T 0237/15 (SAHA/Sloan) 28-01-2019

1. The appeal is admissible.

2. As announced in its letter dated 27 December 2018, the respondent did not attend the oral proceedings.

In accordance with Rule 115(2) EPC and Article 15(3) RPBA, the oral proceedings were held without the respondent. By deciding not to attend the oral proceedings, the respondent has chosen not to make any further submissions during such proceedings. The respondent has been treated as relying on its written case.

3. Admission

3.1 Auxiliary requests 1 to 9

In accordance with Article 12(4) RPBA, auxiliary requests 1 to 9, all filed with the statement setting out the grounds of appeal, have been admitted into the appeal proceedings. Taking into consideration the arguments brought forward by the appellant under point 3 of page 3 of the letter dated 17 February 2016, which were not rebutted by the respondent, the board has considered these requests as an appropriate reaction to the reasoning of the impugned decision.

3.2 Documents

The board has considered the filing of document (30) to be an appropriate reaction to the impugned decision and has thus admitted document (30) in accordance with Article 12(4) RPBA.

The further documents filed in the appeal proceedings are not relevant to the present decision. No decision on their admission has been taken.

4. Inventive step

The patent in suit relates to the use of histone deacetylase (HDAC) inhibitors, especially suberoylanilide hydroxamic acid (SAHA), for inducing terminal differentiation of neoplastic cells and thereby aiding in the treatment of tumours in patients. The invention aims to provide suitable dosages and dosing schedules of these compounds and develop formulations, preferably oral formulations, which give rise to steady, therapeutically effective blood levels of the active compounds over an extended period of time (e.g. paragraphs [0001] and [0017]).

4.1 Main request

Claim 1 of the main requests defines the administration of a single dose of up to 400 mg of SAHA by oral administration in the treatment of cancer in a patient.

4.2 The impugned decision relies on document (2) as the closest prior art. The use of document (2) as the closest prior art has not been contested by the appellant.

Document (2) is a review article discussing HDAC inhibitors in the context of cancer therapy (abstract). Mechanistic considerations involving HDAC are discussed on the first pages of document (2). Table 3 shows 15 HDAC inhibitors of a great variety of molecular structures (short-chain fatty acids, hydroxamic acids, cyclic tetrapeptides, benzamides). A description of animal studies follows. In this chapter of document (2), it is stated that SAHA and MS-275 (a benzamide-type HDAC inhibitor) suppress tumour growth when administered orally to rats or mice that have solid tumours (page 199, right-hand column, paragraph 3). Document (2) then turns to "HDAC inhibitors as new cancer drugs" (heading preceding second paragraph on page 200, left-hand column). SAHA and pyroxamide are said to have recently entered clinical trials (page 200, left-hand column, last paragraph). Tumour regression and symptomatic improvement were observed at doses of SAHA that have no clinical toxicity (page 200, right-hand column, first paragraph). The passage goes on to state that "Studies to define the optimal therapeutic regimen are ongoing. Studies with an oral formulation of SAHA are also underway." Finally, the last two paragraphs of document (2) point to the challenge of finding the optimal dose, timing of administration and duration of therapy by HDAC inhibitors, and state that further research is needed to elucidate certain mechanistic aspects (page 200, right-hand column, last two paragraphs).

While the clinical trials with SAHA rely on intravenous administration of the drug (see reference 91 of document (2), which is on file as document (11)), the animal studies described in the passage on page 199, right-hand column, third paragraph, disclose successful treatment of rats or mice by oral administration of SAHA. In view of the effects achieved in these animal tests, i.e. the suppression of tumour growth in rats or mice, there remain no doubts that SAHA is bioavailable when given orally.

These animal studies are thus the most promising starting point in the assessment of inventive step. Since document (2) discloses specific studies involving SAHA, other parts of document (2) which relate to other HDAC inhibitors or discuss more general aspects are not relevant for the present decision.

4.3 The difference between the subject-matter of claim 1 of the main request is thus the dosage regimen, in particular the dose, and, potentially, the type of patient.

It is irrelevant for the present decision whether the term "patient" refers exclusively to humans or whether it also includes animals. Consequently, the present decision assumes, in line with the appellant's assertion, that a "patient" is necessarily human. However, no decision on this issue is taken.

4.4 The appellant has formulated the technical problem as the provision of improved treatment with SAHA. This problem is based on treatment providing oral administration of SAHA. However, in view of the starting point, i.e. the oral administration of SAHA to rats or mice, chosen by the opposition division and the respondent and, adopted by the board, formulating of the technical problem in this way is not justified. The passage on page 199, right-hand column, paragraph 3, already discloses oral administration. Issues and effects linked to oral administration, such as bioavailability and blood levels over a certain period of time, already form part of this starting point. An improvement which is due to the oral mode of administration can thus not form part of the technical problem.

Consequently, the technical problem is the provision of a treatment regimen for human patients based on oral administration of SAHA.

4.5 The problem has been solved. Reference is made to the data in the patent in suit.

4.6 It remains to assess whether the solution proposed in claim 1 of the main request is obvious.

4.6.1 The step from pre-clinical animal studies to clinical studies involving human patients is an unavoidable step when developing a new medicament. In the present case, the skilled person, aware of the complete disclosure of document (2), would take this step with a reasonable expectation of success. This expectation of success is based on the teaching of page 200, right-hand column, first paragraph, which discloses that SAHA was successfully used in the treatment of solid tumours in human patients (administered intravenously). Consequently, a skilled person, in the knowledge that SAHA is bioavailable when given orally in animal studies and having been given the information that SAHA achieves effective treatment in humans when introduced directly into the blood stream, would expect an effective treatment also for oral administration in human patients.

The determination of the optimum dosage regimen required to achieve the therapeutic effect in the (human) patient is a matter of routine experimentation for the skilled person. Such routine tests do not require inventive skill and can consequently not establish an inventive step.

4.6.2 Further arguments presented by the appellant concerning the absence of a "reasonable expectation of success":

The appellant argued that a skilled person had no reasonable expectation of success. These arguments are based in particular on document (12) and the expert declaration (30).

Document (12) describes problems relating to oral formulations of anti-cancer drugs in form of poor and highly variable oral bioavailability of many anti-cancer drugs (abstract, introduction). Two mechanisms underlie the variable oral pharmacokinetics: firstly the high affinity for drug-transporters, e.g. P-glycoprotein, and secondly the high extraction of the drug by extensive metabolism in the gut wall and/or liver, during "first-pass" (page 104, left-hand column, second paragraph). Document (12) reports that, despite the widespread use of models such as rodents, there are no optimal preclinical in vitro or in vivo models available that enable accurate extrapolation of preclinical data about oral pharmacokinetics to the clinic (page 104, left-hand column, third paragraph). It is stated that a more rational approach based on preclinical concepts and results is urgently needed. Thus, document (12) explains why there can be no certainty of success when transferring animal test results to clinical situations. However, in the context of the assessment of inventive step by the problem-solution approach, no certainty of success is required.

The expert declaration by Dr Sandhu, provided as document (30), discusses aspects of the bioavailability of SAHA when administered orally. Under point 1, the exceptional and unexpected high oral bioavailability of SAHA compared with other cancer drugs is mentioned. In line with document (12), document (30) mentions factors influencing oral bioavailability (point 2). In point 3, it is stated that results of preclinical studies on animal species and in vitro represent indicators which help to decide whether further pursuit in the clinic is justified. It is then explained, that, since oral bioavailability of SAHA in rats, dogs and monkeys was low (data shown in Table 1), and since it was furthermore known that SAHA had a low solubility across the physiological pH range (data shown in Table 3) and was classified as a low permeability compound, the skilled person could not have predicted that SAHA would have high oral bioavailability in humans and be a viable oral drug in the treatment of cancer (point 3). However, the assessment of inventive step is to be based on the skilled person's knowledge at the effective date. Knowledge not available on or before this date (like the knowledge based on the disclosure in post-published document (30) and documents (32), (33) and (34)) cannot be taken into account for the assessment of inventive step. It is thus irrelevant for the assessment of inventive step that the data presented in document (30) points to low oral bioavailability of SAHA in certain animal models. The same applies to solubility across the physiological pH range and permeability. Document (31) cannot have influenced the skilled person's expectations of success as it concerns a different agent, depsipeptide, and, contrary to depsipeptide, SAHA had already been shown to be bioavailable when given orally to rats or mice. In this context it is noted that the admission of documents (31) to (34) has not been discussed. This fact is however irrelevant, since the contents of these documents do not influence the outcome of the proceedings.

It is also noted that developments taking place after the effective date, such as which of the actives mentioned in a document (here the further HDAC inhibitors mentioned in document (2)) were further developed, could not have influenced the skilled person.

4.7 The board therefore concludes that the subject-matter of claim 1 of the main request does not involve an inventive step.

5. Auxiliary requests 1 to 9

The subject-matter of the auxiliary requests differs from the subject-matter of the main request on account of features relating to the form of SAHA, i.e. free compound versus pharmaceutically acceptable salt, and on account of various features related to the dosage regimen. The dosage regimen is further defined by features relating to the frequency of administration (single daily dose) and to limitations in the doses (introduction of a lower limit of the dose or limitation to a specific dose).

The arguments presented by the appellant in the discussion of inventive step of the main request all relate to use of the compound SAHA as such. The reasoning provided in point 4 above for the main requests thus applies directly to the auxiliary requests, which all define the use of SAHA.

The further restrictions concerning the dosage regimen lead to the definition of a more restricted solution to the problem discussed for the main request. It has been found for the main request that the determination of the optimum dosage regimen was well within the skills of a person skilled in the art. This finding also applies directly to more limited dosage regimens. Continuous administration of single daily doses is one of the options the skilled person would consider when performing routine dose escalation studies.

Consequently, the more limited dosage regimens of auxiliary requests 1 to 9 are obvious for the same reasons as given for the main request. The subject-matter of claim 1 of each of auxiliary requests 1 to 9 does not involve an inventive step.

6. Having arrived at a negative conclusion on inventive step for all requests on file, it is not necessary to discuss other grounds for opposition.