Friday, January 24, 2020 T 1491/14 - A medicament for patients who have ceased use of another medicament due to sleep problems

Sleepless nights

This opposition concerns a medicament whose novel feature is that it is prescribed to particular patients. Claim 1 of the main request reads:

1. A use of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl] piperazine and pharmaceutically acceptable salts thereof in the manufacture of a medicament for the treatment of a disease selected from depression, anxiety, abuse or chronic pain, wherein said medicament is for use in a patient who has previously received another medication for the treatment of said disease which medication was ceased or reduced due to sleep or sexually related adverse events.

The board accepts this as a valid claim. It turned out to be novel but obvious to prescribe the medicament to a patient who has previously received another medication which medication was ceased due to sexually related adverse events, but after limiting the claim to sleep problems it was allowed.  

Reasons for the Decision

1. Documents on file

The parties have either withdrawn their objections or not objected (see minutes of the oral proceedings held on 30 July 2019) to the admission of the documents filed by the other party during the appeal proceedings. The board sees no reason to raise any objection in this respect either. Hence, all the documents filed in the appeal proceedings are admitted into the proceedings.

2. Novelty - main request (patent as granted)

The opponent contested the novelty of the subject-matter of claims 1 and 3 over the content of documents D4 and D2.

Document D4 is an international patent application published after the two older priority dates and before the filing date of the contested patent. It was nevertheless undisputed that the claimed invention does not enjoy those older priority dates and that document D4 belongs to the prior art within the meaning of Article 54(2) EPC.

2.1 Document D4 discloses (see claims 1 and 15) the use of vortioxetine for the treatment of depression, anxiety, abuse and chronic pain. Similarly, document D2 discloses (see fifth compound in claim 11, and claim 13) the use of vortioxetine for the treatment of depression and anxiety.

It was common ground that documents D4 and D2 disclose the use of the same compound for the treatment of the same diseases as claims 1 and 3 of the patent in suit. It was also common ground that the claimed uses differ from those in D4 and D2 only by the fact that they are directed to a specific patient group. The board needs then to assess whether that patient group is suitable to render the claimed use novel over the disclosures of D4 and D2, which do not specify any subgroup among the patients suffering from depression, anxiety, abuse or chronic pain.

2.2 In the course of the oral proceedings before the board, the patent proprietors put forward that the criteria for a patient group rendering a previously known therapeutic method novel are that:

i) The patient group is not disclosed in the relevant prior art.

ii) The patients belonging to the group can be distinguished from those of the prior art by their physiological or pathological status.

iii) There is a functional relationship between their characterising physiological or pathological status and the therapeutic treatment and thus the selection of the patients is not arbitrary.

The opponent did not contest this, and the board agrees that - although the case law of the board of appeal does not seem to provide fixed criteria for a patient group - a patient group fulfilling those three criteria is anyhow suitable to render the claimed subject-matter novel. In addition, the board holds that the three criteria are fulfilled by the patient group of claims 1 and 3, as explained below.

2.2.1 Documents D4 and D2 do not specify the condition of the treated patients beyond the fact that they are suffering from depression, anxiety, abuse or chronic pain. The patients of claims 1 and 3 are characterised by the fact that, in addition to suffering from depression, anxiety, abuse or chronic pain, they were previously treated for any of those diseases with a medicament other than vortioxetine, and they discontinued or reduced medication due to the occurrence of sleep or sexually related adverse events. As such patients have not been disclosed in documents D4 and D2, they constitute an undisclosed sub-group which fulfils criterion i).

2.2.2 The patients in claims 1 and 3 are characterised by the fact that they decided to cease or reduce their first-line medication for depression, anxiety, abuse or chronic pain following the incidence of sleep or sexually related adverse events experienced during the treatment. Contrary to the opponent's view, the patients' decision to continue or reduce or cease medication due to adverse effects cannot be regarded as a non-technical feature. In fact, this decision is covered by the more general concept of patient compliance, which concept is accepted in the case law as being of a technical nature. Such a decision is driven by the patients' perception that the burden of the sleep or sexually related side effects experienced is unbearable or at least as limiting as the disease itself. This failure of the previous treatment certainly affects the patients' mental health and their attitude towards antidepressants, making them different from other patients from a pathological point of view, in particular from naive patients.

This becomes even more evident considering that attitude is an important factor in mental diseases and that patients' adherence to the treatment is closely linked to their favourable attitude to the medication and the confidence in managing side effects (see D18, page 368, right-hand column, paragraph 2). Thus, the patients of claims 1 and 3 are conditioned by a potential lack of confidence in the management of side effects or the fear that there might not be an acceptable treatment for them. This circumstance exposes patients to a higher risk of relapse and makes them potentially more difficult to treat. In fact, those patients would be treated differently by their physician, since, as noted in document D18 (page 347, point 2.3, last black dot), one of the factors to consider in choosing an antidepressant is the tolerability and the adverse effects of a previously given drug and the likely side effects of the new drug.

The opponent argued that the patients of claims 1 and 3 are only distinguished from those of the prior art by a mental act and that this situation would be analogous to the one underlying decision T 619/02.

The board disagrees. The case of decision T 619/02 concerns a method of odour selection which involves a purely aesthetic choice deprived of technical character. This situation can in no way be equated with that of the patients of claims 1 and 3, who had to weigh the benefits and drawbacks of their prescribed medication and take a decision between two options, both of which entailed serious consequences for their daily life. Such a decision was, as considered above, not an arbitrary choice based on the patients' free will but rather a technical decision comparable to that of a physician selecting the most suitable treatment for a patient. Hence, the conclusions of decision T 619/02 are not applicable to the present case.

The board therefore holds that the particular history of the patients of claims 1 and 3 makes them pathologically different from other patients, in particular from naive patients, and that criterion ii) is fulfilled too.

In this connection, the issue of whether the patients may in practice be effectively distinguished from other patients will be addressed in the discussion of sufficiency of disclosure (section 6).

2.2.3 With regard to criterion iii), the fact that vortioxetine produces sleep and sexually related adverse events at (or close to) the level of placebo (see e.g. D34, Table 5; D58, Table 5; D36; and D43, page 134, paragraph 3) makes it particularly suitable for treating depression, anxiety, abuse or chronic pain in patients who took the decision to reduce or cease a previous medication due to the occurrence of such adverse events (this issue will be discussed in more detail in the context of inventive step). The functional link between the pathological status of the patients and their therapeutic treatment is therefore clear.

2.3 The board therefore concludes that the subject-matter of claims 1 and 3 is novel over the content of documents D4 and D2.

3. Inventive step - main request (patent as granted)

3.1 The opponent considered document D4 to be the closest prior art. The patent proprietors contested this view with the argument that D4 did not deal with the central problem of the patent, namely the reduction or cessation of a first-line therapy due to the incidence of sleep or sexually related adverse events.

In the board's view, the patent proprietors' argument must fail because document D4 is concerned with the treatment of depression, anxiety, abuse and chronic pain with vortioxetine (see claims 1 and 15, and page 12, lines 12 to 24), which is the primary aim of the patent. In addition, the document mentions in the passage bridging pages 12 and 13 that antidepressants frequently cause sexually related adverse events which may lead to discontinuation of the treatment, and that the occurrence of sexually related adverse events observed in patients treated with vortioxetine was surprisingly low. Hence, it is apparent from its technical field, its aim and its information on vortioxetine side effects that D4 is particularly close to the invention. Document D4 is therefore a highly suitable starting point for the assessment of inventive step.

3.2 It was undisputed that the use of claims 1 and 3 differed from the closest prior art in the specific group of patients to which it was directed.

3.3 In relation to the effect produced by this difference, the board is satisfied that, for the reasons explained in sections 3.3.1 and 3.3.2 below, the evidence on file demonstrates that vortioxetine causes sleep and sexually related side effects at the level of placebo (i.e. at the lowest possible level) or slightly above it. It has also been shown that vortioxetine produces lower sleep and sexually related adverse events than reference SRI antidepressants such as duloxetine and venlafaxine. Accordingly, vortioxetine is particularly suitable for treating patients who could not bear the occurrence of sleep or sexually related adverse events of a previous treatment.

3.3.1 The low incidence of sexually related adverse events caused by vortioxetine is derivable from the results of the clinical tests reported in paragraph [0033] of the patent, where placebo and vortioxetine produced practically no cases of anorgasmia, delayed ejaculation, erectile dysfunction, decreased libido, abnormal orgasm, loss of libido, or decreased orgasmic sensation. This observation was confirmed by the clinical trials reported in documents D34 (see Table 5) and D36 (Table), where the occurrence of sexually related side effects (anorgasmia, delayed ejaculation and erectile dysfunction) at increasing daily doses of vortioxetine from 5 mg to 20 mg was again as low as that of placebo. Lastly, these results were corroborated by the EMEA in its assessment report for marketing authorisation (D43), which concluded on pages 134 (paragraphs 5 and 6) and 156 (paragraph 5) that, although there is an increase in the occurrence of sexual dysfunction going from the 5mg to the 20mg group, the overall incidence during the treatment with vortioxetine was low (38%) and slightly higher than that in the placebo group (32%). Even at the higher daily dose of 20mg, the incidence of sexually related adverse events caused by vortioxetine (43%) was below that of duloxetine (46%).

The opponent contested this conclusion with reference to the publications by the FDA, D56a and D56b, which stated that the occurrence of sexual side effects with vortioxetine was higher than with placebo, appeared to be dose-related, and was similar to duloxetine (see D56a, page 2, left-hand column, paragraph 2; and D56b, page 13, left-hand column, last paragraph). In particular, the opponent referred to Table 3 of document D56b, which showed that the incidence of sexual dysfunction in patients treated with 20mg vortioxetine (34-29%) was higher than with the active control, 60mg duloxetine (28-26%).

As noted by the patent proprietors, this slightly higher incidence of sexual dysfunction for vortioxetine reported by the FDA, which seems to contradict the conclusions of the EMEA, may be explained by the different methodology used by the agencies in their analysis of clinical tests; while the FDA assessed the incidence of sexual side effects on the basis of a positive reporting at two consecutive visits (see the text below Table 3 of D56b), the EMEA noted each incidence of the side effect. Hence, the methodology of the EMEA appears to be more sensitive for the identification of the levels of adverse events, and its conclusions can be considered to be more accurate in this respect. The board therefore holds that documents D56a and D56b do not invalidate the results and conclusions of the patent or documents D34, D36 and D43 in relation to the low incidence of sexually related adverse events of vortioxetine.

3.3.2 Concerning the sleep related adverse events, the results of the clinical tests reported in the patent in paragraph [0032] and depicted in Figures 6 to 8 display the incidence of insomnia in patients treated for depression with vortioxetine. In particular, Figures 6 to 8 show that the incidence of early, middle and late insomnia during the treatment was lower than that of placebo.

The opponent questioned whether these results were suitable to conclude that vortioxetine produces few sleep related side effects, because insomnia is not only a side effect of antidepressants but also a symptom of depression which diminishes along with the treatment, due to the improvement of the patient's state. However, the board is convinced by the patent proprietors' argument that the difference in timing between the onset of an effective level of the treatment for depression and the appearance of the sleep related adverse events allows the discrimination between a low incidence of sleep related side effects and a reduction of sleep related symptoms.

As argued by the patent proprietors, the onset of the antidepressant effect of SRIs often requires weeks of treatment (see D8, page 801, right-hand column, last paragraph, and D9, page 1801, left-hand column, last paragraph), while sleep related adverse events typically occur immediately following the initiation of treatment (see D20, page 2, heading "Central nervous system side effects"). In this context, Figure 2 of document D34 shows that, before the second week of treatment, there is no statistically significant difference between the depressive state of the patients treated with vortioxetine and those treated with placebo. In other words, the antidepressant effect of vortioxetine is not significant during the first two weeks of treatment. The board therefore holds that the low levels of insomnia (below placebo) observed in Figures 6 to 8 of the patent during the first two weeks of treatment necessarily imply a low incidence of sleep related adverse events. Furthermore, this effect has been confirmed by the British Association for Psychopharmacology and the EMEA in documents D58 and D43, respectively. The British Association indicated in Table 5 of document D58, which depicts the side effect profile of commonly used antidepressants, that vortioxetine does not produce insomnia or agitation. Similarly, the EMEA stated on page 134 (see paragraph 3) of document D43, with reference to vortioxetine, that "[t]he incidence of insomnia and somnolence were similar to placebo".

3.4 Based on these effects, the board agrees with the parties that the objective technical problem may be formulated as finding a patient group which particularly benefits from the treatment with vortioxetine.

3.5 The board is also satisfied that the patient group of claims 1 and 3 is a suitable solution to that problem. The question of whether or not that solution was obvious depends first and foremost on the value that the skilled person would have attached to the conclusion drawn by the inventors of document D4 on page 13, lines 1-2, that:

"[t]hese data suggest that clinical intervention using compounds of the present invention is associated with surprisingly few deficits in sexual functioning."

This conclusion was drawn in relation to clinical trials where 114 subjects had been exposed to vortioxetine and only one reported sexual dysfunction.

The patent proprietors considered that this conclusion would not have given the skilled person any expectation of success in relation to the low levels of sexually related adverse events produced by vortioxetine because it was based on phase I clinical trials which, by their nature, are unsuitable for assessing the level of side effects, especially sexually related side effects. The fact that the tests were phase I trials was apparent from the low number of (healthy) subjects involved and the fact that they were not treated with the drug, but exposed to it. The reasons why such tests would be unsuitable are multiple. Firstly, only a small proportion of the subjects is exposed to doses that would be used in therapy. Secondly, the trials are carried out in a clinical environment, which makes the subject's ability to engage in sexual activity difficult. And thirdly, the tests are carried out for a reduced time period, while sexually related adverse events generally emerge after weeks of treatment (see document D32, page 251, paragraph 2).

The board is not convinced by those arguments. The inventors of D4 were aware that vortioxetine was an SRI antidepressant (see page 1, lines 4 to 7) and could then expect it to produce sexually related adverse events, also in healthy subjects (phase I trial). In fact, they recorded the occurrence of such events and found them to be surprisingly low. This conclusion was drawn by clinical experts on the basis of the results obtained from clinical trials carried out on a considerable number of subjects and of which they had all the relevant information. So, they knew exactly which conclusions could be validly drawn from those trials. Accordingly, irrespective of the phase of the trials and the level of detail disclosed in D4, the skilled person would not have considered the conclusion of the inventors of D4 to be unfounded.

3.6 The board therefore holds that at the relevant date of the patent it was obvious to the skilled person that patients who had suffered sexually related adverse events in a previous treatment for depression, and who had reduced or ceased that treatment due to those adverse events, were patients who could particularly benefit from the treatment for depression with vortioxetine. Hence, the subject-matter of claims 1 and 3 as granted does not involve any inventive step.

4. Novelty - auxiliary request 1

In claims 1 and 3 of auxiliary request 1, the patients of the main request have been limited to those who reduced or ceased the previous medication due to the occurrence of sleep related adverse events. Thus, the reasons why the subject-matter of the granted claims is novel apply mutatis mutandis to the subject-matter of the claims of auxiliary request 1.

5. Inventive step - auxiliary request 1

5.1 As for the main request, starting from document D4, the subject-matter of claims 1 and 3 differs in the group of patients treated.

5.2 Also like the main request, the technical problem to be solved may be formulated as finding a patient group which particularly benefits from the treatment with vortioxetine.

5.3 It has already been discussed in section 3.3.2 that vortioxetine produces sleep related side effects at the level of placebo. The board is therefore satisfied that the solution proposed in claims 1 and 3 effectively solves the problem posed.

5.4 With regard to the issue of obviousness, the board notes that no document on file suggests that vortioxetine produces particularly low levels of sleep related adverse events or that it is particularly suitable for treating patients who reduced or ceased their previous medication due to the occurrence of such adverse events. The solution proposed in claims 1 and 3 of auxiliary request 1 was therefore not obvious to the skilled person.

5.5 In this context, the opponent argued that the skilled person would have arrived at the subject-matter of claims 1 and 3 as a result of a one-way-street situation. In order to obtain a marketing authorisation for vortioxetine, the skilled person would have been obliged to carry out clinical tests assessing its level of side effects, especially those known for SRI antidepressants, e.g. sleep disturbances. By doing so, the skilled person would have necessarily observed the low level of sleep related adverse events produced by vortioxetine and, hence, they would have inevitably arrived at the use of claims 1 and 3 without the involvement of an inventive step.

This argument has to be rejected for being fundamentally flawed; it confuses the applicant of document D4 with the skilled person, assuming that the skilled person would be prompted to bring vortioxetine into the market rather than to solve the problem posed.

As established in the case law, a one-way-street situation arises when the skilled person inevitably arrives at a particular combination of technical features due to a lack of alternatives (see Case Law of the Boards of Appeal of the EPO, 8th edition, 2016, I.D.10.8, paragraph 2). This is not the situation in the case at hand, however. The skilled person confronted with the problem of finding a patient group which particularly benefits from the treatment with vortioxetine had multiple choices, e.g. testing patients of different age ranges, with specific concomitant conditions such as depression associated to chronic pain, with particular genetic or physiological features, etc. Hence, the opponent's view that the skilled person inevitably had to carry out clinical tests for assessing the side effects of vortioxetine cannot be accepted.

6. Sufficiency of disclosure - auxiliary request 1

The opponent argued that the invention of auxiliary request 1 was not sufficiently disclosed in two respects.

- The skilled person was not able to identify the patients belonging to the group of claims 1 and 3.

- It had not been proven that vortioxetine was suitable for treating anxiety, abuse and chronic pain.

6.1 With regard to the identification of the patients who belong to the group of claims 1 and 3, it was common ground that the diagnostic of depression, anxiety, abuse and chronic pain is generally made by anamnesis using standard criteria, for example the ICD-10 depression diagnostic criteria disclosed in document D45, where patients are questioned on symptoms of subjective nature like persistent sadness, low mood, loss of interest or pleasure, fatigue, low energy, etc. The validity of the clinical diagnostic obtained in this manner has not been contested.

The board agrees with the patent proprietors that, in a similar way, a physician in the field of mental health is able to establish, by questioning, whether new patients received a previous medication, whether they experienced adverse events during that previous medication and of which nature, and, where applicable, the reasons why they reduced or ceased medication. In this respect, contrary to the opponent's arguments, the measurement of a physical or chemical parameter is not required for identifying the patients. This view is confirmed by the expert declarations D22 (point 9) and D23 (point 8), which state that a physician who treats a patient for the first time will as standard practice question the patient not only on the nature and duration of their symptoms but also on their treatment history. It is also noted that the assessment of sleep related adverse events in patients treated with antidepressants is common practice as also follows from the fact, recognised by the opponent in its arguments of inventive step, that such an assessment is required for obtaining a marketing authorisation.

Thus, the board has no doubts that a physician in the field of mental health can identify patients who have previously received medication for depression, anxiety, abuse or chronic pain, who experienced sleep related adverse events, and who reduced or ceased medication due to those sleep related adverse events. The fact that there are no standard questionnaires for this purpose does not represent an impasse, since gathering that information is part of the aim of anamnesis, which is a generally accepted means for diagnosis and identification of issues in the field of mental health where conditions can mostly only be assessed on the basis of the patient's perception.

6.2 The board acknowledges that in particular cases where the patient had more than one reason for reducing or ceasing medication, there might be some uncertainty about whether the reduction or cessation of medication could be assigned to the sleep related adverse events. This uncertainty, however, amounts to a lack of clarity rather than a lack of sufficiency. As the technical features in question (definition of the patient group) were already present in the claims as granted, and the cause of uncertainty is not the amendment of claims 1 and 3 with respect to their corresponding granted claims (i.e. the deletion of sexually related adverse events from claims 1 and 3), this issue is not within the scope of the opposition appeal proceedings (see Enlarged Board decision G 3/14, catchword).

6.3 With regard to the suitability of vortioxetine to treat abuse and chronic pain, the opposition division acknowledged that the invention was sufficiently disclosed and based its decision on the tests of Examples 1 and 4 in the patent and on the knowledge at the priority date that vortioxetine was SRI, 5-HT1a agonist and 5-HT3 antagonist (see contested decision, last half of page 12). Although the opposition division did not explicitly mention the treatment of anxiety, it was apparent from the patent (paragraphs [0001] and [0002]) that the opposition division's argument also applied to anxiety; the fact that vortioxetine was SRI, 5-HT1a agonist and 5-HT3 antagonist made it suitable for the treatment of anxiety, as confirmed by documents D4 (page 1, lines 4-7 and 10-12) and D2 (page 1, lines 3-5).

In its statement of grounds of appeal, the opponent did not challenge this aspect of the decision. It did so for the first and sole time in section 3.3.5 of its reply to the patent proprietors' statement of ground of appeal. In that section, however, the opponent did not provide any reasons why the contested decision was wrong; it merely stated that the patent did not contain sufficient evidence, ignoring the explanation given by the opposition division of why the invention was sufficiently disclosed. Accordingly, the board considers that the opponent has not substantiated this aspect of its objection and therefore sees no reason to reverse this part of the decision under appeal.

6.4 In conclusion, the board holds that the skilled person is able to carry out the invention of claims 1 and 3 without undue burden.

Order

For these reasons it is decided that:

The appeals are dismissed.

This decision T 1491/14 (pdf) has European Case Law Identifier ECLI:EP:BA:2019:T149114.20190730. The file wrapper can be found here. Photo by  Mylene2401 obtained via Pixabay under the Pixabay License (no changes made).