DCT

1:24-cv-11697

Biomodal Ltd v. New England Biolabs Inc

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:24-cv-11697, D. Mass., 01/16/2025
  • Venue Allegations: Venue is alleged to be proper in the District of Massachusetts because Defendant resides in the district, maintains a regular and established place of business there, and has committed alleged acts of infringement within the district.
  • Core Dispute: Plaintiffs allege that Defendant’s DNA sequencing kits and related products, used for epigenetic analysis, infringe eight patents directed to methods for detecting the methylation status of cytosine in nucleic acids.
  • Technical Context: The technology relates to epigenetics, specifically the enzymatic methods used to distinguish between modified DNA bases like 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC), which is a critical process for research into gene expression and diseases such as cancer.
  • Key Procedural History: This First Amended Complaint was filed after a Court order on November 25, 2024, dismissed certain claims from the original complaint. The Court found the previously asserted claims of U.S. Patent Nos. 10,533,213, 10,731,204, and 11,072,818 were not representative of their respective patents. This amended complaint re-asserts infringement of the '213 patent, but now alleges infringement of dependent claims 5-7 instead of the previously asserted independent claim 1.

Case Timeline

Date Event
2008-09-29 Earliest Priority Date for all Asserted Patents
2019-07-02 U.S. Patent No. 10,337,053 Issues
2019-10-15 U.S. Patent No. 10,443,091 Issues
2020-01-14 U.S. Patent No. 10,533,213 Issues
2020-08-04 U.S. Patent No. 10,731,204 Issues
2020-09-08 U.S. Patent No. 10,767,216 Issues
2020-09-15 U.S. Patent No. 10,774,373 Issues
2021-05-21 Alleged discussion between Plaintiffs' and Defendant's employees regarding patent family
2021-07-27 U.S. Patent No. 11,072,818 Issues
2021-12-28 U.S. Patent No. 11,208,683 Issues
2024-02-12 Alleged launch date for Defendant's 5hmC and 5hmC Kit Products
2024-05-08 Date of notice letter sent to Defendant
2024-11-25 Court dismisses certain claims from original complaint
2025-01-16 First Amended Complaint Filed

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

U.S. Patent No. 10,533,213 - Selective Oxidation of 5-Methylcytosine by TET-Family Proteins

  • Patent Identification: U.S. Patent No. 10,533,213, entitled “Selective Oxidation of 5-Methylcytosine by TET-Family Proteins,” issued January 14, 2020.

The Invention Explained

  • Problem Addressed: The patent background describes the central role of DNA methylation—primarily the modification of cytosine to 5-methylcytosine (5mC)—in regulating gene expression during development and in diseases like cancer (Compl. ¶15; ’213 Patent, col. 2:55-64). A key technical challenge was distinguishing 5mC from other modified forms of cytosine, such as 5-hydroxymethylcytosine (5hmC), to accurately map epigenetic states (’213 Patent, col. 3:5-11).
  • The Patented Solution: The invention provides methods for detecting the methylation status of DNA by using a family of enzymes known as TET proteins (’213 Patent, Abstract). These enzymes are described as having the catalytic activity to specifically convert, or "oxidize," 5mC into 5hmC or other derivatives, as shown in Figure 2 of the patent (’213 Patent, col. 3:55-65; Fig. 2). By enzymatically altering 5mC, the invention allows researchers to then detect this modification, thereby revealing the original location of 5mC in a DNA sequence.
  • Technical Importance: This enzymatic approach provided a novel way to precisely identify and map 5mC at single-base resolution, a capability crucial for advancing epigenetic research and diagnostics (Compl. ¶13, 17).

Key Claims at a Glance

  • The complaint asserts dependent claims 5-7, which rely on independent claim 1 (Compl. ¶55).
  • The essential elements of independent claim 1 are:
    • A method for detecting a 5-methylcytosine residue in a nucleic acid, comprising:
    • (a) oxidizing the 5-methylcytosine residue in the nucleic acid to generate a modified nucleic acid,
    • wherein the oxidizing comprises contacting the nucleic acid with a TET family protein (TET1, TET2, TET3, CXXC4), a catalytic fragment, or a combination thereof; and
    • (b) detecting the modified nucleic acid,
    • wherein detection of the modified nucleic acid is indicative of a presence of the 5-methylcytosine residue in the nucleic acid.
  • The complaint does not explicitly reserve the right to assert other claims of the ’213 Patent.

U.S. Patent No. 10,731,204 - Selective Oxidation of 5-Methylcytosine by TET-Family Proteins

  • Patent Identification: U.S. Patent No. 10,731,204, entitled “Selective Oxidation of 5-Methylcytosine by TET-Family Proteins,” issued August 4, 2020.

The Invention Explained

  • Problem Addressed: Similar to the '213 Patent, this patent addresses the challenge of regulating and detecting the methylation status of DNA, which plays a vital role in biological processes and diseases (’204 Patent, col. 2:55-64). The background highlights the need for tools to screen for and modulate changes in cellular DNA methylation (’204 Patent, col. 4:45-53).
  • The Patented Solution: The patent describes methods for converting a methylated cytosine sequence to a modified base by using a TET family enzyme or a catalytically active fragment thereof (’204 Patent, Abstract; col. 3:55-65). This controlled enzymatic conversion of 5mC to 5hmC provides a foundation for various downstream detection and analysis techniques.
  • Technical Importance: The ability to reliably convert 5mC provides a fundamental tool for research into epigenetics, including the development of diagnostics and therapies related to aberrant DNA methylation (Compl. ¶17; ’204 Patent, col. 4:30-38).

Key Claims at a Glance

  • The complaint asserts independent claim 1 and dependent claim 3 (’204 Patent, col. 221:20-40; Compl. ¶74).
  • The essential elements of independent claim 1 are:
    • A method of converting a methylated cytosine sequence to a modified base, the method comprising:
    • contacting said isolated nucleotide sequence with an enzyme or a fragment thereof,
    • wherein the enzyme or fragment is catalytically active for converting the methylated cytosine residue to a modified base comprising 5-hydroxymethylcytosine, and
    • wherein said enzyme or fragment comprises a TET family protein (TET1, TET2, TET3, CXXC4), a catalytically active fragment, or a combination thereof.
  • The complaint states Plaintiffs reserve the right to assert all claims of the '204 Patent if the court's prior dismissal is reversed or overturned (Compl. ¶85).

U.S. Patent No. 11,072,818 - Selective Oxidation of 5-Methylcytosine by TET-Family Proteins

  • Patent Identification: U.S. Patent No. 11,072,818, "Selective Oxidation of 5-Methylcytosine by TET-Family Proteins," issued July 27, 2021 (Compl. ¶27).
  • Technology Synopsis: This patent, part of the same family, is also directed to methods for regulating and detecting DNA methylation status. It centers on the use of TET family enzymes to hydroxylate 5-methylcytosine to 5-hydroxymethylcytosine, enabling its detection (’818 Patent, Abstract).
  • Asserted Claims: At least claim 1 (Compl. ¶87).
  • Accused Features: The complaint alleges that the use of Defendant's EM-seq and EM-seq Kit Products practices the claimed method (Compl. ¶88).

U.S. Patent No. 11,208,683 - Methods of Epigenetic Analysis

  • Patent Identification: U.S. Patent No. 11,208,683, "Methods of Epigenetic Analysis," issued December 28, 2021 (Compl. ¶28).
  • Technology Synopsis: This patent claims compositions for epigenetic analysis. The invention is a composition comprising a mixture of specific enzymes (a methylcytosine dioxygenase and a DNA glucosyltransferase) along with a nucleic acid that contains glucosylated 5-hydroxy-methylcytosine, a combination which the complaint alleges does not occur in nature (’683 Patent, Abstract; Compl. ¶29).
  • Asserted Claims: At least claim 1 (Compl. ¶100).
  • Accused Features: The complaint alleges that the use of Defendant's EM-seq and EM-seq Kit Products results in a composition meeting the limitations of claim 1 (Compl. ¶101).

U.S. Patent No. 10,337,053 - Labeling Hydroxymethylated Residues

  • Patent Identification: U.S. Patent No. 10,337,053, "Labeling Hydroxymethylated Residues," issued July 2, 2019 (Compl. ¶35).
  • Technology Synopsis: This patent is directed to methods for labeling and detecting hydroxymethylated cytosine residues. The claimed method involves covalently attaching a hydroxyl group on a hydroxymethylated cytosine residue to a label via glycosylation, and then detecting the labeled residue (’053 Patent, Abstract; col. 221:18-24).
  • Asserted Claims: At least claim 1 (Compl. ¶112).
  • Accused Features: The complaint alleges that use of all Accused Products (EM-seq, EM-seq Kit, 5hmC, and 5hmC Kit) infringes the claimed method (Compl. ¶113).

U.S. Patent No. 10,774,373 - Compositions Comprising Glucosylated Hydroxymethylated Bases

  • Patent Identification: U.S. Patent No. 10,774,373, "Compositions Comprising Glucosylated Hydroxymethylated Bases," issued September 15, 2020 (Compl. ¶36).
  • Technology Synopsis: This patent claims an isolated nucleic acid composition derived from an extracellular fluid sample. The key feature is that a hydroxymethylated cytosine within this nucleic acid is glucosylated, a modification the patent asserts is not taught or suggested by the prior art for such samples (’373 Patent, col. 78:26-31; Compl. ¶37, 39).
  • Asserted Claims: At least claims 1 and 5 (Compl. ¶126).
  • Accused Features: The complaint alleges that all Accused Products, when used, result in a product that meets the limitations of the asserted claims (Compl. ¶126).

U.S. Patent No. 10,443,091 - Selective Oxidation of 5-Methylcytosine by TET-Family Proteins

  • Patent Identification: U.S. Patent No. 10,443,091, "Selective Oxidation of 5-Methylcytosine by TET-Family Proteins," issued October 15, 2019 (Compl. ¶42).
  • Technology Synopsis: This patent claims methods for detecting 5-hydroxymethylcytosine (5hmC) in a nucleic acid. The method involves contacting the nucleic acid with an enzyme that can add a glucose donor substrate to the 5hmC residue, which traps a covalent intermediate that can then be detected (’091 Patent, Abstract).
  • Asserted Claims: At least claim 1 (Compl. ¶137).
  • Accused Features: The complaint alleges that the use of all Accused Products infringes the claimed method (Compl. ¶138).

U.S. Patent No. 10,767,216 - Methods for Distinguishing 5-Hydroxymethylcytosine From 5-Methylcytosine

  • Patent Identification: U.S. Patent No. 10,767,216, "Methods for Distinguishing 5-Hydroxymethylcytosine From 5-Methylcytosine," issued September 8, 2020 (Compl. ¶43).
  • Technology Synopsis: This patent claims methods for distinguishing 5-hydroxymethylcytosine (5hmC) from 5-methylcytosine (5mC). The method involves obtaining a sample with both, sequencing the sample, and distinguishing 5hmC based on the sequencing data (’216 Patent, Abstract).
  • Asserted Claims: At least claim 1 (Compl. ¶149).
  • Accused Features: The complaint alleges that the 5hmC and 5hmC Kit Products, when used, meet the limitations of the claimed method (Compl. ¶150).

III. The Accused Instrumentality

Product Identification

  • The accused instrumentalities are four product lines from Defendant New England Biolabs: (i) NEBNext® Enzymatic Methyl-seq ("EM-seq"); (ii) NEBNext® Enzymatic Methyl-Seq Kit ("EM-seq Kit"); (iii) NEBNext® Enzymatic 5hmC-seq Conversion Module ("5hmC"); and (iv) NEBNext® Enzymatic 5hmC-seq Kit ("5hmC Kit") (Compl. ¶47).

Functionality and Market Context

  • The Accused Products are kits sold to third parties, such as research laboratories, for use in scientific protocols related to epigenetics (Compl. ¶46). The complaint alleges that the product manuals and protocols instruct users to perform a series of steps to analyze DNA for the presence of 5mC and 5hmC. These steps are alleged to include adding enzymes, such as the "Oxidation Enhancer T4-BGT" (a beta-glucosyltransferase), to add a glucose molecule to 5-hydroxymethylcytosine residues in a DNA sample, thereby modifying the DNA in a way that allows for its subsequent identification through sequencing (Compl. ¶57, 59).
  • No probative visual evidence provided in complaint.

IV. Analysis of Infringement Allegations

U.S. Patent No. 10,533,213 Infringement Allegations

The complaint alleges that using the EM-seq and EM-seq Kit products in accordance with Defendant's instructions infringes claims 5-7 of the '213 Patent (Compl. ¶56). These claims depend from independent claim 1.

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
(a) oxidizing the 5-methylcytosine residue in the nucleic acid to generate a modified nucleic acid... The complaint alleges Defendant's products incorporate Plaintiffs' patented technologies, which are based on using TET enzymes to oxidize 5mC to 5hmC. ¶14, ¶53 col. 221:22-24
wherein the oxidizing comprises contacting the nucleic acid with TET1, TET2, TET3, CXXC4, a catalytic fragment of any of these, or any combination thereof; The complaint alleges the patented technology is based on exploiting TET enzymes to oxidize 5mC, and that Defendant's products use this technology. ¶14, ¶53 col. 221:25-28
and (b) detecting the modified nucleic acid... The product manuals allegedly instruct the user to identify the modified residues by sequencing. ¶59 col. 221:29
wherein detection of the modified nucleic acid is indicative of a presence of the 5-methylcytosine residue in the nucleic acid. The complaint alleges that at the time of invention, it was not known that detecting an oxidized 5-methylcytosine residue was indicative of the presence of the original 5-methylcytosine. ¶23 col. 221:29-31
  • Identified Points of Contention:
    • Evidentiary Question: The complaint's narrative focuses heavily on the glucosylation step added by dependent claim 5 (Compl. ¶57) rather than the oxidation step of independent claim 1. A central question will be whether discovery shows that the enzymes supplied in the EM-seq kits actually perform the specific oxidation of 5mC using a TET family enzyme, as required by claim 1, before any subsequent steps are performed.
    • Scope Question: The claim recites "detecting the modified nucleic acid." The complaint points to "sequencing" as the detecting step (Compl. ¶59). A potential point of contention may be whether the term "detecting" should be construed more broadly than sequencing and, if so, whether the accused process meets that definition.

U.S. Patent No. 10,731,204 Infringement Allegations

The complaint alleges that the use of the EM-seq and EM-seq Kit Products infringes claims 1 and 3 of the ’204 Patent (Compl. ¶75). The complaint does not provide a narrative breakdown of how the accused products meet the specific limitations of claim 1. Instead, it states that the products meet each limitation and incorporates by reference an external claim chart exhibit that was not included with the complaint (Compl. ¶75). The complaint does not provide sufficient detail for a narrative summary of infringement for this patent.

  • Identified Points of Contention:
    • Evidentiary Question: Given the lack of specific factual allegations in the complaint body for the '204 patent, the primary question for the court will be whether the evidence developed in discovery supports the conclusory allegation that the accused kits contain and instruct the use of a "catalytically active" TET family enzyme to convert "a methylated cytosine sequence."
    • Claim Scope: The relationship between this patent and the '213 patent, which share a similar title and specification, may become a focus. Practitioners may scrutinize whether the scope of "converting a methylated cytosine sequence" in the '204 patent is materially different from "oxidizing the 5-methylcytosine residue" in the '213 patent, and how that distinction affects the infringement analysis.

V. Key Claim Terms for Construction

  • The Term: "oxidizing the 5-methylcytosine residue" ('213 Patent, Claim 1)

  • Context and Importance: This term defines the core chemical transformation of the claimed method. Its construction is critical because it sets the boundaries for what constitutes an infringing enzymatic activity. The dispute will likely center on whether the process performed by the accused kits falls within the scope of this transformation.

  • Intrinsic Evidence for Interpretation:

    • Evidence for a Broader Interpretation: The specification describes the invention as relating to enzymes that "mediate the conversion of 5-methylcytosine to 5-hydroxymethylcytosine by hydroxylation" (’213 Patent, col. 14:1-3). This may support a construction covering any such hydroxylation reaction catalyzed by a TET enzyme.
    • Evidence for a Narrower Interpretation: The abstract and Figure 2 focus specifically on the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) (’213 Patent, Abstract; Fig. 2). A defendant may argue that this specific conversion is what is claimed, potentially excluding other oxidative reactions or incomplete conversions.

  • The Term: "detecting the modified nucleic acid" ('213 Patent, Claim 1)

  • Context and Importance: This step concludes the claimed method, and its definition determines what types of downstream analysis fall within the claim's scope. Whether this term requires a specific technique, like sequencing, or can encompass a broader range of analytical methods will be a key issue.

  • Intrinsic Evidence for Interpretation:

    • Evidence for a Broader Interpretation: The specification discloses multiple methods for detection, including immunohistochemistry and methods using antibodies or binding portions thereof, suggesting "detecting" is not limited to a single technique (’213 Patent, col. 28:40-59).
    • Evidence for a Narrower Interpretation: Asserted dependent claim 7 explicitly adds the limitation of "sequencing" (’213 Patent, col. 222:8-10). Under the doctrine of claim differentiation, a defendant may argue that the term "detecting" in independent claim 1 must mean something other than, or broader than, just sequencing, a point that could become complex in arguing infringement of the dependent claims.

VI. Other Allegations

  • Indirect Infringement: The complaint alleges both induced and contributory infringement for all asserted patents. The inducement allegations are based on Defendant allegedly providing customers with product manuals and protocols that "actively encouraging, instructing and aiding" users to perform the patented methods (Compl. ¶63, 79, 92). Contributory infringement is alleged on the basis that Defendant sells a material component of the invention that is not a staple article of commerce suitable for substantial non-infringing use (Compl. ¶68, 81, 94).
  • Willful Infringement: Willfulness is alleged for all asserted patents. The allegations are based on Defendant’s alleged pre-suit knowledge of the patent family, stemming from a specific discussion between employees of the parties in May 2021, as well as a formal notice letter sent in May 2024 (Compl. ¶60, 76, 89).

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

  • A core issue will be one of evidentiary proof: can Plaintiffs demonstrate through discovery that the enzymes and reagents within Defendant's kits perform the specific chemical reactions recited in the claims? The case will likely involve detailed expert analysis of the biochemical mechanisms of the accused products to determine if they align with the claimed methods of oxidizing and labeling modified DNA bases.
  • A second key question will be one of knowledge and intent: what was the content of the alleged May 2021 discussion between the parties' employees? The court will need to determine whether this communication, coupled with the later notice letter, provided Defendant with knowledge of the patents and infringement that was sufficiently clear to support a finding of willful infringement.
  • Finally, a central legal question will be one of claim construction: how broadly will the court define foundational terms like "oxidizing" and "detecting"? The construction of these terms will directly impact the infringement analysis, particularly given the subtle variations in claim language across a large family of related patents.