DCT

1:25-cv-01197

Factor Bioscience Inc v. Cellectis Inc

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:25-cv-01197, D. Del., 09/26/2025
  • Venue Allegations: Plaintiff alleges venue is proper in the District of Delaware because Defendant Cellectis, Inc. is a Delaware corporation, and the other foreign-domiciled defendants do not reside in any U.S. judicial district.
  • Core Dispute: Plaintiff alleges that Defendants' gene-editing research activities and platforms, used to develop allogeneic CAR-T cells and other potential therapeutics, infringe three patents related to methods for producing gene-edited cells using synthetic messenger RNA (mRNA) encoding TALEN proteins.
  • Technical Context: The technology involves using synthetic mRNA to deliver transcription activator-like effector nuclease (TALEN) gene-editing proteins into cells, a foundational method in the field of cellular therapeutics and gene therapy.
  • Key Procedural History: The complaint notes that all three patents-in-suit underwent anonymous third-party requested reexaminations in 2024, during which the USPTO reaffirmed their patentability. The complaint describes the resulting claim amendments as insubstantial. The complaint also details an extensive history of alleged pre-suit knowledge by both Cellectis and AstraZeneca, based on industry articles, direct meetings, patent prosecution filings, and formal notice letters, which forms the basis for allegations of willful infringement.

Case Timeline

Date Event
2011-12-05 Earliest Priority Date for ’410, ’738, and ’229 Patents
2013-03-01 Article published allegedly giving Cellectis knowledge of the technology
2019-06-08 Presentation sent to AstraZeneca allegedly providing knowledge of the patent family
2020-05-26 U.S. Patent No. 10,662,410 Issues
2020-10-15 Factor allegedly sends Technology Catalog with patent claims to AstraZeneca
2020-11-10 U.S. Patent No. 10,829,738 Issues
2021-03-11 Cellectis allegedly lists ’410 and ’738 Patents in an Information Disclosure Statement
2021-04-20 U.S. Patent No. 10,982,229 Issues
2022-06-15 Meeting where Factor allegedly provided Cellectis with actual knowledge of ’410 Patent
2023-11-01 Cellectis and AstraZeneca enter into Joint Research and Collaboration Agreement
2024-06-05 Reexamination Certificate issues for ’410 Patent
2024-06-21 Reexamination Certificate issues for ’229 Patent
2024-06-28 Reexamination Certificate issues for ’738 Patent
2025-09-26 Complaint Filed

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

U.S. Patent No. 10,662,410 - "Methods and Products for Transfecting Cells"

The Invention Explained

  • Problem Addressed: Prior to the invention, researchers seeking to perform gene editing faced the technical challenge of efficiently and safely introducing gene-editing proteins, such as TALENs, into living cells (Compl. ¶47). Existing methods that relied on introducing exogenous DNA (e.g., plasmids or viral vectors) were described as unreliable, inefficient, and carrying risks of uncontrolled mutations, making them potentially unsafe for therapeutic use (Compl. ¶47; ’410 Patent, col. 3:3-9).
  • The Patented Solution: The patent describes methods for gene editing that avoid exogenous DNA by instead using synthetic RNA molecules to deliver the genetic code for the editing proteins into the cells (’410 Patent, Abstract). The complaint alleges this was the first method to use synthetic mRNA to express TALENs in human cells (Compl. ¶49). Specifically, the method involves contacting cells with synthetic RNA molecules encoding a pair of TALEN fusion proteins, which then create a targeted double-stranded break in the cell's DNA. This break can then be used to insert a new DNA sequence via a co-delivered DNA repair template (Compl. ¶57).
  • Technical Importance: This mRNA-based approach allegedly offered dramatically higher efficiency and safety compared to the prior DNA-based methods for delivering gene-editing tools into cells (Compl. ¶5).

Key Claims at a Glance

  • The complaint asserts at least independent claim 9 (as amended by the Ex Parte Reexamination Certificate issued June 5, 2024) (Compl. ¶59).
  • Essential elements of Independent Claim 9:
    • A method for producing gene-edited cells with an inserted DNA sequence, comprising:
    • Providing and culturing a plurality of human cells with a target DNA sequence.
    • Contacting the cells with a transfection medium containing a plurality of synthetic RNA molecules, which include a first and second synthetic RNA molecule encoding a first and second TALEN fusion protein, respectively.
    • The TALENs are expressed, resulting in a double-stranded break in the target DNA sequence.
    • The synthetic RNA molecules are independently synthesized by in vitro transcription from a DNA template.
    • Transfecting the cell with a DNA repair template to insert a sequence at the double-stranded break.

U.S. Patent No. 10,829,738 - "Methods and Products for Transfecting Cells"

The Invention Explained

  • Problem Addressed: The patent addresses the same technical problem as the related ’410 Patent: the need for safer and more efficient methods of inducing cells to express gene-editing proteins than those available through DNA-based vectors (Compl. ¶47; ’738 Patent, col. 3:3-9).
  • The Patented Solution: The ’738 Patent also discloses methods for producing gene-edited cells by using synthetic RNA encoding TALENs. The claimed method involves adding the synthetic RNA molecules to the medium surrounding the cells, which causes the cells to internalize the RNA and express the TALEN proteins, resulting in a double-stranded break in the target DNA (’738 Patent, col. 68:60-69:11). Unlike claim 9 of the ’410 Patent, the representative claim of the ’738 Patent does not require the additional step of transfecting with a DNA repair template to achieve sequence insertion (Compl. ¶64).
  • Technical Importance: This technology is part of the same family of inventions that allegedly pioneered the use of synthetic mRNA for TALEN-based gene editing, providing a foundational tool for developing cellular therapies (Compl. ¶49).

Key Claims at a Glance

  • The complaint asserts at least independent claim 1 (as amended by the Ex Parte Reexamination Certificate issued June 28, 2024) (Compl. ¶64).
  • Essential elements of Independent Claim 1:
    • A method for producing a plurality of gene-edited cells, comprising:
    • Providing and culturing a plurality of human cells with a target DNA sequence.
    • Contacting the cells with a medium containing a plurality of synthetic RNA molecules, which include a first and second synthetic RNA molecule encoding a first and second TALEN fusion protein, respectively.
    • The synthetic RNA molecules are added to the medium surrounding the cells.
    • The contacting results in the cells internalizing the RNA and expressing the TALENs to create a double-strand break in the target DNA sequence.

U.S. Patent No. 10,982,229 - "Methods and Products for Transfecting Cells"

  • Technology Synopsis: The ’229 Patent is directed to in vitro or ex vivo methods of producing gene-edited cells. The patented solution involves providing a plurality of synthetic RNA molecules encoding TALENs and contacting a plurality of human cells with them in a medium, causing the cells to internalize the RNA and express the TALENs to create a double-stranded break in a target DNA sequence (Compl. ¶¶ 67, 69).
  • Asserted Claims: The complaint identifies independent claim 1 as representative (Compl. ¶69).
  • Accused Features: The accused features are Defendants' research and development processes that utilize synthetic mRNA encoding TALENs to create gene edits in human cells as part of their therapeutic development platforms (Compl. ¶¶ 76-88).

III. The Accused Instrumentality

Product Identification

The complaint accuses Defendants’ research and development methods and platforms that are used to create gene-edited cells, rather than a specific end-product sold to consumers (Compl. ¶1). These include Cellectis’s TALEN-based gene editing technology platform, its "Universal CAR-T" (UCART) cell therapies, and its ".HEAL" gene therapy platform (Compl. ¶¶ 1, 88-89).

Functionality and Market Context

The complaint alleges that Defendants use a process that involves transfecting human cells (e.g., T lymphocytes) with synthetic mRNA encoding pairs of TALENs (referred to as "left and right TALEN arms") (Compl. ¶¶ 77, 82). These TALENs are fusion proteins designed to create double-strand breaks at specific DNA sequences (Compl. ¶83). The diagram from a Cellectis presentation titled ".HEAL Gene therapy treatment" illustrates a process where TALENs are used to eliminate a sickle cell gene, followed by repair with a DNA template (Compl. p. 23). Another diagram titled "TALEN® Powered" shows the technology being used for gene "knockouts" (KO) to modify T-cell receptors (Compl. p. 24). The process is also allegedly used for "knock-ins," which involve inserting a DNA sequence using a repair template with homology to the cut site (Compl. ¶79). The complaint alleges these methods are used as research tools and to identify and design potential allogeneic CAR-T cell therapies and other gene-edited products, which Cellectis then licenses to partners like AstraZeneca for significant fees (Compl. ¶¶ 101-111).

IV. Analysis of Infringement Allegations

U.S. Patent No. 10,662,410 Infringement Allegations

Claim Element (from Independent Claim 9) Alleged Infringing Functionality Complaint Citation Patent Citation
(a) providing a plurality of cells comprising a target DNA sequence, wherein the plurality of cells are human cells Defendants use human cells, including human T lymphocytes, in their gene-editing processes. ¶77 col. 69:3-4
(b) culturing the plurality of cells Defendants cultivate human cells in media prior to performing gene editing. ¶81 col. 69:5
(c) contacting the plurality of cells with a transfection medium...comprises a plurality of synthetic RNA molecules... a first...and a second synthetic RNA molecule encoding a first...and a second...transcription activator-like effector nuclease (TALEN) Defendants add synthetic mRNA encoding pairs of "left and right TALEN arms" to a transfection or cytoporation medium containing the cells. ¶¶ 81, 82, 87 col. 69:6-24
...resulting in...a double-stranded break in the target DNA sequence The expressed TALEN arms combine to create double-strand breaks in targeted DNA sequences to achieve gene knockouts or knock-ins. A Cellectis diagram illustrates using TALEN to make a precise cut to eliminate a gene (Compl. p. 23). ¶¶ 79, 82 col. 69:25-28
...wherein the first synthetic RNA molecule and the second synthetic RNA molecule are independently synthesized by in vitro transcription from a DNA template Defendants produce the synthetic mRNA using an in vitro transcription kit (mMessage mMachine T7 Ultra kit) from a PCR product or linearized plasmid DNA template. ¶85 col. 69:29-33
(d) transfecting the cell with a DNA repair template comprising a sequence for insertion and one or more regions of homology...to result in insertion of the sequence... Defendants’ "knock-in" procedures are alleged to involve inserting an "external DNA matrix sharing homologies with the broken DNA" at the cut site. A diagram titled "Step 4: TALEN-Mediated Gene Editing" describes the technology's ability to perform knock-outs of genes (Compl. p. 31), and another diagram titled "Editing process" illustrates the use of a DNA donor template for knock-in (Compl. p. 40). ¶¶ 79, 86 col. 70:1-11

U.S. Patent No. 10,829,738 Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
(a) providing a plurality of cells comprising a target DNA sequence, wherein the plurality of cells are human cells Defendants use human cells, including human T lymphocytes. ¶77 col. 69:3-4
(b) culturing the plurality of cells Defendants cultivate human cells in media. ¶81 col. 69:5
(c) contacting the plurality of cells with a medium, wherein the medium comprises a plurality of synthetic RNA molecules... a first...and a second synthetic RNA molecule encoding a first...and a second...transcription activator-like effector nuclease (TALEN) Defendants add synthetic mRNA encoding pairs of TALEN arms to the medium surrounding the target cells. ¶¶ 82, 87 col. 69:6-15
wherein the synthetic RNA molecules are added to the medium surrounding the plurality of cells, resulting in the plurality of cells internalizing the synthetic RNA molecules and expressing the first fusion protein and the second fusion protein to result in a double-strand break in the target DNA sequence The process allegedly results in the cells taking up the mRNA from the medium and expressing the TALENs, which then cut the target DNA to create a double-strand break. ¶87 col. 69:16-22

Identified Points of Contention

  • Scope Questions: The complaint preemptively raises the issue of the 35 U.S.C. § 271(e)(1) "Safe Harbor" defense, arguing that Defendants' activities constitute non-exempt research tool use and commercial licensing, not activities "solely for uses reasonably related" to FDA submissions (Compl. ¶¶ 97-99, 127-128). A primary point of contention will likely be whether Defendants' research platforms and their licensing fall inside or outside this statutory exemption.
  • Technical Questions: While the complaint provides extensive documentation, a potential question for the court could be whether the term "producing a plurality of gene-edited cells" as claimed can read on the creation of a heterogeneous mixture of edited and non-edited cells in a research context, which is not itself a final, approvable therapeutic product (Compl. ¶¶ 96, 125).

V. Key Claim Terms for Construction

The Term: "synthetic RNA molecule"

  • Context and Importance: This term is foundational to all asserted claims. The novelty of the patented method, as framed by the complaint, hinges on the use of synthetic RNA to deliver the TALEN genetic code, distinguishing it from prior art methods using DNA plasmids or viral vectors (Compl. ¶¶ 47, 49). The definition will be critical to establishing the scope of the invention and differentiating it from the prior art.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The specification states that "synthetic RNA molecule" means an RNA molecule "produced outside of a cell or that is produced inside of a cell using bioengineering," including RNA produced by in vitro transcription, direct chemical synthesis, or in a genetically engineered cell (’410 Patent, col. 7:31-37). This suggests a broad definition covering various non-natural production methods.
    • Evidence for a Narrower Interpretation: The asserted independent claims explicitly narrow this term by requiring that the molecules "are independently synthesized by in vitro transcription from a DNA template" (’410 Patent, Reexamination Certificate at 2:33-36). Further, the specification provides extensive detail on the use of non-canonical nucleotides to reduce immunogenicity and improve translation, which a defendant might argue characterizes the actual invention disclosed (’410 Patent, col. 3:45-4:44).

The Term: "transfection medium"

  • Context and Importance: This term appears in claim 9 of the ’410 Patent and is the environment in which the cells are contacted with the synthetic RNA. Its definition is important for determining whether Defendants’ specific cell culture and processing conditions meet this claim limitation.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The patent defines "transfection medium" as "a medium that can be used for transfection, for example, Dulbecco's Modified Eagle's Medium (DMEM) or DMEM/F12" (’410 Patent, col. 8:59-62). This suggests the term could encompass any standard medium suitable for transfection.
    • Evidence for a Narrower Interpretation: The specification dedicates significant discussion to the composition of an improved transfection medium, detailing the benefits of specific components like treated albumin, hydrocortisone, and antioxidants for increasing transfection efficiency and cell viability (’410 Patent, col. 13:12-14:42). A defendant may argue that the term should be construed to include at least some of these features described as important for the invention's success.

VI. Other Allegations

Indirect Infringement

The complaint alleges that Cellectis induces infringement by its contractual partners, including AstraZeneca, by licensing its technology and providing instructions and materials (synthetic mRNA) for performing the patented methods (Compl. ¶¶ 149-151). It also alleges AstraZeneca induces infringement by directing and compensating Cellectis to perform the infringing activities on its behalf pursuant to their collaboration agreement (Compl. ¶¶ 208-209).

Willful Infringement

Willfulness is alleged against both Cellectis and AstraZeneca based on purported pre-suit knowledge of the patents. Allegations against Cellectis cite a March 2013 article, a 2017 business development call, a 2021 Information Disclosure Statement citing the patents, and a June 2022 meeting where Factor’s CEO allegedly showed the ’410 patent claims to Cellectis’s CBO (Compl. ¶¶ 129-132). Allegations against AstraZeneca cite June 2019 communications, FedEx delivery of a technology catalog containing patent claims in October 2020, and the expectation of due diligence prior to its 2023 collaboration with Cellectis (Compl. ¶¶ 135-138).

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

  • A central legal issue will be one of statutory exemption: Do Defendants' accused activities—described as research platforms for identifying and designing cell therapy candidates under a commercial collaboration agreement—fall within the 35 U.S.C. § 271(e)(1) "Safe Harbor," or do they constitute non-exempt research tool use and commercial licensing, as the complaint alleges?
  • A key factual question will be one of intent and knowledge: Based on the extensive pre-suit interactions alleged in the complaint, what was each Defendant’s state of mind regarding the patents-in-suit while developing their platforms and entering into their multi-billion-dollar collaboration agreement? The answer will be critical for determining willfulness and potential for enhanced damages.
  • A core issue of claim scope may arise concerning the phrase "producing a plurality of gene-edited cells." The case may explore whether this method claim limitation is met by research activities that generate a heterogeneous mixture of edited and unedited cells that are not themselves a final therapeutic product, but rather an intermediate for further research and development.