The established approach to drug development is based on the assumption that all patients with a particular condition respond similarly to a given drug. Thus, all patients showing the same condition are treated in the same way, even though the treatment may be effective only in the minority of patients. Individual differences between patients (eg, inherited genetic differences, environmental factors or lifestyle) are not considered by this approach.
While the idea of tailoring medical treatment to the individual requirements of a patient dates back to at least the time of Hippocrates, today new diagnostic and informatics approaches (particularly genomics and proteomics) provide a better understanding of the basis of the condition to be treated. The gained insight allows for the tailoring of personalised medical treatment for the individual genetic and molecular profile of the patient.
Although use of the term ‘personalised medicine’ has risen in the past decade, there is no universally accepted definition. EU health ministers in the Council Conclusions on Personalised Medicine for Patients (published December 2015) defined ‘personalised medicine’ as referring to “a medical model using characterisation of individuals’ phenotypes and genotypes (e.g. molecular profiling, medical imaging, lifestyle data) for tailoring the right therapeutic strategy for the right person at the right time, and/or to determine the predisposition to disease and/or to deliver timely and targeted prevention”.
Based on that definition, personalised medicine generally involves a combination of steps, namely a diagnostic step and an actual treatment step based on the results of the diagnostic step and the individual characteristics of the patient. This combination of diagnostic and therapeutic steps provides new options for patenting.
If the diagnostic or therapeutic steps are novel they can form the basis for a patent application. However, under Article 54(5) of the European Patent Convention (EPC) 2000, known substances or compositions are also deemed to be novel if they are intended for a specific use in a therapy method on the human body, provided that such use is not comprised in the state of the art. The claim format under the EPC for second medical use or second medical indication claims reads: “Substance/composition X for use in the treatment of disease Y”.
Such a claim format directed to second medical use is possible only for substances or compositions (ie, pharmaceutical products generally referred to as medicaments or drugs). It is not possible to obtain a patent relating to the second medical use of a device. This issue is discussed in the Boards of Appeal of the European Patent Office (EPO) Decision T2003/08.
In 2010 the board clarified that any specific use of a known medicament in a method of therapy according to Article 54(5) of the EPC permits purpose-related product protection (G02/08; 7.1.2; Dosage regime, Abbott Respiratory), provided that such use is not comprised in the state of the art. The finding that Article 54(5) refers to any specific use that is novel and not only any new indication makes it possible to establish novelty of a therapeutic application in several ways. Consequently, according to the board’s established case law, novelty of the subject matter of a therapeutic application may be based on the group of subjects to be treated, dosage regimen or a different mode of administration.
Hence, it is possible under the EPC to direct applications specifically to the crucial aspect of personalised medicine, namely the treatment of the right patient with the right drug at the right time.
New group of subjects to be treated
In general, the use of the same compound in the treatment of a particular group of subjects suffering from the same disease may constitute a novel therapeutic application, provided that it is carried out in a new group of subjects which is distinguished from former groups by its physiological or pathological status (eg, T19/86, T233/96, T108/09 and T734/12). Inherency or a new subgroup that overlaps with a given group of patients is not usually considered problematic (eg, T734/12 or T1118/12). The choice of such a novelty establishing subgroup must not be arbitrary (ie, there should be a functional relationship between the particular physiological or pathological status of the new subgroup and the therapeutic or pharmacological effect achieved (T1399/04)).
The right patient to be treated (ie, the subpopulation of patients) may be identified in a preceding diagnostic step, which need not necessarily be part of the claim (T734/12). Such a subpopulation of patients may usually be characterised by age, gender, weight, physiological parameters and all kinds of biomarker. Examples of biomarkers for defining a subpopulation of patients may be the presence of germ line gene mutations in cells; the presence of somatic gene mutations in tumours; the translation of ribonucleic acids in cell plasma; and the expression of proteins (particularly biomarker proteins on cell surfaces). It is increasingly important that this approach makes it possible to differ between drug responders and non-responders in a known population of patients.
Established case law
The EPO Boards of Appeal (T1118/12; November 14 2016) had to decide on the following claim:
“*1. A vaccine comprising a glycoconjugate of a Type 5 polysaccharide antigen of* [Staphylococcus aureus (S. aureus)] *and an immunocarrier, and a glycoconjugate of Type 8 polysaccharide antigen of* S. aureus *and an immunocarrier, for use in protecting an immune-comprised individual from staphylococcal bacterial infection, wherein said immune-comprised individual has nasal carriage of* S. aureus.”
*Staphylococcus aureus* causes a wide spectrum of human diseases, the most prominent of which is bacteremia, which is an invasion of the blood stream by *staphylococcus aureus*. It was undisputed that the compound and the treated disorder disclosed in the prior art document D4 fall under the definitions of the presented claim, as well as that the patients disclosed in D4 are immune-comprised. Moreover, D4 described a certain efficacy of the compound for treating haemodialysis patients.
It was known from document D11 that haemodialysis patients showed a mean nasal carriage rate of 51.5% (a range from 30.1% to 84.4%), wherein the nasal carrier rates disclosed in D11 were determined on the basis of eight different studies on the nasal carriage. Thus, considering the disclosure of D11, at least one-third of the haemodialysis patients vaccinated according to D4 carried *staphylococcus aureus* in their nasal cavity.
The board concluded that a skilled person could not have derived directly and unambiguously from D4 as a whole, using general common knowledge, that nasal carriage-positive patients were vaccinated. It was pointed out that the patient group treated according to Claim 1 is therefore distinguished from the patient group of D4 by both its physiological (nasal carriage) and pathological (higher risk of bacteremia) status. Consequently, it was concluded that the subject matter of Claim 1 is novel over the disclosure of D4.
However, Claim 1 was held not to be inventive over a combination of D11 and D4. The subject matter of Claim 1 differs from the teaching of D11 in that a vaccine instead of an antibiotic is used for the protection of *staphylococcus aureus* nasal carriage-positive, immune-comprised individuals from staphylococcal bacterial infection. D11 disclosed further that antibiotics significantly reduce the bacterial infection rate but also carry a risk of producing resistant strains.
The skilled person looking for means for the protection of nasal carriage-positive, immune-comprised individuals from staphylococcal bacterial infection overcoming this drawback would also have been aware of D4. D4 reports that a bivalent *staphylococcus aureus* glycoconjugate vaccine was well tolerated and could significantly reduce the incidence of *staphylococcus aureus* bacteremia in haemodialysis patients. The skilled person would have recognised that the drawbacks associated with the use of antibiotics identified in D11 (ie, the development of resistance), could be avoided by the use of a vaccine such as that disclosed in D4. The skilled person would thus have been motivated to use the vaccine of D4 in nasal carriage-positive, immune-compromised individuals, since its potential benefits would have been immediately obvious.
The board further pointed out that there was no teaching restraining the skilled person from combining the disclosures of D11 and D4 arriving at the subject matter of Claim 1.
It must be concluded that a novel second medical use claim based on a novelty establishing patient subgroup that provides no surprising effect or other technical advantage over the prior art will most likely be rejected for lack of inventive step. Inventive step may be based on data showing, for example, that an administered known compound shows better efficacy with regard to the new identified subgroup of patients or the patients show fewer negative side effects.
The selection of the right group of patients is closely related to the selection of the right drug. However, this aspect should be mentioned only for the sake of completeness. Usually, the common principles for a selection invention are the basis for selecting the right drug for a patient. In this context, an applicant should observe the common rules that the disclosure of a genus does not take away novelty from an individualised species and that inventive step should rely on an unexpected advantage of the selected individualised species.
New dosage regimen
The question of whether a new dosage regimen can result in a European patent was addressed in detail by the Enlarged Board (G02/08). In particular, the board had to decide whether the feature “once per day prior to sleep” can establish novelty of a second medical use claim.
The board confirmed the law on second medical use and stated that: “Where it is already known to use a medicament to treat an illness, Article 54(5) EPC does not exclude that this medicament be patented for use in a different treatment by therapy of the same illness”. The board explained that in this context novelty and non-obviousness are not derived from the substance or composition as such, but from its intended therapeutic use. The board went on to say that “such patenting is also not excluded where a dosage regime is the only feature claimed which is not comprised in the state of the art”.
Even if novelty can be established by a new dosage regimen, this feature must also fulfil the further requirements of patentability (eg, inventive step and sufficiency of disclosure).
In T1592/12 (Herceptin dosage regimen/Genentech, July 24 2017), the board had to decide on the following granted Claim 1:
"*1. Use of the anti-ErbB2 antibody huMab 4D5-8 in the manufacture of a medicament for use in a method for treating a human patient diagnosed with a breast cancer characterized by overexpression of ErbB2, said method comprising the steps of administering to the patient an initial dose of 8 mg/kg of the anti-ErbB2 antibody; and administering to the patient a plurality of subsequent doses of the antibody in an amount that is 6 mg/kg, wherein the doses are separated in time from each other by three weeks.*"
Carrying out the treatment regimen as defined in Claim 1 resulted in success. However, the issue was whether the European patent disclosed the invention in a manner sufficiently clear and complete for it to be carried out by a person skilled in the art.
The anti-ErbB2 antibody Herceptin was known to be effective when administered at a loading dose of 4 milligrams per kilogram (mg/kg) followed by a maintenance dose of 2mg/kg every week. The essential feature distinguishing the claimed invention from the known use of Herceptin was the different dosage regimen. The specification of the patent did not disclose any data regarding the claimed dosage regimen.
The board concluded that the skilled person, having read the general description of the patent which emphasised weekly administration as the most preferred, and having studied Examples 1 and 2 which likewise apply weekly administration, would rely on Herceptin’s well-known half-life of one week to assess the suitability of the claimed dosing regimen. The skilled person would thus have serious doubts that tri-weekly administration of Herceptin would suffice to maintain the serum trough concentration of Herceptin required for effective treatment of breast cancer. Consequently, the suitability of the claimed dosing regimen cannot be considered to have been disclosed at the patent’s filing date. According to this case, the patentee could also not rely on post-published evidence.
It should be concluded that the suitability and effect of the claimed dosage regimen must be disclosed at the patent’s filing date.
New administration mode
A different mode of administration for a pharmaceutical compound can also render a second medical use claim novel (T51/93). According to this case, the only difference between the invention as claimed and the prior art was that the second medical use claim was directed to subcutaneous administration. The board held that patentability should be treated as depending only on whether the modification was in fact novel and inventive.
Novelty of a second medical use claim relying on a known substance or composition may be established by identifying a subgroup of patients to be treated, a new dosage regimen or new mode of administration.
A feature that establishes novelty of this medical use claim must not be chosen arbitrarily. There should be a functional relationship between the therapeutic or pharmacological effect achieved and the novelty establishing feature.
It must also be considered that the other requirements for patentability under the EPC must be fulfilled, particularly inventive step and sufficiency of disclosure. It should at least be made plausible in the application as filed that the novelty establishing feature contributes to the solution of the problem purportedly solved (ie, provides a technical effect). Provided such plausibility, EPO case law allows for the furnishing of additional data that proves the claimed technical effect even after the filing date.
Before starting to draw up a patent application relating to new subgroups of patients to be treated, the applicant should deliberate thoroughly which biomarkers may be used to characterise a subpopulation, how such biomarkers delimit from the prior art and how they are determined.
Besides second medical use claims, a new patent application should comprise all other potential claim categories (eg, diagnostic or prognostic uses and methods, diagnostic apparatuses and kits, pharmaceutical compositions, biomarkers and screening assays for the respective biomarker). The claim wording should reflect different territories.
Further, applicants should closely monitor clinical trials since it may be possible by identifying subpopulations or dosage regimens to develop applications based on the results of clinical studies or even the underlying protocols. Applications based on the protocols of clinical studies may be of importance, as such protocols are often published before the trials are complete and are therefore regarded as relevant prior art.
There are various possibilities for applicants intending to file applications directed to personalised medicine or second medical indications in Europe. This is all the more true if applicants take the prerequisites for protecting their inventions into account when developing their products and drawing up corresponding applications.
published, IAM Life Science 2018, To view the guide in full, please go to www.IAM-media.com