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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 a decision issued by the Federal Circuit on October 24, 2018, the court affirmed a finding by the Patent Trial and Appeal Board (PTAB) that a multiple sclerosis (MS) treatment claimed in A Morass of Possible Combinations Does Not Satisfy the Written Description Requirement under 35 U.S.C. § 112an application owned by FWP IP APS (FWP) was not supported by adequate written description under 35 U.S.C. § 112. While the non-precedential nature of the decision might have indicated to some that the dispute was not all that important, the claims in dispute relate to Biogen’s blockbuster drug Tecfidera, which accounted for over a billion in sales for Biogen last year. As a result of the Federal Circuit’s ruling, Biogen’s patent for Tecfidera remains intact and FWP will not be able to realize its goal of collecting future royalty payments on sales of Tecfidera from Biogen. In addition, the opinion itself serves as a reminder for patent practitioners that laundry lists and kitchen sinks are better suited for households than patent applications.

Background

The case arises from an interference between the named parties, FWP and Biogen. Biogen owns U.S. Patent No. 8,399,514 (the ʼ514 patent), which describes and claims a specific method of treating MS with a daily dosage of 480 mg of fumaric acid esters (fumarates). Prior to the filing of Biogen’s application that issued as the ʼ514 patent, FWP filed a patent application (U.S. Application No. 11/576,871 (the ʼ871 application)) disclosing controlled-release compositions of fumarates. Upon issuance of Biogen’s ʼ514 patent, FWP canceled the then-pending claims in the ʼ871 application and added new claims that closely tracked to Biogen’s ʼ514 patent claims.  The PTAB declared an interference between FWP’s application and Biogen’s ʼ514 patent.

The PTAB distilled the interference count down to three main limitations: (1) an MS treatment, (2) by oral administration of a therapeutically effective amount of dimethyl fumarate and/or monomethyl fumarate, at (3) a specific dosage of 480 mg per day. Biogen moved the PTAB for a judgment that FWP’s claims were not adequately supported by the ʼ871 application’s specification. The PTAB ruled in Biogen’s favor and held that, even though each of the claim limitations were generally mentioned in FWP’s specification, the specification did not disclose the claimed invention in a manner that adequately described the claimed MS treatment to a skilled artisan and thus, the ʼ871 application did not meet the written description requirement.  FWP appealed.

The Federal Circuit’s Decision

Not surprisingly, the Federal Circuit affirmed the PTAB’s decision. While the court agreed with the PTAB that the ʼ871 application identified dimethyl fumarate and/or monomethyl fumarate as useful for treating a large number of described conditions (including MS) and that a dosage of 480 mg per day was generally disclosed, the court held that the ʼ871 application did not adequately teach a specific treatment of MS at a dosage of 480 mg per day.

In addressing the treatment of MS, the court noted that the ʼ871 application merely states that the fumarates in general are “contemplated to be suitable to use in the treatment of one or more of the following conditions.” While the “following conditions” were further described to include over 20 diseases and conditions including, for example, psoriasis, psoriatic arthritis, inflammatory bowel disease, and autoimmune diseases (including MS as one of the 11 listed), the only conditions discussed in any detail in the ʼ871 application were psoriasis and conditions associated with psoriasis. The court determined that, based on the laundry list of diseases and conditions discussed and the wide variability of the pathophysiologies of each of those listed diseases and conditions, the inventors of the ʼ871 application had yet to definitively conclude at the time of invention that fumarates and, more specifically, dimethyl fumarate and/or monomethyl fumarate, were effective for treating all of the 20 diseases and conditions identified.

The court came to a similar conclusion with respect to the dosage requirement. FWP argued that a table in the ʼ871 application expressly discloses a dosage of 480 mg per day during the seventh week of a contemplated nine-week scale-up period and a skilled artisan would have recognized that all of the listed dosages in the table are therapeutically effective dosages for all of the conditions and diseases listed. However, the court disagreed and determined that FWP failed to provide any persuasive evidence why a skilled artisan would have understood that a dosage for only one of the weeks in the nine-week scale-up period would be therapeutically effective for treating MS. Rather, the court determined that the table was simply providing guidance on gradual dosing to help patients’ gastrointestinal systems acclimate to the side effects of fumarates.

Interestingly, in a last attempt to save the claims, FWP further argued that the original claims, which FWP canceled and replaced with new claims to provoke the interference, provided sufficient support for the claims in the interference. Like the PTAB, the court found that the large number of disease conditions, dosages, active ingredients, and pharmaceutical formulations covered in the original claims detracted from FWP’s argument that it possessed and invented the claimed, specific MS treatment. Moreover, the court took issue with the improper multiple dependent format in which the original claims were written, stating “[f]inding a treatment for MS with 480 mg of DMF and/or MMF per day in the morass of possible combinations of the impermissibly drafted original claims would … take ‘the patience of a yogi to decipher their meaning, as they stand.’”

In view of the lack of specificity in the ʼ871 application with regard to a treatment for MS with a precise dosage of 480 mg per day using specific fumarates, the Federal Circuit affirmed the PTAB’s finding that the claimed MS treatment was not supported by the application’s specification as required by 35 U.S.C. § 112.

Key Takeaway

The court’s holding serves as an important reminder that the written description requirement requires more than the mere mention of a claim limitation in the specification. While FWP’s patent application described the use of fumarates in a broad fashion across a variety of medical conditions, there was not sufficient detail in the disclosure such that a person of ordinary skill in the art would be able to appreciate any and all specific treatments that might be possible permutations (including the specific MS treatment claimed in Biogen’s patent). Had FWP’s application described MS in more detail and included one or more working examples of treating MS patients with dosages at or around 480 mg per day of fumarates, the outcome may have been different for FWP.

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.