T 2344/19 - Weight gain related adverse events

Key points

•  Claim 1 is directed to: " 1. [vortioxetine] for use in the long-term treatment of depression or anxiety in a patient who has previously received medication for the treatment of said disease which medication was ceased due to weight gain related adverse events, wherein long-term treatment refers to a treatment period above 12 weeks." 
• The question is whether the feature in italics can provide for novelty, i.e. whether it specifies a valid second medical use under Art. 54(5) EPC. More in particular, whether the feature defines a patient group.
• The Board: " The indication that the previous treatment was stopped due to weight gain related adverse events establishes the fact that the group of patients under consideration is known to develop weight gain related side-effects when administered medication active in the treatment of depression or anxiety. The development of certain side-effects reflects a certain physiological and/or pathological status of the patients concerned. The development of these side-effects during treatment for depression or anxiety creates a link between the patients, their physiological and/or pathological status, and the therapeutic treatment. The patient group under consideration is thus a technical feature of the claims." 
• As to inventive step, D7 " describes weight gain as a common adverse effect of psychotropic drugs (abstract). In the concluding passages, it states that medication should be switched to another drug if weight increase due to a psychotropic drug cannot be stopped or reversed by measures relating to proper nutrition and eating habits, physical exercise and behaviour modification " 
• " The difference between the subject-matter of claims 1 and 3 as granted and the disclosure of document (7) is the use of vortioxetine as the switch drug." 
• " In view of the disclosure of document (7) []and the objective technical problem, it is clear that the person skilled in the art would have avoided the administration of any psychotropic drug for which long-term weight gain related side-effects had not been excluded. They would also have avoided any treatment potentially worsening the overall physiological condition of the patient, or, when leading to non-compliance, worsening the underlying psychiatric condition and potentially leading to relapse, hospitalisation or even fatal consequences. " 
• " In summary, the person skilled in the art would have needed to count on success or, put differently, have a strong expectation of success. Any treatment undertaken with a mere hope to succeed, in the present case a treatment where short-term side-effects had been excluded but nothing was known on long-term side-effects, would not have been envisaged by the person skilled in the art." 
• " Consequently, since no information on long-term weight gain related side-effects was known for vortioxetine, the person skilled in the art would not have considered vortioxetine for solving the technical problem stated above, and thus would not have arrived at the claimed subject-matter." 
• 
  

EPO T 2344/19

The link to the decision is provided after the jump, as well as (an extract of) the text of the decision.

https://www.epo.org/law-practice/case-law-appeals/recent/t192344eu1.html

Reasons for the Decision

1. The appeal is admissible.

2. Novelty (Article 54 EPC)

2.1 The patient's decision to cease medication for the treatment of depression or anxiety as such is not defined in the claims under consideration. The claims (merely) define a group of patients who had previously received medication which was ceased due to weight gain related adverse events. Thus the claims are directed to patients in the following factual situation: their (previous) medication was stopped due to weight gain related adverse events (irrespective of the decision-making process underlying the stop). Consequently, no mental act or thought process forms part of the claimed subject-matter.

The indication that the previous treatment was stopped due to weight gain related adverse events establishes the fact that the group of patients under consideration is known to develop weight gain related side-effects when administered medication active in the treatment of depression or anxiety. The development of certain side-effects reflects a certain physiological and/or pathological status of the patients concerned. The development of these side-effects during treatment for depression or anxiety creates a link between the patients, their physiological and/or pathological status, and the therapeutic treatment.

The patient group under consideration is thus a technical feature of the claims.

2.2 The technical feature defining the patient group under consideration is not disclosed in any of the documents cited by the respondent in the context of novelty, i.e. documents (1), (2), (3) and (6).

2.3 The subject-matter of the claims of the main request is novel within the meaning of Article 54 EPC.

3. Inventive step (Article 56 EPC)

3.1 The patent in suit relates to the use of 1-[2-(2,4-dimethyl-phenylsulfanyl)phenyl]piperazine (vortioxetine) and pharmaceutically acceptable salts thereof in the treatment of CNS diseases. Long-term treatment with vortioxetine has been found not to be associated with weight increase. The patent aims at using this compound in the treatment of depression or anxiety in a patient who has previously received medication for the treatment of this disease which was ceased or reduced due to weight related adverse events (paragraphs [0001] and [0016]).

3.2 It was common ground that document (7) represented the closest prior art. The respondent additionally relied on document (3).

3.3 Problem-solution approach starting from document (7)

3.3.1 Document (7) describes weight gain as a common adverse effect of psychotropic drugs (abstract). In the concluding passages, it states that medication should be switched to another drug if weight increase due to a psychotropic drug cannot be stopped or reversed by measures relating to proper nutrition and eating habits, physical exercise and behaviour modification (paragraph bridging pages 386 and 387).

The difference between the subject-matter of claims 1 and 3 as granted and the disclosure of document (7) is the use of vortioxetine as the switch drug.

3.3.2 Data in the patent in suit

There is no indication on file that weight gain as a side-effect of therapeutic treatment of depression or anxiety is related exclusively to factors such as individual genetic predispositions. Therefore weight gain is considered to be due to various causes, as is also insinuated by the countermeasures of document (7) (paragraph bridging pages 386 and 387, see point 3.3.1 above). Consequently, there is no need for data to be obtained from patients having been treated by (other) actives before switching to vortioxetine. All experimental data relating to weight gain can be taken into account, including the data in the patent in suit.

This data (Tables 1 to 4) does not show that no weight at all is gained by the patients receiving vortioxetine. However, in view of the relatively small relative weight differences and taking into account the percentages of patients displaying a weight gain above 7%, the conclusion can be drawn that in the first year of treatment no weight gain above what can be expected in the population under consideration (= "placebo-like") is found after administration of vortioxetine. The qualitative information provided in the SmPC of Brintellix (active agent vortioxetine hydrobromide) confirms this finding (document (24), page 12, paragraph 4).

However, the data in the patent does not show a comparison with another potential switch drug, which fact has to be reflected in the formulation of the technical problem.

3.3.3 The technical problem is thus the provision of a further active for long-term second-line treatment of depression or anxiety in a patient group prone to weight gain related adverse events.

3.3.4 Obviousness of the solution

3.3.5 Long-term side-effects versus short-term side-effects

Document (7), which is the closest prior art and a document dedicated to weight gain associated with psychotropic drugs (see title), explicitly discloses that short-term clinical trials, which last 6 to 8 weeks, may underestimate the long-term effects (> 18 months) on weight gain (page 379, left-hand column, paragraph 2). This is confirmed by document (14) (page 26, paragraph 2), document (15) (page 411, right-hand column, paragraph 2), and document (17) (page 17, left-hand column, last paragraph). Consequently, the board considers that the person skilled in the art, in the case at hand, would have been aware of the issue and would have sought to provide an alternative psychotropic drug for which it was well established that no long-term weight gain related side-effects were to be expected.

It seems to be a general consensus in literature that the initial period of treatment by psychotropic drugs is up to 3 months. Furthermore, as stated by the respondent, problems with treatment usually tend to arise in the first 5 to 7 weeks. Consequently, a period of above 12 weeks, as defined in claim 1 under consideration, can be considered as long-term treatment in the field concerned.

3.3.6 Vortioxetine - an SSRI?

The respondent based their line of argument, inter alia, on the classification of psychotropic drugs and the side-effects known for drugs of a certain class. In this context they argued that the person skilled in the art would have considered vortioxetine to belong to the class of SSRIs since vortioxetine was known to act on SERT (serotonin transporter).

The classification of vortioxetine in activity schemes of psychotropic drugs is not crucial to the present decision and can therefore be left open. It has been established that not all SSRIs have no weight related side-effects, and furthermore doubts have been raised as to the long-term weight related side-effects of SSRIs. This can be seen from document (7). Document (7) discloses that accumulating evidence suggests that in the short term SSRI treatment may cause weight loss, but may induce weight gain during long-term use, possibly related to serotonin receptor 5-HT2c hyposensitivity (page 383, left-hand column, paragraph 2).

As there seems to be no well-established and generally recognised long-term side-effect profile for the actives belonging to the class of SSRIs, the skilled person dealing with patients known to be susceptible to weight gain would have focused entirely on the side-effect profiles of the individual actives. The classification of vortioxetine (e.g. as an SSRI) is thus irrelevant.

3.3.7 Side-effect profile of vortioxetine

Several documents on file disclose the use of vortioxetine as a psychotropic drug and thus as a drug suitable for use in the treatment of depression or anxiety. Documents (1) to (3) disclose vortioxetine for this treatment. However, they are silent on side-effects. Document (6) relates to a proof-of-concept study to evaluate the efficacy and tolerability of vortioxetine. This study lasted 6 weeks and included 429 patients. Nausea, headache, hyperhidrosis and dry mouth are identified as the most common side-effects. No clinically relevant changes are seen in, inter alia, weight over the course of the study. Document (6) consequently establishes that vortioxetine has no short-term side-effects related to weight. No disclosure of long-term side-effects of vortioxetine made before the effective date of the patent in suit is on file.

Vortioxetine has been described as having or not having activity on various receptors, such as SERT, 5-HT3, 5-HT1A and 5-HT2c. However, the person skilled in the art receives no guidance from the documents on file on how to predict weight gain related side-effects from these activities. Consequently, no conclusion on the occurrence of weight related side-effects in the treatment with vortioxetine may be drawn that goes beyond mere speculation.

3.3.8 Expectation of success versus hope to succeed

The case at hand relates to the treatment of depression or anxiety. As clearly established in document (7), weight gain related adverse effects put the patients at considerable risk - coronary heart disease, hypertension, type II diabetes, dyslipidaemia and cancer being mentioned - but, and this is also of the utmost importance, they may also lead to non-compliance, with the probability of relapse and subsequent (re)hospitalisation (abstract).

In view of the disclosure of document (7) (see paragraph above and points 3.3.1 and 3.3.5) and the objective technical problem, it is clear that the person skilled in the art would have avoided the administration of any psychotropic drug for which long-term weight gain related side-effects had not been excluded. They would also have avoided any treatment potentially worsening the overall physiological condition of the patient, or, when leading to non-compliance, worsening the underlying psychiatric condition and potentially leading to relapse, hospitalisation or even fatal consequences.

In summary, the person skilled in the art would have needed to count on success or, put differently, have a strong expectation of success. Any treatment undertaken with a mere hope to succeed, in the present case a treatment where short-term side-effects had been excluded but nothing was known on long-term side-effects, would not have been envisaged by the person skilled in the art.

3.3.9 Consequently, since no information on long-term weight gain related side-effects was known for vortioxetine, the person skilled in the art would not have considered vortioxetine for solving the technical problem stated above, and thus would not have arrived at the claimed subject-matter.

3.4 Problem-solution approach starting from document (3)

3.4.1 Document (3) discloses the use of vortioxetine hydrobromide for the treatment of depression and anxiety.

The subject-matter of claims 1 and 3 differs in the specific group of patients to which it was directed.

The technical problem is the provision of a further specific use of vortioxetine in the treatment of depression or anxiety.

3.4.2 Obviousness

As established above, see point 3.3.7, the person skilled in the art had not been aware that vortioxetine had a favourable side-effect profile concerning weight gain in long-term treatments. Consequently, the person skilled in the art would have had no incentive to administer vortioxetine as second-line treatment to a group of patients known to have had issues with weight gain related adverse events in a previous treatment of depression or anxiety.

3.5 The subject-matter of claims 1 and 3 of the main request involves an inventive step within the meaning of Article 56 EPC.

3.6 Further arguments

The respondent argued that a clinical phase III study involving vortioxetine was taking place and the presence and absence of adverse events would have been known from this study and therefore could not form the basis for acknowledging the presence of an inventive step.

As stated in T 1491/14, this argument is fundamentally flawed. In addition to the arguments provided in T 1491/14, the person skilled in the art, as a matter of principle, could not have been aware of the outcome of an incomplete study at the effective date of the patent in suit. The future outcome of such a study as such does not represent prior art in the sense of Article 54(2) EPC, and consequently cannot be included in the assessment of inventive step. Concerning the expectation of success of the person skilled in the art for a successful outcome of such a study, the following applies: such expectation has to be assessed for each case separately, as has been done for vortioxetine and long-term weight gain related side-effects, see points 3.3.5 to 3.3.9 above.

Order

For these reasons it is decided that:

- The decision under appeal is set aside;

- The case is remitted to the opposition division with the order to maintain the patent in amended form with the following claims and a description possibly adapted thereto:

Claims 1 to 4 of the main request submitted as auxiliary request 2 with the statement of grounds of appeal.