DCT

1:21-cv-01635

Invitae Corp v. Natera Inc

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:21-cv-01635, D. Del., 11/21/2021
  • Venue Allegations: Venue is alleged to be proper in the District of Delaware because the defendant, Natera, is a Delaware corporation.
  • Core Dispute: Plaintiff alleges that Defendant's Signatera™ genetic testing service, used for detecting minimal residual disease in cancer patients, infringes patents related to methods for DNA sequence assembly and mutation identification.
  • Technical Context: The lawsuit is in the field of next-generation sequencing (NGS) and bioinformatics, a critical domain for personalized medicine and cancer diagnostics.
  • Key Procedural History: The asserted patents issued on October 19, 2021, and October 26, 2021, respectively, with the complaint being filed less than one month after the second patent's issuance, suggesting a proactive enforcement strategy by the Plaintiff.

Case Timeline

Date Event
2012-04-04 Priority Date for '308 and '863 Patents
2017-08-XX Natera begins selling and offering to sell its Signatera™ test
2019-05-XX Natera begins selling and offering to sell the Signatera™ test for clinical use
2021-10-19 U.S. Patent No. 11,149,308 ('308 Patent) issues
2021-10-26 U.S. Patent No. 11,155,863 ('863 Patent) issues
2021-11-21 Complaint filed

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

U.S. Patent No. 11,149,308, "Sequence Assembly," Issued October 19, 2021

The Invention Explained

  • Problem Addressed: The patent describes prior art DNA sequencing methods as "problematic" Compl. ¶14 Specifically, aligning very short sequence "reads" directly to a long reference genome offers poor positional accuracy and makes it difficult to detect certain mutations like long insertions or deletions ("indels") Compl. ¶14 '308 Patent, col. 2:10-17 Furthermore, existing alignment algorithms forced a trade-off between sensitivity to mismatches and sensitivity to indels, meaning it was likely some mutations would be missed Compl. ¶15 '308 Patent, col. 1:65-2:3
  • The Patented Solution: The invention proposes a multi-stage computational method to improve accuracy. First, short sequence reads from a sample are assembled into longer, intermediate sequences called "contigs" Compl. ¶16 '308 Patent, col. 3:1-3 Second, these longer contigs are aligned to a reference genome to identify a first set of differences Compl. ¶16 '308 Patent, col. 3:52-54 Third, the original short reads are aligned back to their respective contigs to identify a second set of differences Compl. ¶16 '308 Patent, col. 4:21-23 By combining the information from both alignments, the invention claims to overcome the limitations of prior art methods and provide an accurate description of a genotype, including the identity and location of mutations Compl. ¶20 '308 Patent, col. 4:56-61
  • Technical Importance: This two-step alignment approach was designed to improve the fidelity of mutation detection from the short-read data produced by prevalent next-generation sequencing platforms, which was previously computationally intractable or inaccurate for certain mutation types Compl. ¶20 '308 Patent, col. 4:50-54

Key Claims at a Glance

  • The complaint asserts at least independent claim 1 Compl. ¶26
  • Claim 1 of the '308 Patent recites a method with the following essential elements:
    • Obtaining nucleic acid from a biological sample from a human subject.
    • Sequencing the nucleic acid using next-generation sequencing to generate sequence reads.
    • Genotyping using a multi-stage alignment, which comprises:
      • Assembling a "contig" from the sequence reads.
      • Aligning the contig to a reference human genome using a "first substitution probability and a first gap penalty" to identify "first differences."
      • Aligning the sequence reads to the contig using a "second substitution probability and a second gap penalty" to identify "second differences."
      • Genotyping by identifying "multiple mutations" (including a substitution and an indel) based on the combined first and second differences to determine the mutation's identity and location.
  • The complaint notes the provided claim chart is an "example" and is "not intended to limit Plaintiff's right to modify it" or assert other claims Compl. ¶27

U.S. Patent No. 11,155,863, "Sequence Assembly," Issued October 26, 2021

The Invention Explained

  • Problem Addressed: The '863 Patent addresses the same problems as the '308 Patent: the inaccuracy and trade-offs inherent in prior art methods for aligning short DNA sequence reads to detect mutations (Compl. ¶14; Compl. ¶15, Compl. ¶¶col. 1:65-2:17).
  • The Patented Solution: The '863 Patent claims a similar multi-stage assembly and alignment process as the '308 Patent Compl. ¶17 However, its claims add specific upfront laboratory steps for generating the sequence reads. These steps include fragmenting the nucleic acid, attaching the fragments to a flow cell, and amplifying them to create "clusters" Compl. ¶17 '863 Patent, col. 6:1-8 The subsequent computational steps involve assembling a contig, identifying mutations by aligning the contig to a reference, aligning reads back to the contig, and then generating a final "read-to-reference description" that maps the mutations' positional information Compl. ¶17 '863 Patent, col. 6:23-38
  • Technical Importance: This invention ties the computational improvement of the multi-stage alignment directly to a specific, widely used method of next-generation sequencing (flow cell-based sequencing, such as that commercialized by Illumina), which generates the short reads that present challenges for mutation detection Compl. ¶18 Compl. ¶21

Key Claims at a Glance

  • The complaint asserts at least independent claim 1 Compl. ¶28
  • Claim 1 of the '863 Patent recites a method with the following essential elements:
    • Obtaining a sample with template nucleic acid.
    • Sequencing the sample to generate reads, where the sequencing comprises: fragmenting the nucleic acid, attaching fragments to a flow cell, and amplifying them to create clusters.
    • Inputting a reference genome and the reads into a computer system that then performs the steps of:
      • Assembling a "contig" from the reads.
      • Identifying "contig-to-reference descriptions" of mutations (including a substitution and an indel) by aligning the contig to the reference genome.
      • Identifying "read-to-contig descriptions" by aligning reads to the contig.
      • Generating a "read-to-reference description" by aligning the contig-to-reference and read-to-contig descriptions to map the positional information of the mutations.
  • The complaint reserves the right to assert claims beyond the exemplary analysis of claim 1 Compl. ¶29

III. The Accused Instrumentality

  • Product Identification: The accused instrumentality is Natera's Signatera™ test, a commercial liquid biopsy service for cancer diagnostics and monitoring Compl. ¶5 Compl. ¶24
  • Functionality and Market Context: The complaint alleges the Signatera™ test is a personalized, tumor-informed test for detecting molecular residual disease Compl. ¶25 The process allegedly involves performing whole-exome sequencing on a patient's tumor and normal tissue to identify patient-specific mutations Compl. ¶26 Compl. ¶28 A custom panel is then used to monitor for the presence of these mutations in the patient's blood over time Compl. Ex. 8, p. 2 A diagram from a 2018 poster, included in the complaint's exhibits, illustrates this multi-step molecular protocol, starting with sequencing a tumor biopsy and ending with analyzing NGS data to detect circulating tumor DNA (ctDNA) Compl. Ex. 8, p. 2 The complaint alleges Natera uses bioinformatics tools like the Genome Analysis Toolkit ("GATK") HaplotypeCaller or Mutect2 to identify these mutations Compl. ¶26 Compl. ¶28

IV. Analysis of Infringement Allegations

'308 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
assembling a contig using the at least some of the sequence reads, the contig including information about positions of the at least some of the sequence reads relative to each other or to a reference Natera's process allegedly uses GATK HaplotypeCaller or a similar method, which requires assembling a contig from a plurality of sequence reads. ¶26 col. 3:1-10
aligning, using a first substitution probability and a first gap penalty, the contig to the reference human genome to obtain a reference alignment... Natera's process allegedly uses GATK or a similar method that aligns contigs to a reference genome to identify "potentially variant sites" of mutations. The complaint alleges these tools use algorithms that accept substitution and gap penalties. ¶26 col. 3:52-62
aligning, using a second substitution probability and a second gap penalty, the at least some of the sequence reads to the contig to obtain sequence read alignments... Natera's process allegedly uses GATK HaplotypeCaller or a similar method, which aligns sequence reads to contigs using a PairHMM algorithm that implements substitution probability and gap penalty. ¶26 col. 4:21-28
genotyping the at least some of the sequence reads by identifying multiple mutations ... including a first substitution and a first indel. Natera's process allegedly aggregates the contig-to-reference and read-to-contig alignments to identify the position of mutations, and identifies multiple mutation types including substitutions and indels. ¶26 col. 4:40-54

'863 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
sequencing the sample to generate the plurality of sequence reads, the sequencing comprising; fragmenting the template nucleic acid, attaching the fragments to a surface of channels in a flow cell, and amplifying the attached fragments to create clusters... Natera's Signatera process allegedly uses Illumina's next-generation sequencing methods, which involve library preparation, random fragmentation, capture of the library on a flow cell, and amplification to form clusters. ¶28 col. 6:1-8
assembling a contig from at least some of the plurality of sequence reads Natera's process allegedly uses GATK HaplotypeCaller or a similar method like Mutect2, which requires assembling a contig from sequence reads. ¶28 col. 6:18-20
identifying a plurality of contig-to-reference descriptions of the mutations by aligning the contig to a sequence of the reference genome, the mutations including a substitution and an indel Natera's process allegedly uses GATK or a similar method to align contigs to a reference genome and identify potentially variant sites, which can include substitutions and indels. ¶28 col. 6:21-25
identifying a plurality of read-to-contig descriptions by aligning each of the at least some of the plurality of sequence reads to the contig Natera's process allegedly uses GATK or a similar method that aligns individual reads to the assembled contigs using a PairHMM algorithm. ¶28 col. 6:26-29
generating a read-to-reference description by aligning at least one of the plurality of contig-to-reference descriptions with a corresponding at least one of the plurality of read-to-contig descriptions... Natera's process allegedly uses GATK or a similar method that aggregates the contig-to-reference and read-to-contig descriptions to produce a final description that maps the positional information of mutations. ¶28 col. 6:30-38
  • Identified Points of Contention:
    • Scope Questions: A central dispute may arise over whether the functionality of the accused bioinformatics tools (e.g., GATK HaplotypeCaller, Mutect2) falls within the scope of the claimed terms "assembling a contig" and "multi-stage alignment". The defense may argue that the integrated algorithms within these tools operate in a technically distinct manner from the specific, sequential process described in the patents.
    • Technical Questions: The '308 patent's claim 1 requires using a "first" and "second" set of substitution probabilities and gap penalties for two different alignment stages. A key technical question will be whether the complaint provides sufficient evidence that the accused Signatera™ process actually uses two distinct and separate sets of such parameters, as opposed to a single, more complex algorithm that does not map to the claimed two-stage structure.

V. Key Claim Terms for Construction

  • The Term: "contig"

  • Context and Importance: This term is foundational to the claimed methods. The patent defines a contig as including "information about positions of the at least some of the sequence reads relative to each other or to a reference" Compl. ¶16 Its construction is critical because the entire multi-stage process depends on the creation and use of this intermediate data structure. Practitioners may focus on this term because the defendant could argue that the "active regions" or "haplotypes" generated by the accused GATK tools are not "contigs" as contemplated by the patent.

  • Intrinsic Evidence for Interpretation:

    • Evidence for a Broader Interpretation: The specification describes a contig broadly as "the relationship between or among a plurality of segments of nucleic acid sequences, e.g., reads" '308 Patent, col. 12:65-67, which may support an expansive definition.
    • Evidence for a Narrower Interpretation: The specification provides an example where reads are assembled using a "greedy algorithm" '308 Patent, col. 3:6-10 A party could argue this example limits the term to contigs created by specific de novo assembly methods, potentially excluding the local re-assembly performed in the accused process.

  • The Term: "genotyping ... by combining the reference alignment and the sequence read alignments" ('308 Patent, Claim 1)

  • Context and Importance: This term describes the final, crucial step of the claimed method where information from two separate alignments is integrated to make a final mutation call. The infringement analysis will turn on whether the accused process performs this specific "combining" step. Practitioners may focus on this term because the accused GATK tools may use a more integrated Bayesian or probabilistic model rather than a simple mechanical combination of two separate alignment outputs.

  • Intrinsic Evidence for Interpretation:

    • Evidence for a Broader Interpretation: The specification states, "By combining information in this way, the limitations of a tradeoff ... is overcome" ('308 Patent, col. 4:56-59), suggesting the "combining" is the key inventive step, which could be argued to cover any method that uses both sources of information to achieve the stated goal.
    • Evidence for a Narrower Interpretation: Figure 2 of the patents depicts a linear, sequential workflow where reads are aligned to contigs (Step 3) and then those alignments are "mapped" to the reference space (Step 4) before genotyping (Step 5) '308 Patent, Fig. 2 A party might argue this figure limits the "combining" step to this specific "mapping" or "translation" of coordinates.

VI. Other Allegations

The complaint does not allege facts to support indirect infringement or willful infringement. The counts are for direct infringement under 35 U.S.C. § 271(a) Compl. ¶33 Compl. ¶38

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

The resolution of this case may hinge on two central questions for the court:

  • A core issue will be one of definitional scope: can the term "multi-stage alignment", which requires sequentially aligning contigs to a reference and then reads back to the contigs, be construed to cover the integrated, probabilistic algorithms used in modern bioinformatics software like GATK HaplotypeCaller?
  • A key evidentiary question will be one of technical equivalence: does the accused Signatera™ process, as a factual matter, implement the claimed use of two distinct sets of "substitution probability" and "gap penalty" for its different alignment phases, or does it utilize a different computational approach that falls outside the patent's claims, creating a fundamental mismatch in technical operation?
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