diagnostics : CAFC Alert

For Biotech, “Method of Preparation” Claims May Survive §101

| April 15, 2020

Illumina, Inc. v. Ariosa Diagnostics, Inc.

March 17, 2020

Lourie, Moore, and Reyna (Opinion by Lourie; Dissent by Reyna)


In a patent infringement litigation between the same parties that were involved in the earlier case, Ariosa Diagnostics, Inc. v. Sequenom, Inc., 788 F.3d 1371 (Fed. Cir. 2015) (diagnostic patent deemed patent ineligible under 35 U.S.C. §101), the United States Court of Appeals for the Federal Circuit (“Federal Circuit”) found the claimed “method of preparation” of a fraction of cell-free fetal DNA (“cff-DNA”) enriched in fetal DNA to be patent eligible, reversing the district court’s grant of summary judgment of patent ineligibility.  A dissent by J. Reyna (author of the earlier Ariosa decision) asserts that there is nothing new and useful in the claims, other than the discovery that cff-DNA tends to be shorter than cell-free maternal DNA, and that use of known laboratory techniques and commercially available testing kits to isolate the naturally occurring shorter cff-DNA does not make the claims patent eligible.


Illumina and Sequenom (collectively, “Illumina”) appealed a summary judgment ruling of patent ineligibility by the United States District Court for the Northern District of California.  The two patents at issue, USP 9,580,751 (the ‘751 patent) and USP 9,738,931 (the ‘931 patent), are unrelated to the diagnostic patent held ineligible in the 2015 Ariosa decision.  While the earlier litigated patent claimed a method for detecting the small fraction of cff-DNA in the plasma and serum of a pregnant woman that were previously discarded as medical waste, the present ‘751 and ‘931 patents claim methods for preparing a fraction of cff-DNA that is enriched in fetal DNA.  A problem with maternal plasma is that it was difficult, if not impossible, to determine fetal genetic markers (e.g., for certain diseases) because the proportion of circulatory extracellular fetal DNA in maternal plasma was tiny as compared to the majority of it (>90%) being circulatory extracellular maternal DNA. The inventor’s “surprising” discovery was that the majority of circulatory extracellular fetal DNA has a relatively small size of approximately 500 base pairs or less, as compared to the larger circulatory extracellular maternal DNA.  With this discovery, they developed the following claimed methods for preparing a DNA fraction that separated fetal DNA from maternal DNA from the maternal plasma and serum, to create a DNA fraction enriched with fetal DNA.

‘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).

‘751 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 Federal Circuit had consistently found diagnostic claims patent ineligible (as directed to natural phenomenon) (Athena Diagnostics, Inc. v. Mayo Collaborative Servs., LLC, 927 F.3d 1333 (Fed. Cir. 2019); Athena Diagnostics, Inc. v. Mayo Collaborative Servs., LLC, 915 F.3d 743 (Fed. Cir. 2019); Cleveland Clinic Found. v. True Health Diagnostics LLC, 859 F.3d 1352 (Fed. Cir. 2017)).  In contrast, the Federal Circuit had also held that method of treatment claims are patent eligible (Endo Pharm. Inc. v. Teva Pharm. USA, Inc., 919 F.3d 1347 (Fed. Cir. 2019); Natural Alternative Int’l, Inc. v. Creative Compounds, LLC, 918 F.3d 1338 (Fed. Cir. 2019); and Vanda Pharm. Inc. v. West-Ward Pharm. Int’l Ltd., 887 F.3d 1117 (Fed. Cir. 2018)).  However, this is not a diagnostic case, nor a method of treatment case.  This is a method of preparation case – which the Federal Circuit found to be patent eligible.

The natural phenomenon at issue is that cell-free fetal DNA tends to be shorter than cell-free maternal DNA in the mother’s bloodstream.  However, under the Alice/Mayo Step 1, the Federal Circuit held that these claims are not directed to a natural phenomenon.  Instead, the claims are directed to a method that utilizes that phenomenon.  The claimed method recites specific process steps – size discrimination and selective removal of DNA fragments above a specified size threshold.  These process steps change the composition of the normal maternal plasma or serum, creating a fetal DNA enriched mixture having a higher percentage of cff-DNA fraction different from the naturally occurring fraction in the normal mother’s blood.  “Thus, the process achieves more than simply observing that fetal DNA is shorter than maternal DNA or detecting the presence of that phenomenon.”

In distinguishing the earlier Ariosa case, the Federal Circuit stated, “the claims do not merely cover a method for detecting whether a cell-free DNA fragment is fetal or maternal based on its size.” 

In distinguishing the Supreme Court decision in Association for Molecular Pathology v. Myriad Genetics, Inc., 569 U.S. 576 (2013), the Federal Circuit noted that the “Supreme Court in Myriad expressly declined to extend its holding to method claims reciting a process used to isolate DNA” and that “in Myriad, the claims were ineligible because they covered a gene rather than a process for isolating it.”  Here, the method “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.”  This is the opposite of Myriad.

As for whether the techniques for size discrimination and selective removal of DNA fragments were well-known and conventional, those considerations are relevant to the Alice/Mayo Step 2 analysis, or to 102/103 issues – not for Alice/Mayo Step 1.  The majority concluded patent eligibility under Step 1 and did not proceed to Step 2.

J. Reyna’s dissent focused on the claims being directed to a natural phenomenon because the “only claimed advance is the discovery of that natural phenomenon.”  In particular, referring to a “string of cases reciting process claims” since 2016, the “directed to” inquiry under Alice/Mayo Step 1 asks “whether the ‘claimed advance’ of the patent ‘improves upon a technological process or is merely an ineligible concept.’” citing Athena, 915 F.3d at 750 and Genetic Techs., 818 F.3d at 1375.  “Here, the claimed advance is merely the inventors’ ‘surprising[]’ discovery of a natural phenomenon – that cff-DNA tends to be shorter than cell-free maternal DNA in a mother’s bloodstream.”  J. Reyna criticizes the majority for ignoring the “claimed advance” inquiry altogether.

Under the claimed advance inquiry, one looks to the written description.  Here, the written description identifies the use of well-known and commercially available tools/kits to perform the claimed method.  Checking for 300 and 500 base pairs using commercially available DNA size markers and kits does not constitute any “advance.”  There is no improvement in the underlying DNA processing technology, but for checking the natural phenomenon of sizes indicative of cff-DNA.

J. Reyna also criticized the majority’s “change in the composition of the mixture” justification.  “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.”  Here, one begins and ends with the same naturally occurring substances – cell-free fetal DNA and cell free maternal DNA.  There is no creation or alteration of any genetic information encoded in the cff-DNA.  Therefore, the claims are directed to a natural phenomenon under Alice/Mayo Step 1. 

J. Reyna also found no inventive concept under Alice/Mayo Step 2.

Take Away

  • Until there is an en banc rehearing or a Supreme Court review of this case, this case is an example of a patent eligible method of preparation claim.
  • For defendants, the “claimed advance” inquiry could help sink a claimed method under Alice/Mayo Step 1. 

The Patent-Ineligibility trend continues to be infectious…

| October 29, 2018

Roche Molecular Systems, Inc. v. Cepheid

October 9, 2018

Before O’Malley, Reyna and Hughes. Opinion by Reyna. Concurring opinion by O’Malley.


The contended patent, U.S. Patent No. 5,643,723 (‘723 patent), owned by Roche is directed to methods for detecting the pathogenic bacterium Mycobacterium tuberculosis (MTB). Prior to the priority date, the general methods of detection were slow (could take three to eight weeks), and they had limitations in that they could not identify if a patient has an antibiotic-resistant strain. The standard of care at the time was treatment with the antibiotic rifampin. However, outbreaks resulted due to delays in diagnosing and reporting of the rifampin-resistant tuberculosis. In 1994, rpoB became a prime candidate for studying rifampin resistance in MTB.

The inventors of the ‘723 patent sequenced the rpoB gene in MTB and discovered that that the rpoB gene in MTB contains eleven “position-specific” “signature nucleotides” (i.e., naturally occurring single nucleotide mutations) that are only present in MTB but not in other bacteria. Based on these eleven MTB-specific signature nucleotides, the Roche inventors devised a diagnostic test that could (1) identify whether or not a biological sample contains MTB, and (2) if MTB is present, predict whether that MTB is a strain that is resistant to rifampin treatment.

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Summary of Oral Arguments in AMP v. USPTO remand

| July 20, 2012

July 20, 2012

In the immortal words of baseball great Yogi Berra, “It’s déjà vu all over again”.  A little more than a year after they previously heard AMP v. USPTO, the CAFC panel of Judges Lourie, Bryson and Moore have once again taken up the question of whether isolated DNA and related methods are patent eligible subject matter under 35 U.S.C. §101.

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| March 23, 2012

No. 10–1150. Argued December 7, 2011—Decided March 20, 2012

For an English discussion of Mayo v. Prometheus, please click here.


Prometheus Laboratories(以下、Prometheus)は、自己免疫疾患を治療するためのチオプリン(thiopurine)ドラッグに関する2つの特許(U.S. Patent No. 6,355,623、No.6,680,302)の独占的使用権を有する。特許クレームは、チオプリンが投与された患者の血中の代謝物量を測定し、それに合わて投与量を調整する方法に関するものである。

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Supreme Court strikes down diagnostic method claims as non-patent-eligible subject matter

| March 20, 2012

Mayo Collaborative Services v. Prometheus Laboratories

March 20, 2012

Supreme Court, 9-0, opinion by Justice Breyer


Although we typically cover the CAFC in this blog, today we will be visiting the Supreme Court.  The Supreme Court unanimously ruled that the diagnostic method claims in this highly-anticipated case were invalid as failing to comply with 35 U.S.C. §101.  In short, the Court ruled that a claim reciting a diagnostic method (which is inherently based upon a law of nature) that applies only conventional, known steps is invalid.

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