Natera Inc v. Inivata Inc

I. Executive Summary and Procedural Information

• Parties & Counsel:
  • Plaintiff: Natera, Inc. (Delaware)
  • Defendant: Inivata, Inc. (Delaware) and Inivata Ltd. (England)
  • Plaintiff’s Counsel: Quinn Emanuel Urquhart & Sullivan, LLP; Morris, Nichols, Arsht & Tunnell LLP
• Case Identification: Natera, Inc. v. Inivata, Inc. et al., 1:22-cv-01609, D. Del., 12/20/2022
• Venue Allegations: Venue is alleged to be proper in the District of Delaware because Defendant Inivata, Inc. is a Delaware corporation and thus resides in the district, and Defendant Inivata Ltd. is not a resident of the United States and may be sued in any judicial district.
• Core Dispute: Plaintiff alleges that Defendants’ cancer monitoring assay infringes a patent related to methods for amplifying and sequencing cell-free DNA to detect specific genetic mutations.
• Technical Context: The lawsuit concerns non-invasive liquid biopsy tests, which analyze trace amounts of circulating tumor DNA in a patient's blood to detect and monitor cancer, a significant alternative to invasive tissue biopsies.
• Key Procedural History: The complaint does not mention any prior litigation between the parties, Inter Partes Review (IPR) proceedings involving the asserted patent, or prior licensing history.

Case Timeline

Date	Event
2015-04-15	U.S. Patent No. 11,530,454 Priority Date
2021-04-28	Defendant allegedly began selling Accused Product (RaDaR)
2022-12-20	U.S. Patent No. 11,530,454 Issued
2022-12-20	Complaint Filed

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

U.S. Patent No. 11,530,454 - "Detecting Mutations and Ploidy in Chromosomal Segments"

• Patent Identification: U.S. Patent No. 11,530,454, "Detecting Mutations and Ploidy in Chromosomal Segments," issued December 20, 2022 (the "’454 Patent").

The Invention Explained

• Problem Addressed: The patent and complaint describe the significant technical challenge of non-invasively detecting cancer by measuring extremely small amounts of circulating tumor DNA (ctDNA) within a much larger volume of a patient's blood sample (Compl. ¶5). This low concentration of target DNA makes it difficult to distinguish true cancer-specific mutations from background noise or to achieve the high sensitivity needed for clinical applications like monitoring for minimal residual disease (MRD) (’454 Patent, col. 44:45-56).
• The Patented Solution: The invention claims a multi-step method to overcome this challenge. First, a patient's tumor sample is sequenced to identify a personalized set of tumor-specific single nucleotide variant (SNV) mutations. Then, a highly sensitive targeted multiplex amplification process is performed on cell-free DNA (cfDNA) from the patient's plasma to amplify a specific number of these pre-identified SNV-containing loci. Finally, the resulting amplicons, which have a tightly controlled length, are sequenced at a very high depth of read to reliably detect the presence of the tumor-specific mutations (Compl. ¶24; ’454 Patent, col. 44:45-67, FIG. 63A).
• Technical Importance: This method provides a non-invasive way to monitor for cancer recurrence or treatment response with high sensitivity and specificity, offering an alternative to invasive tumor biopsies and potentially enabling earlier detection of disease than standard-of-care methods (Compl. ¶¶5, 18-19).

Key Claims at a Glance

• The complaint asserts independent claim 1 (Compl. ¶24, ¶29).
• The essential elements of independent claim 1 are:
  • A method for preparing a plasma sample of a subject with or suspected of having cancer.
  • Performing whole exome or whole genome sequencing on a tumor sample from the subject to identify a plurality of tumor-specific SNV mutations.
  • Performing targeted multiplex amplification on cfDNA from the subject's plasma to amplify 10 to 500 target loci, each encompassing a different tumor-specific SNV.
  • This amplification obtains amplicons with a length of 50-150 bases.
  • The target loci are amplified together in the same reaction volume.
  • Sequencing the amplicons to obtain sequence reads and detecting one or more tumor-specific SNV mutations.
  • The sequencing has a depth of read of at least 50,000 per target locus.
• The complaint alleges infringement of "more than one claim of the '454 patent" (Compl. ¶30), reserving the right to assert additional claims.

III. The Accused Instrumentality

Product Identification

• The accused instrumentality is Inivata's RaDaR™ Minimum Residual Disease Assay (“RaDaR”) and any other products that use the same or similar technology (Compl. ¶¶11, 28).

Functionality and Market Context

• The complaint alleges that RaDaR is a method or test for "preparing, amplifying, sequencing, and analyzing cfDNA to detect and monitor genes and genetic mutations associated with a patient's cancer" (Compl. ¶28).
• It is positioned as a direct competitor to Natera's own Signatera® test in the market for cancer recurrence monitoring (Compl. ¶34).
• The complaint alleges that the accused testing method is performed in Inivata's CLIA-certified laboratory in the United States (Compl. ¶33).
• No probative visual evidence provided in complaint.

IV. Analysis of Infringement Allegations

The complaint alleges that the RaDaR assay practices each limitation of claim 1 of the ’454 patent, either literally or under the doctrine of equivalents (Compl. ¶29). It states that a preliminary claim chart demonstrating this infringement is attached as Exhibit 2; however, this exhibit was not filed with the complaint (Compl. ¶30). The narrative infringement theory alleges that the process by which RaDaR is practiced involves performing the steps recited in claim 1, including identifying tumor-specific mutations, performing targeted multiplex amplification of cfDNA, and sequencing the resulting amplicons to detect those mutations (Compl. ¶¶24, 28, 29).

• Identified Points of Contention: Given the specificity of the claim language and the absence of a detailed claim chart, the infringement analysis will likely focus on whether the accused RaDaR assay can be proven to meet several precise numerical limitations.
  • Scope Questions: Do the specific parameters of the RaDaR assay fall within the claimed ranges? For example, does the assay consistently amplify between "10 to 500 target loci" and produce amplicons within the "50-150 bases" length range, as required by the claim?
  • Technical Questions: A central evidentiary question will be whether the RaDaR assay achieves the claimed sequencing depth. What evidence does the complaint, or will discovery, provide that the accused process performs sequencing with a "depth of read of at least 50,000 per target locus"? This is a particularly high threshold that may be a key point of dispute regarding the actual operation of the accused assay.

V. Key Claim Terms for Construction

• The Term: "depth of read of at least 50,000 per target locus"

• Context and Importance: This term recites a specific and high numerical threshold for sequencing, which is central to the patent's claimed sensitivity. Practitioners may focus on this term because the infringement dispute will likely hinge on whether the accused RaDaR assay can be proven to meet this demanding technical requirement.

• Intrinsic Evidence for Interpretation:

  • Evidence for a Broader Interpretation: The specification discusses a variety of sequencing parameters and embodiments. Parties seeking a broader or more flexible interpretation might point to examples in the specification that describe different depths of read to argue that the "at least 50,000" figure is not an absolute, unyielding minimum for every single locus in every test run (’454 Patent, col. 99:3-7, describing a depth of read of 3,000 as an example).
  • Evidence for a Narrower Interpretation: The plain language of the claim itself provides strong evidence for a narrow interpretation, as it uses the unambiguous phrase "at least 50,000." The prosecution history, if it contains arguments made to overcome prior art based on achieving superior sensitivity via this high depth of read, could further reinforce a narrow construction. The patent also describes how a high depth of read is necessary to detect rare variants, suggesting the number is a critical, not arbitrary, part of the invention (’454 Patent, col. 67:47-55).

• The Term: "amplicons having a length of 50-150 bases"

• Context and Importance: This term defines the size of the DNA fragments being analyzed. This is important because the analysis of cfDNA, which is often fragmented, can be optimized by targeting shorter DNA sequences. The dispute may turn on whether the accused process produces amplicons that fall strictly within this range.

• Intrinsic Evidence for Interpretation:

  • Evidence for a Broader Interpretation: A party might argue this range is merely exemplary by pointing to other parts of the specification that discuss different amplicon lengths. For example, the specification mentions a "maximum of about 220 bp," which is outside the claimed range, potentially suggesting the claimed range is not an exhaustive requirement (’454 Patent, col. 97:16-22).
  • Evidence for a Narrower Interpretation: The patent specification explains that "more efficient measurements" and cost savings can be achieved with "shorter sequence reads," lending technical significance to the specified range and supporting an interpretation that this limitation is a key feature of the invention (’454 Patent, col. 97:45-51). The explicit recitation of "50-150" in the claim itself is the strongest evidence for a strict interpretation.

VI. Other Allegations

• Indirect Infringement: The complaint does not include a separate count for indirect infringement. While it contains general language about Defendants "directly or indirectly" making or using the accused products (Compl. ¶10), it does not plead specific facts to support the knowledge and intent elements required for a claim of induced infringement, such as allegations about user manuals or instructions.
• Willful Infringement: The complaint alleges that Defendants have "actual knowledge of the ’454 patent since at least as early as the date of this Complaint" (Compl. ¶35). This allegation, if proven, could support a claim for willful infringement based on conduct occurring after the filing of the lawsuit, but it does not allege any pre-suit knowledge of the patent.

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

The resolution of this case will likely depend on the answers to two central questions:

• A key evidentiary question will be one of factual proof: Can Natera demonstrate through discovery that Inivata’s RaDaR assay, as commercially practiced, meets every specific numerical limitation recited in claim 1? The case may turn on technical evidence regarding the precise number of loci amplified, the exact length of the resulting amplicons, and, most critically, whether the sequencing achieves the demanding "depth of read of at least 50,000 per target locus."

• A core issue will be one of claim scope: How will the court construe the explicit numerical ranges in the asserted claim? The dispute will explore whether these parameters are to be interpreted as strict, absolute requirements for infringement or if the accused method must only generally operate within these ranges, which could significantly impact the infringement analysis.