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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.

Federal Circuit Decision

Broadsoft, Inc. v. Callwave Communications, LLC, No. 2018-1124, 2018 WL 4999375, at *1 (Fed. Cir. Oct. 16, 2018) (per curiam) (affirming district court’s order finding claims invalid)

District Court Decision

Broadsoft, Inc. v. Callwave Commc’ns, LLC, 282 F. Supp. 3d 771 (D. Del. 2017)

Federal Circuit Affirms Decision Finding Telephone Dialing Claims IneligibleAdd internet telephony systems to the list of computer-related technologies considered for patent eligibility under 35 U.S.C. § 101. Under current law, among other requirements, in order to qualify as patent-eligible under § 101, a patent claim involving computer-related technology must be directed to something more than simply an abstract idea that fails to implement an inventive concept. A patent’s claims will fail this test if a court finds that they are simply directed to “method[s] of organizing human activity” or “a known idea” that “is routine and conventional.”

In Broadsoft, Inc. v. Callwave Communications, LLC, a three-judge Federal Circuit panel issued a per-curiam decision affirming the United States District Court for the District of Delaware’s grant of a motion for judgment on the pleadings as to patent ineligibility under 35 U.S.C. § 101. The trial court’s order examined claims in two patents assigned to Callwave Communications, U.S. Patent Nos. 8,351,591 and 7,822,188. The trial court found that the claims covered telephony methods involving conventional elements and lacking an inventive concept.

The Asserted Patents

The ’591 and ’188 patents have common specifications and are directed to techniques for placing internet telephone calls. The patents had two general types of claims: sequential dialing claims and single number outcall claims. Claim 40 of the ’188 patent was selected as an exemplary “sequential dialing” claim:

40. A method of processing calls, comprising:

receiving at a call processing system a message from an Internet protocol proxy regarding a first call from a caller;

determining if the first call is directed to a telephone address of a subscriber of services offered by the call processing system, wherein at least partly in response to determining that the telephone address is that of a subscriber:

accessing an account record associated with the subscriber, the account record including at least one subscriber instruction;

based at least in part on the subscriber instruction, placing a first outcall to a first communication device associated with the subscriber;

if the first outcall is not answered within a first number of rings or period of time, placing a second outcall to a second communication device associated with the subscriber; and [sic]

receiving a call connect instruction from the subscriber; and

instructing the call processing system to connect the first call to a third communication device.

Claim 1 of the ’591 Patent was selected as an exemplary “single number outcall” claim:

1. A method of processing calls, the method comprising:

storing in computer readable memory associated with a call processing system a first phone address associated with a first subscriber;

storing in computer readable memory a plurality of phone addresses for the first subscriber;

participating at the call processing system in a first call associated with the first subscriber, the first call associated with a second phone address different than the first phone address;

placing a first outcall from the call processing system to a first called party, wherein the call processing system inserts at least a portion of the first phone address in a callerlD field associated with signaling information associated with the first outcall;

causing the first call and the first outcall to be bridged;

participating at the call processing system in a second call associated with the first subscriber, the second call involving a subscriber communication device associated with a third phone address different than the first phone address;

placing a second outcall from the call processing system to a second called party, wherein the call processing system inserts at least a portion of the first phone address in a callerlD field associated with signaling information associated with the second outcall; and

causing the second call and the second outcall to be bridged.

The District Court Proceedings

Broadsoft filed a declaratory judgment action in the United States District Court for the District of Delaware seeking declaratory judgment that claims in Callwave’s patents were invalid. Callwave’s patents came under attack from Broadsoft after Callwave asserted those patents against Telovations, Inc., which had licensed accused software products from Broadsoft, and Bright House Networks, LLC, which had acquired Telovations. The software license agreement between Broadsoft and Telovations specified that Broadsoft owed an obligation to defend Telovations against patent infringement claims based on the software.

Broadsoft submitted motions seeking judgments that Callwave’s ’591 and ’188 patents were directed to patent ineligible subject matter under § 101. The motions also argued that the patents were invalid as anticipated under § 102 and obvious under 35 U.S.C. § 103.

Sequential Dialing Claims

Broadsoft argued that the idea of sequentially dialing a list of telephone numbers is an abstract idea that fails to provide any improvement to computer or technological processes. According to Broadsoft, the claims simply identify steps that automate the task of accessing a list of telephone numbers and sequentially dialing them, a task previously performed manually by a human. Callwave countered that the claims allow a call to be redirected without hanging up and redialing, a process impossible for a human operator who does not know any additional phone numbers for the party being called.

The court agreed with Broadsoft’s arguments, and found the sequential dialing claims were directed to an abstract idea. The court noted that the problem of callers receiving busy signals or being sent to voicemail rather than reaching the called party was a “human unavailability problem” that was not specific to telephone technology.

Broadsoft also argued that the sequential dialing claims lacked an inventive concept, partly because they simply use computer telephony to implement the idea of sequential dialing, and because no inventive concept is conveyed in claims that narrow an abstract idea to a particular technological application. Callwave cited McRo, Inc. v. Bandai Namco Games America, Inc., and argued that its claims did identify an inventive concept, focusing on three limitations addressing: 1) internet protocol proxy messaging for receiving or placing calls, 2) use of timing or number of rings to determine when to place a second call, and 3) use of a hybrid network to handle calls from different interfaces by converting call protocols.

The court found that none of the limitations Callwave identified represented an inventive concept. The court noted that the patent intended to solve the problem of calls ending in busy signals or voicemails, and failed to identify a technological solution for network interoperability, describing its call processing elements as “standard.” Use of timing rules to determine when to place a second call similarly failed to constitute an inventive concept because “there is nothing inventive about using a preset amount of time to determine when to initiate a particular step in a process, and it is difficult to imagine using in this system alternative rules not based on the passage of some period of time.” Unlike the decision in McRo, the sequential dialing claims did not require that the rules be obtained first. The patent lacked discussion about protocol conversion, leading the court to conclude that the process was just “routine.”

Single Number Outcall Claims

The single number outcall claims similarly identified an abstract idea and failed to include an inventive concept. The court found that exemplary claim 1 was essentially “directed to storing data in a database, looking up data from that database in response to the initiation of a phone call, and inserting at least a portion of that data in the already-existing callerID field,” and concluded that the “problem of being unable to reach a particular individual is a practical, human unavailability problem, not a technological one.” The court also noted that the claims could be practiced in an office setting by a human assistant. The court found no improvement to telephony technology or solution to a specific phone problem.

The court also agreed with Broadsoft regarding the lack of an inventive concept, stating that the call processing techniques of the claims were not directed to solving network interoperability problems, and that the patents “simply append[ ] conventional steps, specified at a high level of generality, [which is] not enough to supply an inventive concept.”

The Federal Circuit’s Decision

The Federal Circuit panel’s per curiam affirmance leaves Callwave with the option to request rehearing by the panel or the Federal Circuit as a whole en banc. Callwave has 30 days from the date of the opinion, or until November 16, 2018, to submit a petition for rehearing by the panel or rehearing en banc.

Impact on Current Law

The trial court’s decision occurred before Berkheimer v. HP, Inc., which generally states that factual issues may prevent a grant of judgment on the pleadings as to patent eligibility under § 101. But the Federal Circuit’s post-Berkheimer affirmance here indicates its agreement with the trial court’s conclusion that no such factual issues existed. Notably, the trial court’s decision finds absence of any factual issues as to whether an Internet Protocol proxy server, Session Internet Protocol proxy and computer telephony system are “conventional” elements. The trial court also determined that the problem the claims attempt to solve is that of a caller having to hang up and redial a new number if they get a busy signal or reach voicemail, which the court found is a “human unavailability problem,” not a technical one. Without contradictory evidence to consider, a court may find a lack of factual issues as to patent eligibility when the patent’s specification describes technology as “standard” or “conventional” and the claims identify a problem that can be solved by adding a human actor.

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.