Precision medicine: getting patenting spot on
Precision medicine is an emerging approach to the diagnosis and treatment of disease which is tailored to the individual characteristics of each patient. It relies on the classification of individuals into subpopulations that differ in their susceptibility to a particular disease, in the biology or prognosis of disease, or in their response to a specific treatment. The advent of cheap genome sequencing and ‘big data’ analysis brings unprecedented opportunity for the development of patient-targeted diagnostics and therapies based on genetic profiles.
This year, the UK’s ambitious 100,000 Genomes Project is expected to be completed, focusing on patients with cancer or rare diseases. In addition, the US 21st Century Cures Act of 2016 includes provisions that will advance precision medicine, including the Precision Medicine Initiative, which will review the genetic data of no fewer than one million Americans. Allied to this, a Cancer Moonshot initiative aims to ‘eliminate cancer as we know it’.
While public funding for precision medicine seems to be in the ascendancy, a key question is whether IP or regulatory regimes create commercial incentives and what can be done now to capture IP value.
US developments appear favourable, at least in relation to precision therapeutics. The US Patent and Trademark Office’s (USPTO) pilot programme called ‘patents 4 patients’ to expedite examination of patent applications covering cancer immunotherapy provides one stimulus. Method of treatment claims are patent-eligible subject matter in the US, even when they involve a process of applying a natural product to treat a particular disease .
However, difficulties remain in obtaining patent protection covering other aspects of personalised medicine. Patent claims need to be carefully drafted in order not to fall foul of judicial exceptions to patent eligibility covered by §101 of the US Patent Act. The application of the judicial exceptions, intended to prohibit patenting of laws of nature, products of nature, or abstract ideas, has been extended by various court rulings in the US and guidance for USPTO examiners ( https://www.uspto.gov/patent/laws-and-regulations/examination-policy/subject-matter-eligibility).
In Europe, patent claims should be drafted in the form of second medical uses or treatment selection methods, in order to avoid the prohibition on patenting methods of treatment. Methods of diagnosis are patent-eligible if they do not include a step which necessitates the presence of the human or animal body.
Keytruda
In May, the US Food and Drug Administration (FDA) approved the first cancer treatment for use in patients who have a tumour with a particular biomarker, irrespective of where in the body the tumour originated. Merck’s Keytruda (pembrolizumab) is currently marketed for a number of cancer indications including melanoma and lung cancer.
The new authorisation is for use in patients with unresectable or metastatic solid tumours which have progressed following other treatments and have been found to have one of two genetic biomarkers which, according to early evidence, are indicative of a better treatment response. Specifically, microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR) tumours have defects in the repair of damaged DNA, and thus have a high mutational burden.
Pembrolizumab is an immune checkpoint inhibitor, which works by releasing a brake called PD-1 on cancer-fighting T cells. The defects in MSI-H or dMMR tumours may make them more easily recognised by the immune system, and thus more sensitive to immunotherapy with pembrolizumab. Preliminary evidence from small clinical trials showed tumour shrinkage in patients with MSI-H or dMMR solid tumours which had arisen in various anatomic locations.
Keytruda was approved for the new indication under the FDA’s Accelerated Approval pathway, which allows approval of drugs for serious conditions with unmet clinical need based on preliminary evidence of a reasonable likelihood of clinical benefit. Further trials are underway to establish whether there is a genuine clinical benefit of Keytruda for MSI-H or dMMR tumour patients.
Keytruda joins a growing list of cancer therapeutics authorised for indications which are at least partly defined by reference to biomarkers. A well-known example in the US and Europe is Herceptin (trastuzumab), a monoclonal antibody which targets HER2 positive breast cancer. More recently, poly ADP-ribose polymerase (PARP) inhibitors have been approved for treating ovarian cancer associated with BRCA gene mutations.
New FDA regulations to be developed following the 21st Century Cures Act will create a new category for precision therapeutics that target specific biomarkers for a therapeutic response.
How to avoid §101
New patient subgroups may, in principle, be the subject of US method of treatment patent claims in the form ‘method of treating disease X in a patient determined to have biomarker Y comprising administering therapeutic Z’.
When a therapeutic is available, and an invention resides in the discovery that it is particularly suitable for treatment of a particular patient group, as in the Keytruda example, this type of patent claim may be very useful. However, it is often the case that inventions reside in a process for identifying or monitoring a biomarker, or in the discovery that a biomarker is predictive of disease risk.
The USPTO guidance to the §101 patent eligibility provisions seeks to ensure that not all applications of a particular biological finding are monopolised. A method of allocating risk scores or classifying patients may be considered to include an abstract idea, whereas a method of diagnosing a subject based on the presence of a biomarker may be considered to include a law of nature.
In order to be patent-eligible, the claim as a whole must recite something significantly different from the judicial exception. The presence of inventive features or features that impose a meaningful limitation on the claim scope may be sufficient to achieve this. For example, claims could be limited to require unconventional steps or samples, or recite interactions between the biomarker and a specific detection reagent.
In particular circumstances, the addition of a treatment step to a method of diagnosis may also provide a meaningful limitation. In an example provided in the USPTO guidance ( https://www.uspto.gov/sites/default/files/documents/ieg-may-2016-ex.pdf), a claim encompassing a judicial exception ‘a method of diagnosing julitis in a patient …’ was rendered patent-eligible by the addition of a treatment step of administering anti-TNF antibodies. This was because the combination of accurate diagnosis (on the basis of detection of JUL-1 biomarker) and treatment was not routine and conventional, even though the treatment of patients with julitis with anti-TNF antibodies was routine.
Thus, there may be various options for claiming a biomarker invention in the US, particularly in circumstances where a therapeutic agent is involved.
A European perspective
A simple US-style method of treatment claim may be recast as a second medical use claim at the European Patent Office (EPO) in the form ‘therapeutic Z for use in a method of treating disease X in a patient determined to have biomarker Y’.
In principle, the use of the same compound in the treatment of the same disease for a particular group of subjects can constitute a novel therapeutic application, provided that the new group of subjects is distinguished from the former by its physiological or pathological status. However, where the new group overlaps with the previously treated group, novelty may be denied. This could present a challenge in situations where the biomarker Y is common in disease X and the therapeutic is already known as a treatment for the disease.
One solution may be to argue that the disease is actually different. In Board of Appeal Decision T893/90, the board found that the subject of the claim—tamoxifen and aromatase-resistant breast tumours—was a different disease subset from the tamoxifen-resistant tumours treated in the prior art. A treatment based on the new subset was considered novel. Another approach is to claim a treatment selection method comprising the step of testing a patient sample for the presence of the biomarker.
It is important to include bases for European claim formats in priority and international patent applications, because of the EPO’s strict approach to amendments and entitlement to priority. Methods of diagnosis and treatment, which can be captured in a single claim in the US, would need to be presented as separate claim types at the EPO.
Conclusions
Developments at the FDA and USPTO signal a willingness to engage with industry, particularly in the sphere of precision therapeutics, yet there is an ambivalence towards other aspects of precision medicine, requiring care in order to secure valuable IP. The distinctions between US and EPO patent practice and the possibility of further shifts as the field matures require a thorough and flexible approach to patent drafting.
Sheena Linehan is an associate at Potter Clarkson. She can be contacted at: sheena.linehan@potterclarkson.com
