CareDx, Inc. v. Natera, Inc.

40 F.4th 1371

CAREDX, INC., the Board of Trustees of the Leland Stanford Junior University, Plaintiffs-Appellants

v.NATERA, INC., Defendant-Appellee

CareDx, Inc., the Board of Trustees of the Leland Stanford Junior University, Plaintiffs-Appellants

v.Eurofins Viracor, Inc., Defendant-Appellee

2022-1027, 2022-1028

United States Court of Appeals, Federal Circuit.

Decided: July 18, 2022

Edward R. Reines, Weil, Gotshal & Manges LLP, Redwood Shores, CA, argued for plaintiffs-appellants. Also represented by Derek C. Walter ; Anna Dwyer, New York, NY; Zachary Tripp, Washington, DC.

Gabriel K. Bell, Latham & Watkins LLP, Washington, DC, argued for defendant-appellee Natera, Inc. Also represented by Ashley Fry, Fan Zhang.

William M. Jay, Goodwin Procter LLP, Washington, DC, argued for defendant-appellee Eurofins Viracor, Inc. Also represented by Jordan Bock, Kevin Jon DeJong, Boston, MA; Darryl M. Woo, San Francisco, CA.

Before Lourie, Bryson, and Hughes, Circuit Judges.

Lourie, Circuit Judge.

CareDx, Inc. and The Board of Trustees of the Leland Stanford Junior University ("Stanford") (collectively, "CareDx") appeal from a decision of the United States District Court for the District of Delaware holding that U.S. Patents 8,703,652 (the "'652 patent"), 9,845,497 (the "'497 patent"), and 10,329,607 (the "'607 patent") are ineligible for patent under 35 U.S.C. § 101. See CareDx, Inc. v. Natera, Inc. , 563 F. Supp. 3d 329 (D. Del. 2021) (" Decision "). We affirm.

BACKGROUND

Stanford owns the '652, '497, and '607 patents. All three patents share the same specification and are entitled "Non-Invasive Diagnosis of Graft Rejection in Organ Transplant Patients." These patents discuss diagnosing or predicting organ transplant status by using methods to detect a donor's cell-free DNA ("cfDNA"). When an organ transplant is rejected, the recipient's body, through its natural immune response, destroys the donor cells, thus releasing cfDNA from the donated organ's dying cells into the blood. These increased levels of donor cfDNA—which occur naturally as the organ's condition deteriorates—can be detected and then used to diagnose the likelihood of an organ transplant rejection. Claim 1 of each patent is representative. Claim 1 of the '652 patent reads as follows:

1. A method for detecting transplant rejection, graft dysfunction, or organ failure, the method comprising:

(a) providing a sample comprising [cfDNA] from a subject who has received a transplant from a donor;

(b) obtaining a genotype of donor-specific polymorphisms or a genotype of subject-specific polymorphisms, or obtaining both a genotype of donor-specific polymorphisms and subject-specific polymorphisms, to establish a polymorphism profile for detecting donor [cfDNA], wherein at least one single nucleotide polymorphism (SNP) is homozygous for the subject if the genotype comprises subject-specific polymorphisms comprising SNPs;

(c) multiplex sequencing of the [cfDNA] in the sample followed by analysis of the sequencing results using the polymorphism profile to detect donor [cfDNA] and subject [cfDNA] ; and

(d) diagnosing, predicting, or monitoring a transplant status or outcome of the subject who has received the transplant by determining a quantity of the donor [cfDNA] based on the detection of the donor [cfDNA] and subject [cfDNA] by the multiplexed sequencing, wherein an increase in the quantity of the donor [cfDNA] over time is indicative of transplant rejection, graft dysfunction or organ failure , and wherein sensitivity of the method is greater than 56% compared to sensitivity of current surveillance methods for cardiac allograft vasculopathy (CAV).

'652 patent at col. 27 l. 39–col. 28 l. 40 (emphases added).

Claim 1 of the '497 patent is similar, except that it recites high-throughput sequencing or digital polymerase chain reaction ("PCR") instead of multiplex sequencing for "determining" the amount of donor cfDNA.

1. A method of detecting donor-specific circulating [cfDNA] in a solid organ transplant recipient, the method comprising:

(a) genotyping a solid organ transplant donor to obtain a single nucleotide polymorphism (SNP) profile of the solid organ transplant donor;

(b) genotyping a solid organ transplant recipient to obtain a SNP profile of the solid organ transplant recipient, wherein the solid organ transplant recipient is selected from the group consisting of: a kidney transplant, a heart transplant, a liver transplant, a pancreas transplant, a lung transplant, a skin transplant, and any combination thereof;

(c) obtaining a biological sample from the solid organ transplant recipient after the solid organ transplant recipient has received the solid organ transplant from the solid organ transplant donor, wherein the biological sample is selected from the group consisting of blood, serum and plasma, and wherein the biological sample comprises circulating [cfDNA] from the solid organ transplant ; and

(d) determining an amount of donor-specific circulating [cfDNA] from the solid organ transplant in the biological sample by detecting a homozygous or a heterozygous SNP within the donor-specific circulating [cfDNA] from the solid organ transplant in at least one assay, wherein the at least one assay comprises high-throughput sequencing or digital polymerase chain reaction (dPCR) , and

wherein the at least one assay detects the donor-specific circulating [cfDNA] from the solid organ transplant when the donor-specific circulating [cfDNA] make up at least 0.03% of the total circulating [cfDNA] in the biological sample.

'497 patent at col. 28 l. 2–col. 29 l. 5 (emphasis added).

Claim 1 of the '607 patent is also similar, except that it recites selective amplification of the cfDNA by PCR before high-throughput sequencing.

1. A method of quantifying kidney transplant-derived circulating [cfDNA] in a human kidney transplant recipient, said method comprising:

(a) providing a plasma sample from said human kidney transplant recipient, wherein said human kidney transplant recipient has received a kidney transplant from a kidney transplant donor, wherein said plasma sample from said human kidney transplant recipient comprises kidney transplant-derived circulating [cfDNA] and human kidney transplant recipient-derived circulating [cfDNA];

(b) extracting circulating [cfDNA] from said plasma sample from said human kidney transplant recipient in order to obtain extracted circulating [cfDNA], wherein said extracted circulating [cfDNA] comprises said kidney transplant-derived circulating [cfDNA] and human kidney transplant recipient-derived circulating [cfDNA];

(c) performing a selective amplification of target [DNA] sequences , wherein said selective amplification of said target [DNA] sequences is of said extracted circulating [cfDNA], wherein said selective amplification of said target [DNA] sequences amplifies a plurality of genomic regions comprising at least 1,000 single nucleotide polymorphisms, wherein said at least 1,000 single nucleotide polymorphisms comprise homozygous single nucleotide polymorphisms, heterozygous single nucleotide polymorphisms, or both homozygous single nucleotide polymorphisms and heterozygous single nucleotide polymorphisms, and wherein said selective amplification of said target deoxyribonucleic acid sequences is by polymerase chain reaction (PCR);

(d) performing a high throughput sequencing reaction, wherein said high throughput sequencing reaction comprises performing a sequencing-by-synthesis reaction on said selectively-amplified target [DNA] sequences from said extracted circulating [cfDNA], wherein said sequencing-by-synthesis reaction has a sequencing error rate of less than 1.5%;

(e) providing sequences from said high throughput sequencing reaction, wherein said provided sequences from said high throughput sequencing reaction comprise said at least 1,000 single nucleotide polymorphisms; and

(f) quantifying an amount of said kidney transplant-derived circulating [cfDNA] in said plasma sample from said human kidney transplant recipient to obtain a quantified amount, wherein said quantifying said amount of said kidney transplant-derived circulating [cfDNA] in said plasma sample from said human kidney transplant recipient comprises using markers distinguishable between said human kidney transplant recipient and said kidney transplant donor, wherein said markers distinguishable between said human kidney transplant recipient and said kidney transplant donor comprises single nucleotide polymorphisms selected from said at least 1,000 single nucleotide polymorphisms identified in said provided sequences from said high throughput sequencing reaction, and wherein said quantified amount of said kidney transplant-derived circulating [cfDNA] in said plasma sample from said human kidney transplant recipient comprises at least 0.03% of the total circulating [cfDNA] from said plasma sample from said human kidney transplant recipient.

'607 patent at col. 28 l. 56–col. 30 l. 2 (emphasis added).

In summary, the methods disclosed in the representative claims have four steps for detecting a donor's cfDNA in a transplant recipient:

1. "obtaining" or "providing" a "sample" from the recipient that contains cfDNA;

2. "genotyping" the transplant donor and/or recipient to develop "polymorphism" or "SNP" "profiles";

3. "sequencing" the cfDNA from the sample using "multiplex" or "high-throughput" sequencing; or performing "digital PCR"; and

4. "determining" or "quantifying" the amount of donor cfDNA.

CareDx is the exclusive licensee of the '652, '497, and '607 patents. It sued Natera, Inc. ("Natera"), alleging that Natera's kidney transplant rejection test infringed the '652, '497, and '607 patents. CareDx also sued Eurofins Viracor, Inc. ("Eurofins"), alleging that Eurofins' various organ transplant rejection tests infringed the '652 patent. Natera and Eurofins both moved to dismiss the complaints for failure to state a claim due to lack of patent-eligible subject matter under § 101.

The motions to...