DCT

1:24-cv-00913

Merus NV v. Xencor Inc

Log In

I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:24-cv-00913, D. Del., 08/05/2024
  • Venue Allegations: Venue is alleged to be proper in the District of Delaware because Defendant Xencor, Inc. is a Delaware corporation.
  • Core Dispute: Plaintiff alleges that Defendant’s methods for generating multispecific antibodies using its RenLite mouse and XmAb platform, as well as the resulting antibody products, infringe three patents related to common light chain and heterodimerization technologies.
  • Technical Context: The technology at issue involves advanced antibody engineering to create bispecific and trispecific antibodies, which are a class of biopharmaceuticals with significant applications in oncology and other therapeutic areas.
  • Key Procedural History: The complaint alleges that Defendant was aware of the Heterodimerization Patents prior to the lawsuit, citing Defendant’s Form 10-K SEC filings. The complaint further alleges that Plaintiff provided Defendant with written notice of infringement on May 15, 2024, followed by an in-person meeting on July 2, 2024, during which infringement was explained and Defendant allegedly admitted to using the accused technology.

Case Timeline

Date Event
2009-06-29 U.S. Patent No. 9,944,695 Priority Date
2012-04-20 U.S. Patent Nos. 9,358,286 & 11,926,859 Priority Date
2016-06-07 U.S. Patent No. 9,358,286 Issue Date
2018-04-17 U.S. Patent No. 9,944,695 Issue Date
2020-10-27 Xencor allegedly enters agreement to license RenLite mouse
2024-03-12 U.S. Patent No. 11,926,859 Issue Date
2024-05-15 Merus provides written notice of infringement to Xencor
2024-07-02 Merus and Xencor hold IP meeting
2024-08-05 Complaint Filing Date

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

U.S. Patent No. 9,944,695 - "Antibody Producing Non-Human Mammals"

  • Patent Identification: U.S. Patent No. 9,944,695, "Antibody Producing Non-Human Mammals," issued April 17, 2018.

The Invention Explained

  • Problem Addressed: The conventional method of producing bispecific antibodies in a single host cell is highly inefficient. If a cell is engineered to produce two distinct heavy chains and two distinct light chains, random pairing can result in up to ten different antibody species, only one of which is the desired bispecific product, creating a significant purification challenge (Compl. ¶23).
  • The Patented Solution: The patent describes a method to overcome this problem by using a transgenic mouse engineered to produce antibodies with a "common light chain" (Compl. ¶19). The mouse’s genome contains a pre-arranged human immunoglobulin light chain gene, ensuring that all B cells in the mouse produce the same light chain protein (Compl. ¶79). When immunized, the mouse generates a diverse repertoire of heavy chains that all pair with this single light chain, reducing the number of potential antibody products from ten to three and greatly simplifying the isolation of the desired bispecific antibody (Compl. ¶23; ’695 Patent, col. 4:54-67).
  • Technical Importance: This "common light chain" technology allows for more efficient discovery and manufacturing of multispecific antibodies, which are a critical class of therapeutics for targeting multiple disease pathways simultaneously (Compl. ¶¶ 21, 27).

Key Claims at a Glance

  • The complaint asserts infringement of at least Claim 1 (Compl. ¶78).
  • Independent Claim 1 of the ’695 Patent contains the following essential elements:
    • (a) Immunizing a transgenic mouse with an antigen, where the mouse's genome comprises a transgene with a human immunoglobulin light chain V gene segment fused to a J gene segment, encoding a rearranged human light chain variable region.
    • The transgene is further characterized by either lacking a specific intronic enhancer (MoEki), being inserted at the murine Rosa locus, or comprising other specific enhancer truncations, and being operatively linked to a mouse light chain constant region.
    • (b) Obtaining a population of B cells from the mouse that produce antibodies comprising the rearranged human light chain variable region paired with diverse, rearranged heavy chain variable regions.
    • (c) Isolating nucleic acid encoding a rearranged heavy chain variable region from a B cell.
    • (d) Expressing the nucleic acids for the heavy and light chain variable regions in a host cell.
    • (e) Thus obtaining an antibody that binds the antigen.
  • The complaint does not explicitly reserve the right to assert dependent claims for this patent.

U.S. Patent No. 9,358,286 - "Methods And Means For The Production Of Ig-Like Molecules"

  • Patent Identification: U.S. Patent No. 9,358,286, "Methods And Means For The Production Of Ig-Like Molecules," issued June 7, 2016.

The Invention Explained

  • Problem Addressed: Even when using a common light chain, co-expression of two different heavy chains in a host cell produces an undesirable mixture containing two types of monospecific "parental" antibodies (homodimers) in addition to the desired bispecific antibody (heterodimer) (Compl. ¶23; ’286 Patent, col. 3:42-54). Separating these closely related molecules is difficult and costly.
  • The Patented Solution: The patent describes a method for promoting the formation of heterodimers through electrostatic steering. The invention involves making specific amino acid substitutions in the CH3 domain, which is the primary interface for heavy chain pairing. A neutral amino acid on the first heavy chain is replaced with a positively charged one, and a neutral amino acid on the second heavy chain is replaced with a negatively charged one (Compl. ¶96). The resulting electrostatic attraction between the oppositely charged chains drives the preferential formation of the desired heterodimer, while repulsion between identically charged chains suppresses the formation of unwanted homodimers (Compl. ¶25; ’286 Patent, col. 5:35-50).
  • Technical Importance: This heterodimerization technology increases the yield and purity of bispecific antibodies produced in a single cell culture, a key innovation for making these complex therapeutics manufacturable at an industrial scale (Compl. ¶¶ 26, 27).

Key Claims at a Glance

  • The complaint asserts infringement of at least Claim 1 (Compl. ¶95).
  • Independent Claim 1 of the ’286 Patent contains the following essential elements:
    • (a) Providing a host cell comprising:
      • (i) a first nucleic acid encoding a 1st antibody heavy chain with at least one substitution of a neutral amino acid by a positively charged amino acid in its CH3 domain; and
      • (ii) a second nucleic acid encoding a 2nd antibody heavy chain with at least one substitution of a neutral amino acid by a negatively charged amino acid in its CH3 domain.
    • (b) Culturing the host cell to express the two nucleic acids, wherein the substituted charged residues interact to produce a heterodimeric antibody.
    • (c) Harvesting the heterodimeric antibody from the culture.
  • The complaint does not explicitly reserve the right to assert dependent claims for this patent.

U.S. Patent No. 11,926,859 - "Methods And Means For The Production Of Ig-Like Molecules"

  • Patent Identification: U.S. Patent No. 11926859, "Methods And Means For The Production Of Ig-Like Molecules," issued March 12, 2024.

Technology Synopsis

This patent, related to the ’286 patent, claims the heterodimeric antibody product itself, rather than the method of making it (Compl. ¶109). The invention is a composition of matter defined by specific amino acid substitutions that create opposing charges at key positions in the CH3 domains of two different heavy chains, thereby promoting their preferential pairing through electrostatic interaction (’859 Patent, col. 5:35-50, col. 6:1-6).

Asserted Claims

The complaint asserts infringement of at least Claim 1 (Compl. ¶108).

Accused Features

Xencor's "XmAb" antibodies are accused of infringing the ’859 patent. These antibodies allegedly comprise a first heavy chain with a positively charged lysine at position 364 and a second heavy chain with a negatively charged aspartic acid at position 368 (Compl. ¶¶ 112, 113).

III. The Accused Instrumentality

Product Identification

  • The complaint identifies two main categories of accused instrumentalities:
    1. The method of using the RenLite mouse and its biological products for antibody discovery (Compl. ¶¶ 33, 78).
    2. The XmAb bispecific platform technology and the resulting heterodimeric antibodies, including product candidates such as plamotamab and vudalimab (Compl. ¶¶ 60, 63).

Functionality and Market Context

  • The RenLite mouse, licensed by Xencor from Biocytogen, is alleged to be a transgenic mouse used for bispecific antibody discovery (Compl. ¶¶ 35, 37). It is alleged to carry a "fixed common human light chain VJ gene" and human heavy chain loci, which allows it to generate B cells producing antibodies with a single, common light chain paired with diverse heavy chains after immunization (Compl. ¶¶ 38, 39). A diagram from Biocytogen's website shows the creation of a "Humanized Common Light Chain" from rearranged human DNA segments (Compl. p. 11, FIG. "K Light Chain").
  • The XmAb bispecific platform is described as a technology that engineers amino acid substitutions into the CH3 region of antibody heavy chains to create stable heterodimers (Compl. ¶¶ 63, 64). The complaint alleges this platform uses a substitution of serine to a positively charged lysine at position 364 on one chain and a substitution of leucine to a negatively charged aspartic acid at position 368 on the other chain (Compl. ¶¶ 64, 66, 99). This technology is presented as a "fundamental design feature" used throughout Xencor's antibody portfolio and is marketed as a "plug-and-play" system for creating more effective antibodies (Compl. ¶¶ 67, 68).

IV. Analysis of Infringement Allegations

U.S. Patent No. 9,944,695 Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
(a) immunizing a transgenic mouse with the antigen... Xencor allegedly immunizes the RenLite mouse with antigens to generate antibodies. ¶¶ 46, 84 col. 9:1-10
...wherein the genome of the transgenic mouse comprises a transgene comprising a human immunoglobulin light chain germline V gene segment fused to a human immunoglobulin light chain germline J gene segment... The RenLite mouse is alleged to contain a transgene with a "fixed common human light chain VJ gene," depicted in a diagram showing rearranged human DNA segments. (Compl. p. 11). ¶¶ 40, 85 col. 6:49-55
...such that there is no mutation due to said fusion... The complaint alleges that the fusion of the V/J gene segments in the RenLite mouse transgene results in no mutation. ¶¶ 40, 85 col. 6:55-56
...wherein said transgene lacks the intronic light chain enhancer MoEki... The RenLite mouse transgene is alleged to lack the specific intronic light chain enhancer MoEki, based on analysis of a published sequence and a BLAST comparison. ¶¶ 43, 86 col. 6:60-62
...wherein the transgene... is operatively linked to an endogenous mouse light chain constant region gene segment... The RenLite mouse's transgene is alleged to be linked to an endogenous mouse constant region to ensure normal B cell development. ¶¶ 45, 87 col. 7:1-4
(b) obtaining a population of B cells producing antigen specific antibodies from the transgenic mouse... Xencor allegedly obtains populations of B cells from the immunized RenLite mouse using processes such as FACS-based B cell isolation, as depicted in an online flowchart (Compl. p. 14). ¶¶ 46, 88, 90 col. 9:11-20
(c) isolating nucleic acid encoding a rearranged immunoglobulin heavy chain variable region from a B cell in said population... Biocytogen allegedly describes, and Xencor allegedly uses, processes that include single-cell sequencing to isolate nucleic acids from the B cells. ¶¶ 50, 91 col. 9:21-23

Identified Points of Contention

  • Technical Questions: A primary evidentiary question may be whether the RenLite mouse's transgene is structurally identical to what is claimed. The complaint's allegations rely on third-party (Biocytogen's) marketing materials, websites, and patent applications (Compl. ¶¶ 37-45). The case may turn on factual evidence establishing the precise genetic sequence and configuration of the transgene in the RenLite mouse, including whether it truly "lacks the intronic light chain enhancer MoEki" as specifically recited in the claim.
  • Scope Questions: The complaint alleges infringement through both practicing the claimed method in the U.S. and importing/using antibodies in the U.S. that were obtained by the method practiced abroad (Compl. ¶80). This raises a potential question for the court regarding the scope of 35 U.S.C. § 271(g) as it applies to information (isolated nucleic acids) versus a manufactured product.

U.S. Patent No. 9,358,286 Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
(a)(i) ...a 1st antibody heavy chain comprising at least one substitution of a neutral amino acid residue in the CH3 domain by a positively charged amino acid residue... Xencor's XmAb antibodies are alleged to contain a heavy chain with an S364K substitution, where the neutral serine (S) is replaced by the positively charged lysine (K). ¶¶ 99, 100 col. 19:5-12
(a)(ii) ...a 2nd antibody heavy chain comprising at least one substitution of a neutral amino acid residue in the CH3 domain by a negatively charged amino acid residue... Xencor's XmAb antibodies are alleged to contain a second heavy chain with an L368D substitution, where the neutral leucine (L) is replaced by the negatively charged aspartic acid (D). ¶¶ 99, 100 col. 19:13-20
(b) culturing said host cell... wherein the at least one positively charged amino acid residue... interacts with the at least one negatively charged amino acid residue... to produce a heterodimeric antibody... Xencor allegedly cultures host cells to express the two heavy chains, with the opposite charges driving preferential pairing to form a heterodimer. ¶101 col. 20:34-42
(c) harvesting said heterodimeric antibody from the culture. Xencor is alleged to harvest the resulting heterodimeric antibodies from the cell culture. ¶102 col. 20:43-45

Identified Points of Contention

  • Technical Questions: The infringement analysis will likely focus on whether Xencor's accused XmAb platform universally relies on the specific neutral-to-charged amino acid substitutions recited in the claim (S364K and L368D). The complaint cites a scientific paper and patent applications as evidence (Compl. ¶¶ 64, 65). The central factual question is whether this specific pair of substitutions is the mechanism used across the accused product line.
  • Scope Questions: What level of causation is required by the term "interacts"? The claim requires that the substituted charged residues "interact" to produce the heterodimer. A potential defense could be that while electrostatic attraction exists, it is not the primary force driving heterodimerization in the accused platform, thereby raising a question of whether this claim limitation is met.

V. Key Claim Terms for Construction

  • Term from ’695 Patent, Claim 1: "fused ... such that there is no mutation"

    • Context and Importance: This term defines the required structure of the light chain transgene. Its construction is critical because infringement depends on the precise genetic arrangement in the RenLite mouse. Practitioners may focus on this term because any deviation from a perfect, mutation-less fusion in the accused transgene could be a basis for a non-infringement argument.
    • Intrinsic Evidence for a Broader Interpretation: The specification may describe the goal of the fusion as creating a single, functional open reading frame, potentially tolerating minor non-coding changes that do not affect the final protein. The purpose is to produce a single light chain, suggesting a functional rather than purely structural definition.
    • Intrinsic Evidence for a Narrower Interpretation: The explicit language "no mutation due to said fusion" suggests a very high bar for structural identity (’695 Patent, col. 6:55-56). Specific embodiments or figures might depict a direct, seamless ligation of the V and J coding sequences, which would support a narrow construction requiring no changes to the nucleotide sequence at the junction.

  • Term from ’286 Patent, Claim 1: "interacts"

    • Context and Importance: This term is central to the mechanism of action for the claimed method. The definition of "interacts" will determine whether any electrostatic attraction is sufficient for infringement, or if a specific type or strength of interaction (e.g., a salt bridge) is required.
    • Intrinsic Evidence for a Broader Interpretation: The specification describes the invention in terms of "electrostatic steering" and creating "favorable attractive interactions" generally (’286 Patent, col. 5:44-46). This language may support a construction where any contribution to preferential pairing from the electrostatic attraction satisfies the "interacts" limitation.
    • Intrinsic Evidence for a Narrower Interpretation: The patent may provide specific examples where the substituted residues are shown to form a direct salt bridge or are within a specific distance threshold. Such embodiments could be used to argue that "interacts" requires a direct and primary electrostatic bond, not merely a contribution to an overall binding energy.

VI. Other Allegations

  • Indirect Infringement: The complaint alleges inducement of infringement of the ’695 patent, stating that Biocytogen provides instructions to its customers and licensees, including Xencor, on how to use the RenLite mouse to create and obtain antibodies (Compl. ¶¶ 49, 81). For the Heterodimerization Patents, infringement is alleged in connection with Xencor's "partnered" development work, which may give rise to claims of joint or indirect infringement (Compl. ¶¶ 97, 110).
  • Willful Infringement: The complaint makes detailed allegations to support willfulness for the Heterodimerization Patents. It alleges pre-suit knowledge based on Xencor's own SEC filings, which acknowledged Merus's patents (Compl. ¶¶ 59, 73). It further alleges that Plaintiff sent a notice letter to Xencor on May 15, 2024, and subsequently explained the infringement in a meeting on July 2, 2024, after which Xencor allegedly continued its infringing activities (Compl. ¶75). The complaint also alleges that during this meeting, Xencor admitted to using the infringing amino acid substitutions throughout its antibody portfolio (Compl. ¶76).

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

  • A core issue will be one of evidentiary proof: can Plaintiff demonstrate that the accused RenLite mouse and XmAb platform technologies precisely match the structural and functional limitations of the asserted claims? The dispute will likely move from the complaint's reliance on public-facing documents to a technical battle over the actual genetic makeup of the mouse and the molecular composition of the antibodies.
  • A second central question will concern intent and damages: given the complaint’s strong allegations of pre-suit notice and alleged admissions, the case will likely feature a significant dispute over whether any infringement was willful. This will directly impact the potential for enhanced damages, particularly for activities such as antibody discovery and development that occurred long before any products reached the market.