My colleagues' refusal deflates the Amici's hopeful suggestion that our precedent leaves the eligibility of a diagnostic claim in front of the Federal Circuit "uncertain." It is no longer uncertain. Since Mayo, every diagnostic claim to come before this court has been held ineligible. While we believe that such claims should be eligible for patent protection, the majority of this court has definitively concluded that the Supreme Court prevents us from so holding. No need to waste resources with additional en banc requests.

In the interim it has become clear that even asking the Court to provide any answer other than an affirmance of a district court decision below invalidating claims to diagnostic methods is too much to ask, a reality made evident once again by the Court's recent decision in CareDx, Inc. v. Natera, Inc.

To recap proceedings below, the case arose over the claims in U.S. Patent Nos. 8,703,652, 9,845,497, and 10,329,607 directed to "methods to help predict the status or outcomes of transplant recipients through sequencing of cell-free nucleic acids ("cfDNA") found in the bodily fluids of a recipient." The rationale behind the invention is rejection of a transplanted organ in a recipient is accompanied by cell death, which releases donor-specific DNA into the recipient's bodily fluids. Claim 1 of the '652 patent, claim 1 of the '497 patent, and claim 1 of the '607 patent were illustrative:

Claim 1 of the '652 patent recites:

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).

Claim 1 of the '497 patent recites:

1. A method of detecting donor-specific circulating cell-free nucleic acids 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 cell-free nucleic acids from the solid organ transplant; and
(d) determining an amount of donor-specific circulating cell-free nucleic acids from the solid organ transplant in the biological sample by detecting a homozygous or a heterozygous SNP within the donor-specific circulating cell-free nucleic acids 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 cell-free nucleic acids from the solid organ transplant when the donor-specific circulating cell-free nucleic acids make up at least 0.03% of the total circulating cell-free nucleic acids in the biological sample.

Claim 1 of the '607 patent recites:

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.

The Magistrate Judge resolved the issue of whether these claims were ineligible for patenting under 35 U.S.C. § 101 under the first step of the Supreme Court's test enunciated in Mayo and Alice Corp. v. CLS Bank Int'l. Defendants argued (as they must) that the claims in the patents-in-suit were directed to one of the judicial exceptions (a natural phenomenon, specifically "the correlation between transplant rejection and the presence of naturally occurring [cfDNA] in the bodily fluids of transplant recipients"). The Magistrate, relying on Federal Circuit precedent permitting a court to consider the patent specification in determining "what a patent claim is really directed to at step one [of the Mayo/Alice test]" (Enfish LLC v. Microsoft Corp.) found that:

[T]he patents' [related] specification repeatedly and consistently states that this basic "correlation" between the presence of increased levels of donor-specific cfDNA and transplant rejection . . . -- i.e., the thing that, according to Defendants, the asserted claims were purportedly "directed to" -- had already been well-known in the art for quite a long time.

The District Court, while granting parties the opportunity for discovery and expert testimony, ultimately granted Natera's motion for summary judgment that the claims were invalid under Section 101 for lack of subject matter eligibility, and this appeal followed.

The Federal Circuit affirmed, in an opinion by Judge Lourie joined by Judges Bryson and Hughes. The reasoning is depressingly predictable: that the claims fail the first prong of the Alice eligibility test for being directed to a natural phenomenon and fail the second prong of the test by reciting only conventional, well-understood, and routine methods that did not rise to the ineluctable "something more" required for eligibility. In this, patentees fell into the trap that was sprung on unwary applicants ever since Ariosa v Sequenom. As in that case, the particular petard upon which patentees' eligibility hopes were hoisted was disclosure in the specification regarding this conventionality, the opinion setting out in a footnote in detail the extent of what the Court found was an admission:

See, e.g., '652 patent at col. 9 ll. 8–14 (stating that "[d]etection, identification and/or quantitation of the donor-specific markers (e.g.[,] polymorphic markers such as SNPs) can be performed using real-time PCR, chips (e.g., SNP chips), high throughput shotgun sequencing of circulating nucleic acids (e.g.[,] [cfDNA]), as well as other methods known in the art"); id. at col. 10 ll. 11–12 (stating that, to obtain cfDNA samples, "any technique known in the art may be used, e.g. a syringe or other vacuum suction device"); id. at col. 13 ll. 51–53 (stating that step 2 of claimed methods can be performed "using existing genotyping platforms know[n] in the art"); id. at col. 15 ll. 6–8 (stating that techniques recited in step 2 of claimed methods "can be accomplished through classic Sanger sequencing methods which are well known in the art"); id. at col. 13 ll. 58–61 (stating that "[c]ompanies (such as Applied Biosystems, Inc.) currently offer both standard and custom designed TaqMan probe sets for SNP genotyping that can in principle target any desired SNP position for a PCR based assay"); id. at col. 20 ll. 31–34 (stating that genotyping recited in claimed methods "may be performed by any suitable method known in the art including those described herein such as sequencing, nucleic acid array or PCR"); id. at col. 15 ll. 22–65 (discussing commercial high throughput sequencing products); id. at col. 14 ll. 58–67 (citing articles from 2006 and 2007 as supporting the statement that "digital PCR is a much more accurate and reliable method to quantitate nucleic acid species"); id. at col. 18 l. 55–col. 19 l. 2 (stating that "[m]ethods for quantifying nucleic acids," including high throughput genotyping, "are known in the art"); id. at col. 21 ll. 5–9 (stating that "[t]he presence or absence of one or more nucleic acids from the transplant donor in the transplant recipient may be determined by any suitable method known in the art including those described herein such as sequencing, nucleic acid arrays or PCR").

The opinion states summarily that "[t]he claimed methods are indistinguishable from other diagnostic method claims the Supreme Court found ineligible in Mayo and that we found ineligible on multiple occasions." Natera recites and the panel agrees with the familiar litany of cases coming to the same conclusion, i.e., Athena Diagnostics, Inc. v. Mayo Collaborative Servs., LLC, 915 F.3d 743 (Fed. Cir. 2019); Genetic Veterinary Scis., Inc. v. LABOKLIN GmbH & Co. KG, 933 F.3d 1302 (Fed. Cir. 2018); Roche Molecular Sys., Inc. v. Cepheid, 905 F.3d 1363 (Fed. Cir. 2018); Cleveland Clinic Found. v. True Health Diagnostics LLC, 859 F.3d 1352 (Fed. Cir. 2017); Ariosa Diagnostics, Inc. v. Sequenom, Inc., 788 F.3d 1371 (Fed. Cir. 2015). The similarity to the Ariosa decision (which in some ways propelled the Court down this path of per se ineligibility) is express:

Here, as in Ariosa, the claims boil down to collecting a bodily sample, analyzing the cfDNA using conventional techniques, including PCR, identifying naturally occurring DNA from the donor organ, and then using the natural correlation between heightened cfDNA levels and transplant health to identify a potential rejection, none of which was inventive. The claims here are equally as ineligible as those in Ariosa.

To the extent there is anything remotely new in this opinion it is the acknowledgement that conventionality is an element of step one of the Alice eligibility test, citing Athena and Cleveland Clinic decisions for the principle.

With regard to that conventionality, the opinion illuminates the logical error of its treatment of this part of the equation. The opinion asserts that the methods are conventional because "CareDx does not actually claim any improvements in laboratory techniques—rather, as previously discussed, the actual claims of the patent merely recite the conventional use of existing techniques to detect naturally occurring cfDNA. Furthermore, the specification admits that the laboratory techniques disclosed in the claims require only conventional techniques and off-the-shelf technology" and "the asserted claims add nothing inventive because they merely recite standard, well-known techniques in a logical combination to detect natural phenomena." The case also contains a convenient mantra for this rationale: "We have repeatedly held that applying standard techniques in a standard way to observe natural phenomena does not provide an inventive concept," citing Ariosa, Athena, and Roche. According to the Court, a conclusion of ineligibility is justified because the claimed combination of steps adds nothing inventive, analogous to the factual circumstances in Mayo v. Prometheus.

But what the Court has consistently ignored is the difference between the claims in Mayo and the ones in Ariosa and the Court's other diagnostic method cases. And that difference is that the detection methods reciting in the Prometheus claims were conventional because they were actually being performed in the art on the subject matter and for the purpose (assessing the amount of drug in a patient's blood after administration) recited in the claims. The only distinction from these conventional methods in those claims was the recognition that there were boundary levels of detected drug concentrations that indicated whether the dosage should be increased or decreased. In contrast, in all the diagnostic method cases that have fallen under the Court's ineligibility ax since Mayo there had not been any recognition, much less practice, in the prior art of these methods on this subject matter to detect the natural phenomenon that has been used to satisfy step one of the Alice test. The inventiveness resides there, and refusal to recognize that distinction is the principal reason for the Court's continuing invalidity jurisprudence.

In her dissent in Athena, Judge O'Malley noted that:

Since Mayo, every diagnostic claim to come before this court has been held ineligible. While we believe that such claims should be eligible for patent protection, the majority of this court has definitively concluded that the Supreme Court prevents us from so holding. No need to waste resources with additional en banc requests. Your only hope lies with the Supreme Court or Congress. I hope that they recognize the importance of these technologies, the benefits to society, and the market incentives for American business. And, oh yes, that the statute clearly permits the eligibility of such inventions and that no judicially-created exception should have such a vast embrace. It is neither a good idea, nor warranted by the statute.

In view of the Supreme Court's denial of certiorari in American Axle v. Neapco it appears Congress (other than reliance on trade secret protection) remains the only source of any respite from the scourge of ineligibility for diagnostic methods claims.

CareDx, Inc. v. Natera, Inc. (Fed. Cir. 2022)
Panel: Circuit Judges Lourie, Bryson, and Hughes
Opinion by Circuit Judge Lourie