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Illuminating Section 101: The Federal Circuit Upholds Diagnostic-Related Patent In Illumina, Inc. v. Ariosa Diagnostics, Inc.

Overview

On March 17, 2020, the Federal Circuit reversed the district court’s finding that two patents relating to diagnostic methods involving cell-free fetal DNA were invalid for lacking subject matter eligibility under 35 U.S.C. § 101. The court reached its decision entirely on analyzing step one of the two-part Alice/Mayo test, finding that “the claims are not directed to a patent-ineligible concept” and consequently did not need to reach the second step of the test. This decision adds clarity to the metes and bounds of patent eligibility jurisprudence because it suggests that a claimed method relating to a natural phenomenon may be patent eligible so long as concrete processing steps that go beyond merely observing the natural phenomenon are recited in the claim. Also, while the decision does not go as far as requiring a physical transformation or the production of non-naturally occurring material as a result of such processing steps, it may be instructive to consider whether a material not existing in nature results from performing the steps of the claim.

The Patented Technology

Sequenom obtained a diagnostic patent in 2001 (US 6,258,540) based on its discovery that cell-free fetal DNA is present in the bloodstream of pregnant women. The patent was directed to a paternity test involving amplifying and detecting paternally inherited DNA contained in the fetal DNA fraction. The Federal Circuit held the claims of that patent invalid under 35 U.S.C. §101 because they were, according to the court, directed to a natural phenomenon (i.e., merely that cell-free DNA is present and detectable in maternal blood).   

The technology in the asserted patents relates to an improvement over the earlier work. The inventors discovered that the cell-free fetal DNA was smaller in size than the cell-free maternal DNA in any given blood sample from a pregnant woman and exploited this natural phenomenon as a basis to separate and enrich for the fetal DNA portion prior to genetic analysis. Sequenom obtained US Patent Nos. 9,580,751 (the ‘751 patent) and 9,738,931 (the ‘931 patent) on the improvement, both the subject of this litigation.

The asserted independent claims from each patent are as follows:

The ‘751 patent

The ‘931 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 extracellular circulatory DNA fragments, and

(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).

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).

District Court Decision

Illumina and Sequenom (together as “Illumina”) filed a patent infringement suit against Ariosa Diagnostics, Inc., Roche Sequencing Solutions, Inc. and Roche Molecular Systems, Inc. (together as “Roche”) on May 15, 2018 involving Sequenom’s US Patent Nos. 9,580,751 (the ‘751 patent) and 9,9738,931 (the ‘931 patent). Roche counterclaimed seeking declaratory judgment of noninfringement and invalidity. After discovery, Roche moved for summary judgment of invalidity of both patents based on 35 U.S.C. § 101 as lacking subject matter eligibility. The asserted claims recite methods of preparing a fraction of cell-free DNA that is enriched in fetal DNA and analyzing a genetic locus of the enriched DNA. 

The district court conducted its analysis based on the two-step Alice/Mayo test originally set forth in Mayo Collaborative Servs. v. Prometheus Labs., Inc., 566 U.S. 66 (2012) (“The first step looks to determine whether claims are directed to a patent-ineligible concept. If they are, the second step is to consider whether the additional elements recited in the claim transform the nature of the claim into a patent-eligible application by reciting an inventive concept that is sufficient to ensure that the patent in practice amounts to significantly more than a patent upon the [ineligible concept] itself.”) 

As the first step, the district court agreed with Ariosa, finding that both the asserted “patents are directed towards patent-ineligible concepts, namely naturally occurring phenomena. Both patents claim results from a test of naturally occurring fetal DNA and do not transform the naturally occurring product into something new. Instead the patents lay claim to test results obtained from the use of fetal DNA. This use alone is insufficient to overcome the ‘directed to’ inquiry.” The court looked to its recent prior decisions in Ariosa v. Sequenom, Inc., 788 F.3d 1371, 1376 (Fed. Cir. 2015) (relating to Sequenom’s ‘540 patent mentioned earlier – patent ineligible paternal diagnostic test using cell-free fetal DNA) and Rapid Litig. Mgmt. Ltd. v. CellzDirect, Inc., 827 F.3d 1042 (Fed. Cir. 2016) (patent eligible liver cell preparation technique) for guidance, finding the facts of the case “more analogous to Ariosa than to CellzDirect.”   According to the court, “[i]n CellzDirect, the end result was cryogenically frozen useful liver cells that did not occur in nature. In Ariosa, as is the case here, the claims are directed to a testable quantity of genetic information found in nature. Unlike CellzDirect, the end result is naturally occurring.  Accordingly, the Court finds plaintiffs' arguments unpersuasive and holds that the patents are directed to patent ineligible concepts.”

As the second step, the court again agreed with Ariosa, finding the broadest independent method claims merely recited a collection of routine, well-known, and conventional steps, which failed to render the claims as a whole as being directed to an inventive concept that extended beyond the patent ineligible concept itself. According to the court, “[t]he independent claims require three phases: extraction, size production, and selective removal. Each of the steps is described as well-known and conventional…Plaintiffs suggest that the novelty of their invention is in the use of routine and conventional steps to isolate and analyze smaller DNA fragments.” 

Federal Circuit Decision

The court began by analyzing the underlying discovery in the patents and understanding how the discovery was applied in a useful way. According to the court, the inventors discovered that “the majority of the circulatory extracellular fetal DNA has a relatively small size of approximately 500 base pairs or less, whereas the majority of circulatory extracellular maternal DNA in maternal plasma has a size greater than approximately 500 base pairs.” The inventors then used their discovery to solve the problem of tiny amounts of cell-free fetal DNA in maternal blood by enriching the fetal cell-free DNA based on size fractionation techniques. Claim 1 of the ‘751 patent specifically claims a method for preparing DNA suitable for analyzing a genetic fetal abnormality by “extracting” DNA from a cell-free sample of blood from a pregnant woman and “producing” a fraction of that DNA  by (i) “size discrimination” of the cell-free DNA fragments and (ii) “selectively removing” those fragments greater than 500 bp. The final recited step is “analyzing” a genetic locus in the DNA fraction, which is enriched in cell-free fetal DNA as a result of the processing steps. 

The court acknowledged that “[l]aws of nature and natural phenomena are not patentable, but applications and uses of such laws and phenomena may be patentable. A claim to otherwise statutory subject matter does not become ineligible by its use of a law of nature or natural phenomenon.” The court also recognized that adding “conventional steps, specified at a high level of generality” to a natural phenomenon does not make a claim to that natural phenomenon eligible for patenting, and turned to its analysis of the Mayo test.

The court first considered the nature of the underlying natural phenomenon, noting that Roche struggled to articulate it. The court agreed with Illumina’s characterization of the natural phenomenon, i.e., “that cell-free fetal DNA tends to be shorter than cell-free maternal DNA in a mother’s bloodstream,” and turned to the “crucial question on which this case depends: whether the claims are ‘directed to’ that natural phenomenon.” The court held that the claims are not directed to the natural phenomenon that cell-free fetal DNA is generally shorter than cell-free maternal DNA but instead are directed to “a patent-eligible method that utilizes it.”

In doing so, the court pointed to the recited process steps, including size discrimination and selective removal of DNA fragments above a specified size threshold in order to enrich for the cell-free fetal DNA prior to conducting the recited genetic analysis. The court also looked to the limitations of the dependent claims relating to further defining the process steps (e.g., wherein size discrimination is by centrifugation or high performance liquid chromatography) as further evidence of the “concrete nature of the claimed process steps.”

The court reasoned that “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.”

Importantly, the Federal Circuit distinguished over its earlier Ariosa decision. According to the court, the Ariosa claims, like the invalid diagnostic claims in Mayo, Athena, and Cleveland Clinic, were directed to a method that detected a natural phenomenon. The Ariosa inventors essentially “discovered that cell-free fetal DNA exists” and then patented a method the “covered only the knowledge that it exists and a method to see that it exists.” By contrast, the instant claims go beyond a mere correlation between the size of the cell-free DNA and the source (i.e., fetal or maternal), but changes the relative composition or make-up of the cell-free DNA fraction such that after performing the recited steps of size discrimination and selective removal of the larger fragments (i.e., the maternal DNA), to result in “a fraction of cell-free DNA that is enriched in fetal DNA.” The court thus concluded that under “step one of the Alice/Mayo test…the claims are not directed to a patent-ineligible concept, and we need not reach step two of the test.”

The court rejected Roche’s argument that the “techniques for size discriminating and selectively removing DNA fragments…were well-known and conventional” since these considerations are material only to step two of the Alice/Mayo test, which the court did not need to reach.

Takeaways:

It is important to be able to properly articulate the natural phenomenon central to the claim at issue.  The court criticized Roche for being unable to do so and adopted Illumina’s articulation of the natural phenomenon that cell-free fetal DNA was generally smaller in size than cell-free maternal DNA, ultimately holding in favor of Illumina. Proper articulation is also critical to both claim drafting and eligibility analyses by practitioners, in particular, with regard to step one of the Alice/Mayo test. Once the natural phenomenon is properly articulated (e.g., that fetal cell-free DNA is smaller than maternal cell-free DNA or that, as in CellzDirect, a certain proportion of hepatocytes from a liver biopsy are freeze-resistant), the practitioner can more easily evaluate whether the claimed method is “directed to” that natural phenomenon itself or whether the claimed method includes certain processing steps that changes the properties of the thing about which the natural phenomenon pertains. For example, in CellzDirect, the recited processing step of freezing, thawing, and removing the non-viable hepatocytes, followed by refreezing the viable hepatocytes effectively enriches for freeze-resistant hepatocytes in the sample. This results in a population of hepatocytes that are enriched in freeze-resistant cells, which does not exist in nature. Similarly, in this case, the cell-free DNA is processed by the recited method steps by removing larger-sized DNA (the maternal DNA), thereby enriching for fetal DNA. Like the enrichment in CellzDirect, the fetal-enriched DNA of the asserted patents does not exist naturally in that state. Thus, if the claims at issue include certain processing steps which change the essence of the “thing” (e.g., cell-free DNA) about which the natural phenomenon pertains (e.g., fetal cell-free DNA is smaller than maternal cell-free DNA) such that the thing has been changed to a state not existing in nature, the claimed method is not “directed to” the natural phenomenon. If this determination can be made, then step two of the Alice/Mayo test may not require consideration. It is important to note, however, that the decision does not actually require a physical transformation or the production of non-naturally occurring material although this was helpful in this case to support finding that the process steps were concrete and involved more than just observing a natural phenomenon.