Stanford Asks Supreme Court to Revisit Subject Matter Eligibility on Diagnostic Claims | McDonnell Boehnen Hulbert & Berghoff LLP
“Hope springs eternal [in the human breast]” (Alexander Pope) and “Insanity is doing the same thing over and over and expecting different results” (the latter attributed variably to Albert Einstein and Werner Erhart) are two aphorisms that irresistibly come to mind with the recent filing of a petition for certiorari by patentees in CareDX, Inc. v. Natera, Inc. and CareDx, Inc. v. Eurofins Viracor, Inc.
To recap, the case arose over CareDx’s assertion of 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 was that 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 District Court granted Natera’s motion for summary judgment that the claims were invalid under Section 101 for lack of subject matter eligibility (the petition noting that the District Court characterized the state of Section 101 law as being “fraught, incoherent, unclear, inconsistent, and confusing, and indeterminate and often leading to arbitrary results”), and the Federal Circuit affirmed. The panel found that the claims failed the first prong of the Alice eligibility test for being directed to a natural phenomenon and failed 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. The Federal Circuit relied upon disclosure in the specification that was similar to the disclosure that supported the Court’s affirmance of ineligibility in Ariosa v Sequenom, specifically that the disclosed methods applied to detect cfDNA specific for the transplanted organ were conventional, the panel citing the following disclosure from the ‘652 patent in support of their conclusions:
• 9 ll. 8–14, which stated 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”);
• 10 ll. 11–12, which stated that, to obtain cfDNA samples, “any technique known in the art may be used, e.g. a syringe or other vacuum suction device”);
• 13 ll. 51–53, which stated that step 2 of claimed methods can be performed “using existing genotyping platforms know[n] in the art”);
• 15 ll. 6–8, which stated that techniques recited in step 2 of claimed methods “can be accomplished through classic Sanger sequencing methods which are well known in the art”);
• 13 ll. 58–61, which stated 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”);
• 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”);
• 15 ll. 22–65 (discussing commercial high throughput sequencing products);
• 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”);
• 18 l. 55–col. 19 l. 2 (stating that “[m]ethods for quantifying nucleic acids,” including high throughput genotyping, “are known in the art”); and
• 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”).
(Despite this litany, the petition faults the District Court for relying on a sole statement in the specification that “the methods ’employ[], unless otherwise indicated, conventional techniques'” and disregarding the qualifier “unless otherwise indicated” in assessing the purported conventionality of the disclosed detection methods.) The opinion stated 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,” including 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); and Ariosa Diagnostics, Inc. v. Sequenom, Inc., 788 F.3d 1371 (Fed. Cir. 2015).
The Federal Circuit’s appreciation of the similarity to the Ariosa decision (which in some ways propelled the Court down this path of per se ineligibility) was 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.
Petitioner CareDx and Stanford argue in their certiorari petition that the District Court and the Federal Circuit erred in this conclusion of conventionality to distinguish this case from the earlier precedent, and assert as analytical error in the Federal Circuit’s application of the Supreme Court test under Mayo Collaborative Services v. Prometheus Laboratories, Inc., 566 U.S. 66 (2012), and Alice Corp. Pty. Ltd. v. CLS Bank Int’l, 573 U.S. 208, 217 (2014), consideration of conventionality (and thus Section 103 issues) in the first prong of the Mayo/Alice test.
The focus of Petitioner’s argument is that the invention is an improvement on prior art methods that were ineffective, and that it is this improvement as expressly recited in the statute (“or any new and useful improvement thereof”) that supports eligibility. According to this argument, this improvement distinguishes the invalidated claims from the natural phenomenon that cfDNA from a transplanted organ exist in a recipient’s blood or that such cfDNA could be detected therein. The petition sets forth the history of efforts to detect organ rejection in transplant patients, from “invasive and expensive tissue biopsies from the organ” to detecting increased evidence of cfDNA in patients undergoing organ rejection, including cfDNA specific for Y chromosomes or human leukocyte antigen (HLA) gene fragments, none of which were effective “after ten year of unsuccessful attempts” and all of which were admitted prior art in the common specification of the patents-in-suit.
The petition emphasizes the specific technical solutions of “high-throughput” and “multiplex” sequencing coupled with digital polymerase chain reaction technology using single nucleotide polymorphism detection to identify transplanted organ-specific cfDNA in recipient blood. (These choices, the petition contends, are significant because the technologies were developed after the failed attempts by others and the targets, while not new, were not the targets used in earlier, failed attempts. It should not escape the reader’s attention that these considerations are also ones relevant to non-obviousness.) The petition also notes that patentee disclaimed discovery of the natural phenomenon and preexisting methods for measuring it.
The petition’s asserted reasons for the Court to grant certiorari frankly tell the Court that it “needs to take another Section 101 case” based on the Justices calling for the views of the Solicitor General five times in the past five years (citing Hikma Pharm. v. Vanda Pharm., Inc.; HP Inc. v. Berkheimer; Am. Axle & Mfg., Inc. v. Neapco Holdings LLC; and most recently in Tropp v. Travel Sentry, Inc. and Interactive Wearables, LLC v. Polar Electro Oy) and that the SG has counseled the Court that they should grant cert “in an appropriate Section 101 case.” This, according to the petition, is that case, even more so that Interactive Wearables or Tropp. The reasons petitioner asserts in advocating for the Court to choose this case is that while it raises many of the same issues as in Tropp and Interactive Wearables, in this one “the problems are even worse.” Those cases are abstract-idea cases which, the petition argues “have not been the source of considerable controversy.” Not so application of the natural phenomenon eligibility exception in medical diagnostics claims, where the petition notes both the SG and the Federal Circuit have called for the Court’s intervention (citing Athena Diagnostics, Inc. v. Mayo Collaborative Servs., LLC; Am. Axle & Mfg., Inc. v. Neapco Holdings LLC; Interval Licensing LLC v. AOL, Inc.). In those cases the circuit’s judges have termed the subject matter eligibility question to be “baffling,” leaving them “at a loss as to how to uniformly apply § 101,” that it is “near impossible to know with any certainty whether [an] invention is or is not patent eligible,” and that this situation “ha[s had] a serious effect on the innovation incentive in all fields of technology.” Similar sentiments from district courts and the U.S. Patent and Trademark Office and former Directors of the agency are cited in support of this argument. The objective evidence for this state of affairs is the Federal Circuit’s track record, wherein that Court has invalidated “every single diagnostic method patent it has encountered since Mayo[].” Moreover, the petition notes that the cumulative effect of the Federal Circuit’s jurisprudence on subject matter eligibility for medical diagnostics claims is that these claims are virtually per se ineligible (including citations to Cleveland Clinic Found. v. True Health Diagnostics LLC and Roche Molecular Sys., Inc. v. CEPHEID along with those cases cited earlier in the petition). These decisions have “powerfully undercut[] the incentive to innovate and invest in life-saving medical diagnostics” consequently.
In addition, the petition argues that this case is one where the claimed invention was “on specific improved methods for measuring the relative proportion of the donor’s DNA [that] ensures the absence of any preemption concerns” because “[p]atents that claim specific improvements upon preexisting processes for applying a previously known natural phenomenon cannot monopolize the underlying phenomenon itself, because other methods already exist to apply it and thus remain outside the scope of the patent.” These circumstances, the petition states, provide the Court with an opportunity to “reinvigorate the role of Section 101’s statutory text in a manner consonant with the preemption concerns that animate this Court’s precedents.” The petition notes in support for this argument that the Court has not considered the application of Section 101 to such improvements “upon a preexisting useful process” and that this case provides such an opportunity. The petition cites the Court’s decision in Tilghman v. Proctor, 102 U.S. 707 (1880), as being consistent with these arguments by being “a particular mode of bringing about [a] desired result” (and perhaps being a basis for the Court to be persuaded by them). And petitioners emphasize that claims to such an improvement do not claim either a natural phenomenon nor preexisting methods which are expressly in the prior art.
Finally, the way the District Court and Federal Circuit considered issues of “conventionality” for both the first and second prongs of the Mayo/Alice test (the petition argues) was error needing Supreme Court correction. Concerns over the (im)proper application of conventionality in the Mayo/Alice test was voiced by the Solicitor General in Interactive Wearables with regard to Step 2 but is arguably more erroneous here according to the petition, where the lower courts relied on conventionality in both Step 1 and Step 2 (the Federal Circuit going so far as to state that it had “repeatedly analyzed conventionality at step one,” citing Athena Diagnostics, Inc. v. Mayo Collaborative Servs., LLC and Universal Secure Registry LLC v. Apple Inc. in support of this practice). (This argument has greater force than the corresponding argument regarding Step 2, where considerations of conventionality go hand in hand with the Supreme Court’s instruction for courts to search for an “inventive concept,” although the petition bravely argues that such conflation of Section 103 issues in a Section 101 determination is equally improper.) The petition contends that the Federal Circuit’s practice in this regard “collapses the entire Section 101 inquiry into ‘a search for an inventive concept'” and “effectively conflat[es] Section 101 with the statutory requirements of novelty, 35 U.S.C. 102, nonobviousness, 35 U.S.C. 103, and enablement, 35 U.S.C. 112” (which while a persuasive argument for much of the patent bar may be less so for the Court, which has tended in earlier decisions to consider patent law with much less granularity; see Mayo). And petitioners assert that in doing so the Federal Circuit “circumvented important protections guaranteed by this Court’s obviousness precedents under Section 103,” citing Graham v. John Deere and KSR Int’l Co. v. Teleflex Inc. The petition characterizes the invention at issue here as being closer to an application of a law of nature as sanctioned by the Court’s decision in Diamond v. Diehr than the invention in Mayo and notes that the Court held in Ass’n for Molecular Pathology v. Myriad Genetics, Inc. that “new applications of knowledge about” natural phenomena are patent-eligible.
Finally, the petition asks the Court “at a minimum” to hold the case until the Court has decided the outcome of the Interactive Wearables and Tropp cases.
The arguments in the petition thus thread a very narrow needle in giving the Court a reason to grant certiorari and emphasize (as has been emphasized before) the need to do so. Earlier in the petition the Court’s attention is directed albeit somewhat obliquely to the “heav[y] investment CareDx made in bringing this technology to market” and the frankly infringing behavior of both Natera and Eurofin in bringing their own “copycat” products to market. Those hoping for a certiorari grant (and positive outcome) have reason for such hopes if the Court is listening to these circumstances and the importance and negative consequences to innovation in the medical diagnostic arts that the lower courts’ interpretations of their subject matter eligibility jurisprudence has produced over the past decade.
