T 1941/21 - Clinical trials; Novelty after inventive step

Key points

• "D4 discloses the protocol and design of a clinical trial for evaluating the efficacy and tolerability of [the compound] TUDCA in the treatment of ALS, wherein TUDCA is administered at 1g b.i.d (2g daily) for a year to 18-75 years old Caucasian male or female ALS patients who had first symptoms of ALS by no more than 1.5 years and were in treatment with a steady regime of riluzole and vitamin E for a minimum of three months (see D4: title; page 6, arms and interventions; page 7, outcome measures; page 7, eligibility). Further, document D4 describes in detail the rational for using TUDCA in these clinical trials. It mentions in particular that TUDCA is endowed with antioxidant, antiapoptotic and neuroprotective activities and describes the detailed pharmacological mechanisms of action for each activity (see D4, pages 5-6). The results of the trial announced in D4 have not been made available to the public."
• I.e., D4 discloses the method features of the second medical use claim at issue (""1. Tauroursodeoxycholic acid [TUDCA] or a pharmaceutically acceptable salt thereof for use in the treatment of a neurodegenerative disorder in a mammal, characterized in that said neurodegenerative disorder is amyotrophic lateral sclerosis."')
• "The problem [solved by the claim over D4] was defined by the opposition division in its decision as the provision of an effective treatment for ALS. "
• "The problem appears to be solved in view of the examples of the contested patent in paragraphs [0028]-[0038]. The patent shows for instance that the baseline-adjusted absolute ALSFRS-R score was significantly higher in TUDCA-treated than in placebo-treated patients "
• Note:  "This study shows that one year of treatment with TUDCA at the prescribed dose was associated with slower deterioration of function in ALS patients. This disease modifying effect is additional to that of riluzole, as both treatment groups [i.e. "placebo" and TUDCA] were under riluzole and vitamin E treatment. " (patent, para. [0036]
• "Clinical trials are usually initiated on the basis of encouraging results from preclinical experiments. Thus, the announcement of a phase II clinical trial protocol for a particular therapeutic agent and a disease may provide the skilled person with a reasonable expectation of success. "
• "Such reasonable expectation of success is, however, to be denied in a situation where a skilled person would have been discouraged from carrying out the clinical trials, such as when the state of the art provides the skilled person with reasons for not pursuing the solution envisaged in the clinical trial or provides the skilled person with an expectation of failure. Consequently, "a reasonable expectation of success" is linked with the specific circumstances of the case and requires a case-by-case evaluation of all the facts at hand at the priority date of the contested patent. In the present case, the Board holds that the state of the art suggested to the skilled person a clear expectation of failure."
• "The disclosure of document D9 demonstrates indeed that the skilled person could not base any reasonable expectation of success of the use of TUDCA in treatment of ALS on the announcement in document D4 of a phase II clinical trial for the treatment of ALS with TUDCA.

  D9 is a scientific article published in 2012 which gives a general review of the treatment of amyotrophic lateral sclerosis (ALS) at that time. D9 mentions 89 different drugs which, before the filing date of the opposed patent, had been used in clinical trials for ALS based on allegedly promising preclinical data [...]. 

• "Importantly, [D9] discloses that, for all the drugs listed in the document, promising preclinical data, such as biochemical or cellular assays, have been provided, but nevertheless the majority of the clinical trials failed"

• "Accordingly, the Board concludes that, starting from document D4 and in view of the further cited prior art, the skilled person would not have arrived at the claimed subject-matter in an obvious manner and that the subject-matter of claim 1 of the main request involves an inventive step."

Novelty after inventive step

• "D8 [EP 2 422 787 A1, being prior art under Art.54(2)] relates to compositions comprising low doses of diazoxide for use in the treatment of a mammal afflicted with ALS, in particular a human (see D8, claims 1 and 3). Further, D8 discloses in claim 9 that diazoxide can be combined with "an additional therapeutic agent useful in the treatment of amyotrophic lateral sclerosis" including TUDCA, which constitutes a single selection from a list. Consequently, a composition comprising diazoxide and TUDCA for use in the treatment of a mammal afflicted with ALS is derivable directly and unambiguously from D8."
• "Accordingly, even if D8 does not provide any in vitro or in vivo experiments with regard to the efficacy of TUDCA in the treatment of ALS, D8 provides an enabling disclosure for a combination treatment based on diazoxide and TUDCA, in view of the explicit disclosure in D8 of the efficacy of diazoxide. "
• "D8 supports the utility of low dose diazoxide in the treatment of ALS with experimental results, in particular in Example 2. This example shows that low doses of diazoxide improve survival in the SOD1-G93A transgenic mice model for amyotrophic lateral sclerosis. The utility of diazoxide in treatment of ALS described in D8 has not been disproved."
• Note, for D8, a pre-clinical experiment (animal study) is sufficient for an enabling disclosure. Cf. the remarks about D9 above.
• "As a general rule, a claim to the use of a known compound for a particular purpose or to a product for use in a particular medical purpose, which is aimed at obtaining a technical effect described in the patent, should be interpreted as including that purpose as a functional technical feature, and is accordingly not open to objection under Article 54(1) EPC provided that such technical feature has not previously been made available to the public. This functional feature has however been made public in the present case."
  
  
• "In the Board's view, the discovery of a new property of a particular ingredient of a known composition, i.e. here TUDCA in the composition comprising diazoxide and TUDCA, used for a known and identical general purpose, i.e here the treatment of a mammal afflicted with ALS, can indeed not confer novelty to the particular ingredient used for the same general purpose, namely TUDCA for the treatment of ALS. Novelty can only be recognized if this new property is applied in a new use."
• The claim does not specify "a composition comprising TUDCA for use in the treatment of ALS". The Board's reasoning is difficult to follow.
• Consequently, the disclosure in D8 of treatment of ALS based on diazoxide and TUDCA, wherein the efficacy of diazoxide is supported by experimental data and has not been disproven, anticipates the subject-matter of claim 1 of the main request.
• " Claim 1 of auxiliary request was amended by the addition of the feature " in a human, characterized in that it is administered for at least 30 weeks".
• "Since there is no disclosure of any duration of treatment in D8, the subject-matter of claim 1 of auxiliary request 2 is not anticipated, and auxiliary request 2 meets the requirements of Article 54 EPC."
• As a comment, there is no discussion at all of why the added feature of administration of 30 weeks provides for an inventive step over D8. I don't understand why, except that the opponent had no inventive step objections starting from D8. I understand ALS is a chronic disease?

EPO 

The link to the decision and an extract of it can be found after the jump.

https://www.epo.org/en/boards-of-appeal/decisions/t211941eu1

1. Main request - Inventive step

1.1 The object of the claimed invention is the use of TUDCA or a pharmaceutically acceptable salt thereof in the treatment of ALS.

1.2 D4 was considered to represent the closest prior art by the opposition division in its decision, rather than D1 or D12. The respondent developed its objection of lack of inventive step on the basis of D4 as closest state of the art in its reply to the statement of grounds of appeal.

1.2.1 D4 discloses the protocol and design of a clinical trial for evaluating the efficacy and tolerability of TUDCA in the treatment of ALS, wherein TUDCA is administered at 1g b.i.d (2g daily) for a year to 18-75 years old Caucasian male or female ALS patients who had first symptoms of ALS by no more than 1.5 years and were in treatment with a steady regime of riluzole and vitamin E for a minimum of three months (see D4: title; page 6, arms and interventions; page 7, outcome measures; page 7, eligibility). Further, document D4 describes in detail the rational for using TUDCA in these clinical trials. It mentions in particular that TUDCA is endowed with antioxidant, antiapoptotic and neuroprotective activities and describes the detailed pharmacological mechanisms of action for each activity (see D4, pages 5-6). The results of the trial announced in D4 have not been made available to the public.

1.2.2 The Board agrees with the choice of D4 as closest prior art by the opposition division.

The disclosure of D1 is indeed mainly directed to the use of UDCA for the treatment of ALS and provides experimental results only for UDCA, while mentioning TUDCA as metabolite of UDCA with potential in the treatment of neurodegenerative disease.

The Board considers in particular the teaching of D12 more remote than D4 which envisages a real human treatment with TUDCA. Document D12 provides indeed only some pre-clinical in vitro data showing that TUDCA had a protective effect on motor neuron degeneration caused by mutations in SOD1, making it potentially useful as a treatment in patients with some forms of amyotrophic lateral sclerosis through these mechanisms.

1.3 The problem was defined by the opposition division in its decision as the provision of an effective treatment for ALS. This formulation of the objective technical problem is not contested by the appellant or the respondent.

1.4 The problem appears to be solved in view of the examples of the contested patent in paragraphs [0028]-[0038]. The patent shows for instance that the baseline-adjusted absolute ALSFRS-R score was significantly higher in TUDCA-treated than in placebo-treated patients (see par. [0031] of the specification) and that the rate of responder patients was significantly higher under TUDCA (87%) than placebo (43%) (see par. [0032]). Moreover the average survival time was a bit longer under TUDCA treatment (cf. par. [0034]) and one year of treatment with TUDCA at the prescribed dose was associated with slower deterioration of function in ALS patients (see par. [0036]).

1.5 Clinical trials are usually initiated on the basis of encouraging results from preclinical experiments. Thus, the announcement of a phase II clinical trial protocol for a particular therapeutic agent and a disease may provide the skilled person with a reasonable expectation of success. Such reasonable expectation of success is, however, to be denied in a situation where a skilled person would have been discouraged from carrying out the clinical trials, such as when the state of the art provides the skilled person with reasons for not pursuing the solution envisaged in the clinical trial or provides the skilled person with an expectation of failure. Consequently, "a reasonable expectation of success" is linked with the specific circumstances of the case and requires a case-by-case evaluation of all the facts at hand at the priority date of the contested patent.

In the present case, the Board holds that the state of the art suggested to the skilled person a clear expectation of failure.

1.5.1 The disclosure of document D9 demonstrates indeed that the skilled person could not base any reasonable expectation of success of the use of TUDCA in treatment of ALS on the announcement in document D4 of a phase II clinical trial for the treatment of ALS with TUDCA.

D9 is a scientific article published in 2012 which gives a general review of the treatment of amyotrophic lateral sclerosis (ALS) at that time. D9 mentions 89 different drugs which, before the filing date of the opposed patent, had been used in clinical trials for ALS based on allegedly promising preclinical data (see page 9, at the top). The document explains the complexity of the disease ALS and mentions all the numerous and possible pathophysiological considerations involved in ALS (see page 7, par. 4.1). It furthermore cites all possible corresponding promising groups of compounds in the planning of ALS treatment strategies, with inter alia the anti-oxidants, the neuroprotectants and the anti-apoptotic compounds (see pages 7 and 9 of D9).

Importantly, it discloses that, for all the drugs listed in the document, promising preclinical data, such as biochemical or cellular assays, have been provided, but nevertheless the majority of the clinical trials failed (see D9, page 9 under section 5.1 headed "Programmed failure in clinical trials for AlS?").

Hence, among the tested drugs, solely riluzole had received a marketing authorization and was thus used by patients affected by ALS; but the efficacy of riluzole, as confirmed by D4 and D9, is limited to prolonging survival of patients by approximately two to three months (see D9 page 19, "Riluzole"). Other drugs having the same anti-glutamatergic properties as riluzole, such as gabapentin or topiramate, were also tested without however any benefits for patients with ALS (see D9, pages 15 and 21 of D4). This shows that the choice of compounds on the basis of preclinical data or on the pathophysiological properties of said drugs cannot be seen as an encouraging element in the specific treatment of ALS.

With regard to TUDCA, D9 mentions simply that the drug was found to be neuroprotective, antioxidative and anti-apoptotic in rat models for diseases such as stroke and Huntington's disease, and that it is currently evaluated in a Phase II study, namely the study of D4 (see page 20).

D9 mentions the trials of many drugs having the same pharmacological properties as TUDCA, i.e. anti-oxidant, neuroprotectant and/or anti-apoptotic properties, all of which having been found to be ineffective. D9 highlights in particular that no evidence of a benefit of an anti-oxidant treatment with regard to survival, neither alone or in combination, has been described (see page 11). More specifically, D9 explains that many antioxidants, such as inter alia creatine, lithium or tocopherol, failed in clinical trials on humans. D9 gives the same conclusions with other drugs having anti-apoptotic and/or neuroprotective properties, alone or in combination with other properties. For instance, erythropoietin, which has both neuroprotective and anti-apoptotic properties, did not show any clinical efficacy (see page 14) and sodium valproate, which shows anti-oxidative and anti-apoptotic properties was also not effective with regard to survival and disease progression (see page 20). This shows that drugs having anti-oxidant, neuroprotectant and/or anti-apoptotic properties have a priori no expected efficacy in the treatment of ALS and that a drug having such individual or combined properties, such as TUDCA, would provide the skilled person with at best a "hope of success" for its use in treatment of ALS, but more likely an "expectation of failure".

Consequently, D9 shows that the selection of a treatment based on existing favourable preclinical data does not give an expectation of success when the same drug is used in clinical trials for the treatment of ALS and that, in the specific case of drugs having anti-oxidant, anti-apoptotic and/or neuroprotective properties, there is no expectation of success of the treatment.

1.5.2 A reasonable expectation of success from the trial of D4 is furthermore not supported by any potential effective treatment of ALS by an in vivo precursor of TUDCA, namely UDCA, as described in documents D1 and D15.