Natera Inc v. ArcherDX Inc

I. Executive Summary and Procedural Information

• Parties & Counsel:
  • Plaintiff: Natera, Inc. (Delaware)
  • Defendant: ArcherDX, Inc. (Delaware)
  • Plaintiff’s Counsel: Morris, Nichols, Arsht & Tunnell LLP
• Case Identification: 1:20-cv-01047, D. Del., 08/06/2020
• Venue Allegations: Venue is alleged to be proper based on Defendant being a Delaware corporation.
• Core Dispute: Plaintiff alleges that Defendant’s oncology diagnostic products, which use Anchored Multiplex PCR technology, infringe a patent directed to methods for simultaneously amplifying and sequencing multiple nucleic acid targets from cell-free DNA.
• Technical Context: The technology is in the field of non-invasive genetic testing, or "liquid biopsy," which aims to detect and monitor cancer by analyzing trace amounts of circulating tumor DNA (ctDNA) in a patient's blood.
• Key Procedural History: The complaint notes prior litigation between the parties. It also preemptively argues for the patent's eligibility under 35 U.S.C. § 101, citing the patent examiner’s reasoning during prosecution and Federal Circuit precedent, suggesting this will be a central validity dispute. The complaint further notes that both parties have products that have received FDA "Breakthrough Device" designation.

Case Timeline

Date	Event
2010-05-18	’220 Patent Earliest Priority Date
2015-01-01	Accused Product (VariantPlex) Commercial Launch (approx.)
2015-10-20	’220 Patent Parent Application Filing Date
2016-09-22	Accused Product (LiquidPlex) Commercial Launch
2018-12-01	FDA Breakthrough Device Designation for Accused Product STRATAFIDE (approx.)
2019-01-01	Accused Product (PCM) Commercialization (approx.)
2019-05-06	FDA Breakthrough Device Designation for Plaintiff's Signatera Product
2020-01-01	FDA Breakthrough Device Designation for Accused Product PCM (approx.)
2020-01-15	’220 Patent Application Filing Date
2020-08-04	’220 Patent Issue Date
2020-08-06	Complaint Filing Date

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

U.S. Patent No. 10,731,220 - "Methods for Simultaneous Amplification of Target Loci"

• Patent Identification: U.S. Patent No. 10,731,220, "Methods for Simultaneous Amplification of Target Loci," issued August 4, 2020.

The Invention Explained

• Problem Addressed: The patent addresses a key challenge in "multiplex PCR," which is the simultaneous amplification of many different DNA sequences in a single reaction. When numerous primers are combined, they can incorrectly bind to each other, creating "non-target amplification products" like "primer dimers." These artifacts compete with the intended DNA targets, significantly reducing the accuracy and sensitivity of the analysis, a problem that is especially acute when working with the minuscule amounts of cell-free DNA (cfDNA) found in blood samples. (Compl. ¶35; ’220 Patent, col. 3:4-11, col. 86:11-14).
• The Patented Solution: The invention claims a multi-step method to improve the preparation and sequencing of cfDNA. The process begins by ligating man-made adaptors to the cfDNA fragments; these adaptors contain both a universal priming sequence and a unique "molecular barcode" to tag each original DNA molecule. This is followed by a first PCR amplification using a universal primer and a set of target-specific primers. A second, "nested" PCR is then performed using another universal primer and a set of inner target-specific primers, which bind to sites within the DNA segments created in the first PCR. This two-stage, nested amplification strategy is designed to selectively enrich for the desired DNA targets while minimizing the formation of primer-dimers and other artifacts before the sample is analyzed via high-throughput sequencing. (Compl. ¶33, ¶36; ’220 Patent, Abstract; ’220 Patent, Fig. 5).
• Technical Importance: This method purports to enable the highly sensitive and specific analysis of numerous genetic loci from very small starting quantities of DNA, a fundamental requirement for effective non-invasive cancer detection and monitoring via liquid biopsy. (Compl. ¶6).

Key Claims at a Glance

• The complaint focuses on independent claim 1 and alleges infringement of more than one claim. (Compl. ¶33, ¶45).
• Essential elements of independent claim 1 include:
  • Ligating adaptors to cell-free DNA, where the adaptors comprise a universal priming sequence and a molecular barcode.
  • 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.
  • 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, with at least one primer comprising a sequencing tag.
  • Performing high-throughput sequencing of the amplified DNA.

III. The Accused Instrumentality

Product Identification

• The complaint names ArcherDX’s LiquidPlex, VariantPlex, STRATAFIDE, Personalized Cancer Monitoring (PCM), and ArcherMET products, and any other products using the same underlying "Anchored Multiplex PCR" (AMP) technology. (Compl. ¶1).

Functionality and Market Context

• The accused products are alleged to use the AMP technology to "create target-enriched libraries for next-generation sequencing (NGS)" from cfDNA, such as circulating tumor DNA (ctDNA). (Compl. ¶40, ¶48). The complaint alleges the AMP process involves ligating adaptors with molecular barcodes to cfDNA, followed by two distinct PCR amplifications using universal and gene-specific primers, and subsequent sequencing. (Compl. ¶49-¶78). A workflow diagram taken from a publication describing the accused technology is included in the complaint to illustrate these steps. (Compl. ¶49, p. 13, Figure 1).
• The products are marketed for applications in oncology, including cancer detection and monitoring for research use. (Compl. ¶83-¶85, ¶97-¶98). The complaint asserts they are sold as kits or component parts for "research use only" (RUO) and for customers to develop their own laboratory-developed tests (LDTs). (Compl. ¶89, ¶100, ¶104).

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 accused AMP technology is alleged to ligate adaptors to DNA fragments. These adaptors are alleged to contain a "universal primer binding site" and a "molecular barcode (MBC)".	¶50, ¶51	col. 86:38-40
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 products are alleged to perform a first PCR using a universal primer ("P5 primer") and a mix of gene-specific primers ("GSP1 mix") to amplify numerous gene targets (e.g., 28, 67, or more) simultaneously.	¶55, ¶56, ¶59, ¶64, ¶66	col. 96:55-66
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, wherein at least one of the primers comprises a sequencing tag; and	The AMP technology allegedly performs a "second enrichment amplification" using another universal primer ("P7 primer") and a different, "nested gene specific primer" ("GSP2"), where the second primer is a hybrid containing an "Index 1 region for MiSeq" alleged to be a sequencing tag.	¶69, ¶71, ¶77	col. 97:32-41
performing high-throughput sequencing to sequence the amplified DNA comprising the target loci.	The AMP process is allegedly used to prepare DNA libraries for analysis via next-generation sequencing (NGS) platforms such as Illumina's NextSeq.	¶48, ¶78	col. 86:51-53

• Identified Points of Contention:
  • Scope Questions: A principal dispute may arise over the term "nested PCR." The complaint alleges the accused two-step amplification process meets this limitation. (Compl. ¶69, ¶71). The defense may argue that its use of two separate gene-specific primers (GSP1 and GSP2) does not constitute a "nested" reaction as defined and enabled by the patent specification. The precise structural and functional relationship between the first and second primers will be critical.
  • Technical Questions: The complaint alleges that the accused products' "Index 1 region for MiSeq" meets the "sequencing tag" limitation. (Compl. ¶77). This raises the factual question of whether this index region, typically used to pool and identify different samples, performs the function of a "sequencing tag" as contemplated by the patent. Additionally, while the complaint provides evidence of the accused products' workflow from a publication, as shown in Figure 1 on page 13, a factual question remains as to whether every use of the products necessarily involves the simultaneous amplification of "at least 10 target loci" in a "single reaction volume." (Compl. ¶49).

V. Key Claim Terms for Construction

• The Term: "nested PCR"

• Context and Importance: This term is at the heart of the claimed invention and the infringement dispute. The patent's claimed improvement over the prior art hinges on this specific two-step amplification strategy. Whether the accused AMP technology, with its GSP1 and GSP2 primers, performs a "nested PCR" will likely be a dispositive issue.

• Intrinsic Evidence for Interpretation:

  • Evidence for a Broader Interpretation: The patent describes various multi-step PCR protocols, including "One-Sided Nested Mini-PCR," "Hemi-nested Mini-PCR," and "Triple Hemi-nested Mini-PCR." (’220 Patent, col. 97:4-98:50). Plaintiff may argue these examples support a broader definition that covers a variety of sequential amplifications where a subsequent primer binds internally to the product of a prior amplification.
  • Evidence for a Narrower Interpretation: The patent provides specific graphical representations of nested PCR, such as Figure 5, which shows a second primer (a) binding to a site located within the larger region defined by the first primer (A). (’220 Patent, Fig. 5). Defendant may argue the term should be limited to such specific structural arrangements, potentially excluding their accused process if it differs.

• The Term: "molecular barcode"

• Context and Importance: Molecular barcodes are used to uniquely identify original DNA molecules, which helps distinguish between true mutations and errors introduced during PCR. The complaint alleges Archer's "random 8-mer molecular barcode" meets this limitation. (Compl. ¶53). Practitioners may focus on this term because its construction could determine if the accused product's tagging system falls within the claim scope.

• Intrinsic Evidence for Interpretation:

  • Evidence for a Broader Interpretation: The specification describes barcodes as a "random sequence of one or more nucleotides that is not found in a human or other species genome" that is ligated to the sample DNA. (’220 Patent, col. 21:19-24). This could support an interpretation where any unique, non-native tag ligated to DNA for identification constitutes a "molecular barcode."
  • Evidence for a Narrower Interpretation: The specification also describes a specific function: "These tag techniques in methods in which single molecules are sequenced allow one to determine how many primers are amplified to form correct products." (’220 Patent, col. 119:63-66). Defendant could argue that to be a "molecular barcode," a sequence must not only be a unique tag but must also be used for this specific purpose of quantitative analysis or error correction, and that their accused "MBC" may have a different function.

VI. Other Allegations

• Indirect Infringement: The complaint alleges both induced and contributory infringement. Inducement is based on Archer allegedly instructing end-users on how to perform the infringing method via "instructional materials, product manuals, and technical materials." (Compl. ¶123). Contributory infringement is based on allegations that the accused kits are "especially made or especially adapted for use in infringing" the patent and are not staple articles of commerce with substantial non-infringing uses. (Compl. ¶125).
• Willful Infringement: The complaint alleges that Defendant has knowledge of the ’220 patent "at least as early as the date of this complaint," which, if proven, could support a finding of post-suit willful infringement. (Compl. ¶120).

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

• A central issue will be one of claim construction: Can the term "nested PCR", which defines the inventive two-step amplification, be construed to read on the accused "Anchored Multiplex PCR" process, which uses two sequential gene-specific primers (GSP1 and GSP2)? The resolution of this definitional question may determine the outcome of the infringement analysis.
• A key legal and factual question will be one of patent eligibility: Is the claimed method, as a whole, directed to a patent-ineligible natural law or phenomenon (such as the correlation between cfDNA and disease), or is it, as Plaintiff argues, an improved and unconventional laboratory technique for creating and analyzing non-natural DNA that yields a practical, real-world application?
• A third core question will be one of factual proof: Assuming the claim construction favors the Plaintiff, can it produce sufficient evidence to demonstrate that Defendant's products, as used by Archer or its end-users, consistently meet the quantitative limitations of the claims, such as amplifying "at least 10" loci in a "single reaction volume"?