates, or agents to manufacture, import, and sell SC KEYTRUDA (Compl. ¶¶124-126). For patents with method claims, it is alleged that the product's label will instruct users to administer SC KEYTRUDA in a manner that directly infringes those claims (Compl. ¶143).
  • Willful Infringement: The complaint asserts that Merck's infringement has been willful, knowing, and reckless (Compl. ¶11). The basis for this allegation is Merck's alleged pre-suit knowledge of the patents, stemming from collaboration discussions with Halozyme beginning as early as 2009 and, most notably, from the Post-Grant Review (PGR) petitions Merck itself filed against several of the asserted patents (Compl. ¶¶6, 72, 85-86).

VII. Analyst’s Conclusion: Key Questions for the Case

  • A core issue will be one of claim scope and sequence identity: Does the specific amino acid sequence of Merck's BHA meet the "at least 95% sequence identity" threshold required by certain claims when compared to the appropriate reference sequence(s) defined in the patents? The resolution will depend on detailed claim construction and bioinformatic analysis.
  • A second central issue will be one of proving functional performance: What evidence can Halozyme provide to demonstrate that Merck's BHA, as formulated in SC KEYTRUDA, exhibits "increased hyaluronidase activity" under conditions that are relevant and consistent with the patent's teachings, and how will Merck challenge that evidence?
  • Finally, a key question for damages will be willfulness: Given the complaint's allegations that Merck filed PGRs against the patents-in-suit, the case raises a significant question of whether Merck's alleged infringement was willful, which could expose it to the risk of enhanced damages if infringement is found.