May 30, 2023
On May 16, the Supreme Court distributed the CareDX cert petition for consideration at the June 1 conference since the Respondents waived filing a reply. The CareDX family of three patents, licensed from Stanford University, U.S.Ps. 8,703,652, 9,845,497 and 10,329,607, are directed to the noninvasive diagnosis of the state of a transplanted organ. The test provides the doctor with information on whether everything is okay, or that the organ is showing signs of being rejected. Both the district court and the Federal Circuit held the patent to be patent ineligible based primarily on admissions appearing in the specification of all three patents which are identical. Given the low success rate (recently zero) of requests for certiorari in the diagnostic/biomarker area, this raises the question as to the possibility the petition will be granted. The CareDx petition’s chances seem better than recent certiorari petitions.
First, the petition begins with the claims demonstrating that the claims do not preempt the use of cell free DNA (cfDNA) to determine the state of an organ transplant. It explains, as do the patent specifications, the problems with the previous approaches, one of which predates the patent by over a decade.
The oldest of the prior techniques would work reliably only in women who received the organ from of male donor since it relied upon detecting and quantifying the amount of Y chromosome in the recipient’s blood. Only about 25% of all organ recipients fall into this group and the group is further reduced since the technique is of questionable accuracy in women who have received a blood transfusion where the donor was a male. The second technique, the detection of donor-specific human leukocyte antigen (HLA) alleles in circulating DNA, has been considered as a signal for organ rejection in kidney and pancreas transplant patients. However, this strategy is limited by the inability to distinguish HLA alleles between all donors and recipients, particularly for common HLA types, and the potential complication of microchimerism such as from blood transfusions.
The claims of the CareDx patents as represented by claim 1 of the ‘607 claim are to a multi-step process:
1. A method of quantifying kidney transplant-derived circulating cell-free deoxyribonucleic acids 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 cell-free deoxyribonucleic acid and human kidney transplant recipient-derived circulating cell-free deoxyribonucleic acid;
(b) extracting circulating cell-free deoxyribonucleic acid from said plasma sample from said human kidney transplant recipient in order to obtain extracted circulating cell-free deoxyribonucleic acid, wherein said extracted circulating cell-free deoxyribonucleic acid comprises said kidney transplant-derived circulating cell-free deoxyribonucleic acid and human kidney transplant recipient-derived circulating cell-free deoxyribonucleic acid;
(c) performing a selective amplification of target deoxyribonucleic acid sequences, wherein said selective amplification of said target deoxyribonucleic acid sequences is of said extracted circulating cell-free deoxyribonucleic acid, wherein said selective amplification of said target deoxyribonucleic acid 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 deoxyribonucleic acid sequences from said extracted circulating cell-free deoxyribonucleic acid, 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 cell-free deoxyribonucleic acid 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 cell-free deoxyribonucleic acid 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 cell-free deoxyribonucleic acid in said plasma sample from said human kidney transplant recipient comprises at least 0.03% of the total circulating cell-free deoxyribonucleic acid from said plasma sample from said human kidney transplant recipient.
The broadest claim in the patents is ‘652 claim 1:
1. A method for detecting transplant rejection, graft dysfunction, or organ failure, the method comprising:
(a) providing a sample comprising cell-free nucleic acids 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 cell-free nucleic acids, 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 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 and subject cell-free nucleic acids; 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 cell-free nucleic acids based on the detection of the donor cell-free nucleic acids and subject cell-free nucleic acids by the multiplexed sequencing, wherein an increase in the quantity of the donor cell-free nucleic acids 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).
The problem was Stanford’s admissions that the each of the claimed steps was described as known, but there was no admission they were known in combination, nor did the admission address the specific limitations of, for example, the ‘607 patent claim 1. Further, in the district court, the magistrate had found the claims to be directed to a “purportedly new, unconventional combination of steps" to detect that natural phenomenon.” 563 F. Supp.3d 329 at 337 quoting the magistrates recommendation. The district court relied on Athena Diagnostics, Inc. v. Mayo Collaborative Servs., LLC, 915 F.3d 743, 757 (Fed. Cir. 2019) in overruling the magistrate’s recommendation, quoting “claims that recite only a natural law together with conventional steps to detect that law, ... are ineligible under § 101” from Athena at 757. The district court did not consider that the claims in Athena generically claimed the detection step found conventional and, like the Federal Circuit, ignored that the Athena claims preempted the use of the natural law. The Federal Circuit held in CareDx that the claimed method was nothing more than the logical combination of the standard techniques and that the claims lacked an “inventive concept.” CareDx, Inc., et al. v. Natera et al., 40 F.4th 1371, 1380 (Fed. Cir.2022). The Federal Circuit did not explain why it is a logical combination. The circulation of donor cfDNA in a recipient’s blood was known, and rejection of the transplanted organ could be predicted from the amount of donor cfDAN circulating in the recipient’s blood was also known. The problem was that the prior detection techniques had problems precluding their use to predict organ rejection.
The Federal Circuit relied on Mayo Collaborative Servs. v. Prometheus Lab'ys, Inc., 566 U.S. 66, 70, 132 S.Ct. 1289, 182 L.Ed.2d 321 (2012) for the concept that “‘conventional steps, specified at a high level of generality,’ to a law of nature or natural phenomenon does not make a claim to the law or phenomenon patentable.” Mayo, 566 U.S. at 82, 132 S.Ct. 1289. However, Mayo is not applicable since the steps in Mayo were not only not new and the arrangement of the steps was also old. CareDx’s claims do not recite the steps with a high level of generality as in Mayo. The claims, especially the ‘607 claims, recite the steps with significant specificity and are a new combination. The Federal Circuit ignores that it was a decade between the discovery of the relationship of donor cfDNA in a recipient’s blood and the development of the CareDx process which allowed for the first successful noninvasive technique.
The petition stresses that the Federal Circuit failed to properly apply the two-step Alice test by relying on “conventionality” in applying the obviousness standard in both steps. In doing so the Federal Circuit ignored the statutory language of 35 U.S.C. § 101 which protects “any new and useful process, machine, manufacture, or composition of matter or any new and useful improvement thereof subject to the conditions and requirements of this title.” Here the claims are new since the recited steps had not previously been combined to detect and quantify cfDNA in a transplant recipient’s blood. The statute does not require that the invention be unobvious, only new. Obviousness is controlled by 35 U.S.C. § 103 which involves consideration of the factors relating to an obviousness determination. The petition stresses the language of the claims and the statute. It also stresses the failure of the Federal Circuit to consider the driving force behind the Court’s patent eligibility concerns is preemption and instead relies on “conventionality.” Reliance on “conventionality” undermines the Court’s obviousness jurisprudence as well as the purpose of the 1952 Patent Act’s introduction of the obviousness standard.
It is this writer’s opinion that the CareDx petition presents a more compelling case for the Court to grant certiorari than previous 101 cases. Unlike other petitions it provides detailed reasons why the Federal Circuit has erred and the solution to the problem.