February 22, 2023
CareDx is the exclusive licensee of U.S. Patents 8,703,652, 9,845,497, and 10,329,607 entitled “Non-Invasive Diagnosis of Graft Rejection in Organ Transplant Patients” owned by Stanford. The patents describe 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. The increased levels of donor cfDNA, which occur naturally as the organ’s condition deteriorates, can be detected and used to diagnose the likelihood of an organ transplant rejection. Claim 1 of the ’652 patent reads (simplified):
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 to establish a polymorphism profile for detecting donor [cfDNA];
(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).
Claim 1 of the ’497 patent is similar, except that it recites high-throughput sequencing or digital PCR instead of multiplex sequencing for “determining” the amount of donor cfDNA. Claim 1 of the ’607 patent is also similar, except that it recites selective amplification of the cfDNA by PCR before high-throughput sequencing.
A two-step analysis under Alice/Mayo is used to determine whether a patent claim is directed to patent eligible subject matter. In Step 1, the question is whether the claims are directed to a law of nature, natural phenomenon, or/and abstract idea. If yes, in Step 2 the question is whether the claim elements individually and as a whole contain additional elements that amount to significantly more than the judicial exception (i.e., transform the claim into patent-eligible subject matter). Simply appending well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception do not make the claims patent eligible.
Here, the methods in the representative claims essentially 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 sued Natera, Inc. (“Natera”) and Eurofins Viracor, Inc. (“Eurofins”), alleging that their transplant rejection tests infringed the patents at issue. Natera and Eurofins moved to dismiss the complaints for failure to state a claim due to lack of patent-eligible subject matter under § 101. The motions to dismiss were referred to a magistrate judge, who recommended that they be denied. The magistrate judge held that the claims were a “purportedly new, unconventional combination of steps” to detect natural phenomena.
The district court vacated the magistrate judge’s recommendation. The court noted that language in the specification of the asserted patents suggested that the patented steps were not new or unconventional and that the “specifications raise[d] doubts about the patents’ validity.” However, the court was cautious about ruling prematurely, and denied the motion to dismiss so that the parties could conduct limited discovery and develop the record on conventionality. After the discovery, Natera and Eurofins moved for summary judgment of ineligibility and the district court granted the motions. The court determined that the asserted claims were directed to natural phenomena, i.e., the presence of donor cfDNA in a transplant recipient and the correlation between donor cfDNA and transplant rejection, and concluded that the claims recited only conventional techniques. CareDx appealed.
On Appeal at the U.S. Court of Appeals for the Federal Circuit (“the Court”) CareDx argued that, regarding Alice/Mayo step one, the patents’ claimed advance was not the discovery of a natural correlation between organ rejection and the donor’s cfDNA levels in the recipient’s blood, but rather improved measurement methods in the claims as superior to the inadequate prior art measurement techniques. CareDx argued that the district court did not properly perform the step one analysis because it concluded that step one was essentially the same as step two and centered on “conventionality”. It asserted that there was no basis in the law for a one-step application of Alice/Mayo. Regarding Alice/Mayo step two, CareDx argued that using digital PCR and next-generation sequencing (“NGS”) to identify and measure donor-specific SNPs was an inventive breakthrough and that the patents claim this specific and useful application.
Natera responded that CareDx’s asserted claims were directed to detecting natural phenomena, the presence of an organ donor’s cfDNA in the blood of a transplant recipient and the correlation between elevated levels of that cfDNA and organ transplant rejection. The claims recited performing this detection using collection and measurement techniques that the specification admitted were conventional and could be used without modifications. According to Natera, the claims were indistinguishable from other diagnostic method claims that the Supreme Court found ineligible in Mayo and the Court found ineligible on multiple occasions. Natera added that the district court properly applied Alice step one and relied on the express use of the word “detecting” to conclude that the claims were directed to a natural phenomenon and that the court properly recognized that Alice step one could overlap with step two. The Court agreed with Natera and Eurofins.
The Court noted that this was not a case involving a method of preparation or a new measurement technique, referring to Illumina, Inc. v. Ariosa Diagnostics, Inc., 952 F.3d 1367, opinion modified by 967 F.3d 1319, 1327 (Fed. Cir. 2020). CareDx did not invent or discover the relationship between donor cfDNA and the likelihood of organ transplant rejection. The patents’ specification also expressly stated that the techniques referred to in the claims were conventional and were well within the skill of art. The Court pointed out that CareDx’s patents applied conventional measurement techniques to detect a natural phenomenon and the claimed methods were indistinguishable from other diagnostic method claims.
The Court pointed to Ariosa that involved claims reciting methods for making a diagnosis of certain fetal characteristics based on detecting paternally inherited cell-free fetal DNA (“cffDNA”) in the blood of a pregnant female. 788 F.3d at 1376. The Court explained that here the claims at issue, as in Ariosa, “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.”
The Court then explained that CareDx incorrectly characterized “our precedent as limiting the conventionality inquiry to step two. On the contrary, and as the district court recognized, we have repeatedly analyzed conventionality at step one as well” (the Court referred to Athena, 915 F.3d 743, 751 (Fed. Cir. 2019) and Cleveland Clinic, 859 F.3d 1352, 1361 (Fed. Cir. 2017)). “Indeed, we have explained that ‘the two stages are plainly related: not only do many of our opinions make clear that the two stages involve overlapping scrutiny of the content of the claims, but . . . there can be close questions about when the inquiry should proceed from the first stage to the second. Elec. Power Grp., LLC v. Alstom S.A., 830 F.3d 1350, 1353 (Fed. Cir. 2016) (citations omitted).” The Court concluded that “our precedent rejects CareDx’s effort to draw a bright line between the two steps.”
Concerning CareDx’s arguments that the “claimed advance” was an improved method for measuring increases in donor cfDNA in a recipient’s body to identify organ rejection and that the patents’ claims were directed not to natural phenomena, but to improved laboratory techniques (the use of digital PCR, NGS, and selective amplification to more accurately measure donor SNPs of cfDNA in transplant recipients), the Court explained that CareDx did not “actually claim any improvements in laboratory techniques—rather … 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.” The Court affirmed that the ’652, ’497, and ’607 patents’ asserted claims were directed to natural phenomena under Alice/Mayo step one.
Regarding Alice/Mayo step two, the Court also agreed that the asserted claims added nothing inventive because they merely recite “standard, well-known techniques in a logical combination to detect natural phenomena.” The Court agreed that the district court had thoroughly considered whether any of the claims’ additional elements were unconventional and, based on the specification’s admissions, properly found that they were not. The Court noted again that the specification admitted that each step in the purported invention required only conventional techniques and commercially available technology. “We have repeatedly held that applying standard techniques in a standard way to observe natural phenomena does not provide an inventive concept.” The Court explained that “[a]s in each of these cases [referring to Ariosa, Athena, Roche], CareDx’s asserted claims add nothing inventive at step two because they recite detection methods that ‘simply append conventional steps, specified at a high level of generality’ to natural phenomena.” “Each of the methods in the recited steps was already being performed by those in the art. Furthermore, the claimed combination of steps adds nothing inventive.” “The practice of the asserted method claims does not result in an inventive concept that transforms the natural phenomena into a patentable invention” and affirmed the district court’s holding with regard to Alice/Mayo step two.
The Court held that because the claims in the ’652, ’497, and ’607 patents were directed to a natural law together with conventional steps to detect or quantify the manifestation of that law, they were ineligible under § 101.
The proper claim drafting is essential in the diagnostic field. To be patent-eligible, the claims must be significantly more than an instruction to apply judicial exception using some unspecified/generic/well-known techniques. Conventional technologies can be used in unconventional ways to make the claimed invention patent eligible. Also, specific elements may make claims patent eligible. The invention with a high level of specificity, specific steps/components may lead to patent eligibility of the claim. The claim’s specificity/technical character should be connected to its advance over the prior art.
CareDx, Inc. v. Natera, Inc., 40 F.4th 1371 (Fed. Cir. 2022).