May 28, 2020
In Illumina v. Ariosa, 2019-1419 (Fed. Cir. March 17, 2020) (“Illumina”), the Federal Circuit held “method of preparing” life science claims patent-eligible under § 101, concluding that the claims were distinct from diagnostic claims and not “directed to” a natural phenomenon. The 2-1 panel majority reversed a Northern District of California ruling that the claims of the two related patents-at-issue were patent-ineligible. The decision may have significant doctrinal impacts.
The Patents At-Issue
The patents at issue, US Patent Nos. 9,580,751 and 9,738,931, relate to the isolation of cell-free fetal DNA in a maternal bloodstream. Fetal DNA is a natural phenomenon. It comprises less than 10% of the cell-free DNA in the maternal bloodstream versus the greater than 90% concentration of cell-free DNA derived from the mother. The inventors discovered that fetal DNA is relatively small in size (about 500 base pairs or less) compared to the majority of maternal DNA (generally greater than 500 base pairs). The patented methods exploit this discovery by using known size-discrimination techniques to separate the cell-free DNA fragments smaller than 500 base pairs (smaller than 300 base pairs in the ’931 Patent) from the vast bulk of maternal DNA to enrich for fetal DNA sequences.
The Alice/Mayo § 101 Eligibility Test
In Alice Corporation Pty. Ltd. v. CLS Bank Int’l, 134 S. Ct. 2347 (2014) (Alice), the Supreme Court applied the framework set forth in Mayo Collaborative Services v. Prometheus Laboratories, Inc., 566 U.S. 66 (2012) (Mayo), to analyze all claims directed to laws of nature, natural phenomena, and abstract ideas for subject matter eligibility under 35 U.S.C. § 101. Step one of the Alice/Mayo test requires determining whether a claim is directed to a judicial exception. Alice, 573 U.S. at 217 (2014). If – and only if – a judicial exception is present in the claim, step two of the inquiry examines whether the limitations of the claim apart from the law of nature or natural phenomenon, considered individually and as an ordered combination, “‘transform the nature of the claim’ into a patent-eligible application.” Id. (quoting Mayo, 566 U.S. at 78).
Majority Opinion and Analysis
Judge Lourie, writing for the Illumina majority, immediately distinguished the “method of preparation” claims in this case from both diagnostic claims, judged to be ineligible post Alice/Mayo, and patent-eligible method of treatment claims. He acknowledged the inventors’ discovery of a natural phenomenon, but focused the Alice/Mayo step one analysis on whether the claims recite eligible subject matter that “exploits the discovery of the natural phenomenon.”
For this analysis, the majority first addressed differences between the district court and the parties about how to articulate the natural phenomenon that the inventors discovered. Roche, Ariosa’s co-defendant, appeared to characterize the natural phenomenon as the “size distribution” of fetal vs. maternal cell-free DNA in a mother’s blood reflected in Table 1 of the specification, with a particular focus on the number “500 base pairs” as the critical dividing line between the two. By contrast, Illumina described the natural phenomenon as the discovery that cell-free fetal DNA tends to be shorter than cell-free maternal DNA in a mother’s bloodstream.
The majority concluded that the parties’ respective articulations reflected distinctions without differences. But rather than adopting the district court’s apparent articulation of the relevant natural phenomenon as either the “testable quantity” of fetal DNA or “test results” obtained from that fetal DNA, which suggests a phenomenon most amenable to ineligible diagnostic claims, the majority adopted Illumina’s more straight-forward articulation, i.e., that cell-free fetal DNA tends to be shorter than cell-free maternal DNA in a mother’s bloodstream.
The majority then analyzed the specific process steps of the claims, i.e., size discrimination and selectively removing DNA fragments that are above a specified size threshold to increase the relative amount of fetal DNA as compared to maternal DNA in the sample, and concluded that these steps were evidence that the claims were not directed to the discovered natural phenomenon. Particularly, the majority decided that the process steps “change the composition of the [cell-free DNA] mixture” because they result in a DNA fraction that is different from the naturally occurring fraction in the mother’s bloodstream. Thus, the majority reasoned that the process achieves more than simply observing that fetal DNA is shorter than maternal DNA or detecting the presence of that phenomenon.
The majority also concluded that the dependent claims further illustrate the “concrete nature” of the claimed process steps. Particularly, the majority cited the dependent claims as further defining the physical means by which size discrimination (e.g., centrifugation) and selective removal (e.g., chromatography, electrophoresis, nanotechnology, etc.) can be achieved to exploit, and not merely observe, the natural phenomenon.
Co-defendant Roche argued that the present claims were no more eligible under Alice/Mayo step one than Ariosa’s earlier method of detecting a paternally inherited nucleic acid and performing a prenatal diagnosis. In Ariosa v. Sequenom,788 F.3d 1371, 1373 (Fed. Cir. 2015), the Court found a patent which claimed a method for detecting cell-free fetal DNA in maternal blood ineligible under § 101 as being directed to matter that is naturally occurring. In that earlier case, the operative steps were amplifying (i.e., making more of) the fetal DNA, then detecting it by subjecting it to a test, i.e., performing a nucleic acid analysis on the amplified substance. Roche also analogized the present case to the Supreme Court’s decision in Association for Molecular Pathology v. Myriad Genetics, Inc., 569 U.S. 576, 580 (2013). In Myriad, the Supreme Court held that a naturally occurring DNA sequence is a product of nature and not patent-eligible merely because it has been isolated. Further, the claimed techniques for synchronization and selective removal of the DNA sequence were found to be well-known and conventional.
However, the majority found Rapid Litig. Mgmt. Ltd. v. CellzDirect, Inc., 827 F.3d 1042 (Fed. Cir. 2016), while not directly on point, to be instructive. In CellzDirect, the identified natural phenomenon was that some fraction of hepatocytes is capable of surviving multiple freeze-thaw cycles. But the claims were held to be patent-eligible as being directed to an improved freeze-thaw process of preserving hepatocytes (comprising the operative steps of freezing hepatocytes, thawing the hepatocytes, removing the non-viable hepatocytes, and refreezing the viable hepatocytes) rather than to the natural phenomenon itself.
Further, the majority noted that the well-known or conventional nature of the claimed solutions does not impact the step one question of whether the claims are directed to a natural phenomenon. Particularly, the freeze-thaw solution in CellzDirect was also well known, but such considerations are only relevant in the context of Alice/Mayo step two.
In dissent, Judge Reyna criticized the majority for sidestepping the court’s well-established diagnostic case precedent by categorizing the claims in a unique “method of preparation” bucket that is to be treated differently from other process claims. Instead, he focused on the “claimed advance” in the patent specification, which describes the natural phenomenon of fetal DNA’s relatively small size in comparison to maternal DNA as “surprising”, and placed such an observation of a natural phenomenon in the context of the court’s diagnostic case precedent. According to that precedent, if the specification describes the natural phenomenon as the only “surprising” or “unexpected” aspect of the invention, or if the invention is based on discovery of a natural law, the natural phenomenon likely constitutes the claimed advance. See Ariosa, 788 F.3d at 1376; Athena Diagnostics, Inc. v. Mayo Collaborative Services, LLC, 915 F.3d 743, 751 (Fed. Cir. 2019); Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1360–61 (Fed. Cir. 2017). Here, Judge Reyna concluded that the only “surprising finding” is that fetal DNA tends to be shorter than maternal DNA in a mother’s blood stream. Thus, he argued that this natural phenomenon forms the basis of the invention.
Judge Reyna also disagreed with the majority on the nature of the cell-free DNA mixture resulting from the claimed process, arguing that claims beginning and ending with a naturally occurring substance also suggests ineligibility. He asserted that the claimed advance was not, for example, an improvement in the underlying DNA-processing technology. Rather, according to the dissent, the claimed advance applies a well-known technique to a newly discovered natural phenomenon, and merely changes the composition of naturally occurring substances without altering the substances themselves, i.e., the enriched mixture is not a different composition because it still contains all of the elements of the original mixture.
This panel majority holding is significant for distinguishing method-of-preparation life science claims from diagnostic claims. The Illumina claims present a fascinating and clarifying variation on those considered in the relevant Supreme Court and Federal Circuit precedents. But the facts and reasoning found in those precedents leave openings that at least permit, if not explicitly support, the majority holding in Illumina.
In Mayo, the claims covered a method for determining whether a patient should receive more or less of a particular drug. However, that method merely involved observing how much of a certain substance (a metabolite) was present in a patient after a given quantity of a certain drug was administered, and then drawing a conclusion regarding whether a higher or lower dose should be administered. The claims in Mayo stopped short of doing anything further with that conclusion (and therefore left room for the diagnostic versus treatment distinction made in later Federal Circuit cases). In Illumina, however, the claims go beyond merely identifying the presence of certain substances (fragments of length less than 500 base pairs). Rather, the Illumina claims take action and remove fragments of length greater than 500 base pairs so that a DNA fraction including primarily shorter fragments can be prepared that includes an enhanced percentage of cell-free fetal DNA.
In Myriad, some of the claims covered isolated DNA sequences and other claims covered cDNA sequences, i.e., DNA sequences including exons (coding portions of a sequence) that had been spliced together after intervening introns (non-coding portions of sequences) had been removed. Myriad held the isolated DNA sequence claims ineligible but the cDNA claims eligible. However, as the Illumina majority pointed out, Myriad’s holding was not on point because the Myriad claims covered the end DNA product itself rather than the process of isolating it. Thus, debating whether the enriched DNA fraction resulting from the Illumina method is more like the isolated DNA or the spliced together cDNA of Myriad is beside the point. In fact, as the Illumina majority points out, Myriad explicitly left open the possibility of a different result in the context of claims directed to an innovative method of isolating DNA. See Illumina slip opinion at 12 (quoting Myriad (“It is important to note what is not implicated by this decision. First, there are not method claims before this Court.”)).
The Federal Circuit’s 2015 holding in Ariosa, discussed above, also addressed a method related to use of fetal DNA and provides a particularly challenging precedent for the Illumina majority to have distinguished. However, the Ariosa claims covered a use of a natural phenomenon that was arguably more observational than active. Specifically, the Ariosa claims simply covered using knowledge that the natural phenomenon exists (i.e., that cell-free DNA in maternal blood contains some portion of fetal DNA) to draw new conclusions from routine testing of maternal blood. The claims recited detecting a paternally inherited nucleic acid in maternal plasma. But in essence, such detection is simply based on the knowledge that fetal DNA exists in the maternal sample and, therefore, some paternally inherited nucleic acids would necessarily be present.
In contrast, the method claimed in Illumina goes beyond simply observing that fragments shorter than 500 base pairs exist in a maternal sample and that those fragments are more likely than others to be fetal DNA. Rather, the Illumina claims use that knowledge to then take additional active steps to prepare a sample for analysis that has a higher percentage of fetal DNA by removing longer fragments from the sample. To put it in terms of the USPTO’s 2019 subject matter eligibility guidance, the Illumina claims “integrate” the natural phenomenon into the practical application of preparing enriched samples. Those samples are presumably easier to analyze because they have a higher percentage of fetal DNA than does the original sample.
The Illumina majority followed the reasoning of CellzDirect and characterized that case as “instructive.” Illumina slip opinion at 12. However, in also qualifying CellzDirect as “not directly on point,” the Illumina majority arguably understated its relevance. Id. In CellzDirect, the Federal Circuit “found that the[ ] claimed invention was patent-eligible because it was ‘not simply an observation or detection of the ability of hepatocytes to survive multiple freeze-thaw cycles. Rather, the claims are directed to a new and useful method of preserving hepatocyte cells.’” Illumina slip opinion at 12-13 (quoting CellzDirect, 827 F.3d at 1048). In other words, the CellzDirect inventors did not simply claim a newly discovered physical characteristic of something; rather, they claimed putting that physical characteristic to use in obtaining a desirable cell mixture with a higher concentration of viable frozen hepatocytes. Similarly, the Illumina inventors did not simply claim a newly discovered characteristic of fetal DNA fragments in maternal plasma or serum; rather, they claimed putting that characteristic to use in obtaining enriched samples having a higher proportion of fetal DNA.
The patentee’s framing of the discovered natural phenomenon and the specific steps used to exploit its discovery appear to be key to the majority’s distinction. In that light, Illumina suggests that, to support a case for subject matter eligibility under § 101, a patent specification should not only articulate the natural phenomenon discovered by the inventors, but should also carefully explain and claim how to exploit that natural phenomenon in a practical application. Such a practical application can include a new process for preparing a purified or refined sample of individual substances even if the individual substances themselves are otherwise naturally occurring.
Author: Andrew Noble