DCT
1:20-cv-01352
Natera Inc v. Genosity Inc
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: Natera, Inc. (Delaware)
- Defendant: Genosity Inc. (Delaware)
- Plaintiff’s Counsel: Morris, Nichols, Arsht & Tunnell LLP; McDermott Will & Emery LLP (Of Counsel)
- Case Identification: 1:20-cv-01352, D. Del., 10/06/2020
- Venue Allegations: Venue is asserted to be proper in the District of Delaware because the Defendant, Genosity Inc., is a Delaware corporation.
- Core Dispute: Plaintiff alleges that Defendant’s genetic testing systems, which utilize ArcherDX chemistry for cancer monitoring, infringe a patent related to methods for simultaneously amplifying and sequencing multiple target loci from cell-free DNA.
- Technical Context: The technology at issue involves methods for detecting minute quantities of circulating tumor DNA (ctDNA) in blood samples, a field known as liquid biopsy, which is significant for non-invasive cancer detection and monitoring of minimal residual disease.
- Key Procedural History: The complaint notes that during the prosecution of the asserted patent, the USPTO examiner found the claims to be non-obvious over prior art teaching aspects of the method, stating there was "no motivation to modify" the references to arrive at the claimed invention.
Case Timeline
| Date | Event |
|---|---|
| 2015-10-20 | Earliest Priority Date for '220 Patent (based on parent application filing) |
| 2017 | Natera launches its Signatera cfDNA diagnostic test |
| 2019-03 | Medicare issues a draft Local Coverage Determination for Signatera |
| 2019-05-06 | U.S. FDA grants "Breakthrough Device" designation to Natera's Signatera test |
| 2020-08-04 | U.S. Patent No. 10,732,220 issues |
| 2020-10-06 | Complaint filed |
II. Technology and Patent(s)-in-Suit Analysis
U.S. Patent No. 10,732,220 - "Methods for Simultaneous Amplification of Target Loci"
- Patent Identification: U.S. Patent No. 10,732,220, “Methods for Simultaneous Amplification of Target Loci,” issued August 4, 2020 (the “’220 Patent”).
The Invention Explained
- Problem Addressed: The patent addresses a significant challenge in genetic analysis, particularly with small starting samples like cell-free DNA (cfDNA). When attempting to amplify many different DNA targets in a single reaction (multiplex PCR), the primers used for amplification can bind to each other, creating unwanted "primer-dimer" artifacts. These artifacts compete with the actual DNA targets during sequencing, which "significantly limit[s] the use of amplified products for further analysis" (Compl. ¶33; ’220 Patent, 3:4-9). This problem is exacerbated when the starting DNA quantity is low, as dividing the sample into multiple separate reactions is impractical (Compl. ¶33; ’220 Patent, 86:18-25).
- The Patented Solution: The invention claims a multi-step method to prepare and sequence non-natural DNA while minimizing primer-dimers. The process begins by ligating synthetic adaptors—containing a universal priming sequence and a unique molecular barcode—to cfDNA fragments. This is followed by two distinct PCR steps. A first PCR uses a universal primer and a set of outer target-specific primers to create an initial amplification. A second, "nested" PCR then uses another universal primer and a set of inner target-specific primers to further amplify the desired products, increasing specificity and adding a sequencing tag. This two-step, nested amplification is designed to overcome the limitations of conventional multiplex PCR (Compl. ¶¶31, 34; ’220 Patent, 47:36-55).
- Technical Importance: The method provides an "improved" way to reduce "non-target amplicons during multiplex PCR," enabling more effective high-throughput sequencing of genetic material from very small samples, such as ctDNA for cancer monitoring (Compl. ¶33; ’220 Patent, 3:9-11).
Key Claims at a Glance
- The complaint asserts infringement of at least independent claim 1 (Compl. ¶¶38, 66).
- The essential elements of independent claim 1 are:
- Ligating adaptors to cell-free DNA, where the adaptors comprise a universal priming sequence and a molecular barcode.
- Performing a first PCR in a single reaction volume to amplify at least 10 target loci using a first universal primer and at least 10 target-specific primers.
- Performing a second, nested PCR in a single reaction volume to amplify the at least 10 target loci using a second universal primer and at least 10 inner target-specific primers, wherein at least one primer comprises a sequencing tag.
- Performing high-throughput sequencing on the amplified DNA.
- The complaint does not explicitly reserve the right to assert dependent claims, but the allegation of infringement of "at least one claim" leaves this possibility open (Compl. ¶66).
III. The Accused Instrumentality
Product Identification
- The accused instrumentalities are Genosity's "AsTra testing system, AsTra Profile, AsTra One, AsTra Next, Myeloid NGS Molecular Profile and any other products that use the same technology" (collectively, the "Accused Products") (Compl. ¶1).
Functionality and Market Context
- The complaint alleges these are genetic testing services for applications such as minimal residual disease (“MRD”) and personalized cancer monitoring (Compl. ¶1). The Accused Products are alleged to utilize "ArcherDX, Inc.'s ('Archer's') ctDNA chemistry and region-specific primers" to perform their function (Compl. ¶1). The complaint states that the Archer ctDNA chemistry is a "multistep testing platform" used for MRD testing on ctDNA (Compl. ¶¶38, 53). For example, the Myeloid NGS Molecular Profile test can detect up to 73 genes, while the AsTra Profile can test up to 19,407 genes (Compl. ¶¶49-50).
IV. Analysis of Infringement Allegations
'220 Patent Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| ligating adaptors to cell-free DNA isolated from a biological sample, wherein the adaptors each comprises a universal priming sequence and a molecular barcode; | The Archer ctDNA chemistry used by Genosity allegedly includes "ligating an adapter molecule to the starting...DNA fragments" that contain a "universal primer binding site" and a "molecular barcode (MBC)." A visual from an ArcherDX technical video is provided to show this structure. | ¶¶41, 42, 44, 63 | col. 2:63-3:3 |
| performing a first PCR to simultaneously amplify at least 10 target loci using a first universal primer and at least 10 target-specific primers in a single reaction volume; | The accused chemistry allegedly performs a first PCR using a universal primer ("P5 primer") and "at least 10 gene-specific primers (GSP1)" to amplify targets. The complaint references an ArcherDX video showing the use of a "GSP1" primer. | ¶¶46, 47, 51 | col. 47:36-55 |
| performing a second, nested PCR to simultaneously amplify the at least 10 target loci using a second universal primer and at least 10 inner target-specific primers in a single reaction volume... | The accused chemistry allegedly performs a "second enrichment amplification" described as a "one-sided nested PCR" that "uses a different nested gene specific primer," GSP2. An ArcherDX video screenshot illustrates the use of a "GSP2" primer. | ¶¶54, 55, 59 | col. 47:36-55 |
| ...wherein at least one of the primers comprises a sequencing tag; and | The complaint alleges that in the second PCR, the second primer used is a "hybrid that contains a P7 primer and an Index 1 region for MiSeq," which functions as a sequencing tag. | ¶¶54, 61 | col. 7:1-7:30 |
| performing high-throughput sequencing to sequence the amplified DNA comprising the target loci. | Genosity is alleged to perform high-throughput sequencing, with its product literature stating that "library products are sequenced with 2 by 150 bp reads on either the Illumina MiSeq, NextSeq or NovaSeq sequencing instruments." | ¶62 | col. 8:1-8:67 |
- Identified Points of Contention:
- Scope Questions: A central question may be whether the accused "one-sided nested PCR" (Compl. ¶55) falls within the scope of the claim term "nested PCR." The defense may argue that "nested PCR" requires two pairs of primers flanking a target, whereas the accused method might operate differently.
- Technical Questions: The complaint alleges the accused second PCR uses a "different nested gene specific primer, GSP2" (Compl. ¶55). The court may need to determine if this GSP2 primer is an "inner target-specific primer" as required by the claim, which implies a specific positional relationship to the GSP1 primer used in the first PCR. The evidence presented in the complaint, primarily marketing and technical notes from ArcherDX, will be scrutinized to see if it sufficiently describes this specific relationship.
V. Key Claim Terms for Construction
- The Term: "nested PCR"
- Context and Importance: This term is critical because the patent’s claimed solution to the primer-dimer problem relies on a two-step amplification process, with the second step being a "nested PCR." The complaint alleges the accused process performs a "one-sided nested PCR" (Compl. ¶55). The definition of "nested PCR" will therefore be dispositive of infringement; if the accused method does not meet the court's construction of this term, the infringement claim could fail.
- Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The patent specification describes the invention as a solution to "reduce the formation of non-target amplicons" (Compl. ¶33; ’220 Patent, 3:9-11). Plaintiff may argue that any second PCR step that uses primers internal to the first PCR products to increase specificity should be considered "nested," regardless of whether it uses one or two new primers.
- Evidence for a Narrower Interpretation: The claim language recites using "at least 10 inner target-specific primers" in the second PCR step (Compl. ¶31). Defendant may argue that the term "inner" implies a conventional nested PCR structure where a second pair of primers binds within the amplicon generated by a first pair of primers. If the accused "one-sided" method uses only one new inner primer paired with the original universal primer, the defense could argue this does not meet the common understanding or the specific claim language of a "nested PCR."
VI. Other Allegations
- Indirect Infringement: The prayer for relief requests a judgment that Genosity "induces infringement, and contributorily infringes the '220 patent" (Compl. Prayer for Relief ¶1). However, the body of the complaint focuses on direct infringement by Genosity and does not contain specific factual allegations detailing knowledge or intent required for indirect infringement claims.
- Willful Infringement: The complaint does not contain a separate count for willful infringement or use the word "willful." It does, however, request a determination that this is an "exceptional case under 35 U.S.C. § 285" and an award of attorneys' fees (Compl. Prayer for Relief ¶4), which often accompanies allegations of egregious infringement.
VII. Analyst’s Conclusion: Key Questions for the Case
A core issue will be one of definitional scope: can the term "nested PCR," as used in Claim 1, be construed to read on the accused "one-sided nested PCR" process? The outcome will likely depend on whether the court adopts a functional definition based on increasing specificity or a structural one requiring a specific arrangement of primer pairs.
A second key issue will be evidentiary sufficiency: does the evidence cited in the complaint, which consists of technical marketing materials from a third-party (ArcherDX), provide enough detail to establish that the accused Genosity tests necessarily practice every element of the claimed method, particularly the precise relationship between the primers used in the first and second PCR steps?
Finally, the case raises a question of infringement theory: given that Genosity is a service provider using a third-party chemistry, the dispute may involve questions of divided infringement and control or direction, although the complaint currently frames the allegations as direct infringement by Genosity performing every step of the claimed method (Compl. ¶¶38, 39).