Europe v US: the patentability of diagnostic claims
Patents covering the diagnosis of disease or personalised medicine often include claims in which the presence or level of a biomarker is correlated to a particular disease state. Such claims have been the focus of much attention following some landmark US Supreme Court decisions that have called into question their validity.
Understandably, the situation in Europe has received less attention. Although Europe does have its own set of restrictions on patentable subject matter, in practice the restrictions on claims that correlate a biomarker with a disease state are not as far-reaching as in the US.
The US position
The well-documented US Supreme Court decisions of Mayo v Prometheus, Alice v CLS Bank and Association for Molecular Pathology v Myriad Genetics have been of huge importance in defining what constitutes patent-eligible subject matter under US patent law, specifically section 101 of the US Code.
Of particular significance to diagnostic and personalised medicine claims is the Mayo decision, in which the Supreme Court considered a test for determining the optimal dose of a drug. The claims were directed to administering the drug to a patient and measuring the level of a particular metabolite in the patient’s blood. The measured metabolite indicated whether there should be an increase or decrease in the drug dose when compared to the optimal metabolite range.
The court’s unanimous ruling was that this method was not patent-eligible because the correlation between drug dose and metabolite levels was a law of nature and the additional steps in the claim were considered to be well understood, routine, conventional activities. This decision gave rise to the ‘Mayo framework’, in which the following two steps are considered when assessing patent eligibility:
(1) Does the claim recite an ineligible concept (natural phenomena, natural law or abstract idea)?; and
(2) If so, does the claim recite sufficient additional elements to make the claim to an application of the concept, rather than to the concept itself?
The Mayo framework was applied in the Alice decision (which concerned a computer-implemented invention) and has been adopted by the US Patent and Trademark Office (USPTO) as part of its guidance on assessing patent eligibility.
For diagnostic method claims, or claims involving diagnostic steps, patent eligibility is likely to depend on the analysis in the second step of the Mayo framework. The USPTO guidance has indicated a number of considerations for determining whether a claim with additional elements amounts to significantly more than the judicial exception. These include adding a specific limitation other than what is well understood, routine and conventional in the field, or adding unconventional steps that confine the claim to a particular useful application. Limitations that do not qualify as ‘significantly more’ include simply appending well-understood, routine and conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception; adding insignificant extra solution activity to the judicial exception; or generally linking the use of the judicial exception to a particular technological environment or field of use.
The patent ineligibility of diagnostic tests that apply a discovery of a naturally-occurring principle was reaffirmed on June 12, 2015 by the US Court of Appeal for the Federal Circuit in Ariosa Diagnostics v Sequenom. Independent claims in the patent (US number 6,258,540) were worded as follows:
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.
24. A method for detecting a paternally inherited nucleic acid on a maternal blood sample, which method comprises: removing all or substantially all nucleated and anucleated cell populations from the blood sample, amplifying a paternally inherited nucleic acid from the remaining fluid and subjecting the amplified nucleic acid to a test for the paternally inherited foetal nucleic acid.
25. A method for performing a prenatal diagnosis on a maternal blood sample, which method comprises obtaining a non-cellular fraction of the blood sample amplifying a paternally inherited nucleic acid from the non-cellular fraction and performing nucleic acid analysis on the amplified nucleic acid to detect paternally inherited fetal nucleic acid.
Applying the Mayo two-step test, the court found that in the first step the claims were directed to naturally-occurring subject matter, namely cell-free foetal DNA. In the second step, the court held that the method steps were well understood, conventional and routine. So, the claim was found to be patent ineligible. This is despite Circuit Judge Linn’s acknowledging Sequenom’s “truly meritorious” invention and that there was “no reason, in policy or statute, why this breakthrough invention should be patent-ineligible”. These sentiments would have afforded Sequenom no comfort, because the court was bound by the Mayo decision.
For diagnostic claims, there is uncertainty over what may constitute significantly more than the judicial exception, although further USPTO guidance is expected shortly.
If, for example, the diagnostic method claim includes use of a novel antibody or a novel type of assay or apparatus, this would appear to make it patent-eligible. Another potential solution that has been suggested is to convert medical diagnostic claims into treatment claims directed to a patient population having the characteristics indicated by the biomarker (eg, a method of treatment comprising administering drug A to a patient having a level of a biomarker above X). However, if such claims are allowable, they could be harder to enforce if diagnosis and drug administration steps are carried out by different parties.
So, although claims involving diagnostic steps may still be allowable in the US, the current USPTO guidance suggests that the scope of such claims is likely to be greatly reduced compared to what might have been possible pre-Mayo.
The position in Europe
Article 52(2)(a) of the European Patent Convention (EPC) excludes discoveries, scientific theories and mathematical methods from patent protection. However, unlike the US judicial exceptions, the EPC exclusions are applied rather more narrowly. For example, the European Patent Office (EPO)’s examination guidelines (G-II,3.1) explain that if a new property of a known material or article is found out then it is a mere discovery and is unpatentable because discovery has no technical effect and is therefore not an invention. If, however, that property is put to practical use, then this constitutes an invention which may be patentable.
The decision in G2/88 by the EPO’s Enlarged Board of Appeal explained that if an idea or concept underlying the claimed subject matter resides in a discovery it does not necessarily mean that the claimed subject matter is a discovery “as such”. This attitude has also been reflected in the UK where, for example, the English Court of Appealhas previously established that the practical application of a discovery does not relate to a discovery “as such” even if the practical application might be obvious once the discovery had been made.
So, the discovery of a correlation of a particular biomarker with a particular disease state could form the basis of claim that is not excluded from patentability in Europe, because the discovery has been put to a practical use.
“For patent eligibility of diagnostic claims, or claims involving diagnostic steps, the prognosis in the US is not good, but we await further guidance from the USPTO.”
There are specific restrictions on diagnostic method claims in Europe. Article 53 of the EPC recites that patents shall not be granted in respect of methods for the treatment of the human or animal body by surgery or therapy and diagnostic methods practised on the human or animal body.
The enlarged board’s decision in G1/04 characterised diagnosis as involving the following steps:
- Examination and collection of data;
- Comparison of the data with normal values;
- Recording any deviation from the norm; and
- Attributing the deviation to a particular clinical picture.
It was held that a “method of diagnosis” should be interpreted narrowly, in that only a method that includes all the steps listed above falls within the definition. In practice, however, if a method includes the first and last step, then the intermediate steps may be implied.
A method of taking a sample, or determining internal temperature or pH, does not itself identify a condition and so is unlikely to be excluded. Rather, it would be considered an intermediate finding of diagnostic relevance rather than a diagnostic method. For example, a method of measuring blood pressure does not per se enable identification of a pathology, and so is unlikely to be excluded.
In G1/04, the enlarged board concluded that a method is excluded only if all of the technical steps are practised on the human or animal body. In practice, the first step is the only technical step, and is the only step that can be practised on the body because the subsequent steps are usually abstract or intellectual steps. To decide whether a diagnostic method step is practised on the human or animal body, the question is whether a patient is required to be there to perform it. There is no requirement to show a specific type and intensity of interaction with the human or animal body. In vitro diagnostic tests performed on blood removed from the body would not constitute a diagnostic method step practised on the body.
For method of diagnosis claims, it is irrelevant whether the procedure is invasive, or capable of causing harm to the patient and it does not depend on who carries out the method, eg, a medical professional or the patient himself or herself (G1/04).
Europe v the US
The US patent that was deemed patent-ineligible in the Ariosa decision has a European patent equivalent. The European patent was opposed (although exclusion from patentability under articles 52 and 53 EPC was not at issue during the opposition proceedings), and was upheld in amended form (EP 994963B2) on appeal. Independent claims upheld on appeal were as follows:
1. A detection method performed on a maternal serum or plasma sample from a pregnant female, which method comprises detecting the presence of a nucleic acid of foetal origin in the sample, wherein said nucleic acid is a paternally inherited sequence which is not possessed by said pregnant female.
18. A method of performing a prenatal diagnosis, which method comprises:
(i) providing a maternal blood sample;
(ii) separating the sample into a cellular and non-cellular fraction;
(iii) detecting the presence of a nucleic acid of foetal origin in the non-cellular fraction using the method of any one of claims 1 to 17; and
(iv) providing a diagnosis based on the presence and/or quantity and/or sequence of the foetal nucleic acid.
Similarly, the US patents deemed patent-ineligible in the Mayo decision had a European equivalent (EP 1115403B1) which was granted with the following claim (and not the subject of an opposition):
An in vitro method for determining efficacy of treatment of a subject having an immune-mediated gastrointestinal disorder or a non-inflammatory bowel disease (non-IBD) autoimmune disease by administration of a 6-mercaptopurine drug, comprising determining in vitro a level of 6-thioguanine in a sample from said subject having said immune-mediated gastrointestinal disorder or said non-IBD autoimmune disease, wherein said treatment is considered efficient if the level of 6-thioguanine is in the range of about 230 pmol per 8x108 red blood cells to about 400 pmol per 8x108 red blood cells.
The granted claims in both of these European patents reflect the current understanding that broad claims applying a discovery of a correlation between a biomarker and a disease are patentable in Europe but are not patentable in the US.
The restrictive approach of the USPTO in assessing patent eligibility is exemplified in US patent application number 14/158,976, currently under examination. The application has the current pending claim:
A method for identifying a human as having an increased risk for myocardial infarction, the method comprising:
a) testing nucleic acid from said human for a polymorphism in gene WDR12 as represented by position 101 of SEQ ID NO:25288 or its complement by contacting said nucleic acid with an oligonucleotide that specifically hybridises to G at said position 101 of SEQ ID NO:25288 or C at said complement;
b) detecting the presence of said G or said C; and
c) identifying said human as having an increased risk for myocardial infarction.
In a non-final office action issued in April 2015, the USPTO rejected this claim as being patent-ineligible under section 101. In part one of the Mayo test, the USPTO alleged that the claims encompass the WDR12 gene (a natural product) and involve a correlation between the polymorphism located at position 101 of SEQ ID NO: 25288 and myocardial infarction (natural law).
In step two of the Mayo test, the USPTO alleged that the claim recites insignificant extra-solution activity (“testing” and “detecting” steps) which do not significantly narrow the scope of the claims such that others are not substantially foreclosed from detecting the natural products or applying the natural law, since the claims cover every method for detecting the single nucleotide polymorphism (SNP).
Although the claim requires performing the testing step with “an oligonucleotide that specifically hybridises to G at said position of SEQ ID NO: 25288 or C at said complement”, the USPTO was of the view that numerous methods of detecting the mutation could be performed with the claimed oligonucleotide. Therefore, the claim was considered to be recited at a high level of generality and the hybridising oligonucleotide did not significantly narrow the scope of the claim.
The claim rejected by the USPTO can be contrasted with the following claim in an equivalent European patent (EP 2474632B1), granted on August 12, 2015 by the EPO:
An in vitro method for identifying an individual having an altered risk for developing recurrent myocardial infarction, comprising detecting the SNP in the nucleotide sequence of SEQ ID NO:54323 in said individual’s nucleic acids, wherein said individual has an increased risk for developing recurrent myocardial infarction due to the presence of G at position 101 of SEQ ID NO:54323 or the presence of C at position 101 of its complement.
For patent eligibility of diagnostic claims, or claims involving diagnostic steps, the prognosis in the US is not good, but we await further guidance from the USPTO on what type of claims may be allowable.
However, the current restrictions and uncertainty in the US should not shape people’s perception of diagnostic claims elsewhere. The current situation in Europe is rather more settled and is demonstrably less restrictive than in the US, and the European market remains extremely important for the majority of diagnostic companies.
Currently, many diagnostic companies will be focusing on the limitations they should include in their patent claims to make them patent-eligible in the US. Nevertheless, they should still provide basis for broad diagnostic claims in their patent applications for the purpose of pursuing patent protection in Europe.
Andrew Carridge is an attorney at Reddie & Grose. He can be contacted at: andrew.carridge@reddie.co.uk
Neil Thornton is a partner at Reddie & Grose. He can be contacted at: neil.thornton@reddie.co.uk
