DCT

1:24-cv-00791

Blueallele Corp v. Intellia Therap Inc

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:24-cv-00791, D. Del., 07/08/2024
  • Venue Allegations: Venue is alleged to be proper in the District of Delaware because Defendant Intellia Therapeutics, Inc. is a domestic Delaware corporation.
  • Core Dispute: Plaintiff alleges that Defendant’s bi-directional template gene editing technology, used in the development of in vivo therapeutics, infringes three patents related to methods and compositions for targeted DNA insertion.
  • Technical Context: The dispute is in the field of CRISPR-based gene editing, a technology aimed at correcting genetic mutations to treat diseases by inserting therapeutic DNA sequences into a patient's genome.
  • Key Procedural History: The complaint alleges that Defendant was aware of the asserted patents, or their underlying applications, because Plaintiff's patent filings were reportedly cited during Defendant's own patent prosecution activities. The complaint also references a collaboration agreement between Defendant and Regeneron Pharmaceuticals related to the development of the accused technologies.

Case Timeline

Date Event
2018-10-16 Earliest Priority Date for ’756, ’930, and ’407 Patents
2021-08-17 U.S. Patent No. 11,091,756 Issues
2022-02-22 U.S. Patent No. 11,254,930 Issues
2022-06-21 U.S. Patent No. 11,365,407 Issues
2024-07-08 Complaint Filed

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

U.S. Patent No. 11,091,756 - Methods for Targeted Insertion of DNA in Genes

The Invention Explained

  • Problem Addressed: The patent addresses challenges in gene editing where therapeutic DNA is inserted into a cell's genome. When using the cell's efficient Non-Homologous End Joining (NHEJ) repair pathway, the inserted DNA can integrate in either a correct (forward) or incorrect (reverse) orientation, reducing the therapeutic efficacy (Compl. ¶14). Alternative, more precise pathways have low efficiency, particularly in non-dividing cells targeted for in vivo therapies ('756 Patent, col. 2:1-4).
  • The Patented Solution: The patent claims a method that uses a specially designed "bi-directional" transgene. This DNA construct contains two copies of the therapeutic coding sequence arranged in opposite orientations (a forward copy and a reverse-complement copy), each flanked by the necessary signals (splice acceptors and terminators). When a nuclease like CRISPR/Cas9 cuts the target DNA, this bi-directional template is inserted. Because of its symmetric design, regardless of whether it integrates in the forward or reverse orientation, one of the two coding sequences will be correctly oriented to be read by the cell's machinery and produce the desired protein ('756 Patent, col. 2:5-13; Fig. 2).
  • Technical Importance: This design aims to make NHEJ-mediated gene insertion, an otherwise error-prone process, orientation-independent, thereby increasing the overall yield and predictability of producing a functional therapeutic protein in edited cells (Compl. ¶16).

Key Claims at a Glance

  • The complaint asserts independent claim 1 ('756 Patent, col. 371:1-29; Compl. ¶31).
  • Claim 1 is a method claim with the following essential elements:
    • Administering to a cell a first recombinant nucleic acid comprising a transgene, where the transgene has a specific bi-directional structure (either with two separate terminators or a single bidirectional terminator).
    • Administering to the cell a second recombinant nucleic acid that encodes a CRISPR/Cas9 nuclease targeting a site within an intron of an endogenous gene.
    • Integrating the transgene into the endogenous gene at the target site.
    • The transgene's two coding sequences must encode the same heterologous amino acid sequence.
    • After integration, one of the coding sequences must be "operatively linked" to the endogenous gene's promoter to express a fusion protein.
  • The complaint does not explicitly reserve the right to assert dependent claims for this patent.

U.S. Patent No. 11,254,930 - Methods for Targeted Insertion of DNA in Genes

The Invention Explained

  • Problem Addressed: The technical problem is identical to that described in the ’756 Patent: overcoming the orientation-dependent inefficiency of certain gene editing techniques ('930 Patent, col. 2:32-48).
  • The Patented Solution: Instead of claiming the method of using the bi-directional construct, the ’930 Patent claims the composition of matter itself—the recombinant nucleic acid that contains the bi-directional transgene. The claimed construct comprises, in a specific 5' to 3' order, a first splice acceptor, a first coding sequence, a first terminator, and their reverse complements (second terminator, second coding sequence, second splice acceptor) ('930 Patent, Abstract; Fig. 1). This structure is the tool designed to solve the orientation problem described previously.
  • Technical Importance: Claiming the nucleic acid construct itself provides a different layer of protection, covering the key therapeutic agent regardless of the specific method a third party might use to deliver or integrate it.

Key Claims at a Glance

  • The complaint asserts independent claim 1 ('930 Patent, col. 369:53-65; Compl. ¶40).
  • Claim 1 is a composition of matter claim requiring:
    • A recombinant nucleic acid comprising a transgene.
    • The transgene itself must comprise, in 5' to 3' orientation: a first splice acceptor, a first coding sequence, a first terminator, a second terminator reverse complement, a second coding sequence reverse complement, and a second splice acceptor reverse complement.
    • The first and second coding sequences must encode the same amino acid sequence.
  • The complaint does not explicitly reserve the right to assert dependent claims for this patent.

U.S. Patent No. 11,365,407 - Methods for Targeted Insertion of DNA in Genes

  • Technology Synopsis: This patent claims a transgene composition similar to the ’930 Patent but adds further limitations. The claimed transgene must use a specific type of terminator (SV40 poly(A) or BGH poly(A)), must be equal to or less than 4.7 kb in size, and must encode amino acids corresponding to those of an endogenous Factor IX gene ('407 Patent, col. 369:59-370:12; Compl. ¶47).
  • Asserted Claims: Independent Claim 1 (Compl. ¶47).
  • Accused Features: The complaint alleges that Intellia’s bi-directional insertion template technology, specifically as used for its therapeutic candidates targeting diseases like hemophilia (which involves Factor IX), infringes this patent (Compl. ¶48-49).

III. The Accused Instrumentality

Product Identification

The accused instrumentalities are Defendant Intellia's "bi-directional insertion template technology" and the therapeutic candidates and research programs that utilize it, including NTLA-3001, Hemophilia A, and Hemophilia B programs (Compl. ¶1, ¶20, ¶26).

Functionality and Market Context

The complaint alleges Intellia's technology involves a two-part system for in vivo gene editing. First, a CRISPR/Cas9 nuclease is delivered (e.g., via a lipid nanoparticle or LNP) to create a specific cut in the DNA of a target cell, such as at the albumin locus (Compl. ¶32, ¶34). Second, a "Bi-directional insertion template" containing a therapeutic "Gene of Interest" is delivered (e.g., via an adeno-associated virus or AAV) and integrated at the cut site (Compl. ¶32; Compl. Ex. 4 at 38). This process is designed to achieve "targeted, stable gene insertion" for producing therapeutic proteins to treat genetic diseases (Compl. Ex. 4 at 38). The complaint alleges this technology is central to Intellia's development pipeline and its collaboration with Regeneron Pharmaceuticals (Compl. ¶23, ¶26). One diagram from an Intellia presentation shows how its insertion technology is used to investigate a Human Factor 9 (F9) model system (Compl. Ex. 6 at 4).

IV. Analysis of Infringement Allegations

’756 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A method of integrating a transgene into an endogenous gene in the genome of a cell, comprising administering to the cell a first recombinant nucleic acid comprising a transgene... Defendant's method allegedly involves administering an AAV vector containing a "Bi-directional insertion template" with a "Gene of Interest" and other elements. ¶32, ¶33 col. 4:23-28
...administering to the cell a second recombinant nucleic acid encoding a CRISPR/Cas9 nuclease having a target site within an intron of the endogenous gene, to thereby provide the CRISPR/Cas9 nuclease in the cell... Defendant's method allegedly involves administering an LNP containing Cas9/gRNA to "Precisely Create [an] Insertion Site" within an intron, such as in the albumin gene. ¶32, ¶34 col. 4:29-32
...and integrating the transgene into the endogenous gene at the CRISPR/Cas9 nuclease target site... The combination of Defendant's two-step process allegedly results in the "Targeted, stable gene insertion" of the template into the albumin locus. ¶32 col. 4:32-34
...wherein following integration the first coding sequence or the second coding sequence is operatively linked to a promoter of the endogenous gene to express a fusion protein... Defendant's presentations allegedly show that the method achieves high levels of therapeutic protein production (e.g., hAAT), which Plaintiff alleges demonstrates the required operative linkage. A referenced diagram shows the inserted gene downstream of the endogenous albumin promoter (Compl. Ex. 4 at 38). ¶35 col. 4:35-41
  • Identified Points of Contention:
    • Technical Questions: The complaint relies on high-level corporate presentations to allege infringement. A key question for the court will be whether discovery confirms that the molecular components and mechanisms of Intellia's system—including the specific sequences used as splice acceptors and terminators and the precise nature of the resulting protein—match the technical requirements of the claim language. For example, does the method result in a "fusion protein" as claimed?
    • Scope Questions: The claim requires integration "within an intron of the endogenous gene." Intellia's presentations identify the "albumin locus" as a target (Compl. Ex. 4 at 38). The litigation will likely require evidence confirming the exact integration site and whether it falls within the scope of this limitation.

’930 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A recombinant nucleic acid comprising a transgene... Defendant's "insertion technology" is alleged to include a recombinant nucleic acid construct, specifically the "Bi-directional Insertion Template" delivered via AAV. ¶41 col. 4:23-28
...the transgene comprising in 5' to 3' orientation: a first splice acceptor, a first coding sequence, a first terminator... Plaintiff maps these elements to a diagram of Defendant's template: the gray box is the "first splice acceptor," the orange box labeled "Gene of interest" is the "first coding sequence," and the black box is the "first terminator." ¶42 col. 4:32-35
...a second terminator reverse complement, a second coding sequence reverse complement, and a second splice acceptor reverse complement... Plaintiff maps these elements to the corresponding components on the right side of the diagram, including the upside-down "Gene of interest" element. The diagram from an Intellia presentation visually depicts a bi-directional construct (Compl. Ex. 4 at 38). ¶42 col. 4:35-38
...wherein the first coding sequence encodes an amino acid sequence, and the second coding sequence encodes the same amino acid sequence as the first coding sequence. Plaintiff alleges that both the forward and reverse-oriented "Gene of Interest" elements in Defendant's template encode the same therapeutic protein. ¶42 col. 5:1-4
  • Identified Points of Contention:
    • Technical Questions: While the diagrams provided in the complaint are suggestive, the actual infringement analysis will depend on the precise nucleic acid sequences of Intellia's templates. A central question is whether the sequences Intellia identifies as functional elements (e.g., splice acceptors, terminators) meet the definitions of those terms as understood in the art and as described in the patent.
    • Scope Questions: The primary dispute may focus on whether there are any structural or functional distinctions between Intellia's template construct and the specific arrangement of six elements recited in order by the claim.

V. Key Claim Terms for Construction

  • The Term: "operatively linked" ('756 Patent, Claim 1)

    • Context and Importance: This term is critical for the method claim of the ’756 patent, as it defines the functional outcome required after the transgene is integrated. The infringement case depends on showing not just that the transgene was inserted, but that it was inserted in a way that it is properly expressed using the native gene's promoter. A graph in the complaint shows the production of therapeutic protein, which Plaintiff presents as evidence of this linkage (Compl. Ex. 7 at 20).
    • Intrinsic Evidence for Interpretation:
      • Evidence for a Broader Interpretation: The specification provides a general definition: ""operatively linked" or "operably linked" are used interchangeably and refer to a juxtaposition of two or more components in which the components are arranged such that both components function as intended" ('756 Patent, col. 8:31-35).
      • Evidence for a Narrower Interpretation: The specification also provides a more specific context: "a promoter is operatively linked to a coding sequence if the transcriptional regulatory elements of the promoter control or modulate transcription of the coding sequence" ('756 Patent, col. 8:36-41). A defendant could argue that this requires proof of direct transcriptional control by the endogenous promoter, not just evidence of protein expression.

  • The Term: "splice acceptor" ('756 and '930 Patents, Claim 1)

    • Context and Importance: Splice acceptors are essential for the invention to function; they are the signals that allow the cell's machinery to splice the inserted coding sequence into the messenger RNA produced from the endogenous gene. Practitioners may focus on this term because the functionality of the entire bi-directional system hinges on whether the sequences at the ends of the transgene are functional splice acceptors.
    • Intrinsic Evidence for Interpretation:
      • Evidence for a Broader Interpretation: The patent does not appear to provide a special definition, suggesting the term should be given its plain and ordinary meaning to one of skill in the art. This would encompass any sequence that can be recognized by the cellular spliceosome to initiate splicing.
      • Evidence for a Narrower Interpretation: A defendant might argue that the term should be limited to the specific types of splice acceptors used in the patent's examples or that are known to have high efficiency. The specification mentions that the transgene can comprise "a splice acceptor from an intron of the endogenous gene" or a "synthetic splice acceptor" ('756 Patent, col. 16:11-14), which could be used to argue about the scope of acceptable sequences.

VI. Other Allegations

  • Indirect Infringement: The complaint alleges that Intellia induces infringement by, for example, making and selling compositions to its partner Regeneron for use in research and development of therapeutics (Compl. ¶28). The facts alleged in support of the collaboration agreement may form the basis for this theory (Compl. ¶23).
  • Willful Infringement: Willfulness is alleged based on Intellia's purported knowledge of the Asserted Patents. The complaint asserts that this knowledge stems, at least in part, from "BlueAllele's patent filings hav[ing] been the subject of filings in Intellia's patent prosecution activities," suggesting Intellia was aware of the technology prior to the suit being filed (Compl. ¶27).

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

  • A central evidentiary question will be one of technical correspondence: can Plaintiff prove, beyond the high-level marketing diagrams cited in the complaint, that the specific molecular structures and biological mechanisms of Defendant's proprietary gene editing platform map directly onto the elements recited in the asserted claims?
  • The case may also turn on a question of functional proof: for the method claims, what level of evidence will be required to demonstrate that the integrated transgene is "operatively linked" to an endogenous promoter and expresses a "fusion protein" as claimed, rather than a different protein product through an alternative biological mechanism?
  • A key issue for damages will be willfulness: given the allegation that Defendant was aware of Plaintiff’s patent filings during its own prosecution, the court will likely examine what steps, if any, Defendant took to assess the risk of infringement, which will be critical in determining whether its conduct rose to the level of objective recklessness.