Natera Inc v. CareDx Inc

I. Executive Summary and Procedural Information

• Parties & Counsel:
  • Plaintiff: Natera, Inc. (Delaware)
  • Defendant: CareDx, Inc. (Delaware)
  • Plaintiff’s Counsel: Morris, Nichols, Arsht & Tunnell LLP
• Case Identification: 1:22-cv-00641, D. Del., 05/13/2022
• Venue Allegations: Plaintiff alleges venue is proper because Defendant is a Delaware corporation and therefore resides in the District of Delaware.
• Core Dispute: Plaintiff alleges that Defendant’s organ transplant diagnostic tests infringe a patent related to methods for measuring DNA from a genetically distinct individual (e.g., an organ donor) within a biological sample from a subject (e.g., a transplant recipient).
• Technical Context: The technology at issue involves using cell-free DNA (cfDNA) analysis as a non-invasive method to monitor the health of organ transplants by detecting donor-derived DNA in the recipient's bloodstream.
• Key Procedural History: The complaint notes that Defendant has previously filed its own actions against Plaintiff in the same district, suggesting a history of litigation between these competitors in the molecular diagnostics market.

Case Timeline

Date	Event
2010-05-18	U.S. Patent No. 10,655,180 Earliest Priority Date
2017-01-01	Accused Product AlloSure Launch Date (approx.)
2019-01-01	Accused Product AlloSeq Launch Date (approx.)
2020-05-19	U.S. Patent No. 10,655,180 Issue Date
2021-01-01	Accused Products KidneyCare and HeartCare Launch Date (approx.)
2022-05-13	Complaint Filing Date

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

U.S. Patent No. 10,655,180 - "Methods for Simultaneous Amplification of Target Loci," Issued May 19, 2020

The Invention Explained

• Problem Addressed: The patent addresses the technical challenge of accurately analyzing minute quantities of nucleic acids from one individual that are mixed in with a much larger amount of nucleic acids from another individual (’180 Patent, col. 3:9-16). This is a common problem in non-invasive diagnostics, such as detecting fetal DNA in maternal blood or, as relevant here, detecting DNA from a transplanted organ in the recipient’s blood, which requires highly sensitive and efficient amplification methods ('180 Patent, col. 2:59-63).
• The Patented Solution: The invention provides methods for simultaneously amplifying many (e.g., hundreds or thousands) of specific DNA sequences (target loci) in a single reaction volume using multiplex polymerase chain reaction (PCR) ('180 Patent, col. 4:50-55). By targeting single nucleotide polymorphisms (SNPs)—locations where the DNA of the donor and recipient may differ—the method allows for the quantification of the donor DNA fraction in the sample without needing to separately genotype the donor and recipient beforehand ('180 Patent, col. 143:10-25).
• Technical Importance: This approach enables highly sensitive, non-invasive monitoring of conditions like organ transplant rejection from a simple blood draw, potentially replacing or reducing the need for more invasive and risky biopsy procedures (Compl. ¶2-3).

Key Claims at a Glance

• The complaint asserts independent claims 1 and 14 (Compl. ¶24-25).
• Independent Claim 1 includes the following essential elements:
  • A method for measuring an amount of DNA in a biological sample.
  • Extracting cell-free DNA (cfDNA) of mixed origin from a subject, where the DNA is from the subject and a genetically distinct individual (from a transplant).
  • Performing targeted PCR amplification of the cfDNA at more than 100 SNP loci in a single reaction volume, with the loci located on at least chromosome 1, 2, or 3.
  • Determining the genotypes and measuring an amount of one or more alleles at the SNP loci using high-throughput sequencing.
  • Measuring an amount of the DNA from the genetically distinct individual using the measured allele amounts.
  • Performing the method without prior knowledge of the genotypes of the genetically distinct individual.
• Independent Claim 14 includes the following essential elements:
  • A method for measuring an amount of DNA in a biological sample.
  • Performing targeted PCR amplification for more than 100 SNP loci in a single reaction mixture containing cfDNA of mixed origin (subject and transplant donor).
  • Measuring, via high-throughput sequencing, a quantity of each allele at a plurality of amplified SNP loci that is present in the donor but not the subject.
  • Measuring an amount of donor DNA using the quantity of each allele and an expected quantity of each allele for different DNA fractions.
  • Performing the method without prior knowledge of the genotypes of the genetically distinct individual.
• The complaint does not explicitly reserve the right to assert dependent claims, though such a reservation is standard practice.

III. The Accused Instrumentality

Product Identification

• The accused instrumentalities are Defendant’s transplant diagnostic testing services, including AlloSure, AlloSeq, KidneyCare, and HeartCare (Compl. ¶13).

Functionality and Market Context

• The complaint alleges these are services for monitoring the health of organ transplants (Compl. ¶20-21). AlloSure is described as a "donor derived cell-free DNA (dd-cfDNA) test" that measures the percentage of donor DNA in a recipient's blood to assess the risk of organ rejection (Compl. Ex. A, p. 14). AlloSeq is described as an assay that "enables the amplification and sequencing of 202 single nucleotide polymorphisms (SNPs)" to calculate the percentage of recipient and donor DNA in post-transplant samples (Compl. Ex. A, p. 15). A workflow diagram for the accused AlloSeq product shows a process of DNA extraction followed by amplification, sequencing, and analysis (Compl. Ex. A, p. 17). The complaint positions these products in direct competition with Plaintiff's own cfDNA-based diagnostic tests (Compl. ¶5).

IV. Analysis of Infringement Allegations

U.S. Patent No. 10,655,180 Infringement Allegations

Claim Element (from Independent Claim 1)	Alleged Infringing Functionality	Complaint Citation	Patent Citation
(a) extracting cell-free DNA of mixed origin from a biological sample of a subject, wherein the cell-free DNA comprises DNA from the subject and DNA from a genetically distinct individual... wherein the DNA of mixed origin comprises DNA from a transplant;	The AlloSure and AlloSeq tests process cfDNA extracted from a transplant recipient's blood, which contains a mixture of recipient DNA and donor DNA from the transplanted organ. A diagram from Defendant's marketing material depicts how cfDNA from a transplanted kidney is released into the recipient's bloodstream (Compl. Ex. A, p. 16).	¶24; Ex. A, p. 15-16	col. 95:25-34
(b) performing targeted PCR amplification of the cell-free DNA at more than 100 SNP loci in a single reaction volume using more than 100 PCR primer pairs, wherein the amplified SNP loci comprise SNP loci on at least chromosome 1, 2, or 3;	The AlloSure 3.0 assay allegedly evaluates 405 SNPs, and the AlloSeq assay targets 202 SNPs across autosomal chromosomes (which include 1, 2, and 3) in a single multiplexed reaction.	¶24; Ex. A, p. 18-19	col. 4:50-55; col. 8:52-58
(c) determining the genotypes of the amplified SNP loci and measuring an amount of one or more alleles at the SNP loci, wherein the genotypes of the amplified SNP loci are determined by high-throughput sequencing;	The AlloSure and AlloSeq tests allegedly use next-generation sequencing (NGS), a form of high-throughput sequencing, to determine SNP genotypes and quantify donor-derived cfDNA.	¶24; Ex. A, p. 20-21	col. 109:30-45
(d) measuring an amount of the DNA from the genetically distinct individual present in the biological sample using the amount of one or more alleles at the SNP loci...	The accused tests allegedly calculate the percent of donor-derived cfDNA in a sample based on allele frequencies determined from the sequencing data. A screenshot of the accused AlloSeq HCT software output displays the calculated percentages of recipient and donor DNA (Compl. Ex. A, p. 23).	¶24; Ex. A, p. 22-23	col. 8:30-34
wherein the method is performed without prior knowledge of genotypes of the genetically distinct individual.	The accused tests are allegedly performed "without separate genotyping of either the donor or the recipient."	¶24; Ex. A, p. 24-25	col. 143:10-25

• Identified Points of Contention:
  • Scope Questions: The infringement analysis may focus on whether the accused products' use of population-level SNP frequency data and proprietary algorithms to infer the donor DNA fraction constitutes performing the method "without prior knowledge of genotypes." A dispute may arise over whether using statistical information about genotypes is equivalent to having "prior knowledge" as contemplated by the patent.
  • Technical Questions: For Claim 14, a central question may be whether Defendant's bioinformatics software performs the specific step of "measuring an amount of the DNA... using the quantity of each allele at the SNP loci and an expected quantity of each allele... for different DNA fractions." The details of Defendant's algorithm, which the complaint alleges uses "known population frequencies... and expected distribution of alleles" (Compl. Ex. A, p. 22), will be compared against the methods disclosed and claimed in the patent.

V. Key Claim Terms for Construction

• The Term: "without prior knowledge of genotypes of the genetically distinct individual"

• Context and Importance: This negative limitation is central to the asserted claims and appears to be a primary point of novelty. The patent distinguishes its methods from those that require a separate, direct genotyping of the donor. Infringement will turn on whether Defendant's method, which allegedly uses population statistics instead of direct genotyping, falls within the scope of this limitation.

• Intrinsic Evidence for Interpretation:

  • Evidence for a Broader Interpretation (favoring infringement): The specification repeatedly frames the invention's benefits in the context of avoiding the need to obtain a physical sample from the father (in the prenatal context) or donor ('180 Patent, col. 143:10-25). Plaintiff may argue that "prior knowledge" should be construed to mean knowledge obtained from direct genotyping of a sample from the specific donor, and that using general population data is not "prior knowledge" of that specific individual's genotype.
  • Evidence for a Narrower Interpretation (favoring non-infringement): The patent itself discloses using population frequencies and statistical models as part of its analytical methods (e.g., '180 Patent, col. 173:1-5). Defendant may argue that using this type of population-level genetic information constitutes a form of "prior knowledge" about likely genotypes, and therefore its methods do not meet this limitation.

• The Term: "an expected quantity of each allele at the SNP loci for different DNA fractions" (from Claim 14)

• Context and Importance: This term specifies a key input for the calculation recited in Claim 14. The construction of this phrase will be critical to determining if the algorithm used in the accused products performs the claimed measurement step.

• Intrinsic Evidence for Interpretation:

  • Evidence for a Broader Interpretation: The specification describes various statistical approaches that model expected allele counts based on different hypotheses about the fraction of fetal (or donor) DNA ('180 Patent, col. 161:1-162:14). Plaintiff may argue that any algorithm that compares observed allele counts to a statistical expectation based on a potential donor DNA percentage meets this limitation.
  • Evidence for a Narrower Interpretation: The specification provides highly detailed mathematical frameworks and embodiments for calculating these expected quantities ('180 Patent, cols. 161-172). Defendant may argue that this term should be limited to the specific models disclosed in the patent, and that its own proprietary algorithm uses a fundamentally different, non-infringing calculation.

VI. Other Allegations

• Indirect Infringement: The complaint makes a conclusory allegation of inducement and contributory infringement (Compl. ¶13) but does not plead specific facts, such as identifying instructions or user manuals, that would be necessary to support a claim for indirect infringement.
• Willful Infringement: The complaint does not contain an explicit allegation of willful infringement or facts supporting pre-suit knowledge of the patent. It does, however, request that the court find the case "exceptional" under 35 U.S.C. § 285 (Compl. ¶32; Prayer for Relief ¶4).

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

• A core issue will be one of definitional scope: can the term "without prior knowledge of genotypes," which the patent contrasts with methods requiring direct sampling of the donor, be construed to encompass methods that use population-level statistical data about genotype frequencies to perform their analysis?
• A key evidentiary question will be one of algorithmic correspondence: does the proprietary bioinformatics algorithm used in Defendant's AlloSure and AlloSeq products perform the specific calculation recited in Claim 14, which requires using both a "quantity of each allele" and an "expected quantity of each allele"? This will likely require a detailed technical comparison between the patented methods and the accused software.