Illumina, Inc. v. Ariosa Diagnostics, Inc. (Fed. Cir. 2020)

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The latest Federal Circuit decision on subject matter eligibility in the life sciences came down (by a divided court) in favor of eligibility, in Illumina, Inc. v. Ariosa Diagnostics, Inc.  The claims at issue fell into the third "bucket" of eligibility, being neither diagnostic method claims (always ineligible at the Federal Circuit) nor method of treatment claims (eligible, at least until the Supreme Court grants certiorari in the next iteration of Vanda Pharmaceuticals Inc. v. West-Ward Pharmaceuticals), but rather (as denoted in the majority opinion), method of preparation claims, a philosophical cousin to the claims in Rapid Litig. Mgmt. Ltd. v. CellzDirect, Inc And as an added bonus, Judge Reyna dissented in a manner that illustrates his thinking on patent eligibility of inventions involving natural phenomena (and natural products).

The case arose over U.S. Patent No. 9,580,751 (the '751 patent) and U.S. Patent No. 9,738,931 (the '931 patent), directed to the solution of an unexpected difficulty in detecting cell-free fetal DNA (cffDNA):

[T]he major proportion (generally >90%) of the extracellular DNA in the maternal circulation is derived from the mother.  This vast bulk of maternal circulatory extracellular DNA renders it difficult, if not impossible, to determine fetal genetic alternations [sic] . . . from the small amount of circulatory extracellular fetal DNA.

The inventors found that cffDNA was significantly smaller (300-500 bp) than the "interfering" maternal DNA, and thus using admittedly conventional techniques of size separation the cffDNA could be isolated and rendered detectable.

Illumina and Sequenom asserted claims 1, 2, 4, 5, 9, and 10 of the '751 patent and claims 1, 2, and 10–14 the '931 patent against Ariosa and Roche Diagnostics; the Court considered claim 1 from each patent to be representative:

'751 patent:

1.  A method for preparing a deoxyribonucleic acid (DNA) fraction from a pregnant human female useful for analyzing a genetic locus involved in a fetal chromosomal aberration, comprising:
    (a) extracting DNA from a substantially cell-free sample of blood plasma or blood serum of a pregnant human female to obtain extracellular circulatory fetal and maternal DNA fragments;
    (b) producing a fraction of the DNA extracted in (a) by:
        (i) size discrimination of
        (ii) selectively removing the DNA fragments greater than approximately 500 base pairs,
        wherein the DNA fraction after (b) comprises a plurality of genetic loci of the extracellular circulatory fetal and maternal DNA; and
    (c) analyzing a genetic locus in the fraction of DNA produced in (b).

'931 patent:

1.  A method, comprising:
    (a) extracting DNA comprising maternal and fetal DNA fragments from a substantially cell-free sample of blood plasma or blood serum of a pregnant human female;
    (b) producing a fraction of the DNA extracted in (a) by:
        (i) size discrimination of extracellular circulatory fetal and maternal DNA fragments, and
        (ii) selectively removing the DNA fragments greater than approximately 300 base pairs,
    wherein the DNA fraction after (b) comprises extracellular circulatory fetal and maternal DNA fragments of approximately 300 base pairs and less and a plurality of genetic loci of the extracellular circulatory fetal and maternal DNA fragments; and
    (c) analyzing DNA fragments in the fraction of DNA produced in (b).

The District Court on summary judgment held these claims and all asserted claims to be ineligible under 35 U.S.C. § 101 and the Supreme Court's Alice/Mayo test (see "Illumina, Inc. v. Ariosa Diagnostics, Inc. (N.D. Cal. 2018)"), and this appeal followed.

The Federal Circuit reversed, in an opinion by Judge Lourie joined by Judge Moore; Judge Reyna (the author of the Court's Ariosa Diagnostics Inc. v. Sequenom, Inc. decision) dissented.  Judge Lourie got right to the point, stating "[t]his is not a diagnostic case.  And it is not a method of treatment case.  It is a method of preparation case."  The opinion acknowledged the consistent precedent post-Mayo that diagnostic method claims are ineligible, and method of treatment claims are eligible, citing Judge Moore's dissent from denial of rehearing en banc in Athena Diagnostics, Inc. v. Mayo Collaborative Servs., LLC ("Since Mayo, we have held every single diagnostic claim in every case before us ineligible."); the panel decision in Athena Diagnostics, Inc. v. Mayo Collaborative Servs., LLC; Cleveland Clinic Found. v. True Health Diagnostics LLC, 859 F.3d 1352 (Fed. Cir. 2017); and Cleveland Clinic Found. v. True Health Diagnostics LLC.  The panel majority also recognized that the Court had consistently held method of treatment claims to be patent-eligible, citing Endo Pharm. Inc. v. Teva Pharm. USA, Inc.; Natural Alternatives Int'l, Inc. v. Creative Compounds, LLC; and, of course, Vanda Pharm. Inc.

The majority appreciated a distinction lost on the dissent:  "[h]ere, it is undisputed that the inventors of the '751 and '931 patents discovered a natural phenomenon.  But at step one of the Alice/Mayo test, 'it is not enough to merely identify a patent-ineligible concept underlying the claim; we must determine whether that patent-ineligible concept is what the claim is 'directed to," citing Rapid Litig. Mgmt. Ltd. v. CellzDirect, Inc.

The majority understood the natural phenomenon underlying the claimed invention to be "that cell-free fetal DNA tends to be shorter than cell-free maternal DNA in a mother's bloodstream" despite some apparent inconsistencies in how at least Roche enunciated its interpretation.  The critical question as understood by the majority was "whether the claims are 'directed to' that natural phenomenon."  The majority held that the claims were not directed to the natural phenomenon but rather were directed to "a patent-eligible method that utilizes it."  In support of this conclusion, Judge Lourie wrote regarding the specificities of the claims (albeit not the five specificities he identified in his Vanda opinion).  These include "specific process steps—size discriminating and selectively removing DNA fragments that are above a specified size threshold" that increased the relative amount of cffDNA in the processed sample compared to maternal DNA.  The claimed method "change[d] the composition of the mixture" and produced a DNA-containing fraction that was different from what naturally occurs in maternal blood.  This was what distinguished, for the majority, what was claimed from merely "observing that fetal DNA is shorter than maternal DNA or detecting the presence of that phenomenon."

The written description of the invention (upon which the dissent extensively relied to draw the opposite conclusion) supported this view, according to the opinion:

As described by the specification, the inventors used these concrete process steps, not merely to observe the presence of the phenomenon that fetal DNA is shorter than maternal DNA, but rather to exploit that discovery in a method for preparation of a mixture enriched in fetal DNA.

The panel majority distinguished the decision in Ariosa, where the claims were directed to a method "for detecting a paternally inherited nucleic acid" (claims 1 and 24) or a method "for performing a prenatal diagnosis" (claim 25).  The only steps recited in those claims were related to making more of the cffDNA by amplification, followed by a detecting or sequencing step.  As in Mayo, Athena, and Cleveland Clinic, the Sequenom claims were directed to detecting a natural phenomenon:  the Sequenom inventors "discovered that cell-free fetal DNA exists, and then obtained patent claims that covered only the knowledge that it exists and a method to see that it exists.  Those claims were thus ineligible."  In contrast, the claims at issue here were not directed to the correlation between cffDNA size and its "tendency" to be maternal or fetal in origin.  The claims at issue here is produced a fraction enriched in fetal DNA, which distinguished them from the invalid claims in Ariosa for the panel majority.

And regarding the effect the Supreme Court's AMP v. Myriad Genetics decision has on these claims, the majority states:

Thus, in Myriad, the claims were ineligible because they covered a gene rather than a process for isolating it.  Here, we encounter the opposite situation, i.e., the claims do not cover cell-free fetal DNA itself but rather a process for selective removal of non-fetal DNA to enrich a mixture in fetal DNA.  Thus, the Supreme Court's decision in Myriad is not on point.

With regard to the Cellzdirect precedent, the panel majority analogized by noting that those inventors did not "invent" hepatocytes, but rather invented a method for making preparations of them that relied on the hepatocytes natural ability to be subjected to multiple rounds of freezing and thawing unappreciated in the prior art.  For the majority, the '751 and '931 patents similarly do not claim (and the inventors do not assert they had invented) cffDNA or even the differential size distribution between maternal and fetal DNA in maternal blood.  The panel majority recognized that the inventors here relied on this natural phenomenon to invent a method of separating cffDNA into an enriched fraction by "physical process steps" that "selectively remove some maternal DNA in blood to produce a mixture enriched in fetal DNA."

The majority summarized its opinion as follows:

The inventors here patented methods of preparing a DNA fraction.  The claimed methods utilize the natural phenomenon that the inventors discovered by employing physical process steps to selectively remove larger fragments of cell-free DNA and thus enrich a mixture in cell-free fetal DNA.

Judge Reyna dissented, his dissent nicely setting forth the philosophical differences between the members of this Court (as well as the Supreme Court) for whom the eligibility/ineligibility dichotomy is categorical:  once a "natural phenomenon" is identified, the invention cannot be patented (despite Judge Reyna's protestations at the end of his dissent that "process claims that involve naturally occurring phenomena from beginning to end could be directed to patent eligible subject matter, but this is not such a case" -- there will never be such a case).

The dissent recites the conventional view that applying routine, well-understood, and conventional methods to a newly discovered natural phenomenon is enough, per se, to preclude patent eligibility.  What Judge Reyna continues to refuse to acknowledge (and he is not alone in this particular brand of short-sightedness) is that there is nothing routine, well understood, and conventional (and cannot be) in using old techniques in new ways.  Indeed, there would be very little patenting if the use of older technology could not be a part of innovation; after all, the goal of building a better mousetrap would be considerably more difficult if the existence of a mousetrap itself preluded patenting a better one.

Judge Reyna states that "the claims are directed to a natural phenomenon [because the] patents' only claimed advance is the discovery of that natural phenomenon," which for him categorically precludes patent eligibility.  Ignoring the fact that the claimed methods permit cffDNA to be detected, in his view "[t]he inventors discovered a natural phenomenon: that cffDNA tends to be shorter than cell-free maternal DNA in a mother's blood.  Other than the surprising discovery, nothing else in the specification or the record before us indicates there was anything new or useful about the claimed invention."  And he disregards the distinction drawn by the majority between "method of preparation" claims and method of treatment or diagnostic claims, stating that "[a] 'method of preparation case' is treated no differently than any other process claim under our law," not considering the differential treatment (even by Justice Breyer in Mayo) between cases like Parker v Flook and Diamond v Diehr.

Regarding the significance of the written description to the question of whether the claims are "directed to" a natural phenomenon, the dissent appears to assert that if the invention identifies or recites a natural phenomenon, it is per se directed to the natural phenomenon, wherein the written description supports ineligibility merely by identifying the natural phenomenon (and seemingly equating an invention "based on" a natural phenomenon with one that is directed to it):

If a written description highlights the discovery of a natural phenomenon—e.g., by describing the natural phenomenon as the only "surprising" or "unexpected" aspect of the invention or that the invention is "based on the discovery" of a natural law—the natural phenomenon likely constitutes the claimed advance" [citing Ariosa, Athena, and Cleveland Clinic].

(Somewhat annoyingly, the dissent consistently brackets the term "surprising" with quotation marks; a jurist doesn't need to agree that "surprisingness" is enough to confer patent eligibility, but there is nothing in the record to refute that the results were surprising to one of ordinary skill in the art, the only actor whose "surprise" at the discovery is legally relevant).

Touching sub silentio on how the Court has interpreted claims involving natural products after Myriad, the dissent further states that ineligibility is supported by "[t]he fact that the claimed method steps begin and end with a naturally occurring substance, as in Ariosa" and that "[t]he inventors did not create or alter any of the genetic information encoded in the cff-DNA in the claimed method steps," which seems on its face to be contrary to the Supreme Court's Diamond v Chakrabarty decision.  Nevertheless, Judge Reyna states:

Likewise, the claimed method here begins and ends with a naturally occurring substance.  The claimed method begins with extracting a sample of blood plasma or serum from a pregnant mother that consists wholly of various naturally occurring substances, including cff-DNA.  The claimed method separates those naturally occurring substances by size, leaving a "fraction" of the original sample that is predominantly cff-DNA.  The claimed method ends with analyzing the components of the "fraction," which contains cff-DNA.  The substances present throughout the process are naturally occurring substances, and the claimed method steps do not alter those substances [except, of course, by enriching them in the resulting fraction].  The claimed method is therefore directed to a natural phenomenon.

The dissent is also focused on whether the claims constitute an "advance" in the art (ignoring the "advance" that the invention permits cffDNA to be analyzed):

Where a written description identifies a technology as well-known or performed using commercially available tools or kits, that technology cannot logically constitute a claimed advance" [citing Ariosa, Athena  (identifying the claimed "immunological assay techniques [as] known per se in the art" and therefore not the claimed advance); and Cleveland Clinic (relying on the patent's disclosure of "commercially available testing kits" for detecting the natural law)].

There is an apparent difference between how the majority and the dissent consider the Court's CellzDirect precedent.  Judge Reyna appreciates as a distinction that, in Cellzdirect, "the inventors created a new and useful cryopreservation technique comprising multiple freeze-thaw cycles" that went beyond applying a known laboratory technique to a newly discovered natural phenomenon and, instead, created an entirely new laboratory technique."  The claim in the Cellzdirect case does not support this interpretation:

1.  A method of producing a desired preparation of multi-cryopreserved hepatocytes, said hepatocytes being capable of being frozen and thawed at least two times, and in which greater than 70% of the hepatocytes of said preparation are viable after the final thaw, said method comprising:
    (A) subjecting hepatocytes that have been frozen and thawed to density gradient fractionation to separate viable hepatocytes from non- viable hepatocytes,
    (B) recovering the separated viable hepatocytes, and
    (C) cryopreserving the recovered viable hepatocytes to thereby form said desired preparation of hepatocytes without requiring a density gradient step after thawing the hepatocytes for the second time, wherein the hepatocytes are not plated between the first and second cryopreservations, and wherein greater than 70% of the hepatocytes of said preparation are viable after the final thaw.

The only difference between conventional method of cryopreservation and the claimed invention was that the claims direct that conventional methods be performed twice.  It is ironic that this repetition is sufficient to distinguish the claims here under these circumstances.

The biggest risk of the philosophy enunciated in this dissent is this:

The Majority's reasoning is shortsighted.  A process that merely changes the composition of a sample of naturally occurring substances, without altering the naturally occurring substances themselves, is not patent eligible" [citing Genetic Techs. and Ariosa, both of which involved claims reciting PCR amplification of specific DNA sequences].

If this was ever to be the law it would preclude on patent eligibility grounds claims to any natural product that differed solely by its isolation and concentration, again seemingly contrary to Supreme Court precedent.

Illumina, Inc. v. Ariosa Diagnostics, Inc. (Fed. Cir. 2020)
Panel: Circuit Judges Lourie, Moore, and Reyna
Opinion by Circuit Judge Lourie; dissenting opinion by Circuit Judge Reyna

DISCLAIMER: Because of the generality of this update, the information provided herein may not be applicable in all situations and should not be acted upon without specific legal advice based on particular situations.

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