Mayo Update: Some Reason for Guarded Optimism

DNA-based Diagnostic Methods

The first category of patent claims to be considered in this survey of post-Mayo case law are those directed towards DNA-based genetic diagnostic testing methods, the type of invention most squarely in the Supreme Court's crosshairs in Mayo and Myriad. Not surprisingly, claims of this type have not fared well under the Mayo framework.

Of course, method of genetic testing claims were vulnerable to patent-eligibility challenges even prior to Mayo. In a pre-Mayo decision, the Federal Circuit held that claims directed towards methods for testing genetic variations in the BRCA genes correlated with an elevated risk of breast or ovarian cancer were patent ineligible, finding that the recited steps of “comparing” and “analyzing” DNA sequences constituted nothing more than “abstract mental concepts.” ⁵ The Supreme Court vacated that decision and remanded for reconsideration in light of Mayo (which had just been decided), but on remand the Federal Circuit came to the same conclusion of patent eligibility, finding the claims virtually indistinguishable from those invalidated in Mayo. ⁶

In a pair of more recent decisions, the Federal Circuit struck down as patent ineligible claims directed broadly towards improved methods of performing DNA-based genetic diagnostic tests. The first, Ariosa Diagnostics v. Sequenom, involved patent claims directed towards methods of diagnosis that included detecting the presence of a paternally inherited nucleic acid of fetal origin in a blood sample taken from a pregnant woman. ⁷ The invention arose out of the discovery that cell-free fetal DNA (cffDNA) is detectable in maternal serum or plasma samples. A representative claim from the case recited a “method for detecting a paternally inherited nucleic acid of fetal origin performed in a maternal serum or plasma sample from a pregnant female, which method comprises amplifying a paternally inherited nucleic acid from the serum or plasma sample and detecting the presence of a paternally inherited nucleic acid of fetal origin in the sample.” The “invention enables non-invasive prenatal diagnosis, including for example sex determination, blood typing and other genotyping, and detection of pre-eclampsia in the mother.”

In the decision below, the district court invalidated the claims for lack of patent eligibility, and on appeal, the Federal Circuit affirmed, in spite of the undisputed merits of the claimed invention. In applying the Mayo framework, the court began by finding that the existence of paternally inherited cffDNA in maternal plasma is a natural phenomenon, and promptly concluded that the claims were directed to methods that “begin[] and end[] with a natural phenomenon, i.e., paternally inherited cffDNA.” After finding the claims to be directed towards “matter that is naturally occurring,” thereby satisfying Step I of the framework, the court turned to Step II.

At Step II, the Federal Circuit found that none of the additional elements recited in the claims introduced sufficient “inventive concept” to render the claims patent eligible. In particular, while some of the challenged claims recited steps such as the use of polymerase chain reaction (PCR) for preparing, amplifying, and detecting DNA, the court held that techniques such as PCR were “well-understood, routine, and conventional” at the time of the invention, and thus failed to provide enough inventive concept to satisfy Mayo. The Federal Circuit denied the patent owner's petition for en banc rehearing, although four judges filed concurring and dissenting opinions calling out the policy concerns associated with the panel's interpretation and application of the Mayo framework, particularly as applied to inventions arising out of the life sciences. ⁸

In Genetic Techs. Ltd. v. Merial, the Federal Circuit ruled that claims directed towards methods of detecting an allelic variation in a coding region of genomic DNA by analyzing non-coding genomic DNA were patent ineligible. ⁹ The invention was based on the discovery that, as a result of linkage disequilibrium, variations in non-coding DNA are often correlated with clinically significant allelic variations in an adjacent stretch of coding DNA. ¹⁰ The prosecution history of the patent identified various advantages over prior art methods involving direct analysis of a coding region of the genome. For example, the patent owner stated that “analysis of relatively short regions of non-coding sequences, of a size which can be amplified, can provide more information than prior art analyses such as cDNA RFLP [restriction fragment length polymorphic] analyses which involve the use of significantly larger DNA sequences.”

In applying Step I of the Mayo framework, the Federal Circuit found the challenged claims to be “directed to the relationship between non-coding and coding sequences in linkage disequilibrium and the tendency of such non-coding DNA sequences to be representative of the linked coding sequences—a law of nature.” The court noted that one of the broader claims covered “essentially all applications, via standard experimental techniques, of the law of linkage disequilibrium to the problem of detecting coding sequences of DNA,” and that the patents were not limited “to methods of detecting any particular alleles linked to any non-coding sequences.” The court went on to characterize the product of the claimed methods as “information about a patient's natural genetic makeup,” and concluded that in this respect the challenged claims were “quite similar to the claims invalidated in Mayo itself,” and “remarkably similar” to the claims invalidated in Ariosa.

Moving to Step II, the court found that the physical steps recited in the claims, “amplifying genomic DNA with a primer pair” and “analyzing the amplified DNA sequence to detect the allele,” were “well-understood, routine, conventional activity,” thus failing to provide the necessary inventive concept to render the claims patent eligible. The patent owner argued that at the time the application was filed “no one had before analyzed man-made non-coding DNA in order to detect a coding region allele,” and that this additional feature, at least, provided sufficient inventive concept to pass Step II. However, the court rejected this argument, responding that “[t]he term ‘to detect the allele’ (in the sense of examining the non-coding region to detect an allele in the coding region) is a mental process step, one that provides claim 1 with a purpose but does not create the requisite inventive concept, because it merely sets forth a routine comparison that can be performed by the human mind.” The court found that regardless of the novelty and utility of the claimed invention, “the simple mental process step of ‘detect[ing] the allele’ in claim 1, either alone or in combination with the physical steps described above, does not supply sufficient inventive concept to make the claim patent-eligible under § 101.”

The court further found that the patent owner's “attempts to distinguish this case on the ground that the method of claim 1 is useful have no basis in case law or in logic. Claim 1 stands rejected under § 101 as ineligible for claiming unpatentable subject matter, not for lack of utility. The method claims of Mayo and Ariosa were apparently also useful, and also invalid.” Thus, in this case the Federal Circuit appeared to reject the notion that the novelty and utility of a claimed method had any bearing on its patent eligibility. As discussed later, this is in conflict with the court's subsequent decision in Rapid Litig. Mgmt. Ltd. v. CellzDirect, Inc., ¹¹ which seemed to place a great deal of weight on the novelty and utility of a non-diagnostic method which the court held patent eligible.

Claims directed towards genetic tests that target variations in specific genes have also been invariably deemed patent ineligible post-Mayo. In Genetic Techs. Ltd. v. Lab. Corp. of America Holdings, a district court ruled that claims directed towards a method of predicting “potential sprinting, strength, or power performance in a human” by testing for the presence of specifically identified allelic variations in a gene purportedly associated with athletic performance was declared patent ineligible. ¹² The court found the link between a particular genetic variation and the potential for elite athletic performance embodied in claim 1 to be “a natural process, an eternal truth that ‘exists in principle apart from any human action.’” Turning to Step II, the active steps recited in the claim of “analyzing” a sample, “detecting” a genetic variation, and “predicting” athletic performance were analogous to the steps found insufficiently inventive in Mayo.

Similarly, in Esoterix Genetic Labs. LLC v. Qiagen Inc., a district court declared patent ineligible claims that recited the steps of obtaining DNA from a non-small cell lung cancer tumor sample from an individual and determining the presence or absence of at least one of a small number of specifically identified genetic variations in a particular gene, wherein the presence of one of these variations “indicates an increased likelihood of pharmacological effectiveness of treatment by [one or more known pharmaceutical compounds].” ¹³ The court found that the claims were “directed to a law of nature,” in that they described the correlation between a naturally occurring mutation in a cancer cell, and the likelihood that a particular type of known pharmaceutical compound will be effective in treating that type of cancer. The court further held that there was nothing “transformative” in the claims amounting to a novel application of the natural law, or that would otherwise warrant patent protection.

In Genetic Veterinary Scis., Inc. v. Canine EIC Genetics, a district court held that claims directed towards a genetic diagnostic method for determining whether a dog is predisposed to develop Exercise Induced Collapse (EIC) was patent ineligible, based on its determination that the correlation between a specific allele and EIC is a natural law, and the DNA analysis techniques used to detect the allele “were at the time the patent was issued well-understood, routine, and conventional techniques that a scientist would have thought of when instructed to test whether a certain allele exists at a specific genetic location.” ¹⁴

Non-DNA-based Diagnostic Methods

While there is nothing in Mayo explicitly singling out DNA-based diagnostic testing methods, and indeed, the claims at issue in that case were directed towards a non-DNA molecular diagnostic test, there is reason to believe that claims directed towards a non-DNA-based diagnostic test could in some instances fare better than a DNA-based test.

For example, in Rutgers v. Qiagen, a district court denied an accused infringer's motion to dismiss, after finding it plausible that a protein-based diagnostic test might survive a patent-eligibility challenge. ¹⁵ The claims at issue are directed towards improved in vitro diagnostic methods for testing for exposure to the bacteria responsible for tuberculosis, and recite a single physical step of “testing for the presence of CD4 T lymphocytes that respond to MTBN4 [or antigenic segments of MTBN4].” The court found particular significance in the fact that MTBN4 is a protein, stating that “the special characteristics of proteins as compared to those of DNA may support patent-eligibility.” The court seemed to give some credence to the patent owner's argument that protein-based diagnostics should be treated differently than DNA-based diagnostics, based in part on the informational character of DNA. The court noted that:

Plaintiff objects to Defendant's argument that DNA and proteins should be treated similarly because they both have “sequences.” Isolating a sequence of DNA will not change its informational character, nor its ability to bind complementary sequences, according to Plaintiff. On the other hand, proteins and polypeptides are “molecular machines” whose activity is “highly dependent on its surrounding environment.” Also, unlike DNA, isolated proteins and peptides usually have different properties in vitro. Combinations of proteins and peptides changes the “sensitivity and reactivity of the molecules,” according to Plaintiff. Additionally, the Federal Circuit has noted that DNA sequences and amino acid sequences of the proteins encoded by DNA are not the same. See Genentech, Inc. v. Chiron Corp., 112 F.3d 495, 501 (Fed. Cir. 1997) (“Although a close relationship exists between a DNA construct and the protein it encodes, the two are not equal.”) Plaintiff emphasizes the “functional” character of the peptides as compared to the informational character of DNA. ¹⁶

It is important to note that the decision in Rutgers v. Qiagen could be an outlier, and that other cases assessing the patent eligibility of non-DNA-based diagnostics have not recognized this distinction between DNA and other molecular analytes.

In PerkinElmer, Inc. v. Intema Ltd., the Federal Circuit struck down as patent ineligible claims directed towards non-DNA-based analytical methods useful in determining the risk of fetal Down's syndrome. ¹⁷ An exemplary claim required two “measuring” steps, i.e., observation of a screening marker from the first trimester of pregnancy and then observation of a marker from the second trimester. The claim further recited a “determining” step in which the risk of Down's syndrome is calculated by comparing both screening marker measurements with known statistical information. The court found that the claims recited mental processes and a law of nature, i.e., the relationship between screening marker levels and the risk of fetal Down's syndrome. The court held that the fact that “an increased risk of fetal Down's syndrome produces certain analytical results is a natural process, an eternal truth that exists in principle apart from any human action.” Under Step II, the court found that steps of “measuring” biomarkers involved known methods and were insufficient to render the claims patent eligible. In this case, the fact that the claims did not recite a DNA-based test did not change the outcome. To the contrary, the Federal Circuit found the claims to be “indistinguishable” from the diagnostic method claims found to be patent ineligible in Myriad.

Similarly, in Cleveland Clinic Found. v. True Health Diagnostics, a district court found claims to be patent ineligible that were directed towards methods for assessing a test subject's risk of having atherosclerotic cardiovascular disease by measuring levels of the protein myeloperoxidase, wherein elevated levels of the protein is indicative of the test subject's risk of having atherosclerotic cardiovascular disease. ¹⁸ Under Step I, the court found that the claims were directed towards a law of nature, i.e., the relationship between myeloperoxidase levels in the bloodstream and the risk of having or developing cardiovascular disease. Proceeding to Step II, the court found that the claim did not specify any particular method for assaying myeloperoxidase levels, and that “a myriad of methods well-known in the art existed at the time of invention.” Again, the court did not recognize any distinction between DNA-based and protein-based diagnostic methods.

Can Specifically Recited Implementation Steps Render a Diagnostic Claim Patent Eligible?

In principle, a diagnostic claim could be deemed patent eligible under Step II of the framework if it recites implementation steps of a sufficiently non-conventional nature to constitute an inventive concept. However, as a practical matter diagnostic method claims generally recite the use of known techniques such as PCR, probe hybridization, and detection of antibody binding, and courts tend to characterize these technologies as “well-understood, routine, and conventional,” and as such, insufficient to render the claim patent eligible. ¹⁹ In Mayo, the Supreme Court explicitly stated that “[s]imply appending conventional steps, specified at a high level of generality,” is not enough to provide the “inventive concept” required under Step II. ²⁰

In In re BRCA1- & BRCA2-Based Hereditary Cancer Test Patent Litig., the Federal Circuit addressed the patent eligibility of some method claims that appeared in the patents that were at issue in Myriad but that were not challenged in the original Myriad lawsuit. ²¹ These claims recited not only comparing a subject's genetic sequence with the corresponding wild-type sequence, but also included additional steps reciting the specific molecular biology technique to be used in performing the comparison, i.e., either by use of a hybridization probe or PCR amplification. While the patent owner argued that this additional, active step rendered the claims patent eligible, the court found that the use of hybridization probes and PCR constitutes “well-understood, routine and conventional activity engaged in by scientists at the time of Myriad's patent applications,” thus not adding “enough” to the claims to satisfy Step II of the Mayo test. ²²

Similarly, in Ariosa Diagnostics v. Sequenom, some of the claims that the Federal Circuit held to be patent ineligible specifically recited the use of PCR or detection via a sequence-specific probe, but the court found that these techniques were conventional at the time of invention and thus insufficient to render the claims patent eligible. Likewise, in Genetic Techs. Ltd. v. Merial, the court found that specifically reciting the use of PCR was patent ineligible based on the conventionality of PCR. In Genetic Veterinary Scis., Inc. v. Canine EIC Genetics, the district court invalidated a number of dependent claims identifying specific techniques for detecting the allele associated with EIC, finding them to be conventional techniques used for genetic analysis at the time of the invention. And in Cleveland Clinic Found. v. True Health Diagnostics, the court rejected the patent owner's argument that recitation of the use of “immunological techniques” constituted a sufficient inventive concept, observing that the patent itself stated that commercial kits for quantifying myeloperoxidase were available.

On the other hand, in Athena Diagonistics, Inc. v. Mayo Collaborative Servs., a district court denied an accused infringer's Rule 12(b)(6) motion to dismiss because it was unable to conclude that the techniques used in the claims at issue in the case were sufficiently conventional and well understood to fail Step II. ²³ These claims were directed towards molecular methods for diagnosing a form of Myasthenia Gravis, a chronic autoimmune disorder, based on the detection of certain autoantibodies in a patient sample. All of the claims specifically recite the use of antibodies tagged or labeled with a reporter molecule, and some of the claims specifically recite the use of a radioactive label, or the specific radioactive label iodine-125. The defendant introduced as evidence of “conventionality” publications from 1976 and 1985 (easily predating the patent) that, according to the defendants, described “(1) the introduction of a ¹²⁵I-labeled antigen (AChR) into a bodily fluid sample, (2) immunoprecipitation, and (3) detecting the radioactive label.” However, the court found that at such an early point in the litigation, prior to any factual determination as to whether techniques involved in detecting radioactively labeled antibody were “standard in the art,” it was premature to rule the claims patent ineligible. The court did indicate, however, that if it was later established that the techniques for detecting an antibody-antigen complex recited in the claims were “standard in the art,” the claims would be invalid for lack of sufficient inventive concept.

Can the Inclusion of an “Applying” Step Render a Diagnostic Claim Patent Eligible?

Some have speculated that the claims at issue in Mayo might have been deemed patent eligible if they had explicitly recited an additional step of applying the information gleaned from the diagnostic test to optimize a drug dosage administered to a patient. For example, what if the claims had included an additional step of actually administering the drug to a patient in an amount indicated by the test? In PerkinElmer, decided shortly after Mayo, the Federal Circuit explicitly pointed out that the method claims found to be patent ineligible in that case did not require any action “beyond the comparison” of data to evaluate risk, implying that perhaps a claim would be patent eligible if it included some additional step applying the risk information generated by the method. Since then, two district court decisions have split on the question of whether an additional “applying” step renders a method-of-diagnosis claim patent eligible.

In Endo Pharmaceuticals v. Actavis, the court found that the inclusion of an applying step in a personalized medicine claim that was in other respects quite similar to the claims invalidated in Mayo was essentially irrelevant to the patent eligibility analysis. ²⁴ The representative claim specifically addressed by the court recited a method of treating pain comprising an initial two steps that mirrored the active steps in some of the Mayo claims, i.e., providing a specific drug to a patient (oxymorphone in this case) and then measuring the “creatine clearance rate” of the patient. ²⁵ This creatine clearance rate purportedly correlates with the appropriate dosage of the drug to be administered to a patient, and is thus analogous to the level of drug metabolite that was correlated with optimal dosage in the Mayo claims. But while the claims at issue in Mayo did not recite any active step subsequent to the determination of metabolite level in the patient's blood, merely reciting passive “wherein” clauses, i.e., “wherein the level [drug metabolite] indicates a need to [increase/decrease] the amount of said drug subsequently administered to said subject,” the claim in Endo Pharmaceuticals positively recited “orally administering to said patient, in dependence on which creatinine clearance rate is found, a lower dosage of the dosage form to provide pain relief.” The patent owner argued that its claims were distinguishable over the claims at issue in Mayo because while the Mayo claims “did not require that anyone act upon or apply the method in a tangible way, [Endo Pharmaceuticals' claim] actually requires that the lower dose be administered.” The district court judge rejected this notion however, concluding that “limitations at issue in Mayo do in fact mirror the analogous limitations of [Endo's claims],” and that the “slight difference in phrasing is immaterial, because neither formulation provides any sort of ‘inventive concept.’” In its Mayo analysis, the district court found that “the connection between the severity of renal impairment and the bioavailability of oxymorphone” was a natural law to which the claims were directed, and rejected the notion that the novelty and utility of the process over the prior art had any relevance to the patent-eligibility inquiry.

More recently, however, in Vanda Pharm. Inc. v. Roxane Labs., Inc., a district court arrived at a very different conclusion, finding that claims directed towards a personalized medicine invention reciting steps of performing a genotyping assay to determine whether a patient is a poor metabolizer of a specific drug (iloperidone) and then administering the drug to the patient in an amount dictated by the results of the genotyping assay are patent eligible. ²⁶ In Step I of its analysis, the court found that the asserted claims “depend upon laws of nature,” in particular the association between the genetic polymorphisms recited in the claims and the ability of a patient to metabolize a drug. However, moving to Step II the court found that:

While it may have been conventional to investigate for side-effects, Roxane has not proven by clear and convincing evidence that the precise test and the discovered results were routine or conventional. The court finds it persuasive that the dosage step in the '610 Patent does not apply to all patients, but only a specific patient population based upon their genetic composition. The dosage step requires applying genetic tests in a highly specified way. Moreover, the process of using this genetic test to inform the dosage adjustment recited in the claims was not routine or conventional and amounted to more than a mere instruction to apply a natural relationship. This combination of elements is sufficient to ensure that the claims amount to significantly more than just a natural law. ²⁷

Notably, Vanda was decided subsequent to the Federal Circuit's important decision in CellzDirect, discussed below, and it could be that the lowered bar for patent eligibility set forth in CellzDirect might have been critical to the outcome in Vanda. Vanda cites CellzDirect for the proposition that a “particular ‘combination of steps’ can lead to valid patent claims that depend upon a natural relationship … even though the individual steps may have been well known. To require something more … would be to discount the human ingenuity that comes from applying a natural discovery in a way that achieves a ‘new and useful end.’” ²⁸ The district court also found significance in the fact that the patent would not “preempt biological sampling or genotyping.” Vanda suggests that perhaps CellzDirect has opened the door to the patenting of methods in which a court finds sufficient novelty, utility, and ingenuity, and where the claim is found not to preempt all diagnostic applications of the purported law of nature.

Non-Diagnostic Biotechnology Inventions

Mayo is, of course, not limited to diagnostic claims, and in fact, the vast majority of cases in which the Mayo framework has been invoked involved claims directed towards business and financial methods. Although most of the biotechnology claims which have been subject to the Mayo framework have involved diagnostics, a literal reading of Mayo would appear to threaten the patent eligibility of a wide swath of biotechnology and pharmaceutical innovation. This troubling potential of Mayo is largely attributable to the Supreme Court's expansive definition of what constitutes a patent-ineligible law of nature/natural phenomenon. In particular, Mayo found that the interaction of a synthetic, non-naturally occurring chemical compound with the human body is a “law of nature.” But if that is the case, what could be more “conventional” than to use a chemical compound whose interaction with the human body provides a therapeutic benefit as a drug, so as to derive the benefit of the interaction? Regardless of the expansive language used in Mayo, it seems evident that this was not the Supreme Court's intention, and that in fact the Court assumed that Mayo would not generally render pharmaceuticals and other biotechnology inventions patent ineligible. In fact, while it is still early to arrive at a definitive conclusion, there is some indication that the lower courts will interpret Mayo in a manner that generally maintains the patentability of non-diagnostic biotechnology inventions.

The most encouraging decision in this regard is Rapid Litig. Mgmt. Ltd. v. CellzDirect, decided by the Federal Circuit on July 5, 2016. ²⁹ The patent at issue in the case, U.S. Patent Number 7,604,929, claims improved methods for preserving hepatocytes, generally involving steps of “(A) subjecting previously frozen and thawed cells to density gradient fractionation to separate viable cells from non-viable ones; (B) recovering the viable cells; and (C) refreezing the viable cells.” By separating out and refreezing only the viable cells, the preserved hepatocyte preparations can be thawed and used later without an unacceptable loss of viability. The process allows for hepatocyte samples from single donors to be pooled together to create a composite preparation that can be refrozen for later use, something not possible prior to the invention. The invention has a wide variety of applications in research.

In the decision below, on a motion for summary judgment, the district court declared the claims invalid for lack of patent eligibility. But on appeal, the Federal Circuit vacated that decision and remanded, finding that under Step I of the analysis, the claims are not directed towards a patent-ineligible concept, and furthermore, that the claimed invention incorporates sufficient inventive concept to satisfy Step II. In particular, while the district court concluded that the claims were directed to an ineligible law of nature, i.e., “the discovery that hepatocytes are capable of surviving multiple freeze-thaw cycles,” the Federal Circuit disagreed, and found that the claims “are simply not directed to the ability of hepatocytes to survive multiple freeze-thaw cycles. Rather, the claims … are directed to a new and useful laboratory technique for preserving hepatocytes. This 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 a patent.”

The Federal Circuit seemed well aware of the Pandora's box it would be opening if it were to find that this non-diagnostic method failed to clear Step I. The court specifically distinguished between methods of “observing” or “detecting” (i.e., diagnostics), as opposed to methods of “producing” something, in this case preserved hepatocyte cells capable of retaining viability through multiple freeze cycles. The court noted that the claims at issue:

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.” Here, the … patent does not simply claim hepatocytes' ability to survive multiple freeze-thaw cycles[, but] instead claims a ‘method of producing a desired preparation of multi-cryopreserved hepatocytes.’ This new and improved technique, for producing a tangible and useful result, falls squarely outside those categories of inventions that are “directed to” patent-ineligible concepts. ³¹

Interestingly, in CellzDirect the Federal Circuit appears to be circling back to the “useful, concrete, and tangible result” test employed by the Federal Circuit prior to Bilski—a welcome development for patent owners, although some might question whether it is consistent with Supreme Court precedent.

The court then turned to Step II, and found that even if the claims at issue in the case were found to be “directed to” a patent ineligible concept under Step I, they would still be patent eligible because they “improve an existing technological process,” thereby transforming the process into an “inventive application” of the concept. In particular, the court found that the claimed invention was a new, useful, and improved process providing significant benefits over the prior art. “That each of the claims' individual steps (freezing, thawing, and separating) were known independently in the art does not make the claim unpatentable.” The court found that while freezing and thawing hepatocytes was well known, repeating those steps, as required by the claims, was “far from routine and conventional,” and to “require something more at [Step II] would be to discount the human ingenuity that comes from applying a natural discovery in a way that achieves a ‘new and useful end.’”

While the interpretation and application of Step II set forth in CellzDirect is welcome news to innovators in biotechnology, it is hard to reconcile with Ariosa. In my view, the court provided no convincing explanation as to why the freezing and thawing steps recited in CellzDirect were sufficiently unconventional to transform a natural phenomenon into a patent-eligible invention, while the PCR and hybridization probe steps in Ariosa were too conventional to be inventive. I think the most likely explanation for the divergence between Ariosa and CellzDirect is that one involves a diagnostic invention and the other does not, and CellzDirect might signal a move by the Federal Circuit to cabin a strict interpretation of the Mayo test to inventions relating to diagnostics.

In Myriad, the Federal Circuit also seemed to apply a different standard to diagnostic and non-diagnostic claims. ³² While the court ruled all of the challenged diagnostic-method claims patent ineligible, it held that a claim directed towards a method of performing a cell-based assay to identify potential cancer therapeutics was patent eligible. The cell-based assay involved the use of genetically modified cells, i.e., host cells transformed with an altered BRCA1 gene, and the Federal Circuit found this involvement of a non-naturally occurring cell of particular significance to the patent eligibility analysis. The court found significance in the fact that cells were man-made, like the patent-eligible cells in Chakrabarty, ³³ and that “by definition,” performing known operations “on, or to create, novel, i.e., transformed subject matter is the stuff of which most process or method invention consists. … In situations where the objects or results of such steps are novel and nonobvious, they should be patent-ineligible, [it is the] transformed, man-made nature of the underlying subject matter [that] makes the claim patent-eligible.”

One could argue that, under a literal reading of Mayo, patent claims directed towards methods of pharmaceutical treatment are generally patent ineligible, and the argument could even potentially be pushed so far as to encompass pharmaceutical product claims as well. However, so far the courts appear to be holding the line against this expansive interpretation of Mayo. Indeed, in Mayo itself, Justice Breyer specifically mentioned drug method-of-treatment claims and implied that he believed that they would not be imperiled by the Court's decision. As discussed above, in Endo Pharmaceuticals a district court invalidated a patent claim that might be characterized as a method-of-treatment claim, given that the preamble of the representative claim characterized the invention as “a method of treating pain,” and the claim recited as a positive limitation a step of orally administering oxycodone to a patient. However, the Endo claims are not representative of most method-of-treatment claims, in that the point of novelty is not the use of a new pharmaceutical in the treatment of a disease, or a new use of an existing drug to treat a new indication. At its heart, the Endo claims are directed towards a personalized medicine invention, i.e., a method of performing a diagnostic test on a patient to determine the optimal dosage of a known drug used to treat a known indication. Notably, the district court gave little, if any, weight to the inclusion of a step of administering the drug to the patient, indicating that the court viewed the claim as closely analogous to the claims invalidated in Mayo.

In Endo Pharmaceuticals, the patent owner tried to argue that if the court were to find its claims patent ineligible, then by that logic “in effect … all pharmaceutical method-of-treatment patents using an existing, well-known compound” would be invalid. But the district court gave short shrift to this argument, responding that “this case is hardly the poster child for [such] a policy argument,” and positing that patent protection would still be available for method-of-use claims that are directed towards an invention embodying “creative steps or inventive leaps aside from the discovery of a natural law.” The court explicitly pointed out that “oxymorphone is ‘widely used’ for acute and chronic pain relief, thus showing that the utilization of oxymorphone is not the invention,” implying that in a case where the “invention” is the discovery of a new pharmaceutical agent for the treatment of some medical condition, a method-of-treatment claim could still be patent eligible under Mayo.

In the few cases I have seen where the court has addressed the patent eligibility of more conventional pharmaceutical product and method-of-use claims, the courts have yet to declare the challenged claim patent ineligible. In one of the earliest cases applying Mayo to a biotechnology-related invention, Shire LLC v. Amneal Pharm, defendant generic companies in an Abbreviated New Drug Application (ANDA) case argued on a motion for summary judgment that almost 250 composition of matter claims (in six patents) directed towards abuse-resistant amphetamine prodrugs were patent ineligible because they allegedly claimed “laws of nature.” ³⁴ The exemplar claims in Shire, taken from U.S. Patent Number 7,671,030, generally recited compositions comprising a specified amount of a pharmaceutical active ingredient (lisdexamfetamine or a salt thereof) satisfying various specified pharmacokinetic properties. While the defendants argued that the patents were “on all fours with Mayo,” the district court rejected this argument because, in this court's view, Mayo only applies to method claims, not composition-of-matter claims. The court stated that while Mayo “provide[s] valuable insights and illuminate[s] broad, foundational principles, the Supreme Court's decisions in Chakrabarty and Funk Brothers set out the primary framework for deciding the patent eligibility of compositions of matter.” Note that the case was decided shortly before Myriad, which now stands as the primary framework for assessing the patent eligibility of product claims of this type.

A district court in Delaware has issued two closely related decisions denying motions to dismiss pharmaceutical method-of-treatment claims for alleged patent ineligiblity. ³⁵ The two cases (both entitled Bristol-Myers Squibb Co. v. Merck & Co.) involve the same drug, and the patents in both cases are very similar. Both patents claim methods of treatment comprising intravenous administration of an “anti-PD-1 monoclonal antibody,” the only difference being that one of the patents recites treatment of lung cancer and the other treatment of metastatic melanoma. In a somewhat interesting twist, the court found that the patents satisfied Step I since they “touched upon” a natural phenomenon, i.e., “the scientific fact that blocking activation of the PD–1 pathway enables the patient's T cells to perform their normal biological activity of removing cancer cells.” This “touched upon” standard seems inconsistent with Mayo, and if applied in other cases could be problematic, since it is hard to imagine any invention in the life sciences that does not somehow “touch upon” a natural phenomenon. It also appears to be inconsistent with CellzDirect, a decision in which the Federal Circuit observed that virtually all inventions involve a practical application of natural phenomena, and emphasized that Step I is only satisfied in cases where the claim is “directed to” a natural phenomenon or law of nature. The “directed to” language is in fact taken directly from Alice.

Biotechnology and Pharmaceutical Product Claims

Mayo involved only method claims, which raised the question of whether, and to what extent, the Mayo framework is applicable to product claims. In Shire LLC v. Amneal Pharm, as discussed above, the district court soundly rejected the suggestion that Mayo applies to drug product claims. ³⁶

Alice, however, found the Mayo framework applicable to at least some product claims, particularly if the product claim adds “nothing of substance” to an underlying abstract idea. In Alice the court considered not only method claims, but also claims to a computer system and a computer-readable medium, which the patent owner conceded would “rise or fall with its method claims.” The Court found these product claims to be “no different from the method claims in substance,” merely reciting the abstract idea implemented on a generic computer.

In Esoterix Genetic Laboratories, a district court recently applied similar logic to invalidate product claims reciting “kits” comprising specific nucleic acid probes, reagents, and instructions for performing a genetic diagnostic test. ³⁷ The court had already found the corresponding method claims to be patent ineligible, as discussed above, and had little trouble extending the rationale to encompass product claims specifically directed towards performing the patent-ineligible method, using reasoning analogous to that used by the Supreme Court in Alice. Although the patent owner argued that claims directed towards a physical product should be treated differently under Mayo, the court disagreed and found that the claims were directed towards nothing more than a kit for practicing a patent-ineligible method by routine and conventional means, therefore failing to provide the necessary “inventive concept.”

PTO Examination Post-Mayo Could be Relevant

Most of the patents that have been challenged under Mayo arose from patent applications that were examined by the PTO prior to Mayo, and thus under a more-lenient patent eligibility standard. However, we are starting to see judicial decisions addressing the patent eligibility of claims examined post-Mayo, and thus presumably subjected to the higher standard set forth in Mayo. District courts have indicated that they will give some weight to the fact that a patent claim has been examined and allowed by the PTO post-Mayo.

For example, in Rutgers v. Qiagen, the plaintiff found that the patentability of the challenged claims was “bolstered by the fact that the Patent Office applied the more stringent standards in Mayo and Myriad to the '800 patent and found that the invention was patent-eligible.” ³⁸ In Vanda Pharm. Inc. v. Roxane Labs., Inc., the district court noted “that the U.S. Patent Office explicitly considered subject matter eligibility of the '610 Patent claims in light of Mayo Collaborative Services, and upheld the patentability of the claims after specific doses were added to the claims,” apparently attributing some significance to this fact. ³⁹

Conclusion

Although it has been nearly five years since Mayo was decided, the ultimate impact of the decision on biotechnology remains an open question. It has clearly impacted the availability of patent protection for diagnostics and personalized medicine, especially—but not exclusively—DNA-based diagnostics. Although Mayo left the door ajar for potential patent eligibility of a diagnostic method incorporating non-conventional implementation steps, as a general matter, a diagnostic method claim will have little value if it does not encompass the conventional methods and reagents used in the analysis of DNA and other biomolecules, such as PCR or hybridization. But the recent decisions in CellzDirect and Vanda suggest that the courts might be moving toward a less-stringent application of the Mayo framework, at least outside the context of diagnostics, and perhaps some of the language in Alice is proving helpful in this regard. There is reason to believe that most patent claims directed towards new pharmaceuticals, the use of new pharmaceuticals, or the use of known pharmaceuticals for treating new indications, will generally prove patent eligible, as will claims in general directed towards products, so long as the product is not solely useful for performing a patent-ineligible method. The primary obstacle to the patenting of biotechnology products appears to be Myriad, as evidenced by the Federal Circuit's decision in In re Roslin Inst. finding claims directed towards cloned mammals to be patent ineligible for not having “markedly different characteristics” from naturally occurring mammals. ⁴⁰