Precision medicine (also known as personalised medicine) has been identified as one of the ten key opportunities for biomedical innovation over the next decade. It generally involves a diagnostic step and a patient-tailored treatment based on the results of the diagnostic step. In Europe, patent protection can be sought for both elements — but crafting effective claims requires a particularly careful use of language.

According to Article 53 (Exceptions to patentability) of the European Patent Convention (EPC), “European patents are not to be granted in respect of methods for treatment of the human or animal body by surgery or therapy and diagnostic methods practised on the human or animal body”.

This exception doesn’t apply to products, in particular substances or compositions, for use in any of these methods — as long as these products meet the other requirements of the European Patent Convention.

Here are some useful examples to help innovators in the biomedical space construct claims relating to precision medicines which are compliant with the EPC.

Example one: The humanised monoclonal antibody OSE-703

Interleukin-7 (IL-7) is an immune mediator known for its role in hematopoietic growth of T- and B-lymphocytes. An association has been demonstrated between the aberrant expression of IL7 receptor (IL-7Ralpha, IL-7Ra, or CD127) on human cells and a poor prognosis in a range of cancers.

OSE-703 is a humanised monoclonal antibody (mAb) being developed by OSE Immunotherapeutics in partnership with Memorial Sloan Kettering Cancer Center. The mAb is directed against the extracellular domain of the alpha chain of CD127 and is cytotoxic for human cells expressing CD127.

For an oncologist provided with a range of potential treatment options, it would be clinically valuable to be able to selectively treat a patient with OSE-703 based on whether the patient’s cells are CD127+ — or indeed, selectively exclude a CD127- patient from this form of therapy because it would likely be ineffective and could result in adverse effects.

This treatment selection could be achieved by using a companion diagnostic device. Some of the first companion diagnostic assays were developed by LabCorp for detecting HER-2 overexpression and a HER-2 gene overamplication in breast cancer tissues to identify whether a patient would be responsive to trastuzumab (Herceptin).

The Enlarged Board of Appeal in G1/04 set out a rigid framework for assessing whether a claimed diagnostic method is excluded from patentability. It held that first, it must be established whether all of the following phases are in the claim:

  • the examination phase, involving the collection of data
  • the comparison of the data with standard values
  • the finding of any significant deviation (i.e. a symptom)
  • the deductive medical or veterinary decision phase (i.e. the attribution of the deviation to a particular clinical picture)

The method is only regarded as a diagnostic method if each and every step which isn’t purely intellectual in nature satisfies the criterion of being “practised on the human or animal body”, whether the interaction is invasive or non-invasive.

A method that merely provides information or intermediate results, without leading to a final diagnosis, isn’t a method that attributes the information to a clinical picture and can be claimed at the EPO.

EP3423496B1 demonstrates suitable claim language for a companion diagnostic that identifies patients in which OSE-703 will likely be efficacious and which doesn’t fall foul of Article 53 of the European Patent Convention.

The claims of EP3423496B1 include:

“An in vitro or ex vivo method of diagnosis, in particular a method of diagnosis suitable for use in personalized medicine, more particularly companion diagnostics, where an anti-CD127 antibody or an antigen-binding fragment thereof according to any of claims 1 to 12 or a chimeric molecule according to claim 13 or a chimeric antigen receptor according to claim 14 is used for the detection of CD127+ cells in a sample previously obtained from a subject and optionally for the quantification of the expression of CD127”.

“A method of in vitro or ex vivo determining the presence of CD127+ cells in a sample previously obtained from a subject which comprises determining presence of CD127 as a biomarker that is predictive for the response of a subject to a treatment, in particular a response of a subject diagnosed with a cancer wherein said method comprises: - determining the expression level of CD127 in a tumor sample of a subject using anti-CD127 antibody or antigen-binding fragment thereof according to any one of claims 1 to 12 or chimeric molecule according to claim 13 or a chimeric antigen receptor according to claim 14, and - comparing the expression level of CD127 to a value representative of an expression level of CD127 in a non-responding subject population, wherein a higher expression level of CD127 in the tumor sample of the subject is indicative for a subject who will respond to the treatment”.

The patent also includes the following purpose-related process claim:

“The use of an anti-CD127 antibody or an antigen-binding fragment thereof according to any of claims 1 to 12 or a chimeric molecule according to claim 13 or a chimeric antigen receptor according to claim 14, in the manufacture of a medicament suitable for use in a diagnostic test, in particular for use in personalized medicine, or in a companion diagnostic test”.

This claim is in the Swiss format which, following the Decision of the Enlarged Board of Appeal in G 5/83, is now only allowable if the application has a filing or earliest priority date of 29 January 2011 or later. A purpose-related product claim such as “Anti-CD127 antibody for useas a medicamentsuitable for use in a diagnostic test” is an acceptable claim formulation.

Example two — The nutritional composition SOUVENAID®

In EP2170104, N. V. Nutricia sought to protect the nutritional composition SOUVENAID® — a once-daily drink which contains a mixture of precursors and cofactors (long-chain omega-3 fatty acids, uridine, choline, B vitamins, vitamin C, vitamin E and selenium).

It was developed to support the formation and function of neuronal membranes and synapses, and may be used in the dietary management of prodromal dementia patients. These are subjects who, although not yet suffering from dementia, are bound to develop it.

By pre-selecting patients using certain markers in the cerebrospinal fluid, a substantial number of patients who wouldn’t benefit from the therapeutic properties of the composition, and would even incur the risks of side-effects, can be screened from having the treatment.

A recent Boards of Appeal case (T0694/16) against the revocation of the EP2170104, following successful oppositions filed by Fresenius Kabi Deutschland GmbH and Nestec S.A., found that the gist of the invention is to identify the prodermal dementia patient group by identifying the presence of specific markers in the CSF which distinguishes these patients from others who present symptoms of mild cognitive impairment and won’t necessarily develop dementia — and to purposively and selectively target this prodermal dementia patient group to carry out the preventative treatment.

Under the European Patent Convention, a specific use of a known medicament in a method of therapy can be patented via purpose-related product protection, provided that the specific use isn’t already known or obvious. The specific use may be based, for example, on the group of subjects treated, the dosage regimen or a different mode of administration.

The following claim demonstrates the type of purpose-related product protection that the European Patent Office considers to be novel:

“Composition comprising (a) one or more of w-3 fatty acids selected from DHA, DPA and EPA, (b) uridine, selected from the group consisting of uridine, deoxyuridine, uridine phosphates, uracil and acylated uridine derivatives, and (c) choline and/or phosphatidylcholine, wherein the composition further includes vitamin B12 and folate, for use in the prevent or delay of the onset of dementia in a person having characteristics of a prodromal dementia patient, wherein said characteristics comprise at least:

  • a level of more than 350 ng Total-tau per litre cerebrospinal fluid (CSF); and
  • a weight ratio of abeta-42/Phospho-tau-181 of less than 6.5 in CSF. “

The case has been remitted back to the Opposition Division for a decision on inventive step.

Example three — CAR-T cells within oncology

The ultimate aim of precision medicine is to treat a patient with a drug that perfectly fits their disease and genetic make-up while causing minimal side effects. Precision medicine moves away from a one-size-fits-all approach to disease treatment and prevention, but conventionally stops short of customising a drug for each individual patient. There are, however, some instances of truly personalised medicine.

CAR-T cell therapy consists of the infusion of engineered autologous T cells that carry a chimeric antigen receptor (CAR) on the cell membrane. The external domain of the receptor is designed to recognise a specific tumour antigen. Binding causes the internal signalling domain of the molecule to be activated, stimulating the T cell to attack the tumour cell. KYMRIAH® (Novartis) and YESCARTA® (Gilead) are CD19-genetically modified autologous T cell immunotherapies, indicated for the treatment of patients with blood cancer. There are some 800 CAR-T clinical trials in progress.

According to Rule 27 of the EPC:

“Biotechnological inventions shall also be patentable if they concern:

  • biological material which is isolated from its natural environment or produced by means of a technical process even if it previously occurred in nature”

As the CAR-T cell therapy involves isolating T cells by apheresis, genetically engineering and expanding the cells in the laboratory and then reinfusing the genetically modified T cells back into the patient, the cells meet this criterion. Additionally, patent protection for CAR-T products may be directed to protect the specific CAR construct designs that are typically defined by the binding moiety and costimulatory moiety, medicaments that include the CAR-T cells and methods of manufacturing the CAR-T cells.

Recently granted EP3205720B1 (UNIV YAMAGUCHI) includes the following product claims:

“1. A CAR expression vector comprising a nucleic acid encoding a chimeric antigen receptor (CAR) and a nucleic acid encoding a T cell immune function-enhancing factor, wherein the nucleic acid encoding an immune function-enhancing factor is a nucleic acid encoding interleukin-7 and a nucleic acid encoding CCL19.

7. A CAR-expressing T cell introduced with the following vector (a) or (b) : (a) the CAR expression vector according to any one of claims 1 to 6; (b) a CAR expression vector containing a nucleic acid encoding CAR and a nucleic acid encoding interleukin-7, and a CAR expression vector containing a nucleic acid encoding CAR and a nucleic acid encoding CCL19.

8. An anticancer agent comprising the CAR-expressing T cell according to claim 7 and a pharmaceutically acceptable additive.”

As discussed above, a method of treatment of the human or animal body is considered an exception to patentability under the EPC. This difference can be seen when comparing the claim language in US10457730 and EP3265490B1 (UCL BUSINESS PLC).

The US patent includes a method of treatment claim:

“24. A method of treating a B cell malignancy, the method comprising administering to a subject with the B cell malignancy:

a cell according to claim 18, or

a pharmaceutical composition which comprises said cell or a plurality of said cells, together with a pharmaceutically acceptable carrier, diluent, or excipient.”

This claim cannot simply be formulated in the European claims as “Use of a cell comprising a CAR for the treatment of cancer”, as this is still considered to be a method claim. Instead, EP3265490B1 illustrates the use of an allowable purpose-related product claim:

“A cell according to claim 11, a cell composition according to claim 12 or a pharmaceutical composition according to claim 14 for use in treating cancer, preferably wherein the cancer is a B cell malignancy.”

Summary

The patent eligibility of innovative therapies and companion diagnostics that are being developed in this rapidly evolving field of precision medicine vary depending on jurisdiction. We have a wealth of experience in crafting claims that not only meet the requirements of the EPC, but also take into account a claiming strategy that meets the needs of a global patent portfolio.