Natera Inc v. ArcherDX Inc

I. Executive Summary and Procedural Information

• Parties & Counsel:
  • Plaintiff: Natera, Inc. (Delaware)
  • Defendant: ArcherDX, Inc., ArcherDX, LLC and Invitae Corp. (Delaware)
  • Plaintiff’s Counsel: Morris, Nichols, Arsht & Tunnell LLP
• Case Identification: 1:20-cv-00125, D. Del., 10/27/2021
• Venue Allegations: Venue is asserted in the District of Delaware based on both Defendants being Delaware corporations.
• Core Dispute: Plaintiff alleges that Defendants’ oncology genetic testing products and services infringe five patents related to methods for amplifying and sequencing small amounts of cell-free DNA.
• Technical Context: The technology relates to molecular diagnostics, specifically methods for analyzing circulating cell-free DNA (cfDNA) from biological samples like blood, which is a key technology for non-invasive cancer detection and monitoring.
• Key Procedural History: This is a Third Amended Consolidated Complaint in an ongoing litigation. The complaint notes that Defendant Invitae acquired Defendant ArcherDX after the initial suit was filed and assumed control of the litigation. For each asserted patent family, the complaint cites the patent examiner's reasoning for allowance during prosecution, preemptively arguing that the claimed methods were non-routine and unconventional over the prior art at the time of invention.

Case Timeline

Date	Event
2010-05-18	Priority Date for ’814, ’172, ’482, ’708, and ’220 Patents
2015-01-01	Accused Product VariantPlex Commercial Launch (approx.)
2016-09-22	Accused Product LiquidPlex Commercial Launch
2019-01-01	Accused Product PCM Commercialization (approx.)
2020-01-21	U.S. Patent No. 10,538,814 Issued
2020-02-11	U.S. Patent No. 10,557,172 Issued
2020-03-17	U.S. Patent No. 10,590,482 Issued
2020-03-24	U.S. Patent No. 10,597,708 Issued
2020-08-04	U.S. Patent No. 10,731,220 Issued
2020-10-02	Defendant Invitae acquires Defendant ArcherDX
2021-10-27	Third Amended Consolidated Complaint Filed

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

U.S. Patent No. 10,538,814 - "Methods for Simultaneous Amplification of Target Loci"

• Patent Identification: U.S. Patent No. 10,538,814, "Methods for Simultaneous Amplification of Target Loci," issued January 21, 2020 (Compl. ¶42).

The Invention Explained

• Problem Addressed: The patent addresses the technical challenge in "multiplex PCR" (simultaneously amplifying many DNA targets at once), where increasing the number of primers in a single reaction increases the risk of generating "non-target amplification products ... such as amplified primer dimers," which interfere with subsequent analysis (’814 Patent, col. 3:4-9). This problem is particularly acute when the starting sample, such as cfDNA, is very limited, making it impractical to split the sample into multiple, smaller reactions (’814 Patent, col. 86:18-25).
• The Patented Solution: The patent claims a method to improve multiplex PCR from cfDNA by first ligating engineered "adaptors" containing a universal priming site onto the DNA fragments. This is followed by a two-step amplification process: a first PCR using the universal primer and target-specific primers, and then a "second, nested PCR" using the universal primer and "inner" target-specific primers that bind inside the region amplified by the first PCR. This nested approach is designed to selectively amplify only the intended targets, thereby increasing specificity and yield before final analysis by high-throughput sequencing (’814 Patent, Abstract; col. 86:26-51).
• Technical Importance: This method provided a way to simultaneously and accurately analyze many different genetic locations from a very small amount of starting DNA, a key requirement for developing clinically viable non-invasive tests for cancer detection from blood samples (Compl. ¶¶6, 32).

Key Claims at a Glance

• The complaint asserts independent claim 1 (Compl. ¶43).
• The essential elements of Claim 1 are:
  • Ligating adaptors to cell-free DNA isolated from a biological sample, wherein the adaptors each comprises a universal priming site;
  • Performing a first PCR to simultaneously amplify at least 10 target loci using a 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 the 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
  • Performing high-throughput sequencing to sequence the amplified DNA comprising the target loci.
• The complaint reserves the right to assert infringement of claims other than claim 1 (Compl. ¶80).

U.S. Patent No. 10,557,172 - "Methods for Simultaneous Amplification of Target Loci"

• Patent Identification: U.S. Patent No. 10,557,172, "Methods for Simultaneous Amplification of Target Loci," issued February 11, 2020 (Compl. ¶44).

The Invention Explained

• Problem Addressed: Similar to the ’814 Patent, this invention addresses the problem of non-specific amplification and errors that arise during multiplex PCR, especially with low-quantity DNA samples (’172 Patent, col. 3:4-9).
• The Patented Solution: The solution is a multi-step amplification method that incorporates "molecular barcodes" into the initial DNA fragments. After cfDNA is isolated, it is tagged so that each original DNA molecule receives a unique molecular barcode. This allows sequencing reads from the same original molecule to be grouped together for analysis, which helps distinguish true genetic variants from errors introduced during the PCR process (’172 Patent, Abstract; col. 119:25-40). The subsequent steps of two, nested PCR amplifications and sequencing are similar to those described in the ’814 Patent.
• Technical Importance: The use of molecular barcodes provides a method for error correction and more accurate quantification, increasing the sensitivity and reliability of detecting rare mutations from cfDNA, a critical factor in applications like monitoring for cancer recurrence (Compl. ¶6).

Key Claims at a Glance

• The complaint asserts independent claim 1 (Compl. ¶45).
• The essential elements of Claim 1 are:
  • Isolating cell-free DNA from a biological sample and tagging the isolated cell-free DNA, wherein each tagged DNA molecule comprises a molecular barcode;
  • Performing a first PCR to simultaneously amplify at least 10 target loci using a 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 the universal primer and at least 10 inner target-specific primers in a single reaction volume; and
  • Performing high-throughput sequencing to sequence the amplified DNA comprising the target loci.
• The complaint reserves the right to assert infringement of claims other than claim 1 (Compl. ¶80).

U.S. Patent No. 10,590,482 - "Amplification of cell-free DNA using nested PCR"

• Patent Identification: U.S. Patent No. 10,590,482, "Amplification of cell-free DNA using nested PCR," issued March 17, 2020 (Compl. ¶46).
• Technology Synopsis: This patent claims a method for nested PCR amplification of cfDNA to achieve high specificity. The process involves ligating adaptors that comprise either a molecular barcode or a sequencing tag (or both) to cfDNA, followed by two rounds of PCR where the primers for the second round bind internally to the sites targeted by the primers from the first round, ensuring that at least 80% of the final amplified DNA maps to the intended targets (Compl. ¶47).
• Asserted Claims: Independent claim 1 (Compl. ¶47).
• Accused Features: The accused "Anchored Multiplex PCR" (AMP) technology is alleged to perform a nested PCR amplification of cfDNA that satisfies the claimed limitations (Compl. ¶¶1, 82, 106).

U.S. Patent No. 10,597,708 - "Methods for Simultaneous Amplifications of Target Loci"

• Patent Identification: U.S. Patent No. 10,597,708, "Methods for Simultaneous Amplifications of Target Loci," issued March 24, 2020 (Compl. ¶48).
• Technology Synopsis: This patent describes a method for amplifying multiple DNA targets using specific reaction conditions to minimize the formation of primer-dimers. The key conditions include setting an annealing temperature that is higher than the melting temperature of at least two of the primers and using an annealing step that is longer than three minutes (Compl. ¶49). The complaint highlights prosecution history where these unconventional conditions were cited as a reason for allowance over prior art (Compl. ¶68).
• Asserted Claims: Independent claim 1 (Compl. ¶49).
• Accused Features: The accused AMP technology is alleged to use the specific primer annealing temperatures and times claimed by the patent to amplify cfDNA (Compl. ¶¶1, 75).

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 (Compl. ¶50).
• Technology Synopsis: This patent claims a method for amplifying and sequencing cfDNA that combines several features from the other asserted patents. The method includes ligating adaptors that contain both a universal priming sequence and a molecular barcode, followed by two nested PCR steps using a combination of universal and target-specific primers, with at least one primer including a sequencing tag (Compl. ¶55).
• Asserted Claims: Independent claim 1 (Compl. ¶55).
• Accused Features: The accused AMP technology is alleged to use a process that includes ligating adaptors with universal priming sites and molecular barcodes, followed by two rounds of PCR amplification using universal and gene-specific primers, and subsequent high-throughput sequencing (Compl. ¶¶75, 82, 86, 104, 113).

III. The Accused Instrumentality

Product Identification

• The accused instrumentalities are Defendants' LiquidPlex, VariantPlex, FusionPlex, STRATAFIDE, Personalized Cancer Monitoring (“PCM”), and ArcherMET products, as well as any other oncology products using the same underlying technology (Compl. ¶1).

Functionality and Market Context

• The complaint alleges all accused products are based on Archer’s "Anchored Multiplex PCR" (“AMP”) technology, which is used to "create target-enriched libraries for next-generation sequencing (NGS)" from cfDNA (Compl. ¶¶1, 75).
• The complaint provides a diagram describing the AMP workflow, which includes repairing cfDNA fragments, ligating adaptors containing a "Molecular Barcoding technology (MBC)," and then amplifying the fragments with two rounds of PCR (PCR1 and PCR2) using a universal primer (P5) and gene-specific primers (GSPs) (Compl. ¶84, Figure 1). The complaint includes a screenshot from an Archer video showing that the second round of PCR uses a "different nested gene specific primer," GSP2 (Compl. p. 32; ¶106).
• These products are marketed for cancer detection and monitoring and are sold as kits for "research use only" and for use in laboratory-developed tests (Compl. ¶¶78-79, 135). The complaint alleges products such as LiquidPlex are pre-configured to detect dozens of gene targets associated with solid tumors (Compl. ¶98, ¶99).

IV. Analysis of Infringement Allegations

U.S. Patent No. 10,538,814 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 site	Defendants’ AMP process ligates adaptors to cfDNA fragments, and the adaptors include a "universal primer binding site" (shown as the P5 primer site).	¶85, ¶86, ¶90	col. 86:29-33
performing a first PCR to simultaneously amplify at least 10 target loci using a universal primer and at least 10 target-specific primers in a single reaction volume	The AMP process performs a first PCR (PCR1) using a universal primer ("P5 primer") and a mix of at least 10 gene-specific primers ("GSP1") to amplify numerous gene targets (e.g., 28 genes in LiquidPlex).	¶90, ¶91, ¶94, ¶99	col. 86:34-38
performing a second, nested PCR to simultaneously amplify the at least 10 target loci using the 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	The AMP process performs a second PCR (PCR2) using the universal primer (P5) and a mix of "different nested gene specific primer[s]" ("GSP2"). The second PCR is alleged to use a hybrid primer containing a P7 primer and an "Index 1 region for MiSeq," which functions as a sequencing tag.	¶104, ¶106, ¶108, ¶112	col. 86:39-47
performing high-throughput sequencing to sequence the amplified DNA comprising the target loci	The amplified libraries generated by the AMP process are sequenced using next-generation sequencing (NGS) platforms such as Illumina's MiSeq or NextSeq.	¶83, ¶113, ¶116	col. 86:48-51

• Identified Points of Contention:
  • Scope Questions: A central question may be whether the accused "one-sided nested PCR" (Compl. ¶106) meets the claim limitation of a "nested PCR" that uses "at least 10 inner target-specific primers." The construction of "nested PCR" and "inner target-specific primers" will be critical, as the complaint alleges the second PCR uses the original universal primer (P5) and a new set of nested gene-specific primers (GSP2) (Compl. ¶104).
  • Technical Questions: The complaint alleges that various accused products target well over the claimed "at least 10 target loci" (e.g., 28 genes for LiquidPlex, 67 for VariantPlex) (Compl. ¶¶99, 101). A factual question for the court will be whether Defendants or their end-users actually perform the method by simultaneously amplifying at least 10 loci in a single reaction volume as required by the claim.

U.S. Patent No. 10,557,172 Infringement Allegations

Claim Element (from Independent Claim 1)	Alleged Infringing Functionality	Complaint Citation	Patent Citation
isolating cell-free DNA from a biological sample and tagging the isolated cell-free DNA, wherein each tagged DNA molecule comprises a molecular barcode	Defendants’ AMP process ligates adaptors containing a "molecular barcode (MBC)" to cfDNA fragments. A screenshot from an Archer video identifies this component explicitly.	¶84, ¶86, ¶88	col. 86:29-33
performing a first PCR to simultaneously amplify at least 10 target loci using a universal primer and at least 10 target-specific primers in a single reaction volume	The AMP process performs a first PCR using a universal primer (P5) and a mix of gene-specific primers (GSP1) to amplify numerous gene targets simultaneously.	¶90, ¶91, ¶99	col. 86:34-38
performing a second, nested PCR to simultaneously amplify the at least 10 target loci using the universal primer and at least 10 inner target-specific primers in a single reaction volume	The AMP process performs a second, "nested" PCR using the universal primer (P5) and a different set of inner, gene-specific primers (GSP2).	¶104, ¶106, ¶108	col. 86:39-45
performing high-throughput sequencing to sequence the amplified DNA comprising the target loci	The resulting libraries are sequenced using NGS platforms.	¶83, ¶113	col. 86:46-49

• Identified Points of Contention:
  • Scope Questions: The primary scope question is the same as for the ’814 Patent: whether the accused "one-sided nested PCR" falls within the claim scope of "nested PCR."
  • Technical Questions: The complaint provides strong evidence for the "molecular barcode" element, including a diagram from a technical publication and a screenshot from Defendants' marketing video identifying an "Adapters with MBC" and "Molecular Barcode (MBC)" (Compl. ¶84, Figure 1; p. 26). A potential point of contention could be whether the accused "random 8-mer molecular barcode" (Compl. ¶88) performs the function described in the patent specification for error correction and unique molecule identification.

V. Key Claim Terms for Construction

• The Term: "nested PCR"

• Context and Importance: This term appears in the independent claims of the ’814, ’172, and ’482 patents and is central to the invention's claimed novelty. The complaint alleges Defendants' process uses a "one-sided nested PCR" (Compl. ¶106). The case may turn on whether this accused process, which allegedly uses the original universal primer and a new set of internal gene-specific primers, meets the definition of the claimed "nested PCR."

• Intrinsic Evidence for Interpretation:

  • Evidence for a Broader Interpretation: The specification describes multiple variations of the amplification method, including "fully nested mini-PCR," "semi-nested mini-PCR," and "one-sided mini-PCR" (’814 Patent, col. 42:58-66; Figs. 3, 5-8). This disclosure of multiple nesting strategies, including a "one-sided" version, may support a construction that is not limited to traditional two-sided nesting and covers the accused process.
  • Evidence for a Narrower Interpretation: A defendant might argue that the term's plain meaning, or its depiction in certain embodiments like Figure 3 ('fully nested mini-PCR'), requires two new primers in the second PCR, both of which are internal to the first primer pair. The complaint’s description of the accused process as using the original P5 primer and a new GSP2 primer (Compl. ¶104) could be argued to fall outside a narrow construction.

• The Term: "molecular barcode"

• Context and Importance: This term is a key limitation in the independent claims of the ’172 and ’220 patents. The complaint alleges the accused products use adaptors with a "random 8-mer molecular barcode" (Compl. ¶88). Practitioners may focus on this term because its definition will determine if the accused products' tagging system infringes.

• Intrinsic Evidence for Interpretation:

  • Evidence for a Broader Interpretation: The specification explicitly describes that the barcode can be a "random sequence of nucleotides" and that "a barcode of eight bases can yield 65536 unique barcodes," directly supporting the allegation that the accused "random 8-mer" falls within the claim scope (’172 Patent, col. 119:54-62).
  • Evidence for a Narrower Interpretation: The specification describes the function of the barcode as enabling "the data representing the sequence of a single molecule" to be grouped, which "allows for more accurate data on the sequence of single molecules" (’172 Patent, col. 119:62-66). A defendant might argue that if its "random 8-mer" serves a different primary purpose (e.g., merely as a sample index rather than for error correction of individual molecules), it does not meet the functional requirements implied by the specification.

VI. Other Allegations

• Indirect Infringement: The complaint alleges both induced and contributory infringement. Inducement is based on Defendants allegedly instructing end-users to perform the claimed methods through "instructional materials, product manuals, and technical materials" (Compl. ¶167, ¶180). Contributory infringement is based on allegations that the accused kits are a material part of the invention, are not staple articles of commerce, and are sold with the knowledge they are especially adapted for infringing use (Compl. ¶168, ¶181).
• Willful Infringement: Willfulness is alleged based on Defendants' knowledge of the patents. The complaint alleges knowledge of the ’814 patent as of January 2020 and knowledge of the other patents as of the filing dates of earlier complaints in the litigation (Compl. ¶¶158-162). It is also alleged that Invitae gained full knowledge of the patents and infringement allegations during its due diligence for the ArcherDX acquisition (Compl. ¶163).

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

• A core issue will be one of claim construction: can the term "nested PCR," as used in the patents, be construed broadly enough to read on the accused "one-sided" amplification method, where one of the original primers is re-used in the second amplification step? The patents' own disclosure of multiple nesting variants, including "one-sided," will be central to this dispute.
• A key evidentiary question will be one of technical operation: will discovery show that the accused products, when used by Defendants or their customers, simultaneously amplify "at least 10 target loci" within a "single reaction volume" as required by the independent claims? While the product literature suggests this capability, infringement will depend on how the methods are actually performed.
• A final question will be one of damages and willfulness: assuming infringement is found, the litigation will focus on the extent of Defendants' knowledge of the patents and the timing of that knowledge, which will be critical for determining whether any infringement was willful and for calculating the appropriate royalty or damages award.