DCT
1:19-cv-00567
CareDx Inc v. Natera Inc
Key Events
Complaint
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: CareDx, Inc. (Delaware) and The Board of Trustees of the Leland Stanford Junior University (California)
- Defendant: Natera, Inc. (Delaware)
- Plaintiff’s Counsel: Farnan LLP
- Case Identification: 1:19-cv-00567, D. Del., 03/26/2019
- Venue Allegations: Venue is asserted in the District of Delaware based on Defendant Natera, Inc. being a Delaware corporation and conducting business within the district.
- Core Dispute: Plaintiffs allege that Defendant’s Kidney Transplant Rejection Test infringes patents, owned by Stanford University and exclusively licensed to CareDx, related to non-invasive methods for detecting organ transplant rejection by measuring donor-derived cell-free DNA in a recipient's blood.
- Technical Context: The technology uses genetic sequencing to identify and quantify small amounts of a transplant donor's DNA circulating in the recipient's bloodstream, which can serve as a biomarker for organ injury or rejection, potentially replacing the need for invasive tissue biopsies.
- Key Procedural History: The complaint states the patents-in-suit originated from research at Stanford University, which holds the patent rights and has granted an exclusive license to CareDx in the field of non-invasive monitoring of organ transplant rejection.
Case Timeline
| Date | Event |
|---|---|
| 2009-11-06 | Priority Date for ’497 and ’652 Patents |
| 2014-04-22 | U.S. Patent No. 8,703,652 Issues |
| 2017-12-19 | U.S. Patent No. 9,845,497 Issues |
| 2018 (Mid) | Natera allegedly began preparing to develop its Kidney Transplant Rejection Test |
| 2018-12-05 | Natera-affiliated scientists list clinical trial for "Natera KidneyScan" |
| 2018-12-23 | Natera-affiliated scientists publish article on methodology for detecting transplant injury |
| 2019-01-07 | Natera press release confirms purpose of study was to validate its test methodology |
| 2019-02-01 | Natera announces partnership to begin distributing its kidney transplant rejection test |
| 2019-03-26 | Complaint Filed |
II. Technology and Patent(s)-in-Suit Analysis
U.S. Patent No. 9,845,497 - "Non-Invasive Diagnosis of Graft Rejection in Organ Transplant Patients," issued December 19, 2017
The Invention Explained
- Problem Addressed: The patent describes the monitoring of organ transplant patients for rejection as a difficult, expensive, and often invasive process, with existing surveillance methods lacking adequate sensitivity (’497 Patent, col. 1:19-27).
- The Patented Solution: The invention provides a non-invasive method to diagnose rejection by analyzing a biological sample (e.g., blood plasma) from a transplant recipient. The method involves first creating genetic profiles for both the donor and the recipient to identify genetic differences, such as single nucleotide polymorphisms (SNPs) (’497 Patent, col. 13:1-15). After the transplant, the recipient’s plasma is analyzed to detect and quantify the amount of donor-specific DNA. An elevated level of this donor DNA can indicate transplant rejection (’497 Patent, col. 1:33-44, Fig. 5).
- Technical Importance: The technology proposes a universal method for monitoring all types of organ transplants that is not limited by factors such as the gender of the donor and recipient, a limitation of some prior art techniques (’497 Patent, col. 8:55-59).
Key Claims at a Glance
- The complaint asserts at least independent Claim 1 (Compl. ¶20).
- The essential elements of Claim 1 include:
- (a) genotyping a solid organ transplant donor to obtain a single nucleotide polymorphism (SNP) profile;
- (b) genotyping a solid organ transplant recipient to obtain a SNP profile;
- (c) obtaining a biological sample (e.g., blood, serum, plasma) from the recipient post-transplant, which contains circulating cell-free nucleic acids from the donated organ; and
- (d) determining the amount of donor-specific nucleic acids by detecting a homozygous or heterozygous SNP using high-throughput sequencing or dPCR, where the assay can detect donor DNA when it constitutes at least 0.03% of the total circulating cell-free nucleic acids.
- The complaint does not explicitly reserve the right to assert dependent claims but references infringement of the patent generally (Compl. ¶20).
U.S. Patent No. 8,703,652 - "Non-Invasive Diagnosis of Graft Rejection in Organ Transplant Patients," issued April 22, 2014
The Invention Explained
- Problem Addressed: The patent identifies the significant risk and mortality associated with transplant rejection, particularly cardiac allograft vasculopathy (CAV), and notes that standard diagnostic tools like coronary angiography are invasive and lack sufficient sensitivity for early detection (’652 Patent, col. 6:1-13).
- The Patented Solution: The invention describes a method for detecting transplant rejection by using genetic differences (polymorphisms) between a donor and recipient as a basis for a diagnostic test. A polymorphism profile is established, and then multiplex sequencing is performed on cell-free nucleic acids from the recipient's sample. This allows for the detection and quantification of both donor and subject nucleic acids, with an increase in the quantity of donor DNA over time indicating rejection (’652 Patent, Abstract; col. 1:30-41).
- Technical Importance: The method aims to provide a reliable, non-invasive, and cost-effective clinical test that can be used for early diagnosis and risk stratification, allowing for more timely and appropriate therapeutic intervention (’652 Patent, col. 6:21-29).
Key Claims at a Glance
- The complaint asserts at least independent Claim 1 (Compl. ¶23).
- The essential elements of Claim 1 include:
- (a) providing a sample of cell-free nucleic acids from a transplant recipient;
- (b) obtaining a genotype of donor-specific and/or subject-specific polymorphisms to establish a profile for detecting donor cell-free DNA;
- (c) performing multiplex sequencing of the cell-free nucleic acids and using the profile to detect donor and subject nucleic acids; and
- (d) diagnosing a transplant status by determining the quantity of donor cell-free nucleic acids, where an increase over time indicates rejection and the method's sensitivity is greater than 56% compared to surveillance methods for CAV.
- The complaint does not explicitly reserve the right to assert dependent claims but references infringement of the patent generally (Compl. ¶23).
III. The Accused Instrumentality
Product Identification
- The accused instrumentality is Natera's Kidney Transplant Rejection Test, also referred to as an "organ transplant rejection assay," "allograft rejection" test, and "Natera KidneyScan" (Compl. ¶¶10, 17).
Functionality and Market Context
- The complaint alleges that Natera's test functions by measuring the fraction of donor-derived cell-free DNA (dd-cfDNA) in a transplant recipient's blood (Compl. ¶16). The process allegedly involves extracting cfDNA from the recipient's plasma, amplifying it via "massively multiplex PCR (mmPCR)," and then subjecting the amplified SNPs to next-generation sequencing (NGS) to determine the amount of dd-cfDNA (Compl. ¶¶21, 24).
- The complaint highlights a Natera press release stating the test leverages its "core single nucleotide polymorphism (SNP)-based massively multiplexed PCR (mmPCR) technology, to more accurately measure dd-cfDNA levels without the need for donor genotyping" (Compl. ¶16).
- Regarding market context, the complaint alleges Natera announced a partnership in February 2019 to begin distributing the test in the United States, with its CEO stating the partnership would "accelerate" Natera's entry into the market (Compl. ¶19).
Visual Evidence
- No probative visual evidence provided in complaint.
IV. Analysis of Infringement Allegations
’497 Patent Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| (a) genotyping a solid organ transplant donor to obtain a single nucleotide polymorphism (SNP) profile of the solid organ transplant donor; | The complaint alleges that performance of Natera's test leads to infringement of the claim, describing a process where a plasma sample is genotyped to obtain a SNP profile and determine the amount of donor-derived cfDNA. | ¶¶20-21 | col. 13:1-4 |
| (b) genotyping a solid organ transplant recipient to obtain a SNP profile of the solid organ transplant recipient... | The complaint's infringement narrative describes genotyping a post-transplant plasma sample from the recipient, which contains both donor and recipient DNA, to obtain a SNP profile. | ¶21 | col. 13:1-4 |
| (c) obtaining a biological sample from the solid organ transplant recipient after the... recipient has received the solid organ transplant... wherein the biological sample is selected from the group consisting of blood, serum and plasma... | The accused test allegedly involves extracting cell-free DNA from a recipient's plasma sample post-transplant. | ¶21 | col. 9:4-10 |
| (d) determining an amount of donor-specific circulating cell-free nucleic acids... by detecting a homozygous or a heterozygous SNP... wherein the at least one assay comprises high-throughput sequencing... and wherein the at least one assay detects the donor-specific... nucleic acids... when [they] make up at least 0.03%... | The accused test allegedly uses next-generation sequencing (NGS) to determine the amount of donor-derived cfDNA by detecting homozygous or heterozygous SNPs. | ¶21 | col. 17:6-12 |
’652 Patent Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| (a) providing a sample comprising cell-free nucleic acids from a subject who has received a transplant from a donor; | The accused test is performed on a plasma sample containing cell-free DNA from a kidney transplant recipient. | ¶24 | col. 10:36-40 |
| (b) obtaining a genotype of donor-specific polymorphisms or a genotype of subject-specific polymorphisms... to establish a polymorphism profile for detecting donor cell-free nucleic acids... | The complaint alleges Natera's test genotypes a plasma sample to obtain a SNP profile to determine the quantity of donor-derived cfDNA. | ¶24 | col. 8:56-62 |
| (c) multiplex sequencing of the cell-free nucleic acids in the sample followed by analysis of the sequencing results using the polymorphism profile to detect donor cell-free nucleic acids... | The accused test allegedly uses massively multiplex PCR (mmPCR) and next-generation sequencing (NGS) to detect and quantify donor-derived cfDNA. | ¶24 | col. 10:25-26 |
| (d) diagnosing... a transplant status... by determining a quantity of the donor cell-free nucleic acids... wherein an increase in the quantity... is indicative of transplant rejection... and wherein sensitivity... is greater than 56%... | The test is allegedly used to diagnose rejection. The complaint cites publications indicating the accused test can detect active rejection with at least 89% sensitivity. | ¶24 | col. 2:45-46 |
- Identified Points of Contention:
- Scope Questions: A primary question is whether the claim term "genotyping a solid organ transplant donor" (in the ’497 Patent) and "obtaining a genotype of donor-specific polymorphisms" (in the ’652 Patent) requires a direct analysis of a sample obtained from the donor, or if it can be satisfied by inferring the donor's genetic information from a mixed sample of donor and recipient DNA taken from the recipient post-transplant. The complaint alleges infringement while simultaneously citing a Natera press release that claims its test works "without the need for donor genotyping" (Compl. ¶16), creating a facial tension that will be central to claim construction and infringement analysis.
- Technical Questions: Evidentiary questions will surround the quantitative limitations in the claims. Plaintiffs will need to prove that Natera's test, as performed, meets the "at least 0.03%" detection threshold of Claim 1 of the ’497 Patent and the "greater than 56% sensitivity" requirement of Claim 1 of the ’652 Patent. The complaint makes a factual allegation of 89% sensitivity for the accused test, which, if proven, would satisfy that limitation (Compl. ¶24).
V. Key Claim Terms for Construction
- The Term: "genotyping a solid organ transplant donor" (’497 Patent, Claim 1(a)) and "obtaining a genotype of donor-specific polymorphisms" (’652 Patent, Claim 1(b)).
- Context and Importance: The definition of these terms is critical. Practitioners may focus on these terms because the central infringement question is whether Natera's alleged method—which Plaintiffs describe as not requiring separate donor genotyping—can meet a claim limitation that explicitly recites obtaining a donor genotype. The outcome of this construction could be dispositive of infringement.
- Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The patent specifications may contain general descriptions of genotyping that do not explicitly require a pre-transplant sample directly from the donor, which could support an argument that inferential genotyping from a mixed sample is sufficient.
- Evidence for a Narrower Interpretation: The specifications provide strong support for a narrower definition. Both patents state that in some embodiments, "the methods, devices, compositions and kits are used to establish a genotype for both the donor and the recipient before transplantation" (’497 Patent, col. 11:57-60; ’652 Patent, col. 12:59-62). This language suggests the conventional and intended method involves separate, direct genotyping of donor and recipient materials.
VI. Other Allegations
- Indirect Infringement: The complaint does not contain separate counts for indirect or induced infringement. While it makes a passing reference to Natera "directly or indirectly" using or selling the test (Compl. ¶14), the formal counts are limited to direct infringement under 35 U.S.C. § 271(a) (Compl. ¶¶30, 36).
- Willful Infringement: The complaint does not contain an explicit allegation of willful infringement. It does include a prayer for a determination that this is an "exceptional case" under 35 U.S.C. § 285, which could entitle Plaintiffs to attorneys' fees, but this is a separate legal standard from willfulness (Compl. p. 10, ¶D).
VII. Analyst’s Conclusion: Key Questions for the Case
- A core issue will be one of definitional scope: does the claim language requiring the "genotyping" of a donor necessitate a direct analysis of a biological sample from the donor, as the patent specification appears to describe in its embodiments? Or can the term be construed more broadly to cover methods that infer the donor's genetic information from a mixed-DNA sample obtained from the recipient, which is how Plaintiffs characterize the accused test?
- A key evidentiary question will be one of process and performance: what is the precise methodology of Natera's accused test? The infringement analysis will turn on whether Plaintiffs can prove, through discovery, that the accused test's process and quantitative performance characteristics (e.g., detection thresholds and sensitivity) fall within the specific limitations of the asserted claims.