How to succeed in the business of biotech patentability
The US Supreme Court has thrown down the gauntlet for patent eligibility in the biotechnology field. In spite of (or due to) their significant contributions to medicine, Mayo v Prometheus, Association for Molecular Pathology v Myriad Genetics, and Ariosa Diagnostics v Sequenom exemplify the harsh reality of recent changes in defining patent-eligible subject matter. These recent changes have left companies wondering how best to protect their products.
In the US, patent eligibility is defined under 35 USC §101, which states that “whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor”. Historically, patents have been issued for compounds purified from nature such as adrenaline, acetyl salicylic acid (aspirin), and the antibiotic streptomycin.
Furthermore, in Diamond v Chakrabarty the Supreme Court set the precedent that “anything under the sun that is made by the hand of man” is patent-eligible subject matter. Post Diamond, tens of thousands of biotech-based patents have been issued—most notably, patents directed to “purified” matter such as nucleic acid or amino acid. Roughly 30 years after Diamond, the courts have begun to severely restrict what is considered patentable subject matter in the biotech field.
Mayo
The first major change in the patent eligibility of biotech subject matter came in 2012 in Mayo. This decision focused on the patentability of a method of optimising the therapeutic efficacy of a drug based on the level of metabolites in the patient’s blood. The claims at issue were summarised as (1) administering the drug to a patient, (2) determining the drug or metabolite levels in the patient’s blood, and (3) adjusting the drug dosage based on the blood levels.
The court noted that “at the time the discoveries embodied in the patents were made, scientists already understood that the levels in a patient’s blood of certain metabolites ... were correlated with the likelihood that a particular dosage of thiopurine drug could cause harm or prove ineffective ... But those in the field did not know the precise correlations between metabolite levels and the likely harm or ineffectiveness”.
The Supreme Court determined that: “Prometheus’ patents set forth laws of nature—namely, relationships between concentrations of certain metabolites in the blood and the likelihood that a dosage of a thiopurine drug will prove ineffective or cause harm ... While it takes a human action (the administration of a thiopurine drug) to trigger a manifestation of this relation in particular a person, the relation itself exists in principle apart from any human action. The relation is a consequence of the ways in which thiopurine compounds are metabolised by the body—entirely natural processes. And so a patent that simply describes that relation sets forth a natural law.”
In explaining its decision, the court stated that “to transform an unpatentable law of nature into a patent-eligible application of such law, one must do more than simply state the law of nature while adding the words ‘apply it’”. It added: “Beyond picking out the relevant audience, namely those who administer doses of thiopurine drugs, the claim simply tells doctors to: (1) measure (somehow) the current level of the relevant metabolite, (2) use particular (unpatentable) laws of nature (which the claim sets forth) to calculate the current toxicity/inefficacy limits, and (3) reconsider the drug dosage in light of the law.
“These instructions add nothing specific to the laws of nature other than what is well-understood, routine, conventional activity, previously engaged by those in the field. And since they are steps that must be taken in order to apply the law in question, the effect is simply to tell doctors to apply the law somehow when treating their patients.”
To add to the confusion, the court acknowledged that the “administering”, “determining” and “wherein” steps “are not themselves natural laws but neither are they sufficient to transform the nature of the claim.” This leads to the question of what is sufficient to transform the nature of the claim? According to the court, the answer lies somewhere between Diamond v Diehr and Parker v Flook. The patents in Diehr were directed to the use of the Arrhenius equation to determine curing time in moulded rubber products. The patents in Flook were directed to the use of an algorithm to monitor the catalytic conversion of hydrocarbons. The claims in question for each case are shown in Table 1.
Table 1: Comparison of claims in the Diehr and Flook cases
Diehr claim | Flook claim |
1. A method of operating a rubber-moulding press for precision molded compounds with the aid of a digital computer, comprising: |
- providing said computer with a database for said press including at least, natural logarithm conversion data (ln), the activation energy constant (C) unique to each batch of said compound being molded, and a constant (x) dependent upon the geometry of the particular mould of the press,
- initiating an interval timer in said computer upon the closure of the press for monitoring the elapsed time of said closure,
- constantly determining the temperature (Z) of the mould at a location closely adjacent to the mould cavity in the press during molding,
- constantly providing the computer with the temperature (Z),
- repetitively calculating in the computer, at frequent intervals during each cure, the Arrhenius equation for reaction time during the cure, which is
ln(v)=CZ+x
where v is the total required cure time, - repetitively comparing in the computer at said frequent intervals during the cure each said calculation of the total required cure time calculated with the Arrhenius equation and said elapsed time, and
- opening the press automatically when a said comparison indicates equivalence.
1. A method for updating the value of at least one alarm limit on at least one process variable involved in a process comprising the catalytic chemical conversion of hydrocarbons wherein said alarm limit has a current value of Bo + K, wherein Bo is the current alarm base and K is a predetermined alarm offset which comprises: 1) determining the present value of said process variable, said present value being defined as PVL; 2) determining a new alarm base B1, using the following equation: 3) determining an updated alarm limit which is defined as B1 + K; and thereafter 4) adjusting said alarm limit to said updated alarm limit value. |
At face value, the claims are similar—both use mathematical formulae to monitor chemical reactions and both calculate reaction limits. The Supreme Court in Mayo distinguished Flook and Diehr based on (1) the fact that the monitoring and adjusting that occurred in Flook was common practice, and (2) that the Flook claims “did not limit the claim to a particular application.” For example, in Flook, the claims did not “explain how the variables used in the formula were to be selected, nor did the [claims] contain any disclosure relating to chemical processes at work or the means of setting of an alarm or adjusting the alarm limit.”
This is in contrast to the Diehr claims, which included “installing rubber in a press, closing the mould, constantly determining the temperature of the mould, constantly recalculating the appropriate cure time through the use of the formula and a digital computer, and automatically opening the press at the proper time”.
The court decided that the claims at issue in Mayo were closer to those in Flook because monitoring and adjusting the drug dosage in the Mayo patent was common practice and because the determining step was “set forth in highly general language covering all processes that make use of the correlations after measuring metabolites, including later discovered processes that measure metabolite levels in new ways ... Unlike, say, a typical patent on a new drug or a new way of using an existing drug, the patent claims do not confine their reach to particular applications of those laws”.
The decision in Mayo opened the door for invalidating biotech patents by showing that the application of “natural law” involved purely conventional steps and broad coverage.
Myriad
The second major change in the area of patenting biotech subject matter came in 2013 in Myriad. This ruling focused on the patentability of DNA mutations found in breast cancer. The claims at issue were directed to isolated DNA and isolated complementary DNA (cDNA). The Supreme Court determined that “a naturally occurring DNA segment is a product of nature and not patent-eligible merely because it has been isolated, but that cDNA is patent-eligible because it is not naturally occurring”.
“Gone are the days when you could broadly claim isolated genetic material and any technique known in the art to manipulate the genetic material.”
The court reasoned that “cDNA does not present the same obstacles to patentability as naturally occurring, isolated DNA segments” The court also distinguished isolated DNA from other chemical compounds, noting that “Myriad’s claims are simply not expressed in terms of chemical composition, nor do they rely in any way on the chemical changes that result from the isolation of a particular section of DNA. Instead, the claims understandably focus on the genetic information encoded in the BRCA1 and BRCA2 genes ... [Myriad] is concerned primarily with the information contained in the genetic sequence, not with the specific chemical composition of a particular molecule”.
Last, the court noted that the Myriad decision was limited to genes and the information they encode, and specifically carved out three areas that the decision does not affect, namely method claims, new applications, and DNA with an altered sequence order. The decision in Myriad opened the door for invalidating biotech patents directed to isolated nucleic acid and amino acid.
Ariosa
The application of Mayo and Myriad came in June 2015 in Ariosa. Here, the court focused on the patentability of cell-free foetal DNA (cffDNA) circulating in maternal blood.
An example of the claims at issue is “1. A method for detecting a paternally inherited nucleic acid of foetal origin performed on a maternal serum or plasma sample from a pregnant female, which method comprises amplifying a paternally inherited nucleic acid from the serum or plasma sample and detecting the presence of a paternally inherited nucleic acid of foetal origin in the sample.”
The US Court of Appeals for the Federal Circuit applied the framework set out in Mayo. “First, we determine whether the claims at issue are directed to a patent-ineligible concept. If the answer is yes, then we next consider the elements of each claim both individually and as an ordered combination to determine whether additional elements transform the nature of the claim into a patent-eligible application.”
Under the first step, it was undisputed that the existence of cffDNA in maternal blood is a natural phenomenon. Accordingly, the claims at issue were determined to be directed to a patent-ineligible concept. Under the second step, it was determined that the amplification and detection steps were well-understood, conventional and routine in the art. In conclusion, the federal circuit determined that “the practice of the method claims does not result in an inventive concept that transforms the natural phenomenon of cffDNA into a patentable invention”.
In a concurring opinion, Judge Richard Linn noted that he was “bound by the sweeping language of the test set out in Mayo ... This case represents the consequence—perhaps unintended—of that broad language in excluding a meritorious invention from the patent protection it deserves and should have been entitled to retain ... The Supreme Court’s blanket dismissal of conventional post-solution steps leaves no room to distinguish Mayo from this case, even though here no-one was amplifying and detecting paternally-inherited cffDNA using the plasma or serum of pregnant mothers”.
Patent eligibility
The US Patent and Trademark Office has issued several interim guidances on subject matter eligibility to help examiners navigate these Supreme Court cases that have changed the landscape. The 2014 guidance set out three questions, which are shown below.
- Is the claim to a process, machine, manufacture or composition of matter? If no, the claim is not eligible subject matter under 35 USC §101. If yes, proceed to step 2A.
2A. Is the claim directed to a law of nature, a natural phenomenon, or an abstract idea (judicially recognised exceptions)? If no, the claim qualifies as eligible subject matter under 35 USC §101. If yes, proceed to step 2B.
2B. Does the claim recite additional elements that amount to significantly more than the judicial exception? If no, then the claim is not eligible subject matter under 35 USC §101. If yes, the claim qualifies as eligible subject matter under 35 USC §101.
According to the guidance, “significantly more” can be demonstrated by (i) improvements to another technology or technical field; (ii) adding a specific limitation other than what is well-understood, routine and conventional in the field; (iii) adding unconventional steps that confine the claim to a particular useful application; and (iv) other meaningful limitations beyond generally linking the use of the judicial exception to a particular technological environment.
Additionally, the following should be considered: combinations of natural elements that produce unnatural results; specific chemical isomers; modified chemical structures; and treatment of specific medical conditions. When in doubt, be specific: eg, include information on a specific disease, specific techniques, or specific applications.
How to get protection
What does this mean for a biotech company looking to protect its products? First, we go back to the beginning, Diamond, and think about ways to modify “naturally occurring” compounds to introduce the “hand of man”. For example, this may include adding non-naturally occurring substitutions into naturally occurring nucleic acid or amino acid sequences; vectors containing naturally occurring nucleic acid; or recombinant proteins; or adding detectable labels to naturally occurring nucleic acid or amino acid sequences.
If you are unable to introduce the “hand of man”, then add as much specificity as possible. Table 2 illustrates claim amendments that were successful in overcoming a rejection of patent-eligible subject matter.
Table 2: Claim amendments that overcame rejections based on patent-ineligible subject matter
US patent no. | Originally filed claim | Allowed claim |
8,563,327 | 6. A method for diagnosing of type 1 diabetes mellitus comprising a step of detecting an anti-alanyl tRNA synthetase antibody, an anti-glycyl tRNA synthetase antibody, and an anti-asparaginyl tRNA synthetase antibody from an individual test sample. | 1. A method for diagnosing type 1 diabetes mellitus comprising: |
- obtaining a sample from a subject suspected of having type 1 diabetes mellitus;
- contacting the sample with two or more purified recombinant proteins selected from the group consisting of alanyl tRNA synthetase, glycyl tRNA synthetase, asparaginyl tRNA synthetase, and tryptophanyl tRNA synthetase, and fragments thereof;
- detecting the binding of two or more of an anti-alanyl tRNA synthetase antibody, an anti-glycyl tRNA synthetase antibody, an anti-asparaginyl tRNA synthetase antibody, and an anti-tryptophanyl tRNA synthetase antibody in the sample with the two or more purified recombinant proteins,
wherein detecting the binding of two or more of the antibodies with the two or more purified recombinant proteins indicates that the subject has type 1 diabetes mellitus. | |
9,040,286 | 1. A method for facilitating the diagnosis of malignant cancer in a subject, the method comprising: |
- measuring the level of SETDB1 in a biological sample obtained from a subject who has at least one solid tumour or growth or a nevus, wherein the biological sample is derived from at least one solid tumour or growth or nevus; and
- comparing the measured level of SETDB1 to a reference, wherein an increase of at least 10% in the SETDB1 level in the biological sample compared to the reference is indicative of malignant cancer in the subject.
1. A method for facilitating the diagnosis of lung cancer or melanoma in a subject, the method comprising: |
- selecting a subject having at least one solid tumor or growth or a nevus;
- measuring the level of SETDB1 in a biological sample obtained from the subject who has at least one solid tumour or growth or a nevus, wherein the biological sample is derived from at least one solid tumour or growth or nevus from the subject wherein the level of SETDB1 is detected at the mRNA level by a PCR procedure or at the protein level by an immunoassay; and
- identifying the likelihood of cancer in the subject by comparing the measured level of SETDB1 to a reference level, wherein the reference level is the level of SETDB1 in a subject or group of subjects who are clinically free of cancer and the level of SETDB1 in the cancer-free subject(s) is detected in the same manner as the measured subject, either at the mRNA level by a PCR procedure or at the protein level by an immunoassay; and
- determining whether the subject has cancer and therefore requiring cancer treatment or whether the subject has a benign growth based upon the comparison wherein an increase of at least 10% in the SETDB1 level in the biological sample compared to the reference level is indicative of cancer in the subject.
9,040,298 | 1. A method of identifying a capability of a stem cell to differentiate and/or induce a cell into a chondrocyte, the method comprising: |
- culturing a stem cell in a medium;
- measuring a concentration of at least one selected from the group consisting of thrombospondin 1 (TSP-1), TSP-2, and interleukin 17B receptor (IL-17BR) from the culture; and
- identifying a capability of the cultured stem cell to differentiate into a chondrocyte, based on the measured concentration.
1. A method of selecting a stem cell capable of differentiating into a chondrocyte or inducing chondrocyte differentiation, the method comprising: |
- culturing a stem cell in a monolayer or pellet in a maintenance medium; and
- measuring a concentration of TSP-2; and selecting and isolating a stem cell having a high chondrogenic differentiation capability from the culture medium if
a) the concentration of TSP-2 in cell culture is larger than 72pg/ml/1.0X105 cells when the stem cell is monolayer-cultured for 1 day, or
b) the concentration of TSP-2 in cell culture is larger than 550pg/ml/1.0X105 cells when the stem cell is pellet-cultured for 7 days,
wherein the selected stem cell is capable of differentiating into a chondrocyte or inducing chondrocyte differentiation.
Gone are the days when you could broadly claim isolated genetic material and any technique known in the art to manipulate the genetic material. For now, best practices dictate that you avoid claim language such as “isolated” or “purified” that will trigger a rejection based on subject matter ineligibility and keep method claims as specific as possible while still covering your product.
Kathryn Hull is a senior counsel at Gordon Rees. She can be contacted at: khull@gordonrees.com
