United States: Diagnostic Method Claims And Primer Tools Lack Patent-Eligibility

In Roche Molecular Systems, Inc. v Cepheid, (Slip Op. 2017-1690, October 9, 2018), the Federal Circuit held that patent claims directed to primers and methods of detecting pathogenic bacteria using the primers are invalid for failing to claim patent-eligible subject matter. The decision summarizes this panel's current thinking on the patent-eligibility of unmodified polynucleotides and methods to detect "natural phenomena" using "conventional" tools. Also, the panel deferred opining on the patent-eligibility of modified polynucleotides and the use of polynucleotides as therapeutics.

U.S. Patent No. 5,643,723 – Detecting Rifampin Resistance

U.S. Patent No. 5,643,723 ("the '723 Patent"), titled "Detection of a Genetic Locus Encoding Resistance to Rifampin in Microbacterial Cultures and in Clinical Specimens" is owned by Appellant Roche Molecular Systems, Inc. ("Roche"). The '723 Patent claims methods for detecting pathogenic bacterium Mycobacterium tuberculosis ("MTB") and in particular, rifampin-resistant MTB in cultured or clinical samples. MTB infection is a major cause of tuberculosis and rifampin is first-line treatment for treating MTB infection.

Claims 1 and 17 are representative of Roche's asserted claims.

  1. A method for detecting Mycobacterium tuberculosis in a biological sample suspected of containing M. tuberculosis comprising: (a) subjecting DNA from the biological sample to polymerase chain reaction [PCR] using a plurality of primers under reaction conditions sufficient to simplify a portion of a M. tuberculosis rpoB [gene] to produce an amplification product, wherein the plurality of primers comprises at least one primer that hybridizes under hybridizing conditions to the amplified portion of the [gene] at a site comprising at least one position-specific M. tuberculosis signature nucleotide selected, with reference to FIG. 3 (SEQ ID NO: 1), ...:

a G at nucleotide position 2312,

a T at nucleotide position 2313,

an A at nucleotide position 2373,

a G at nucleotide position 2374,

an A at nucleotide position 2378,

a G at nucleotide position 2408,

a T at nucleotide position 2409,

an A at nucleotide position 2426,

a G at nucleotide position 2441,

an A at nucleotide position 2456, and

a T at nucleotide position 2465; and

(b) detecting the presence or absence of an amplification product, wherein the presence of an amplification product is indicative of the presence of M. tuberculosis in the biological sample and wherein the absence of the amplification product is indicative of the absence of M. tuberculosis in the biological sample.

  1. A primer having 14–50 nucleotides that hybridizes under hybridizing conditions to an M. tuberculosis rpoB [gene] at a site comprising at least one position-specific M. tuberculosis signature nucleotide selected, with reference to FIG. 3 (SEQ ID NO: 1), ...:

a G at nucleotide position 2312,

a T at nucleotide position 2313,

an A at nucleotide position 2373,

a G at nucleotide position 2374,

an A at nucleotide position 2378,

a G at nucleotide position 2408,

a T at nucleotide position 2409,

an A at nucleotide position 2426,

a G at nucleotide position 2441,

an A at nucleotide position 2456, and

a T at nucleotide position 2465.

The '723 Patent exploits the discovery that certain mutations are present only in MTB. If a clinician detects one of the eleven "signature nucleotides" from a biological sample, it is a positive result for MTB and in particular, a specific species of MTB – rifampin-resistant MTB. The genetic tests, expressed by the methods and primer tools to perform these tests in the '723 Patent, are faster and more specific than tests available at the time the '723 patent application was filed. Physicians, armed with this knowledge, can avoid prescribing rifampin to patients who will not receive any therapeutic benefit from the drug. Thus, similar to certain companion diagnostics used in precision cancer therapy, genetic tests are employed to determine the most appropriate treatment for the patient at the time of diagnosis, thus avoiding the use of ineffective treatments.

Claims Fail 35 USC § 101

The United States District Court for the Northern District of California found on a motion for summary judgment that the asserted claims of the '723 patent are directed to patent-ineligible subject matter and therefore invalid under 35 U.S.C. § 101. The Federal Circuit affirmed.

The Alice/Mayo Two-Step Test

The Federal Circuit relied on the US Supreme Court's two-step test for distinguishing patents that claim laws of nature, natural phenomena, and abstract ideas from those that claim patent-eligible applications of those concepts. Slip Op. at 8-9, citing Alice Corp. v. CLS Bank Int'l, 134 S. Ct. 2347, 2354 (2014) and Mayo Collaborative Servs. v. Prometheus Labs., Inc., 566 U.S. 66, 77–79 (2012). The Alice/Mayo two-step test requires the court to determine whether the claims at issue are directed to a patent-ineligible concept. Slip Op. at 9. At the first step, it is insufficient to merely identify a patent-ineligible concept underlying the claim; the court must also determine whether that patent-ineligible concept is what the claim is "directed to." Slip Op. at 9, citing Rapid Litig. Mgmt. Ltd. v. CellzDirect, Inc., 827 F.3d 1042, 1050 (Fed. Cir. 2016). If the claim is directed to a patent-ineligible concept, then the claim is evaluated to "examine the elements of the claim to determine whether it contains an 'inventive concept' sufficient to 'transform' the claimed abstract idea into a patent-eligible application." Id., citing Alice, 134 S. Ct. at 2357 (quoting Mayo, 566 U.S. at 72–73, 78). The court noted that at this second step, there must be a further inventive concept to take the claim into the realm of patent-eligibility. "For claims that encompass natural phenomena, the method steps are the 'additional features that must be new and useful.'" Id., citing Ariosa Diagnostics, Inc. v. Sequenom, Inc., 788 F.3d 1371, 1377 (Fed. Cir. 2015) and Genetic Techs. Ltd. v. Merial L.L.C., 818 F.3d 1369, 1376 (Fed. Cir. 2016), cert. denied, 137 S. Ct. 242 (2016).

The Primer Claims

Roche argued that the primer claims were patent-eligible because as artificial, man-made primers they are different from naturally occurring DNA specifically because the claimed primers have both a 3-prime end and a 3-prime hydroxyl group. Naturally occurring, counterpart bacterial MTB DNA contains neither of these. Slip Op. at 10.

The Federal Circuit disagreed with Roche and agreed with the lower court's analysis of the primer claims. The district court had determined that because the primer claims are identical in genetic sequence to those found in nature, the primers are indistinguishable from those held to be directed to nonpatentable subject matter in In re BRCA1- & BRCA2-Based Hereditary Cancer Test Patent Litig., 774 F.3d 755, 760 (Fed. Cir. 2014) ("BRCA1")). In BRAC1, the Federal Circuit found that similar primer claims were not distinguishable from native DNA. The court stated that:

"It is well established that primers are short, single stranded nucleic acid molecules that bind to their complementary nucleotide sequence. ... As this court found in BRCA1, [p]rimers necessarily contain the identical sequence of the [nucleotide] sequence directly opposite to the [DNA] strand to which they are designed to bind. They are structurally identical to the ends of DNA strands found in nature."

Slip Op. at 10-11, citations omitted.

In reaching this result, the Federal Circuit noted that the Roche inventors did not introduce any mutations that would have made the primers' nucleotide sequences different from those found in nature.

The Federal Circuit also rejected Roche's argument that the linear primers are distinguishable from native MTB DNA that has a circular chromosome, and thus, contains neither a 3-prime end nor a 3-prime hydroxyl group. Slip Op. at 11. The court opined that "the subject matter eligibility inquiry of primer claims hinges on comparing a claimed primer to its corresponding DNA segment on the chromosome—not the whole chromosome." Slip Op. at 12.

Roche's argument that the specificity of the primers distinguishes them from native DNA also was rejected by the court. Roche argued that the claimed primers hybridize to only one of eleven position specific signature nucleotides on the MTB rpoB gene thereby transforming the primers into patent-eligible subject matter. The court did not find the function of the primers as evidence to distinguish the primers from native DNA because in the court's opinion, a primer having an identical nucleotide sequence to naturally occurring DNA without further chemical modification is a natural phenomenon. Slip Op. at 14.

While the court reaffirmed that unmodified nucleotides are patent-ineligible, it expressly withheld judgment on whether modified primers would be patent-eligible. "We do not address the subject matter eligibility of primers that have been altered—e.g., investigator induced mutation(s) such that their nucleotide sequences are not found in nature, or primers which are chemically modified or labeled by investigators such that they cannot be isolated directly from naturally occurring DNA" citing Myriad, 569 U.S. at 596 ("Scientific alteration of the genetic code presents a different inquiry, and we express no opinion about the application of § 101 to such endeavors."). Slip Op. at 13, footnote 5.

The Method Claims

The methods of claim 1 and its dependents were determined by the court to be directed to a patent-ineligible relationship between the eleven naturally occurring position-specific signature nucleotides and the presence of MTB in a sample. In the court's opinion, this "relationship between the signature nucleotides and MTB is a phenomenon that exists in nature apart from any human action, meaning the method claims are directed to a natural phenomenon, which itself is ineligible for patenting." Slip Op. at 15.

Something More Requirement

The court analyzed the method claims in light of the specification which noted in the Summary of the Invention section that "[t]his invention involves a comparative analysis of the rpoB sequences in MTB, other mycobacteria and related . . . bacteria . . . demonstrating the heretofore undiscovered presence of a set of MTB specific position-specific 'signature nucleotides' that permits unequivocal identification of MTB .... Slip Op. at 15, citing the '723 Patent at column 2, lines 60–65 (emphasis added).

The court also focused on the patent language itself which characterized the inventors' discovery as a previously undiscovered natural phenomenon found upon inspection of MTB sequence alignment. The specification noted that the inventors' discovery related to eleven sites at which the nucleotide observed for MTB were different from all or most related organisms. Id. The court concluded that because these signature nucleotides are naturally occurring, the method claims are ineligible for patenting.

The court continued in its analysis by stating that the use of primers in a PCR step in the claims also fails to satisfy the "something more" requirement of the Alice/Mayo test because PCR was "routine" at the time the patent application was filed. The court divorced the use of this technique from its application for MTB detection, noting that "[w]hile it may be true that Roche inventors were the first to use PCR to detect MTB in a biological sample, being the first to discover a previously unknown naturally occurring phenomenon or a law of nature alone is not enough to confer patent eligibility. Many groundbreaking, innovative, and brilliant discoveries have been held patent-ineligible." Slip Op. at 16-17, citing Mayo, 566 U.S. at 73–77 (discovery of natural correlation between level of certain metabolites and drug dosage, resulting in claimed method of optimizing treatment using standard techniques to administer the drug and then check if the metabolite level indicated the need for a dosage change); Genetic Techs., 818 F.3d at 1374 (discovery of natural correlation between non-coding regions of DNA and the presence of an allele in the coding region, resulting in claimed method of detecting alleles using standard PCR to amplify and detect); and Ariosa, 788 F.3d at 1373 (discovery of natural phenomenon that pregnant women's blood contains cffDNA, resulting in claimed methods using standard techniques to amplify and detect cffDNA in maternal blood).

The court also rejected Roche's argument that the use of PCR to detect MTB is no less inventive than the use of an artificial new drug to treat MTB. The court disagreed stating that the primers in the methods do not perform a significantly new function. "Thus, unlike a method of treating a disease with a new drug, Roche's method claims do not involve 'a significantly new function' for the primers. . . This case is distinguishable from CellzDirect, where this court vacated a district court's decision that the method claims at issue were ineligible for patenting. ... This court held that while the claims were based on the discovery of a natural phenomenon (the ability of certain liver cells, or hepatocytes, to survive multiple freeze cycles), they were 'directed to a new and useful laboratory technique for preserving hepatocytes'— namely, freezing and thawing hepatocytes twice even though the prior art taught away from this process. . . This court held that '[t]his type of constructive process, carried out by an artisan to achieve 'a new and useful end,' is precisely the type of claim that is eligible for patenting . . . [The inventors] employed their natural discovery to create a new and improved way of preserving hepatocyte cells for later use." Slip Op. at 18.

The court also distinguished its more recent Vanda Pharmaceuticals Inc. v. West-Ward Pharmaceuticals International Ltd. decision where claimed methods of treatment are subject matter eligible because they claim a new way of using an existing drug. The court emphasized that Vanda underscores the distinction between method of treatment claims and those in Mayo, i.e., claims "directed to a diagnostic method." Slip Op at 19, footnote 7. In the court's opinion, Roche's method claims, consisting of a standard PCR amplification step and a mental determination step, are not directed to a method of treatment.

The panel further expressly reserved its opinion on the subject matter eligibility of method claims that exploit DNA or RNA (e.g., siRNA or RNAi) for drug-like new applications. Slip Op. at 18, footnote 6.

Patenting Personalized Methods and Tools

The Roche panel made clear that isolated polynucleotides that are identical in primary sequence to a naturally occurring polynucleotide molecule are not patent-eligible. Whether modified polynucleotides are patent-eligible, and if so, what modifications transform patent-eligibility, was left unanswered by the court.

This panel also held that methods of detecting specific genetic mutations in a patient sample are not patent-eligible unless there is "something more" recited in the claim because they are directed to a natural phenomenon. That "something more" must be more than the use of conventional techniques such as PCR, even if the inventors were the first to use the tool for the claimed medical application. Thus, diagnostic or prognostic methods that use conventional techniques to identify natural phenomenon such as genetic alterations, are unlikely to survive a patent-eligibility challenge, absent a recitation of that "something more."

However, even though polynucleotides having identical sequence to a naturally occurring polynucleotide and methods for detecting natural phenomenon that use conventional tools are not patent-eligible, the court reaffirmed that methods of treatment that include diagnostic elements, remain patent-eligible. The court also reaffirmed that use of conventional tools in an unconventional manner to create a new product as explained in CellzDirect, remains patent-eligible.

The content of this article is intended to provide a general guide to the subject matter. Specialist advice should be sought about your specific circumstances.

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