DCT

1:21-cv-00056

Natera Inc v. Inivata Inc

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:21-cv-00056, D. Del., 05/03/2021
  • Venue Allegations: Venue is alleged to be proper in the District of Delaware because Defendant Inivata, Inc. is incorporated in Delaware, and Defendant Inivata Ltd. is not a U.S. resident and may be sued in any judicial district.
  • Core Dispute: Plaintiff alleges that Defendant’s cell-free DNA cancer diagnostic tests infringe patents related to methods for detecting genetic mutations from blood samples and for simultaneously amplifying multiple DNA targets.
  • Technical Context: The technology at issue involves non-invasive "liquid biopsy" methods for detecting and monitoring cancer by analyzing minute quantities of circulating-tumor DNA (ctDNA) found in a patient's bloodstream.
  • Key Procedural History: The complaint notes that Plaintiff's own commercial product, Signatera®, which allegedly practices the patented technology, received an FDA "Breakthrough Device" designation in May 2019 and was the subject of a draft favorable Medicare Local Coverage Determination in March 2019.

Case Timeline

Date Event
2014-04-21 Earliest Priority Date for ’755 and ’709 Patents
2019-04-16 U.S. Patent No. 10,262,755 Issues
2020-03-24 U.S. Patent No. 10,597,709 Issues
2020-06-29 Alleged Launch of Accused InVisionFirst-Lung Product
2021-05-03 Complaint Filed

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

U.S. Patent No. 10,262,755 - "Detecting Cancer Mutations and Aneuploidy in Chromosomal Segments"

  • Patent Identification: U.S. Patent No. 10,262,755, "Detecting Cancer Mutations and Aneuploidy in Chromosomal Segments," issued April 16, 2019 (the "’755 Patent").

The Invention Explained

  • Problem Addressed: The patent background identifies the need for improved methods to detect cancer-associated genetic abnormalities, such as copy number variations (CNVs) and single nucleotide variants (SNVs), with high sensitivity from biological samples. (Compl. ¶6; ’755 Patent, col. 2:45-56). A significant challenge is detecting these variations in samples containing very small amounts of tumor DNA, such as cell-free DNA (cfDNA) from blood plasma. (Compl. ¶6).
  • The Patented Solution: The invention provides a two-pronged method for analyzing ctDNA from a blood sample to detect genetic mutations indicative of a solid tumor. The first part of the method detects aneuploidy (an abnormal number of chromosomes, a type of CNV) by amplifying at least 1,000 specific DNA locations, sequencing them, and computationally generating "phased allelic data" to identify a statistically significant "allelic imbalance." The second part detects SNVs by amplifying and sequencing a plurality of other DNA locations known to be associated with cancer. (’755 Patent, Abstract; col. 3:9-20).
  • Technical Importance: This approach claims to enable non-invasive cancer detection and monitoring from a blood sample, offering a potential alternative to more invasive procedures like tumor biopsies. (Compl. ¶6).

Key Claims at a Glance

  • The complaint asserts independent claim 1. (Compl. ¶28).
  • The essential elements of claim 1 include:
    • A. Determining whether an aneuploidy mutation is present by analyzing a blood sample to determine a level of allelic imbalance, which comprises:
      • isolating circulating tumor DNA (ctDNA);
      • amplifying at least 1000 polymorphic loci from the ctDNA;
      • generating sequence data for those loci via high throughput sequencing;
      • using the sequence data to generate phased allelic data; and
      • determining the level of allelic imbalance, where a detectable imbalance indicates an aneuploidy mutation.
    • B. Determining whether a single nucleotide variant (SNV) is present, which comprises:
      • isolating ctDNA;
      • amplifying polymorphic loci associated with cancer-related SNVs; and
      • performing high throughput sequencing, where the presence of an SNV is indicative of a mutation in the solid tumor.
  • The complaint alleges infringement of "at least one claim" and "more than one claim" of the ’755 Patent, reserving the right to assert others. (Compl. ¶¶38, 50).

U.S. Patent No. 10,597,709 - "Methods for Simultaneous Amplifications of Target Loci"

  • Patent Identification: U.S. Patent No. 10,597,709, "Methods for Simultaneous Amplifications of Target Loci," issued March 24, 2020 (the "’709 Patent").

The Invention Explained

  • Problem Addressed: The patent's background addresses the technical challenges of multiplex PCR, a process for simultaneously amplifying many different regions of DNA in a single reaction. Key problems include inefficient amplification and the formation of non-target products, such as "primer-dimers," which can interfere with accurate analysis. (’709 Patent, col. 1:32-47).
  • The Patented Solution: The invention discloses a method for multiplex PCR that uses a specific and counter-intuitive thermal cycling parameter: setting the "annealing temperature" to be higher than the "melting temperature" (Tm) of the primers. The patent asserts that this technique, contrary to conventional wisdom, allows for the efficient and simultaneous amplification of at least 50 target loci while reducing or preventing the formation of undesired byproducts. (’709 Patent, Abstract; col. 46:50-67).
  • Technical Importance: This patented method facilitates the large-scale DNA amplification required for modern, high-throughput genetic sequencing and analysis, which is foundational for complex diagnostic tests. (’709 Patent, col. 1:48-56).

Key Claims at a Glance

  • The complaint asserts independent claim 1. (Compl. ¶30).
  • The essential elements of claim 1 include:
    • contacting a nucleic acid sample comprising at least 50 target loci with a library of at least 50 different primers to produce a reaction mixture;
    • subjecting the reaction mixture to primer extension reaction conditions, wherein the annealing temperature is greater than a melting temperature of the at least 50 primers, and wherein at least 50 target loci are simultaneously amplified; and
    • sequencing the amplified products.
  • The complaint alleges infringement of "at least one claim" and "more than one claim" of the ’709 Patent, reserving the right to assert others. (Compl. ¶¶40, 55).

III. The Accused Instrumentality

Product Identification

The accused instrumentalities are "Inivata's InVisionFirst-Lung cancer diagnostic test ('InVisionFirst-Lung') and any other products that use the same or similar technology." (Compl. ¶13).

Functionality and Market Context

The complaint describes the accused products as non-invasive, blood-based tests that analyze cfDNA to detect and monitor cancer mutations. (Compl. ¶¶13, 36). The tests are alleged to be performed in Inivata's CLIA-certified laboratory in the United States. (Compl. ¶43). Plaintiff Natera alleges that Inivata is a direct competitor in the market for cancer recurrence monitoring. (Compl. ¶44).

IV. Analysis of Infringement Allegations

The complaint references preliminary and exemplary claim charts in Exhibits 3 and 4 that describe infringement of claim 1 of the ’755 Patent and claim 1 of the ’709 Patent, respectively. (Compl. ¶¶38, 40). However, these exhibits were not included with the filed complaint available for this analysis. The infringement summary is therefore based on the narrative allegations.

No probative visual evidence provided in complaint.

  • Identified Points of Contention:
    • ’755 Patent - Technical Questions: The complaint makes a general allegation that the accused test performs the steps of claim 1. (Compl. ¶37). A central point of contention may be whether the InVisionFirst-Lung test, in fact, performs each specific sub-step for detecting both aneuploidy and SNVs. For instance, what evidence does the complaint provide that Inivata's method uses sequence data to "generate phased allelic data" and then determines an "allelic imbalance" from that phased data, as strictly required by the claim?
    • ’709 Patent - Technical Questions: The infringement allegation for the ’709 Patent hinges on a very specific process parameter: an annealing temperature that is "greater than a melting temperature of the at least 50 primers." A key question will be evidentiary: what proof can be offered that Inivata's proprietary amplification protocol, which is not public, actually operates under this unconventional condition? The determination of both "annealing temperature" and "melting temperature" can be subject to different measurement and calculation methodologies, which may be a source of dispute.

V. Key Claim Terms for Construction

’755 Patent, Claim 1

  • The Term: "phased allelic data"
  • Context and Importance: This term is central to the aneuploidy detection step of the claim. The definition of what constitutes "phased" data will be critical to the infringement analysis. Practitioners may focus on this term because its technical meaning—whether it requires determining the parental origin of alleles (i.e., haplotypes)—will dictate the type of evidence needed to prove infringement.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The specification provides a definition equating "Phased data" with "Haplotype data" and "ordered genetic data," defining it as "a set of SNPs on a single chromatid or a diploid chromosome." (’755 Patent, col. 37:51-55). This could support a broader definition not strictly tied to a specific method of determination.
    • Evidence for a Narrower Interpretation: The detailed description discloses specific methods for determining phase, such as using genetic data from relatives (e.g., parents) or using population-based haplotyping algorithms. (’755 Patent, col. 139:26-41). A defendant may argue that these embodiments narrow the scope of the term to data that has been computationally processed to infer haplotypes.

’709 Patent, Claim 1

  • The Term: "annealing temperature ... is greater than a melting temperature"
  • Context and Importance: This relative temperature requirement is the inventive concept of the claim. The entire infringement case for this patent turns on its meaning. The dispute will likely focus on the proper methods for determining the "melting temperature" (Tm) and "annealing temperature" for a complex mixture of at least 50 different primers.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The claim language is facially broad, not specifying a particular method for measuring or calculating the temperatures. A plaintiff may argue that any scientifically acceptable method that shows the annealing temperature exceeds the Tm falls within the claim scope.
    • Evidence for a Narrower Interpretation: The specification states that the melting temperature can be "empirically measured or calculated (such as by the empirically measured or calculated Tₘ of the primers)." (’709 Patent, col. 3:3-5). A defendant could argue that the term's meaning is informed by the specific calculation models and experimental conditions described in the patent's examples, potentially limiting the scope to those methodologies.

VI. Other Allegations

  • Willful Infringement: The complaint alleges that Defendants have "actual knowledge" of both asserted patents "since at least as early as the date of this Complaint." (Compl. ¶¶45-46). This allegation forms the basis for a claim of post-filing willful infringement, which could support a request for enhanced damages under 35 U.S.C. § 284. The complaint does not allege pre-suit knowledge. The prayer for relief also seeks a determination that the case is "exceptional" under 35 U.S.C. § 285. (Compl. p. 15, ¶4).

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

  1. A central issue will be one of evidentiary proof: Given the proprietary, non-public nature of the accused diagnostic method, what discovery evidence will emerge to show that Inivata’s "InVisionFirst-Lung" test actually performs the specific computational steps of the ’755 patent (e.g., generating "phased allelic data") and operates under the precise and unconventional temperature parameters of the ’709 patent (annealing above primer Tm)?

  2. The case may also present a significant question of patent eligibility. The complaint proactively argues that the claims are not directed to a natural phenomenon and are non-routine. (Compl. ¶¶31-34). This anticipates a likely defense under 35 U.S.C. § 101. A key legal question for the court will therefore be whether the claims, which analyze naturally occurring cfDNA, are patent-eligible by virtue of reciting specific, non-conventional laboratory and data processing techniques that transform the underlying genetic information into a cancer diagnosis.