Patenting Diagnostics and Biomarkers Six Years After <i>Mayo</i>In 2012, the U.S. Supreme Court decided the landmark case of Mayo Collaborative Services v. Prometheus Laboratories, Inc., 566 U.S. 66 (2012), which was hailed by some as banning patents on methods of medical diagnosis. It appeared to be the end of the road for the development of personalized medicine for profit, at least in the United States. However, in the years since the lower courts have interpreted Mayo to still allow inventors to patent certain diagnostics and biomarkers, but only to a limited extent. 2018 has been a very active year for judicial decisions on this topic (there were at least four significant decisions this year).

THE PRE-2018 LANDSCAPE

The U.S. Court of Appeals for the Federal Circuit (CAFC) is the highest court that decides patent questions below the Supreme Court.  Like the Supreme Court, the CAFC interprets diagnostics inventions to concern three types of subject matter that cannot be patented: natural laws (such as the relationship between an analyte and a disease), natural phenomena (such as genes), and abstract mental steps (such as reaching diagnoses based on observations). The CAFC made two critical decisions that have controlled their later decisions: Ariosa Diagnostics, Inc. v. Sequenom, Inc. in 2015 and Classen Immunotherapies, Inc. v. Biogen Idec in 2011 (before Mayo but after the Supreme Court’s decision in Bilski v. Kappos).

In Classen the invention was a method of designing a schedule of immunizations to reduce the occurrence of side effects, coupled with administering the immunizations according to the schedule. Although calculating the schedule was held to be an unpatentable abstract mental step based on an unpatentable natural law, but because immunizing patients was a concrete step and following the inventive schedule was neither conventional nor well-understood, the court decided that it added an “inventive concept” to the understanding of the natural law underlying the relationship between the immunization schedule and the side effects. Therefore the invention could be patented.

In Sequenom the invention was a method of fetal genetic testing by amplifying free paternal DNA from the mother’s blood. There was no evidence that anyone had ever conceived of testing a pregnant woman’s blood for fetal DNA (paternal or otherwise) for any purpose. No abstract steps were involved. The ability to amplify paternal DNA was considered to be nothing more than a recognition of a natural phenomenon: that fetal DNA is present in the mother’s bloodstream. The CAFC decided that additional limitations, such as the use of the polymerase chain reaction (PCR), were too well known and conventional to add any inventive concept to the recognition of the natural phenomenon. Although the CAFC recognized that the invention in question was quite brilliant and highly useful, replacing the risky procedure of amniocentesis with a simple blood test, they famously repeated the Supreme Court’s commandment that “groundbreaking, innovative, or even brilliant” inventions do not necessarily involve an “inventive concept” under the law.

DEVELOPMENTS IN 2018

This year the CAFC built on its own decisions and the Supreme Court’s decisions in Roche Molecular Systems, Inc. v. Cepheid, Vanda Pharmaceuticals v. Aventisub, LLC, and Exergen Corp. v. Kas USA, Inc. In addition, the U.S. District Court for the District of Delaware rendered an interesting decision in Mallinckrodt Hospital Products IP Ltd. et al. v. Praxair Distribution, Inc. in December of 2017.

Vanda

Of these new decisions, Vanda is the most significant. It involved a patent for treating schizophrenia patients with iloperidone that is tied to genotyping the patient to determine the patient’s tolerance for iloperidone. More specifically, the inventors discovered certain cytochrome P450 2D6 genotypes that indicate poor metabolism of iloperidone that increases the patient’s risk of cardiac complications of iloperidone treatment for doses of about 12 mg/day. The claims comprised determining whether the patient had the poor metabolizer gene, administering 12 mg/day or less iloperidone if the patient has the poor metabolizer gene, but otherwise administering 12-24 mg/day iloperidone.

The CAFC found the claim to be patent eligible, essentially for the same reason that the immunization method in Classen was patent eligible: treating a patient according to a diagnosis is more than just the diagnosis itself. This decision squarely reaffirms Classen’s holding on methods of treating or preventing disease.

Roche v. Cepheid

On the other hand, in Roche v. Cepheid, the CAFC considered the opposite situation: a patent for a breakthrough test to detect the bacterium that causes tuberculosis and simultaneously determine the bacterium’s drug resistance, but that was not coupled to any form of treatment or intervention.  Specifically, the claims in Roche involved a PCR test for Mycobacterium tuberculosis that also reports certain mutations that confer rifampicin resistance, and specific primers for use in the test. The CAFC found that the primers themselves were “natural phenomena,” because the nucleotide sequence was identical to natural nucleotide sequences found in M. tuberculosis. The CAFC then found that using the primers in PCR to detect the bacterium did not add an inventive concept to the primers themselves, because PCR is a routine procedure in medical diagnostics. In the absence of any treatment step, the claims were found invalid.

You can read more about Roche v. Cepheid here.

Exergen

The invention in Exergen was slightly different: it involved a method of calculating body temperature by measuring the peak radiant heat over the skin of an artery, and an electronic thermometer configured to execute the method. An exemplary claim reads as follows:

A method of detecting human body temperature comprising making at least three radiation readings per second while moving a radiation detector to scan across a region of skin over an artery to electronically determine a body temperature approximation, distinct from skin surface temperature.

The CAFC found this method to be patent eligible. They found the claims were directed to the law of nature that physiologic core temperature is a function of skin temperature above an artery and ambient temperature; but also found that the specific method of measuring body temperature based on these two factors, combined with the unconventional method of measuring radiant heat at least three times per second, added an inventive concept to the application of the natural law. The invention was not only the discovery of the relationship between core temperature, air temperature, and skin temperature above an artery, but it was also a new and more accurate way of measuring the skin temperature.

You can read more about the Exergen decision here.

Mallinckrodt

A lower court made a decision at the end of 2017 that is inconsistent with Classen and Vanda in Mallinckrodt Hospital Products IP Ltd. et al. v. Praxair Distribution, Inc. In that case the inventors discovered that infants with impaired function of the left ventricle are at elevated risk for pulmonary edema if treated with nitric oxide (which is used to treat neonatal hypoxia). The U.S. District Court for the District of Delaware considered claims for treating hypoxic newborns using nitric oxide, if and only if an echocardiogram shows that the newborn is not also suffering from left ventricular dysfunction. The district court judge concluded that the claims were not eligible for patenting, because nitric oxide treatment is a conventional hypoxia treatment. Classen involved conventional immunizations, administered according to a new schedule. Vanda involved a conventional schizophrenia treatment, administered according to new criteria. The district court’s decision in Mallinckrodt does not seem readily reconcilable with these appellate court decisions, and could be reversed on appeal.

You can read more about the Mallinckrodt decision here.

HOW CAN DIAGNOSTICS AND BIOMARKERS BE PATENTED NOW?

Although the CAFC has created relative certainty in terms of what can be patented, it also introduces some serious complications to obtaining effective patent rights. There are a few apparent strategies for patenting diagnostics and biomarkers, but each has attendant drawbacks.

Methods of Treatment/Prevention Tied to the Test

As discussed above, Classen set a precedent that methods of treatment or prevention of disease tied to diagnostic methods are eligible for patenting. The USPTO recognizes this rule in their guidance documents (see Claims 5-6 in Example 29 in “Subject Matter Eligibility Examples: Life Sciences”). However, claims for such methods can be complicated to enforce. In order for patent infringement to occur, the patented method must either be performed by one person in its entirety, or performed by multiple parties all under the control or direction of a single party. When a patient is treated based on the result of a diagnostic test, often the diagnostic test is performed by a contract laboratory and the treatment is provided by a physician. Physicians are unattractive targets for patent infringement lawsuits, both because they are usually the customer base of the patented product (and nobody likes to sue their customers) and because they have limited immunity from patent infringement under 35 U.S.C. § 287(c). Even if the physician ordered the test (and so the test was performed under the physician’s direction and control), suing the physician might not be desirable or possible. It might be argued that the testing lab induced the physician to both order the test and administer the treatment, but such an argument failed in Cleveland Clinic Foundation v. True Health Diagnostics LLC.

In Cleveland Clinic, the Clinic had determined that lipid lowering drugs are particularly effective in patients with elevated myeloperoxidase (MPO) activity. Accordingly, their patent claimed testing a patient for MPO activity, then administering a lipid lowering drug if MPO activity was elevated. The CAFC found the claim to be patent eligible under the Classen rule, but found that the testing lab had not infringed. The doctor had performed the step of administering the drug, and the testing lab did not direct him to do so. This fact pattern is likely to come up in numerous situations. Accordingly, when using this approach, patents should be carefully drafted to attempt to include only steps that will be performed by one party.

Novel Way of Measuring the Analyte

As Exergen teaches, a novel way to measure a recognized property or analyte can still be patented, even if not tied to a diagnostic step (see Claims 3-4 in Example 29 in “Subject Matter Eligibility Examples: Life Sciences”). This includes new assays, reagents, protocols, and equipment. Claims to a specific way to measure the analyte have the inherent weakness that others can simply measure the analyte in some other way to evade patent infringement. This risk can be mitigated if the test requires FDA approval, as approval can be sought only by the patented method. This tactic will not work if another party seeks separate approval using another method, so it is not foolproof.

Measuring the Analyte Without a Diagnostic Step

The USPTO has taken the position that steps to measuring an analyte can be patented, in the absence of any diagnostic or other mental steps. In Claims 1 and 7 of the USPTO’s Example 29 in “Subject Matter Eligibility Examples: Life Sciences,” steps of determining the concentration of an imaginary analyte are recited without any treatment or diagnosis step. The USPTO’s analysis is that, without a diagnosis step, the claim does not involve a mental step or a natural phenomenon. So far no judicial opinions support or refute this position. Without judicial affirmation, this might be a useful secondary way to patent a diagnostic test. However, it will only be effective if the analyte has never been measured before in a patient, at least not in the manner as claimed. Otherwise the claim, although directed to patent eligible subject matter, will lack novelty. There is also significant risk that the courts might not adopt the USPTO’s analysis of the eligibility of this type of claim.

Look to Foreign Markets

The complex and vague constraints U.S. courts have placed on patents for diagnostics and biomarkers are unique to the United States. Most other developed nations allow diagnostic tests to be patented in some form or another. For example, in Europe diagnostics tests may be patented, so long as they are performed outside of the patient’s body. Therefore, when preparing patent applications for diagnostics tests, those hoping to enter the European market should make it clear if the test can be performed ex vivo. Other developed countries have their own conventions that must be considered. Overall, the difficulties of patenting diagnostic tests in the U.S. should guide the development of new tests to focus on the needs of developed countries apart from the U.S.

THE OUTLOOK FOR THE FUTURE

At present there is no immediate prospect for changes in U.S. law that would return us to the regime that was in place until the Mayo decision. Mayo and Myriad changed U.S. law in ways that have put us out of step with the rest of the world and in violation of the Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS). Ironically, the United States expended significant diplomatic capital to create the TRIPS regime and other treaties to increase the international harmonization of patent law. Although several pro-inventor organizations have proposed legislative changes to return the U.S. to the original patent regime, none have been introduced in Congress so far. However, efforts have begun in Congress to strengthen America’s patent laws by reversing certain aspects of the America Invents Act of 2011. It is possible that amid these efforts proposals to improve patents for diagnostic tests and personalized medicine could be introduced. Of course, this blog will update the reader with news of any such developments.

In 2011 the Supreme Court announced that methods of diagnosing disease are ineligible for patenting under its landmark decision, Mayo Collaborative Services v. Prometheus Laboratories, Inc., 566 U.S. 66 (2011). The decision, authored by Justice Stephen Breyer, reasoned that measuring the concentration of a biomarker (in that case a drug metabolite) and diagnosing a patient as either overdosed or under-dosed is nothing more than making a decision based on a natural law. This was the first of three major Supreme Court decisions remaking U.S. patent law to exclude many forms of biotechnology and information technology (the other two being Association for Molecular Pathology v. Myriad Genetics, 133 S.Ct. 2107 (2013) and Alice Corp. v. CLS Bank Int’l, 134 S.Ct. 2347 (2014)). A recent decision by a federal district court, Mallinckrodt Hospital Products IP Ltd. et al. v. Praxair Distribution, Inc., Case No. 15-170-GMS (D. Del., Sep. 5, 2017), imposed new restrictions on how these decisions are applied to diagnostic methods.

The Alice Test for Patent Eligibility

The current test for subject matter eligibility under these decisions (as restated in Alice) has been described as a two-part test, but in fact the test has three distinct parts. The first step is to determine whether the claim is one of the categories of subject matter Congress intended should be patented, as expressed in 35 U.S.C. § 101: “any new and useful process, machine, manufacture, or composition of matter, or new and useful improvement thereof” (the “statutory categories”). If the first answer is “no,” then the claim is not eligible subject matter. If the first answer is “yes,” the second step is to determine whether the claim is “directed to” one of the judge-made exceptions to the statutory categories: an abstract idea, a physical phenomenon, or a law of nature. If the second answer is “no,” then the claim is eligible. If the second answer is “yes,” then the third step is to determine whether the claim as a whole encompasses “substantially more” than the judicial exception itself. Finally, if the answer to the third step is “yes,” then the claim is patent eligible; if it is “no,” then the claim is not patent eligible.

Treatment Based on Diagnosis Prior to Mallinckrodt

Decisions following Mayo generally concluded that an invention involving the diagnosis of a disease is eligible for patenting if it involves another unconventional step, such as administering a course of medication based on the diagnostic step. A treatment step is considered to add “substantially more” to the claim, particularly when the treatment depends on the diagnosis. Such decisions follow the Federal Circuit’s decision in Classen Immunotherapies, Inc. v. Biogen Idec, 659 F.3d 1057 (Fed. Cir. 2011). In Classen the invention was a method of designing a schedule of immunizations to reduce the occurrence of side effects, coupled with administering the immunizations according to the schedule. Because immunizing patients is a concrete step, and because following the inventive schedule was neither conventional nor well-understood, the court decided that it added “substantially more” to the claim than just the understanding of the natural law underlying the relationship between the immunization schedule and the side effects.

The Classen rule is followed by the USPTO, which incorporated a similar example in its official guidance on subject matter eligibility (Subject Matter Eligibility Examples: Life Sciences, May 4, 2016), and cites Classen in its patent examiner’s manual (see MPEP 2106.05(e), inter alia). In Example 19 of the Life Sciences Examples, a hypothetical claim is presented for performing a diagnostic test that distinguishes between two frequently confused diseases (julitis and rosacea) followed by administering a treatment for julitis (that is ineffective against rosacea) if the biomarker is present. The public has of course relied upon the Classen decision, the MPEP, and the USPTO’s guidance in evaluating whether diagnostic technologies can be patented.

In a later decision by the Federal Circuit, claims for diagnosis alone were held ineligible, but the patent eligibility for accompanying claims for treatment based on a diagnosis were not even challenged by the accused infringer. See Cleveland Clinic Foundation v. True Health Diagnostics LLC, Case No. 2016-1766 (Fed. Cir., June 16 2017).

The Conflicting Mallinckrodt Decision

Infant being examined in an incubatorIn a departure from the previous trend, a district court judge in the Federal District Court of Delaware (one of the more influential patent venues) held that diagnosing a disease followed by treating the disease based on the diagnosis is not eligible for patenting.

In Mallinckrodt, the district court considered claims to a method of treating hypoxia in newborns with nitric oxide while reducing the risk of a deadly side effect, pulmonary edema. The inventors discovered that infants with impaired function of the left ventricle are at elevated risk for pulmonary edema if treated with nitric oxide. The asserted claims of the patents in suit included claims to diagnosing a hypoxic infant for left ventricular dysfunction by echocardiography, and administering an appropriate concentration of nitric oxide only in the absence of left ventricular dysfunction. As in Classen, the claims involved a medical intervention based on the result of the diagnostic step. Unlike Classen, the trial court in Mallinckrodt held that the use of previously known treatment methods based on the diagnosis does not add “significantly more” to the understanding of the natural law.

The trial court found that the connection between left ventricular dysfunction and an infant’s vulnerability to pulmonary edema when given nitric oxide is an ineligible law of nature, and that administering nitric oxide only when left ventricular dysfunction is absent is not “substantially more” than recognizing the connection, because nitric oxide is a conventional and well-understood treatment for hypoxia. The court found that echocardiography as the method of detecting left ventricular dysfunction did not add “substantially more” to the claim, either, because echocardiography was also a conventional and well-understood way to detect left ventricular dysfunction.

Oddly, the court in Mallinckrodt neither cited nor considered Classen. Although it cited Cleveland Clinic, the important distinction between the claims that included the treatment step and those with only the diagnosis step was not discussed or even recognized. This decision then appears to conflict with Classen, and without any analysis of Classen in Mallinckrodt it can only be guessed why the two decisions diverge (apart from the usual lack of judicial consistency when it comes to patent eligibility). In Classen the immunizations, while claimed at a high level of generality, were administered according to a new and unconventional schedule. In Mallinckrodt, a known treatment (nitric oxide) was claimed to be withheld from a certain population of patients, which was new and unconventional. In both cases the drugs themselves were well-known, but the pattern of whether and when to administer the drugs was not. One distinction between the inventions in these cases is that Mallinckrodt involved a binary decision to “administer or not administer” the drug, while Classen involved chronologically scheduling the administration of the drug. If the lesson of Mallinckrodt is that providing or withholding a given treatment based on a diagnosis is not “significantly more” than the treatment itself, then it conflicts with the USPTO’s public guidance in the MPEP and the Life Sciences Examples.

Does Mallinckrodt Change Anything?

The trial court’s decision has been appealed to the U.S. Court of Appeals for the Federal Circuit, which is the appeals court with jurisdiction over all patent appeals. If the Federal Circuit adopts Mallinckrodt and abandons Classen, it will deal another significant blow to those developing advanced diagnostic methods. At the very least it would call into question the settled understanding of the public (and the officials at the USPTO) that methods of treatment tied to methods of diagnosis can still be patented. However, even if the decision in Mallinckrodt is affirmed, planning the funeral for American diagnostic patents may be premature. For those who value predictability in the application of the law, it may be hoped that the Federal Circuit will either reverse the decision in Mallinckrodt, or somehow reconcile these cases.