The Federal Circuit Continues to Grapple with the Question of Patent Eligibility for Diagnostic Methods

OPINIONS CONCURRING WITH THE DECISION NOT TO REHEAR ATHENA EN BANC

Seven of the judges on the Federal Circuit joined in four opinions concurring with the decision not to rehear Athena. ⁹

Judge Lourie authored one of the concurring opinions, joined by Judges Reyna and Chen, in which he explains his view that the Federal Circuit could accomplish little by rehearing the case, since the panel's decision was dictated by Mayo precedent. But he goes on to argue that claims of this sort should be patent eligible under a properly functioning patent system.

Judge Lourie explained:

If I could write on a clean slate, I would write as an exception to patent eligibility, as respects natural laws, only claims directed to the natural law itself, e.g., E = mc ² , F = ma, Boyle's Law, Maxwell's Equations, etc. I would not exclude uses or detection of natural laws. The laws of anticipation, obviousness, indefiniteness, and written description provide other filters to determine what is patentable.

Responding to critics who complain that the Federal Circuit's application of Mayo has been confusing and inconsistent, Judge Lourie explains his view that:

our cases are consistent. They have distinguished between new method of treatment claims and unconventional laboratory techniques, on the one hand, and, on the other hand, diagnostic methods that consist of routine steps to observe the operation of a natural law, a clear line. Beyond that, I do not see a way clear to distinguish Mayo in a useful, principled, fashion. Software is another matter, but such patents are not before us here.

Judges Hughes, joined by Chief Judge Prost and Judge Taranto, wrote a concurring opinion that points to the plethora of concurring and dissenting opinions as “illustrative of how fraught the issue of § 101 eligibility, especially as applied to medical diagnostics patents, is.” He agrees with the other concurring judges that Mayo, as later reinforced by Alice, dictates the panel's decision finding the claims ineligible, and that

He goes on to state that he

Judge Dyk wrote his own concurring opinion, joined by Judges Hughes and Chen, ¹⁰ expressing their view that, although Mayo did not make all diagnostic claims patent ineligible, the decision “left no room for us to find typical diagnostic claims patent eligible, absent some inventive concept at Mayo step two,” and thus the panel's decision was dictated by Supreme Court precedent.

Judge Dyk's concurrence expresses overall satisfaction with the way the Mayo/Alice framework has functioned with respect to claims found patent ineligible under the “abstract idea” prong of the inquiry, which generally recited purported inventions involving computer programs, information technology, financial methods, etc. (although this prong has been found applicable to some diagnostic method claims; see In re Stanford I and II, for example). He opines that “few would contend” the patent claims “screened out” under Mayo for being directed towards abstract ideas should be patent eligible, pointing in particular to claimed inventions that “merely apply well-known business methods and other processes using computers or the Internet. ¹¹ ” On the other hand, he finds that the Supreme Court's § 101 precedent “has allowed room for claims that do more than recite conventional applications of abstract concepts.” ¹²

Furthermore, Judge Dyk's concurrence expressly disagrees with the view set forth by Judge Lourie that the statutory requirements of patentability set forth under §§ 102, 103, and 112 are entirely adequate to address the public policy concerns that animate Mayo and its progeny. Judge Dyk states that:

Despite assertions to the contrary, the doctrines of novelty under § 102, obviousness under § 103, and enablement and written description under § 112 cannot adequately guard against the dangers of overclaiming. Those sections … do not adequately address the risk that a patent on the natural law would significantly impede future innovation. Nor do these other provisions typically allow early stage resolution of the “threshold” issue of patent eligibility necessary to avoid the costs of lengthy litigation.

A simple example in the area of diagnostic patents illustrates this point. If the first person to identify the relationship between a genetic abnormality and a disease had sought a broad patent on a method of searching for genetic abnormalities and determining their relationship to disease, the claims would have been neither anticipated nor obvious. Nor is it likely that they would they have been invalid for lack of enablement (since a representative species was disclosed) or written description (the overall conception being in the mind of the inventor). The only barrier to such broad patent claiming is § 101.

As an example of this, Judge Dyk points to the Federal Circuit's decision in In re BRCA1- & BRCA2, in which genetic testing claims were found to be directed to the “patent-ineligible abstract idea of comparing BRCA sequences and determining the existence of alterations” of the gene, as discussed elsewhere in this article. ¹³

Speaking for myself, I think Judge Dyk is incorrect to assume that a patent claim broadly encompassing any diagnostic test to identify the relationship between a genetic abnormality and a disease, in a manner that “significantly impede[s] future innovation,” would be unlikely to be found invalid under § 112 for lack of enablement or adequate written description, particularly if only a single representative species is disclosed, as posited by his hypothetical. It is well-established, for example, that the scope of the claim must be commensurate with the scope of disclosure, and a disclosure of a single representative species (or relatively small number of species falling within the scope of the claim) is often found insufficient to satisfy the enablement requirement. I agree with Judge Lourie that the enablement requirement, properly interpreted and enforced, would be sufficient to address the concerns expressed by Justice Breyer and Judge Dyk regarding preemption and overly broad claiming.

After defending the Mayo/Alice framework as applied in the abstract idea context, Judge Dyk proceeds to bemoan the problems that have arisen out of the implementation of “the natural law approach of Mayo” (by which Judge Dyk is presumably referring to the law of nature and natural phenomenon judicial exceptions). Judge Dyk agrees with the other judges on the Federal Circuit that:

the Mayo test for patent eligibility should leave room for sufficiently specific diagnostic patents. But it is the Supreme Court, not this court, that must reconsider the breadth of Mayo.

Although the Supreme Court's decision in Mayo did not make all diagnostic claims patent ineligible, Mayo left no room for us to find typical diagnostic claims patent eligible, absent some inventive concept at Mayo step two. The panel here correctly concluded that Mayo controls.

Thus, it would be desirable for the Supreme Court to refine the Mayo framework to allow for sufficiently specific diagnostic patent claims with proven utility. In the life sciences, development of new diagnostic methods is often based on researching complex biological systems. The inventive concepts in this area may lie primarily in the application of a natural law.

Judge Dyk went on to opine that “the holding of Mayo may be overbroad,” implying that the Supreme Court (or perhaps Congress) should revisit the issue. In particular, Judge Dyk points out what he sees as a “tension between Mayo and the Supreme Court's later decision in Myriad. ¹⁴ ” He correctly notes that the language of § 101 explicitly identifies “discover[ies],” as patentable subject matter, and that “there is no doubt that determining the relationship between specific genetic abnormalities and specific diseases constitutes an important discovery with proven utility.” He then points out that in Myriad the Supreme Court seemed to “suggest that such discoveries may be patent eligible.” (Note that Mayo was written by Justice Breyer, perhaps the Justice most concerned about the potential for patent rights to impede scientific inquiry and innovation, while Myriad was written by Justice Thomas, who at one time worked for Monsanto, and thus might have some appreciation for the role of patents in promoting science and innovation).

In particular, he explains that in Myriad the Supreme Court suggested that claim 21 of Myriad's U.S. Patent No. 5,753,441,

which covered a method of detecting (using conventional methods) any of several specific mutations in the BRCA1 gene, newly discovered by the patent applicant and shown to increase a person's risk of developing particular cancers (a far narrower claim than the claims held unpatentable in BRCA1- & BRCA2)[,] could be patent eligible[.] Myriad thus recognized that an inventive concept can sometimes come from the discovery of an unknown natural phenomenon and its application for a diagnostic purpose. This appears to be in tension with Mayo. Under Mayo, a natural phenomenon itself, no matter how narrow and specific, cannot supply the requisite “inventive concept.”

Thus, it would be desirable for the Supreme Court to refine the Mayo framework to allow for sufficiently specific diagnostic patent claims with proven utility. In the life sciences, development of new diagnostic methods is often based on researching complex biological systems. The inventive concepts in this area may lie primarily in the application of a natural law.

Judge Dyk suggests that the Mayo framework should be refined in the following “limited respects.”

Judge Dyk then proceeds to walk through a number of Supreme Court decisions that he argues support a requirement of specific application as part of the patent eligibility inquiry as applied to natural laws. He goes on to propose that, in order to “ensure against overbroad claims, the scope of the § 101 natural law exception is necessarily informed by the utility requirement of § 101.” Judge Dyk argues that under the Supreme Court's 1966 decision in Brenner,

the scope of patents involving the application of natural laws should not extend beyond established utility[;] claims that extend further are not patent eligible. Under this approach, because of their breadth, the claims in Mayo would not be eligible at step one. However, if the claim is sufficiently tied to a specific and useful application of a natural law at Mayo step one, that application itself should serve as the necessary inventive concept at Mayo step two.

Judge Dyk then distinguishes between the claims at issue in Mayo and Athena Diagnostics, and explain why, under his interpretation of Mayo, the Mayo claims were patent ineligible, while the Athena Diagnostics claims might very well have been patent eligible. Under his proposed interpretation of Mayo, the application must be more than “determining the precise correlation of a known relationship using prior art processes, as was the case in Mayo itself.” He points out that in Mayo the prior art already understood the correlation between the metabolites of thiopurine compounds and optimal drug dosage, and that the sole contribution of the purported inventors was “the precise correlations between metabolite levels and likely harm or ineffectiveness.” In contrast, he finds that the Athena Diagnostics claims involve a “discovery” of a previously unknown relationship, not “mere determination of the precise correlations of a known natural law using prior art processes.” As such, Judge Dyk felt that Athena “could provide the Supreme Court with the opportunity to refine the Mayo framework as to diagnostic patents.”

Judge Dyk proposes that:

[r]equiring specific and useful application for the entire scope of the claim at Mayo step one, and more than determining precise correlations of a known natural law using prior art processes at Mayo step two, would ensure that the claims truly recite an “inventive application” of the natural law that should be eligible under § 101. This approach would help ensure that the reward of a patent goes to those who have actually done the work to develop a specific application of a natural law, not those who are the first to the patent office with broad, conceptual claims lacking proven utility in many applications.

Judge Chen penned his own concurring opinion, expressing his view that:

New methods for diagnosing medical conditions, as a general matter, intuitively seem to be the kind of subject matter the patent system is designed for: to encourage the risky, expensive, unpredictable technical research and development that people would not otherwise pursue in the hope that if they discover something of great medical value, then they will be protected and rewarded for that successful effort with a patent. This category of invention, after all, is not the same as methods of entering into contracts, or horse whispering, or speed dating or other methods that animated many of the concerns underlying Bilski. The kind of lab work undertaken in discovering new diagnostics and performing the steps of such claimed inventions can only be described as being technical in nature. For several decades before Mayo, this has been the basis for why the Patent Office granted patents for many medical diagnostics—not just for the law of nature in the abstract, but as applied in the real-world medical context to diagnose patient health conditions. In any meaningful sense, this represents a practical application of the discovered law of nature, that is, it is applied science in every sense of that term. And it should be patentable subject matter in a well-functioning patent system.

Judge Chen recounts that, prior to Mayo, the controlling Supreme Court precedent with respect to the patent eligibility of processes was that set forth in the 1991 decision of Diamond v. Diehr. ¹⁵ According to Judge Chen, in Diehr the Court adopted a “relatively narrow and more administrable version of the judicial exceptions to the statutory text of 35 U.S.C. § 101 compared to what the Court had articulated three years earlier in Parker v. Flook.” ¹⁶ He opines that “[u]nder Diehr's “claim as a whole” principle, which does not divide the claim into new versus old elements, Athena's claims, particularly claims 7 and 9, likely would have been found to be directed to a patent-eligible process comprising a set of technical, transformative steps to test a patient for a particular medical condition.”

He goes on, however, to conclude that in Mayo the Court had “set forth an inventive concept/point of novelty framework, which is a more far-reaching, aggressive version of the judicial exceptions to the statute and is largely incompatible with Diehr's core rationale.” On the other hand, he notes that “nothing in Mayo suggests that it sought to repudiate Diehr's analysis.” Judge Chen suggests that the Federal Circuit “would benefit from the Supreme Court's guidance as to whether it intended [Mayo] to override central tenets of Diehr.”

Judge Chen complains that “the Mayo analytical approach is considerably harder to apply consistently than the Diehr framework, and more aggressive in its reach.” As case in point, he points out that the representative claim in Mayo begins with an initial step of administering a synthetic drug to a patient, which in isolation is surely patent eligible subject matter (although it would not have been novel). Furthermore, the addition of a second step of subsequently determining the level of a non-naturally occurring metabolite in a patient should not render the claim patent ineligible (although the claim would still lack novelty). However, the Mayo claim further recites a relationship between a metabolite level and its efficacy in a patient, and it is the recitation of this relationship that suddenly renders the claim patent ineligible for violating the law of nature exception. Under the Mayo analysis, the “administering” and “determining” steps “get pushed aside and declared insignificant, and the last step is designated as the “focus” of the claim, i.e., the heart of the invention.” Judge Chen finds “the notion that adding claim language can convert an otherwise patent-eligible claim into a patent-ineligible claim [to be] counterintuitive and a very difficult thing to explain to 8,000 patent examiners.”

Judge Chen complains that:

[T]he process of determining what the claim is “really about” when the claim is viewed in pieces, rather than as a whole, can be highly subjective and impressionistic. This approach puts courts and examiners in the position of assigning value judgments to individual limitations, designating some as “significant” and others as “insignificant,” and hoping everyone else reaches the same conclusion as to whether the claim contains a truly meritorious inventive contribution as opposed to a judicial exception embellished with insignificant window dressing. And all this just to resolve the threshold question of whether an invention is eligible for the patent system.

Judge Chen urges the Supreme Court to clarify the extent to which Diehr remains good law in light of Mayo, explaining that:

[r]esolution of the present confusion is important because if Mayo in fact overruled the principles in Diehr (as reiterated in Bilski), then that would be a significant incursion on the settled expectations that had existed for 30 years since Diehr. Relying on the Diehr framework, the Patent Office examined and granted many patents for medical diagnostic methods, establishing settled expectations in those granted property rights, and prompted companies and research institutions to organize their conduct and choices accordingly. Many of these diagnostic claims, including the ones at issue here, do not hold up well against Mayo's more searching, claim dissection scrutiny.

OPINIONS DISSENTING FROM THE DECISION NOT TO REHEAR ATHENA EN BANC

Five of the judges on the Federal Circuit joined in a total of four dissenting opinions written by Judges Moore, Newman, Stoll, and O'Malley (who happen to be four out of the five female judges on the Federal Circuit). ¹⁷ These dissenting judges agree with the seven concurring judges that life-changing diagnostic inventions of the type at issue in Athena Diagnostics should not be subject to a de facto per se rule of patent ineligibility. The primary point of divergence between the dissenting and concurring judges is that the dissenting judges take the position that, in fact, Mayo does not mandate a per se rule against the patenting of diagnostic methods, and that the Federal Circuit has erred in treating it as such. They distinguish between the Mayo and Athena claims, identifying meaningful distinctions that would permit the Federal Circuit to uphold the patent eligibility of Athena Diagnostics' claims without violating Supreme Court precedent. Significantly, these dissenting judges do not believe that it is necessary to wait for intervention by the Supreme Court or Congress, but rather that the Federal Circuit has it within its own power to correct the problem the Federal Circuit's interpretation and application of Mayo has caused for diagnostic patents.

Judge Moore's dissenting opinion, which was joined by Judges O'Malley, Wallach, and Stoll, begins by observing that “the patent system exists to promote exactly this sort of specific, targeted application of a life-saving discovery, which is characterized by extraordinarily high initial market entry costs.” She goes on to point out that since Mayo was decided the Federal Circuit has held every single diagnostic claim that has come before it to be patent ineligible, effectively rendering diagnostics per se ineligible. ¹⁸ She explains the life-changing and often life-saving value of diagnostic inventions, and their critical role in modern health care, using examples taken from the invalidated diagnostic claims to illustrate her point.

For instance, she notes that cardiovascular disease is the number one cause of death in the United States, killing more than 600,000 people per year, and costing over $200 billion annually, and that the claimed invention found to be patent ineligible in Cleveland Clinic I allowed for early diagnosis of cardiovascular disease, providing a better predictive value than the clinically used risk factors employed by physicians at the time of the invention. Another example she points to is In re BRCA1, wherein the claims deemed patent ineligible were directed to methods of screening for alterations in genes linked to hereditary breast and ovarian cancer, and that breast cancer would likely kill more than 40,000 people in 2019. Other examples pointed to in her opinion include Roche, where the claims were directed to a method for detecting tuberculosis, one of the world's deadliest diseases, and Ariosa, where the claimed diagnostic methods related to fetal health, characteristics, and genetic disorders such as Down syndrome. Judge Moore characterized the Ariosa method of detecting fetal abnormalities as “an absolute game changer,” allowing for testing based on a simple blood test, as opposed to higher cost and higher risk procedures such as amniocentesis, that had been the standard. Finally, there are the Athena claims, directed towards diagnostic methods that provide the means for identifying patients suffering from an autoimmune disease who would not have been identified by prior art diagnostic testing methods, thereby allowing for early intervention and treatment that was not possible prior to this invention.

Judge Moore points to statements and testimony from Senate hearings that occurred in 2019 to assess the “state of patent eligibility in America.” For example, in his opening statement, Senator Coon recognized that “for medical diagnostics, … [there is] a presumption against eligibility that is nearly impossible to overcome.” ¹⁹ Expanding upon that concern, Hans Sauer of the Biotechnology Innovation Organization (BIO), testified that “it is unclear whether diagnostic methods are patentable in any meaningful way.” ²⁰

Much of Judge Moore's opinion is devoted to expounding upon the importance of diagnostics for healthcare, and the high cost of developing new diagnostics, two factors that point in favor of the availability of robust intellectual property protection. She notes that while diagnostic techniques account for less than 2.5% of healthcare expenses, they guide approximately 66% of clinical decisions. She notes that:

Diagnostic medicine saves lives and money through early detection and reduces the need for high cost pharmaceuticals or curative procedures, but developing diagnostic kits and techniques is expensive and time consuming. Development of a new diagnostic test is estimated to cost up to $100 million and to take nearly 10 years. … Because they are typically characterized as very expensive to develop but relatively cheap to reproduce, patent protection is required to make it financially viable for continued investment in their development.

Judge Moore points to a statement by Senator Tillis at the Senate hearing, in which he asked, “[w]hy would anyone in their right mind risk millions if not billions of dollars to develop a product when they have no idea if they're eligible for protection? From a business perspective, it simply isn't worth the risk for many endeavors.”

She identifies various aspects of the crucial role innovative diagnostics play in healthcare, such as mitigating the effect of disease outbreaks. The specific example she points to is the 2015 Ebola outbreak (if Judge Moore had penned her decision a year later, COVID-19 would have no doubt provided an even more compelling illustration of this point). She further notes that diagnostics “are pivotal to addressing the advent and increase in drug-resistant infections,” which current estimates project will lead to 10 million people dying every year by 2050, at a cost of up to 100 trillion dollars. She further notes that the effects of diagnostics in improving the detection and treatment of cancer, human immunodeficiency virus, as well as in vitro care should not be overlooked.

Judge Moore essentially argues that innovative, specific diagnostic testing methods are no less deserving of patent protection than innovative pharmaceuticals:

The math is simple, you need not be an economist to get it: Without patent protection to recoup the enormous R&D cost, investment in diagnostic medicine will decline. To put it simply, this is bad. It is bad for the health of the American people and the health of the American economy. And it is avoidable depending on our interpretation of the Supreme Court's holding in Mayo.

Judge Moore then goes on to explain why she believes that the nature of the Athena claims is such that they can be distinguished from the Mayo claims and the binding precedent established by Mayo. In her view, the Mayo claims recited nothing more than a natural law, and it is this breadth and generality that led to their demise. In contrast, the Athena claims “contain specific, concrete steps applying the law of nature.” She goes on to explain that

Judge Newman, who was joined by Judge Wallach in her dissenting opinion, reiterates many of the points made by Judge Moore. She identifies a critical role for the patent system in incentivizing the development of new diagnostic methods, emphasizing the high cost of R&D, from scientific discovery through federal approval, and the substantial public benefit that flows from innovations in diagnostics, noting that:

[t]he patent system provides the economic foundation for the cycle of experimental study, clinical evaluation and proof, and implementation in commerce. This foundation applies to diagnosis as well as to treatment.

Judge Newman argues that the majority's interpretation of Mayo is flawed, and that the Federal Circuit has mistakenly enlarged the holding of Mayo, applying it in a manner that effectively subjects diagnosis methods to unique patent eligibility rules.

In Judge Newman's view, the Federal Circuit, when assessing the patent eligibility of medical diagnostic claims, is ignoring the principle that patent claims are to be considered “as a whole.” She argues that this long-standing principle was not discarded by the Supreme Court in Mayo, and that in fact the Federal Circuit adheres to it when assessing the patent eligibility of non-diagnostic inventions, pointing to McRO, Inc. v. Bandai Namco Games America Inc. as an example of this. ²¹

She also emphasizes that she shares Judge Lourie's view that the “appropriate analysis of patentability is under sections 102, 103, and 112; not section 101.”

Judge Newman goes on to argue that Mayo “did not hold that every diagnostic method ties up a natural law, and that the Athena panel majority had acknowledged that “claim 9 leaves open to the public other ways of interrogating the correlation between MuSK autoantibodies and MuSK-related disorders without practicing the claim's concrete steps.”

She also points to concerns that have been raised by biotechnology innovators. BIO, for example, has advised the court that “[t]he panel decision reflects a troubling divergence in this court's section 101 jurisprudence between software and biotech inventions,” explaining that in software cases the threshold analysis focuses on whether the claims contain a technical improvement over the prior art, whereas this aspect is absent from the Federal Circuit's analysis of biotech inventions.

Judge Newman warns that “the public interest is poorly served by adding disincentive to the development of new diagnostic methods. This is a severe criticism; and when presented by the entire industry, and stressed by thoughtful scholars, it warrants judicial attention.”

Judge Stoll filed a dissenting opinion, joined by Judge Wallach, emphasizing the importance of the issues presented by the case and the need for en banc clarification of the patent eligibility of diagnostic methods under Mayo. In her view, “by consistently bypassing en banc review of a critical issue that goes to the heart of this court's jurisdiction, we are abdicating our responsibility.” Judge Stoll argues that the Federal Circuit has, based on its misinterpretation of Mayo, established a bright line rule of ineligibility for all diagnostic claims, a flawed test that “undermines the constitutional rationale for having a patent system—promoting the progress of science and useful arts[.] The eligibility of life-saving inventions is not only one of the most important issues of patent law, but of human health.”

Judge O'Malley also filed a dissenting opinion, in which she agrees “with all aspects of Judge Moore's thoughtful dissent,” but writes separately to explain her belief that “confusion and disagreements over patent eligibility have been engendered by the fact that the Supreme Court has ignored Congress's direction to the courts to apply the Patent Act as written, and instead has” instructed federal courts to read into Section 101 an “inventive concept requirement—a baffling standard that Congress removed when it amended the Patent Act in 1952.”

As correctly noted by Judge O'Malley, prior to 1952 the Supreme Court had created a non-statutory requirement of “invention” that eventually resulted in federal courts “invalidating patents at break-neck speed.” Prominent jurists complained that this “invention requirement” was unworkable, and that because inventiveness “is an unmeasurable quantity having different meanings for different persons,” the invention requirement “left every judge practically scot-free to decide this often controlling factor according to his personal philosophy of what inventions should be patented.” In 1952, explains Judge O'Malley, “Congress attempted to address these criticisms by amending the Patent Act to replace the ill-defined and judicially-created invention requirement with the more workable anticipation and obviousness tests codified in Sections 102 and 103.”

Judge O'Malley points out (I believe correctly) that in Mayo and its progeny, the Supreme Court has effectively resurrected the judicial inquiry into “inventiveness” that Congress sought to do away with the 1952. History has repeated itself, and it is not surprising that we are seeing the same problems and the same sorts of criticisms as we had prior to that enactment of the 1952 Patent Act.

By dissenting, Judge O'Malley explains, she hopes to “encourage Congress to clarify that there should be no such requirement read into § 101; to clarify that concepts of novelty and ‘invention’ are to be assessed via application of other provisions of the Patent Act Congress designed for that purpose.”

DIAGNOSTIC CLAIMS FOUND PATENT INELIGIBLE

In this section I review all of the Federal Circuit decisions I could identify that find diagnostic method claims patent ineligible under Mayo. The decisions are broken down into several categories based on the nature of the claimed diagnostic method. These categories include diagnostic methods based on the identification of a specific biomarker, methods for detecting a specific bacterium, methods for detecting a specific medical condition (but not based on a specific biomarker), general diagnostic methods, and diagnostics useful in personalized medicine.

DIAGNOSTIC CLAIMS FOUND PATENT ELIGIBLE

Over the last few years, some judges on the Federal Circuit have begun to uphold the patent eligibility of diagnostic methods, circumventing the stricture of Mayo by characterizing the claimed invention as something other than a diagnostic method. Perhaps the most notable example of this is the court's split decision in Vanda Pharmaceuticals Inc. v. West-Ward Pharmaceuticals International Ltd., decided in 2018. ³⁷ The claims at issue are directed to a diagnostic method, useful in the practice of personalized medicine, that is based upon the discovery of a biomarker that can be used to determine the optimal dosage of a specific drug (iloperidone). In particular, the inventors discovered that some patients are poor metabolizers of the drug, and that by genotyping a patient's CYP2D6 gene these poor metabolizers can be identified. Certain commonly occurring polymorphisms in the gene result in poor metabolism of the drug, and for these patients a reduced dosage is appropriate. A representative claim reads as follows:

A method for treating a patient with iloperidone, wherein the patient is suffering from schizophrenia, the method comprising the steps of:

determining whether the patient is a CYP2D6 poor metabolizer by:

obtaining or having obtained a biological sample from the patient;

and

performing or having performed a genotyping assay on the biological sample to determine if the patient has a CYP2D6 poor metabolizer genotype; and

if the patient has a CYP2D6 poor metabolizer genotype, then internally administering iloperidone to the patient in an amount of 12 mg/day or less, and

if the patient does not have a CYP2D6 poor metabolizer genotype, then internally administering iloperidone to the patient in an amount that is greater than 12 mg/day, up to 24 mg/day,

wherein a risk of QTc prolongation for a patient having a CYP2D6 poor metabolizer genotype is lower following the internal administration of 12 mg/day or less than it would be if the iloperidone were administered in an amount of greater than 12 mg/day, up to 24 mg/day.

The panel majority held that, “[c]onsistent with Supreme Court precedent,” the claims are not directed to patent-ineligible subject matter. As such, the court saw no need to address step two of the Mayo inquiry. In response to the accused infringer's contention that the Supreme Court had held similar claims patent ineligible in Mayo, the majority explained that:

This case [is] not Mayo. First, the claims in Mayo were not directed to a novel method of treating a disease. Instead, the claims were directed to a diagnostic method[.] In this case, the ’610 patent claims are directed to a method of using iloperidone to treat schizophrenia. The inventors recognized the relationships between iloperidone, CYP2D6 metabolism, and QTc prolongation, but that is not what they claimed. They claimed an application of that relationship. Unlike the claim at issue in Mayo, the claims here require a treating doctor to administer iloperidone in the amount of either (1) 12 mg/day or less or (2) between 12 mg/day to 24 mg/day, depending on the result of a genotyping assay. . … 

Moreover, unlike the claim in Mayo, to the extent that preemption is a concern, the ’610 patent claims do not “tie up the doctor's subsequent treatment decision.” The claim was not a treatment claim. It was “not limited to instances in which the doctor actually decreases (or increases) the dosage level where the test results suggest that such an adjustment is advisable.” … Here, the ’610 patent claims recite the steps of carrying out a dosage regimen based on the results of genetic testing. The claims require doctors to “internally administer[ ] iloperidone to the patient in an amount of 12 mg/day or less” if the patient has a CYP2D6 poor metabolizer genotype; and “internally administer[ ] iloperidone to the patient in an amount that is greater than 12 mg/day, up to 24 mg/day” if the patient does not have a CYP2D6 poor metabolizer genotype. These are treatment steps.

Notably, the decision was authored by Judge Lourie, the Federal Circuit's preeminent voice when it comes to pharmaceutical patent law. Recall that Judge Lourie was one of the concurring judges in the court's decision not to rehear Athena, stating his position that, although claims directed towards diagnostic techniques employing “well-understood and conventional” techniques to detect new natural phenomena are not patent eligible under Mayo, “new method of treatment patents do not fall prey to Mayo's prohibition,” specifically pointing to Vanda as an example of this distinction.

Chief Judge Prost, on the other hand, who was also one of the concurring judges in Athena, dissented in Vanda, arguing that the majority's “efforts to distinguish Mayo cannot withstand scrutiny.” She explained her view that:

The majority fails to reconcile [the] substantive similarity between [this] case and Mayo. … The claims here specify a means of identifying a patient's genotype (a “genetic assay”), while the claims in Mayo left open the means of measuring the relevant metabolite. But the genetic assay is purely conventional pre-solution activity that cannot be used to circumvent eligibility under § 101.

The majority notes the claims here require treatment with iloperidone within the dosage range indicated, while the claims in Mayo could be infringed by treatment with thiopurine “whether that treatment does, or does not, change in light of the inference” indicated by the natural law. But that inquiry in Mayo also came as part of the search for an inventive concept, and requiring a dosage instead of indicating a dosage is not sufficient at step two. The difference is of no moment.

The majority points to the Supreme Court's statement in Mayo that “[u]nlike, say, a typical patent on a new drug or a new way of using an existing drug, the patent claims do not confine their reach to particular applications of those laws.” . … Whatever weight can be ascribed to the foregoing statement[] about methods of treatment, we remain beholden to the holding of Mayo, which, in my view, requires us to find the claims directed to a natural law at step one. (And I find no inventive concept in the claims once the natural law at issue is properly understood in view of Mayo.)

Subsequently, in Endo Pharm. Inc. v. Teva Pharm. USA, Inc., a unanimous panel of the Federal Circuit reversed a district court's decision finding claims directed towards a diagnostic method applicable to personalized medicine to be patent ineligible. ³⁸ The claimed invention is strikingly similar to the invention claimed in Mayo, the crucial distinction being that the Endo claims, like the Vanda claims, explicitly recite a step of administering a specific drug in accordance with the outcome of the diagnostic test. The claimed invention arose out of the inventor's discovery that patients suffering from renal impairment need less oxymorphone than non-renally impaired patients to achieve a similar level of pain management, and identified a statistically significant correlation between the degree of renal impairment, which can be measured by creatine clearance rate, and the optimal dosage of oxymorphone for that patient. A representative claim recites:

A method of treating pain in a renally impaired patient, comprising the steps of:

a. providing a solid oral controlled release dosage form, comprising:

i. about 5 mg to about 80 mg of oxymorphone or a pharmaceutically acceptable salt thereof as the sole active ingredient; and

ii. a controlled release matrix;

b. measuring a creatinine clearance rate of the patient and determining it to be

(a) less than about 30 ml/min,

(b) about 30 mL/min to about 50 mL/min,

(c) about 51 mL/min to about 80 mL/min, or

(d) above about 80 mL/min; and

c. 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;

wherein after said administration to said patient, the average AUC of oxymorphone over a 12-hour period is less than about 21 ng·hr/mL.

The Federal Circuit found the claims to be directed to a patent eligible method of using oxymorphone to treat pain in a renally impaired patient, a conclusion “supported by the claim language itself and confirmed by the specification.” In particular, the claims specifically recite “[a] method of treating pain,” and the specification “predominantly describes the invention as a method that treats renally impaired pain patients with less oxymorphone while still treating their pain.” The court found the claims to be “legally indistinguishable from the representative claim in Vanda.” Perhaps there is some significance to the fact that the decision was authored by Judge Stoll, one of the Athena dissenters who believes Mayo did not create a per se rule of patent ineligibility for diagnostic methods.

In a 2020 opinion authored by another Athena dissenter (Judge Moore), Boehringer Ingelheim Pharm. Inc. v. Mylan Pharm. Inc., a unanimous panel once again found the personalized medicine claims at issue to be patent eligible. ³⁹ The claims relate to the treatment and/or prevention of metabolic diseases such as type 2 diabetes mellitus with DPP-IV inhibitors such as linagliptin “in patients for whom normal metformin therapy is not appropriate … due to intolerability or contraindication.” A representative claims recites:

A method of treating and/or preventing metabolic diseases in a patient for whom metformin therapy is inappropriate due to at least one contraindication against metformin comprising orally administering to the patient a DPP-IV inhibitor wherein the contraindication is selected from the group consisting of: renal disease, renal impairment or renal dysfunction, unstable or acute congestive heart failure, acute or chronic metabolic acidosis, and hereditary galactose intolerance.

The district court, in a judgement on the pleadings, held the claims patent ineligible, finding them to be directed to an “abstract idea,” namely, “the act of administering the DPP-IV inhibitor to the targeted patient population,” and lacking an inventive concept. The Federal Circuit reversed, holding that, “consistent with this court's decision in [Vanda], the claims are directed to a particular method of treatment under step one and are therefore patent eligible.”

Note the similarity between the claimed method deemed patent ineligible in INO Therapeutics and the patent eligible method of Boehringer Ingelheim. In both cases the basis for the invention was a discovery that a particular therapeutic treatment is contraindicated for an identifiable patient population. In INO Therapeutics the therapeutic treatment was the administration of iNO, in Boehringer Ingelheim it was metformin. The key distinction I see between the claims is that the Boehringer Ingelheim claims recite a step of positively administering an alternative therapeutic, a DPP-IV inhibitor, while in INO Therapeutics the claims simply recite a negative step of not administering iNO.

In another 2020 decision, Illumina, Inc. v. Ariosa Diagnostics, Inc., Judge Lourie authored a divided decision upholding the patent eligibility of a diagnostic claim, this time by characterizing the claimed invention as a “method of [DNA] preparation,” as opposed to a method of diagnosis, and as such outside the stricture of Mayo. ⁴⁰ The named inventors on the patents at issue are the same as in Ariosa v. Sequenom, and the nature of the inventions in the two cases are similar. Recall that in Ariosa the claimed invention was based on the inventors' discovery of extracellular fetal DNA in maternal blood plasma. In Illumina, it is based on their discovery that there is a difference in the size of the maternal and fetal DNA present in maternal blood plasma. Based on this discovery, they developed a method of genotyping fetal DNA that involves extracting extracellular DNA from the blood plasma of a pregnant woman, enriching that sample for fetal DNA by selectively removing the relatively larger maternal DNA, and then analyzing a genetic locus in the fetal DNA-enriched sample. A representative claim recites:

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).

The district court judge (the same judge who decided Ariosa) found the claims to be patent ineligible and analogous to the claims ruled patent ineligible by the Federal Circuit in Ariosa. In both cases, the district court found, the claims are “directed to a testable quantity of genetic information found in nature,” and the end result of the claimed method is naturally occurring.

Notably, the patent claims at issue in Illumina were prosecuted post-Mayo, giving the patentee the opportunity to draft the claims in a manner presumably intended to avoid the appearance of a diagnostic method. During prosecution, the claims were rejected for patent eligibility, and the applicant filed a declaration stating that “[t]he claimed methods are not directed to a natural phenomenon—a difference in size of the maternal and fetal DNA in maternal blood plasma do[es] not result in a natural phenomenon.” ⁴¹ The declarant successfully argued that “the DNA in maternal blood plasma is not the size discriminated fraction produced by the claimed methods” and that “[t]he fetal and maternal DNA found in nature is structurally different and does not exhibit the discussed new utility. After size discrimination, the ratio of fetal DNA to maternal DNA changes and has a new value that does not exist in nature.” ⁴²

Judge Lourie's opinion reversing the district court in finding the claims patent eligible begins by emphasizing that:

This is not a diagnostic case. And it is not a method of treatment case. It is a method of preparation case. Under Mayo, we have consistently held diagnostic claims unpatentable as directed to ineligible subject matter. In contrast, we have held that method of treatment claims are patent-eligible. The claims in this case do not fall into either category, and we consider the claims under the Alice/Mayo test. [emphasis added]

The majority found it “undisputed that the inventors [had] discovered a natural phenomenon[,] i.e., that cell-free fetal DNA tends to be shorter than cell-free maternal DNA in a mother's bloodstream.” However, they went on to conclude that:

the claims are not directed to that natural phenomenon but rather to a patent-eligible method that utilizes it[, i.e.,] methods for preparing a fraction of cell-free DNA that is enriched in fetal DNA. The methods include specific process steps—size discriminating and selectively removing DNA fragments that are above a specified size threshold—to increase the relative amount of fetal DNA as compared to maternal DNA in the sample. … The claimed size thresholds are human-engineered parameters that optimize the amount of maternal DNA that is removed from the mixture and the amount of fetal DNA that remains in the mixture in order to create an improved end product that is more useful for genetic testing than the original natural extracted blood sample.

Moreover, the claimed methods achieve more than simply observing that fetal DNA is shorter than maternal DNA or detecting the presence of that phenomenon. The claims include physical process steps that change the composition of the mixture, resulting in a DNA fraction that is different from the naturally occurring fraction in the mother's blood.

The majority found meaningful distinctions between the Illumina claims and the claims at issue in Ariosa.

Judge Reyna dissented from the majority's decision to reverse. It bears noting that Judge Reyna authored the Ariosa decision, and concurred in the decision to deny en banc rehearing of Athena Diagnostics. In his Illumina dissent, he argues that:

The asserted claims are directed to a natural phenomenon, the patents' sole claimed advance is the discovery of that natural phenomenon, and the application of the natural phenomenon utilizes routine steps and conventional procedures that are well known in the art. … My conclusion that the method steps are directed to a natural phenomenon is bolstered by our precedent that looks to the “claimed advance” for determining whether a claim is directed to patent ineligible subject matter.

In Ariosa, we concluded that the claims were directed to a natural phenomenon relying, in part, on the patent's disclosure that the natural phenomenon was a “surprising and unexpected finding.” In Athena, we concluded that the claimed advance was “only in the discovery of the natural law” by relying, in part, on the patent's disclosure that the inventors “surprisingly found” the natural law. In Cleveland Clinic, we concluded that the claims were directed to a natural law relying, in part, on the patent's disclosure that “the inventions are ‘based on the discovery’” of the natural law.

Here, the claimed advance is 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. Like in Ariosa and Athena, the patent's written description identifies only the natural phenomenon as the “surprising finding.” And the patent explains that the natural phenomenon “forms the basis of the present invention,” like the patent in Cleveland Clinic. Id. at col. 2 ll. 1–6. It is undisputed that the surprising discovery is a natural phenomenon. The claimed advance is, therefore, the discovery of the natural phenomenon.

Judge Reyna seems to be on solid ground when he argues that the outcomes in Ariosa and Illumina are inconsistent. For example, consider claim 24 of U.S. Patent Number 6,258,540, one of the claims ruled ineligible in Ariosa:

24. A method for detecting a paternally inherited nucleic acid on a maternal blood sample, which method comprises: removing all or substantially all nucleated and anucleated cell populations from the blood sample, amplifying a paternally inherited nucleic acid from the remaining fluid and subjecting the amplified nucleic acid to a test for the Paternally inherited fetal nucleic acid. [emphasis added]

In Illumina, the majority justified its decision by pointing out that the claims involve a process step of “selectively removing DNA fragments that are above a specified size threshold—to increase the relative amount of fetal DNA as compared to maternal DNA in the sample.” I do not see how this is meaningful distinguishable from claim 24's step of selectively removing cell populations from a blood sample to increase the relative amount of fetal DNA as compared to maternal DNA.

In Abbott Lab'ys v. Grifols Diagnostic Sols. Inc., a district court recently denied a motion to dismiss based on the alleged infringers assertion that the asserted patent claims are patent ineligible. ⁴³ The claims are directed towards methods of replicating HIV-specific DNA, the sort of claim Judge Lourie might characterize as a “method of preparation.” In this case, the diagnostic products accused of infringing the patent do not directly employ the replicated DNA, but rather the replicated DNA is used to produce proteins that are used as reagents in the accused tests (Abbott's PRISM HIV O Plus assay and ARCHITECT HIV Ag/Ab Combo assay).

A representative claim at issue in the case recites:

A method for replicating DNA specific for HIV, which comprises:

(a) providing a DNA construct comprising an origin of replication recognized by a unicellular microorganism and a DNA sequence comprising at least a 20 bp sequence of a human immunodeficiency virus (HIV) genome; and

(b) growing a unicellular microorganism containing said DNA construct under conditions whereby said DNA sequence is replicated[,]

wherein the unicellular microorganism is a bacterial cell.

I think it is interesting to consider whether some of the claims that the Federal Circuit has ruled patent ineligible in recent years (In re BRCA1- & BRCA2 or Ariosa, for example) would survive post-Illumina if the specification and claims had been drafted to emphasize that the claimed invention is primarily a method of preparing DNA as opposed to a method of analyzing the resulting DNA. Perhaps they would, depending upon which Federal Circuit judges decide the issue.