Toolgen Inc v. Vertex Pharma Inc

I. Executive Summary and Procedural Information

• Parties & Counsel:
  • Plaintiff: ToolGen, Inc. (Republic of Korea)
  • Defendant: Vertex Pharmaceuticals, Inc. (Massachusetts); CRISPR Therapeutics AG (Switzerland); CRISPR Therapeutics Inc. (Delaware); Lonza Group AG (Switzerland); Lonza Netherlands B.V. (Netherlands); Roslin Cell Therapies Limited (Scotland); RoslinCT US Holdings, LLC (Delaware); Biomay AG (Austria); and BioSpring Gesellschaft für Biotechnologie mbH (Germany)
  • Plaintiff’s Counsel: Nutter, McClennen & Fish, LLP
• Case Identification: 1:25-cv-13441, D. Mass., 02/05/2026
• Venue Allegations: Venue is alleged to be proper in the District of Massachusetts based on certain defendants being incorporated or having their principal places of business in the district, and because the remaining foreign-entity defendants may be sued in any judicial district.
• Core Dispute: Plaintiff alleges that the manufacturing process for Defendants’ gene therapy product, CASGEVY®, infringes a patent related to methods of CRISPR-Cas9 genome editing in eukaryotic cells.
• Technical Context: The dispute centers on CRISPR-Cas9 technology, a foundational tool for gene editing with significant applications in therapeutics, including treatments for genetic disorders such as sickle cell disease and β-thalassemia.
• Key Procedural History: The complaint notes that Plaintiff and certain Defendants are engaged in ongoing litigation in foreign jurisdictions, including the U.K., the Netherlands, and at the European Patent Office, concerning foreign patents related to the patent-in-suit.

Case Timeline

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

U.S. Patent No. 12,473,559 - Cas9/RNA Complexes for Inducing Modifications of Target Endogenous Nucleic Acid Sequences in Nucleuses of Eukaryotic Cells

The Invention Explained

• Problem Addressed: The patent's background describes limitations of prior art genotyping and genome editing methods, such as Restriction Fragment Length Polymorphism (RFLP) analysis, which are constrained by the need for specific, naturally occurring DNA sequences for enzymes to recognize ’559 Patent, col. 2:13-33 This limitation restricts the locations in a genome that can be targeted.
• The Patented Solution: The invention provides a programmable method for targeted gene editing inside eukaryotic cells using a CRISPR-Cas9 system ’559 Patent, abstract The solution involves creating a complex composed of a Cas9 protein and a guide RNA, which directs the Cas9 protein to a specific target DNA sequence to be modified ’559 Patent, col. 2:49-65 By simply changing the sequence of the guide RNA, the system can be reprogrammed to target almost any DNA sequence, overcoming the site-availability limitations of older technologies ’559 Patent, col. 13:5-12
• Technical Importance: This approach provided a more versatile and convenient tool for genome engineering, as it relies on an easily synthesized RNA component for targeting rather than requiring the complex design and synthesis of new DNA-binding proteins for each new target site ’559 Patent, col. 2:1-9

Key Claims at a Glance

• The complaint asserts infringement of at least independent claim 1 Compl. ¶¶51-53
• The essential elements of Claim 1 are:
  • A method step of preparing a Cas9 protein that includes a nuclear localization signal (NLS).
  • A method step of preparing a single-guide RNA (sgRNA) that is transcribed in vitro or chemically synthesized.
  • A method step of providing a buffer in an in vitro environment.
  • A method step of disposing the Cas9 protein into the buffer.
  • A method step of disposing the sgRNA into the buffer in at least a two-fold molar excess over the Cas9 protein.
  • A method step of allowing the Cas9 protein and sgRNA to form a complex in the in vitro environment.
  • A method step of transfecting the resulting complex into a human cell via electroporation, causing a modification of the target DNA.
• The complaint does not explicitly reserve the right to assert dependent claims.

III. The Accused Instrumentality

Product Identification

The accused instrumentality is the process for manufacturing CASGEVY® (exagamglogene autotemcel), a cellular gene therapy product Compl. ¶¶1, 28

Functionality and Market Context

CASGEVY® is a therapy for sickle cell disease and transfusion-dependent β-thalassemia Compl. ¶¶24-25 The manufacturing process involves obtaining a patient's own hematopoietic stem cells (HSCs), enriching them for CD34+ cells, and editing their genome ex vivo Compl. ¶¶38-39 This editing is accomplished by introducing a CRISPR/Cas9 ribonucleoprotein (RNP) complex into the cells using electroporation Compl. ¶39 The specific goal of the editing is to disrupt the BCL11A gene, which leads to increased production of fetal hemoglobin and alleviates disease symptoms Compl. ¶28 Compl. ¶39 A flowchart provided in the complaint outlines the manufacturing steps, including enrichment of cells, electroporation, and cryopreservation Compl. p. 12

The complaint alleges that CASGEVY® is a commercially significant "first ever U.S. Food and Drug Administration (FDA) approved CRISPR-based gene therapy" and that Defendants have established a network of manufacturing partners and authorized treatment centers for its distribution Compl. ¶¶27, 34

IV. Analysis of Infringement Allegations

’559 Patent Infringement Allegations

• Identified Points of Contention:
  • Scope Questions: A potential point of contention may arise over the claim term "in vitro environment." The complaint alleges the complex is formed “in situ just prior to electroporation” Compl. ¶45 This raises the question of whether this process meets the claim’s apparent sequence of first forming a complex in a distinct in vitro environment and then transfecting that pre-formed complex, or if complexing and transfection are alleged to occur in a manner that blurs this distinction.
  • Technical Questions: Claim 1 requires the sgRNA to be in “at least a two-fold molar excess.” The complaint alleges a 1:1 weight ratio corresponds to “about a 5:1 molar ratio” Compl. ¶¶45-46 A factual dispute may arise over whether the specific molecular weights of the components used in the CASGEVY® process consistently yield a molar ratio that satisfies this quantitative limitation, particularly given the complaint’s use of the qualifier “about.”

V. Key Claim Terms for Construction

• The Term: "in vitro environment"

• Context and Importance: This term is critical for determining whether the accused process meets the sequence of steps laid out in Claim 1. The claim recites forming the Cas9/sgRNA complex in an "in vitro environment" (step vi) before transfecting that complex into the cell (step vii). The complaint’s allegation that the complex is formed "in situ just prior to electroporation" Compl. ¶45 makes the definition of this environment—and its separation from the transfection step itself—a central issue for infringement analysis.

• Intrinsic Evidence for Interpretation:

  • Evidence for a Broader Interpretation: The specification frequently uses "in vitro" to refer to any process occurring outside of a living organism, such as in a reaction buffer or tube ’559 Patent, col. 19:20-29 This could support an argument that any mixing of components in a buffer before electroporation, however brief, satisfies the limitation.
  • Evidence for a Narrower Interpretation: The sequential structure of Claim 1, which lists complex formation as a distinct step before transfection, may support an interpretation that the "in vitro environment" for complexing must be temporally and physically separate from the environment where the cells are present for electroporation.

• The Term: "at least a two-fold molar excess"

• Context and Importance: This quantitative limitation is a specific requirement of the claimed method. The infringement allegation hinges on the assertion that a "1:1 weight ratio" of the specific sgRNA and Cas9 protein used corresponds to "about a 5:1 molar ratio" Compl. ¶¶45-46 Practitioners may focus on this term because demonstrating that the accused process meets this numerical threshold is essential for the plaintiff's infringement case.

• Intrinsic Evidence for Interpretation:

  • Evidence for a Broader Interpretation: The patent does not provide a specific definition for the term, suggesting its plain and ordinary meaning applies. The phrase "at least" sets a clear, non-negotiable floor, and the complaint's allegation of "about 5:1" facially clears this hurdle, suggesting any ratio proven to be 2.0 or greater would infringe.
  • Evidence for a Narrower Interpretation: While the patent does not offer a specific definition, a defendant could argue that evidence from the prosecution history or expert testimony is needed to understand what a person of ordinary skill in the art would have understood the term to mean in this context. The factual basis for the "about 5:1" calculation will likely be scrutinized to determine if manufacturing variability or other factors could cause the ratio to fall below the claimed 2:1 floor.

VI. Other Allegations

• Indirect Infringement: The complaint alleges induced infringement, stating that certain Defendants knowingly encourage infringement by "directing and coordinating manufacturing, importation, commercialization activities and uses relating to Casgevy®" Compl. ¶64 The complaint also references instructional materials that allegedly inform and instruct third parties on the use of the product Compl. ¶27
• Willful Infringement: The complaint seeks a judgment of willful infringement, alleging that Defendants had knowledge of the patent-in-suit at least as of the publication of the underlying U.S. patent application on February 15, 2024 Compl. ¶23 Compl. p. 18, prayer c

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

• A central factual question will be one of quantitative compliance: does the manufacturing process for CASGEVY®, which allegedly uses a 1:1 weight ratio of sgRNA to Cas9 protein, consistently result in a molar ratio that meets the "at least a two-fold molar excess" limitation required by Claim 1?
• A key issue of claim scope will be one of procedural interpretation: can the accused process of forming the ribonucleoprotein complex "in situ just prior to electroporation" be shown to satisfy the claim's sequential requirement to first form the complex in an "in vitro environment" and then separately transfect that pre-formed complex into the human cell?