Photo of Nicholas J. Landau, Ph.D.

Dr. Nicholas Landau is experienced in the procurement, protection, and litigation of patents, trademarks, and other forms of intellectual property. He has drafted, prosecuted, and successfully appealed dozens of patent applications. Dr. Landau has worked with patents in a broad array of technological disciplines and has extensive knowledge in the areas of biotechnology, pharmaceuticals, nutraceuticals, and environmental technology. View articles by Nicholas

B.S. Environmental Science
Ph.D. Environmental Science with a Concentration in Environmental Microbiology

Patent Registration Number: 57,120

Rules for Patenting Genetic Biomarkers Are Updated in Roche v. CepeidAs the readers of this blog are no doubt aware, patenting DNA defined only by a naturally occurring nucleotide sequence was banned by the U.S. Supreme Court in the landmark case of Association for Molecular Pathology v. Myriad Genetics, Inc. The patentee in that case attempted to patent “isolated” DNA with the natural sequence of the BRCA1 breast cancer gene. The Supreme Court believed this was an attempt to claim the natural gene itself, which it believed to be an ineligible “natural phenomenon.” Prior to this decision, newly discovered DNA sequences could be patented, so long as they were claimed to be “isolated” from their original host organism.

However, the Supreme Court opinion specifically left open the possibility that artificial methods of using natural DNA could still be patented; some of Myriad’s claims were for such methods, and their eligibility for patenting was unchallenged, and thus not directly consider by the court.

The Supreme Court in Myriad also did not consider whether properties of artificial DNA other than its sequence could distinguish it from a natural product. The patentee in Myriad had simply relied on the magic word “isolated” to draw a distinction between its invention and what is natural, and the Supreme Court was not enchanted.

Questions have lingered over to what extent artificial processes using DNA can be patented, and to what extent DNA with a natural sequence but other artificial properties can be patented. The U.S. Court of Appeals answered both questions in the October 9 decision in Roche Molecular Systems, Inc. v. Cepheid.

The invention in Cepheid arose from the discovery of unique genetic biomarkers found in the pathogenic bacterium Mycobacterium tuberculosis. M. tuberculosis is the causative agent of tuberculosis, one of the most devastating diseases. Roche patented, among other things, primer sets for polymerase chain reaction (PCR) that are complementary to the biomarker sequences, and the process of detecting the biomarkers through use of PCR.

In the past the Federal Circuit has considered other patents that claim PCR primers having natural sequences, and the process of performing PCR with them, concluding they are not patent eligible. However, this case is different: In this case the natural DNA sequence is found on a circular DNA chromosome. M. tuberculosis, like all bacteria, has a single circular chromosome, unlike eukaryotes, which have linear chromosomes. In contrast, PCR primers must be linear, or they cannot function to prime DNA polymerization during PCR.

Therefore, Roche argued that the patent claims were directed to DNA that is not identical to the natural DNA in the bacterium, and so it is not a “product of nature.” The Federal Circuit disagreed. It cited In re BRCA1- & BRCA2-Based Hereditary Cancer Test Patent Litig. for the proposition that an abbreviated segment of a longer piece of natural DNA is no different from the natural DNA. Roche pointed out that the BRCA1 & BRCA2 case involved natural DNA on a linear molecule, not natural DNA on a circular molecule, as in the case at bar. The Federal Circuit found this structural distinction to be of no importance, opining “the subject matter eligibility inquiry of primer claims hinges on comparing a claimed primer to its corresponding DNA segment on the chromosome—not the whole chromosome” (emphasis from original). This would seem to be somewhat at odds with the statement elsewhere in the opinion that the presence of a free 3’ hydroxyl group on the claimed PCR primer does not distinguish the primer from the natural DNA, as this is a chemical difference with the corresponding DNA segment. The Federal Circuit’s position could be interpreted to mean that the nucleotide sequence of the natural DNA segment is the only thing that matters, to the exclusion of any other chemical or physical property of the molecule, because courts have interpreted the nucleotide sequence to embody the “information” that is the critical function of DNA. This line of reasoning could logically be extended to ban patenting of artificial polynucleotides such as locked nucleic acid and morpholinos (although to date no court has so held). Alternatively, the decision could be read to mean eligibility requires a difference between the natural and artificial DNA that affects the functioning of the invention – in this case the circularity of the entire genome hosting the natural sequence was of no consequence to the functionality of the sequence as a PCR primer.

For the first time this decision considered whether artificial DNA with an identical sequence to what is natural, but a different higher order of structure, can be patented. This decision reaffirms that PCR performed with a primers complementing a previously unknown, but naturally occurring nucleic acid sequence, cannot be patented, regardless of whether something about the gross structure of the natural genome could have prevented its use as a primer. The reason for this conclusion seems to be that the higher level structure of the natural DNA does not affect the functioning of the claimed primer, by itself or as used in PCR. It is possible that other chemical differences between a natural DNA molecule and an artificial DNA molecule with the same sequence could still distinguish the artificial DNA from its natural counterpart.

The Roche patent in this case was drafted many years before the Supreme Court’s Myriad ban went into effect, during which time it was unquestionably patent eligible subject matter. This may be why Roche’s arguments have the definite sound of post-hoc rationalizations, because the patent was not drafted with the goal of satisfying the Myriad standard. Those present patent applicants, with the luxury of being forewarned, should consider this case a lesson. Reliance on the differences in the gross structure of the chromosome in which a natural sequence is found and the claimed DNA may be misplaced. Instead, seek to rely on differences in the primary structure (nucleotide sequence), conjugation between natural nucleic acids (DNA and RNA) with synthetic moieties (such as fluorophores, etc.), or chemical differences in the nucleotides themselves (such as LNA or triplex molecules). Last but not least, remember that the Myriad ban is not the law in most major jurisdictions outside of the United States, and consider such foreign markets when planning your patenting strategy.

Inventors of methods of medical testing have had a rough time since the Supreme Court decided Mayo Collaborative Services v. Prometheus Labs. Inc. In the Mayo case, the Court considered whether a method of determining whether a patient is receiving the proper dosage of thioguanine drugs is eligible for patenting, when the method involved measuring the concentration of a specific metabolite of thioguanine in the patient’s blood. The inventor had determined the safe range of dosages was not based not on the dosage itself (which varied a great deal from person to person), but depended on the concentration of the metabolite. The Court concluded that the patent merely claimed a relationship between metabolite concentration, safety, and efficacy of the drug, which without more is not an invention.

Since Mayo was decided, courts have invalidated numerous medical testing patents as subject matter that is not eligible for patenting (See, e.g., Cleveland Clinic Foundation v. True Health Diagnostics, LLCGenetic Tech. Ltd. v. Merial LLC, Ariosa Diagnostics, Inc. v. Sequenom, Inc., SmartGene, Inc. v Advanced Biological Labs.,  and PerkinElmer Inc. v Intema Ltd.).

A Rare Win for a Medical Testing Patent in <i>Exergen Corporation V. Kaz USA, Inc.</i>This makes the recent decision by a panel of the U.S. Court of Appeals for the Federal Circuit in Exergen Corp. v. Kas USA, Inc. something of a unicorn. Exergen patented a forehead thermometer that functions by measuring the radiative output of the skin at least three times per second, identifying a peak temperature that indicates that the thermometer has passed over an artery, and executing an algorithm based on the peak temperature and the ambient air temperature to calculate the patient’s core body temperature. Some of the asserted patent claims included the limitation that the artery is the temporal artery (located in the side of the forehead). The Exergen thermometer has the advantage over prior art thermometers of measuring a patient’s core temperature noninvasively, a benefit every parent can appreciate. Several companies, including Kaz, offered similar forehead thermometers, and Exergen filed several infringement suits in the U.S. District Court for the District of Massachusetts, which were consolidated only for claim construction purposes. Among other defenses, Kaz alleged that all of Exergen’s asserted patent claims were invalid as non-eligible subject matter for patenting under the Mayo decision.

The Trial Court Decision

At trial the judge ruled from the bench that the asserted claims were eligible subject matter as a matter of law. The jury found that Kaz infringed the patents and awarded damages. On appeal Kaz argued that the trial court had impermissibly decided the question of patent eligibility without sending the relevant factual questions to the jury, and, in the alternative, that Exergen’s claims were not patent eligible as a matter of law.

The Appellate Decision

Among the claims at issue were both method claims and apparatus claims. Claim 24 of the ‘685 was considered by the appellate court as typical of the apparatus claims, and reads as follows:

A body temperature detector comprising:

a radiation detector; and

electronics that measure radiation from at least three readings per second of the radiation detector as a target skin surface over an artery is viewed, the artery having a relatively constant blood flow, and that process the measured radiation to provide a body temperature approximation, distinct from skin surface temperature, based on detected radiation.

Note that the electronics are defined mainly by their function. Claim 14 of the ‘938 was considered by the appellate court as typical of the method claims, and reads as follows:

  1. 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 court applied the general test in Alice for patent eligibility (readers of this blog can review the Alice test here). The court found that the claims fell under the categories of subject matter Congress intended should be patented, as expressed in 35 U.S.C. § 101, as “machines” and “processes.” The court went on to conclude the claims were “directed to” one of the judge-made exceptions to the statutory categories, specifically the “law of nature” that physiologic core temperature is a function of skin temperature above an artery and ambient temperature. Based on these two conclusions, a claim would not be eligible for patenting unless as a whole it encompasses “substantially more” than natural law itself.

Kaz argued that the claims were not substantially more than the simple recognition of the relationship between skin temperature above an artery, ambient temperature, and core temperature. In Kaz’s view, the remaining parts of the claims were “conventional, well understood” elements. In support of this argument, Kaz cited the undisputed fact that the use of infrared radiation measurements of the skin to detect internal injuries was known before Exergen’s invention, and such measurements were made at a rate exceeding three readings per second.

The appellate court disagreed with Kaz’s argument and affirmed the district court’s finding that the claims were directed to substantially more than the natural law. Regarding the older method of detecting internal injury, the court pointed out that “Something is not well-understood, routine, and conventional merely because it is disclosed in a prior art reference… This case is not like either Mayo or Ariosa, where well-known, existing methods were used to determine the existence of a natural phenomenon.” In other words, the inventors in Mayo and Ariosa identified the relationship between an analyte and a condition, and claimed measuring the analyte by only well-understood, routine, and conventional methods (in Mayo the broadest claims were not specific to the measurement methods at all). Exergen’s claims included an unconventional method of determining core body temperature, which was novel independent of the recognition of the specific relationship between the temperature of the skin above an artery and the patient’s core body temperature. Although body radiation sensors were known, none had been configured to convert skin temperature to core temperature; although methods of measuring skin temperature with a radiation sensor were known, none had specifically measured skin temperature above and artery and converted it to core temperature.

How Does Exergen Fit with Current Case Law?

Comparing Exergen to Mayo, in Mayo the measurement of the metabolite was claimed generally, not by any specific method, conventional or otherwise. Measuring the metabolite was well-known and conventional. The claims in Mayo thus involved only a well-known and conventional step, in combination with reaching a diagnosis. Although the criteria used for the diagnosis were not previously known, others had tried to use the metabolite concentration to diagnose the same condition using different criteria. In contrast, Exergen claimed steps that had never been performed before — measuring skin temperature over an artery by radiometry, in addition to the more abstract steps of calculating core temperature.

The distinctions between this case and Ariosa are more subtle, and the two cases might seem inconsistent. The patent in Ariosa did claim steps that had never been performed before; namely, it recited amplifying paternal DNA in a maternal whole blood sample. The court focused on the fact that the paternal DNA was claimed to be measured by conventional methods (polymerase chain reaction), so that nothing substantial was added to the concept of measuring the paternal DNA itself. In Exergen, the court defined the measured property as body core temperature, and found that it was neither routine nor conventional to measure body core temperature as claimed. However, if the court had considered ultra-arterial skin temperature to be the measured property, instead of core temperature, it might have concluded that the claimed steps were conventional and well-understood ways of measuring it.

This distinction can serve as guidance going forward: Defining exactly what is being measured can be determinative of the Alice analysis of medical tests. Those seeking to patent or defend medical testing claims could benefit from defining the measured property narrowly. Alternatively, those seeking to invalidate medical testing patents should seek to define the measured property broadly as something that has been measured before in the same way. For example, does the invention measure core temperature by measuring ultra-arterial skin temperature by radiometry, or does it measure skin temperature by radiometry? The latter steps were known in the prior art, while the former were not.

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.