T 1133/18 (Sublingual apomorphine/SUNOVION) 15-12-2021
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SUBLINGUAL APOMORPHINE
Generics (U.K.) Limited
LTS LOHMANN Therapie-Systeme AG
Amendments - allowable (yes)
Sufficiency of disclosure - (yes)
Inventive step - (yes)
I. European patent No. 2 442 650 is based on European patent application No. 10786915.8, filed as an international application published as W2010/144817.
II. It was opposed under Article 100(a), (b) and (c) EPC on the grounds that the claimed subject-matter lacked an inventive step, was not disclosed in a manner sufficiently clear and complete for it to be carried out by a person skilled in the art, and extended beyond the content of the application as filed.
In the opposition proceedings, the patent proprietor requested the maintenance of the patent based on a main request or auxiliary requests 1 to 8, all filed on 27 September 2017.
III. The opposition division decided in its interlocutory decision that the main request met the requirements of the EPC.
Opponent 1 appealed this decision.
IV. The following documents, cited during the opposition and appeal proceedings, are referred to below:
(2) (WO2006/120412)
(3) (WO98/26763)
(23) (US2004/0204440)
(41) Declaration of Dr Thierry Bilbault, dated 26 September 2017, 3 pages
V. With its reply to the statement of grounds of appeal, the patent proprietor (respondent) resubmitted the sets of claims of auxiliary requests 1 to 8. With the letter dated 14 October 2021, it submitted the sets of claims of auxiliary requests 9 to 26.
VI. Oral proceedings before the board took place in the absence of the appellant (opponent 1) and opponent 2, as announced by letter dated 25 November 2021 and phone call of 25 November 2021, respectively.
During the oral proceedings, the respondent changed the order of its requests. The set of claims of the former main request was renumbered auxiliary request 2, while the set of claims of former auxiliary request 2 became the main request.
Claims 1, 12 and 13 of the main request (former auxiliary request 2) read as follows.
"1. A pharmaceutical composition in unit dosage form formulated for sublingual administration, wherein said unit dosage form is a film or a strip having a first layer and a second layer, wherein the first layer is acidic and comprises apomorphine particles comprising an acid addition salt of apomorphine and the second layer comprises a pH neutralizing agent.
12. The pharmaceutical composition of any of claims 1-11 for use in the treatment of Parkinson's disease, dyskinesia, akinesia in a mammal afflicted with Parkinson's disease.
13. The pharmaceutical composition of any of claims 1-12 for use in the treatment of sexual dysfunction."
VII. The appellant's arguments, submitted in writing and in so far as relevant to the present decision, may be summarised as follows.
Amendments
The content of a patent application could not be considered a reservoir from which features pertaining to separate embodiments of the application could be combined to artificially create a particular embodiment. Films or strip were not preferred, and alternative dosage forms were both described and exemplified. There was no disclosure in the application that films or strips should be combined with apomorphine particles. Pharmaceutical formulations could include apomorphine particles having a certain effective particle size, but there was no disclosure that these formulations were films or strips. In sum, there was no mention in the application of the specific combination of films or strips with apomorphine particles. The combination of these features did thus not emerge clearly and unambiguously from the application as filed.
Sufficiency of disclosure
There was no information in the patent on how the skilled person should determine the dimensions of a film for it to be big enough to fit in a sufficient amount of apomorphine for the treatments according to claims 12 and 13.
Inventive step
The starting point for the assessment of inventive step could be found in the disclosure of document (3). The difference between claim 1 of the main request and document (3) was the presence of apomorphine in particulate form. Since the patent in suit included no teaching that the particulate form of apomorphine had any technical effect on stability and/or shelf life, the data of document (41) should not be taken into account for the assessment of inventive step. The objective technical problem was thus the provision of an alternative. The solution to this problem was obvious. Document (23) taught a pharmaceutical composition comprising apomorphine particles having an effective particle size of from 2 nm to 10 micron (paragraphs [0015] and [0030]). Similarly, document (2) taught kits comprising in separate compartments a composition comprising an apomorphine acid addition salt and a solution including a pH modifying agent (claim 1). The apomorphine acid addition salt could be in the form of particles (page 6, line 2). Therefore, the person skilled in the art, faced with the problem of providing an alternative, would readily have provided a pharmaceutical composition comprising apomorphine particles and thus would have arrived at the claimed invention.
VIII. The respondent's arguments, in so far as relevant to the present decision, may be summarised as follows.
Amendments
The current main request was based on the former main request on which the decision under appeal was based (current auxiliary request 2). Films and strips and apomorphine particles were prioritised in the application as filed (see page 6, lines 14 to 16 and the chapter entitled "Apomorphine particles"). The combination of these features was thus clearly evident, and the person skilled in the art was not presented with any new technical information. In addition, the presence of two layers, where the first layer is acidic, could be found in claim 8 of the application as filed and paragraph [0016] of the patent as granted.
Sufficiency of disclosure
The person skilled in the art had experience in formulating medicaments. Apomorphine was a medicament known for over a century. Sublingual formulations comprising apomorphine were described in the art (see document (3)). Therefore, the person skilled in the art was able to determine the dimensions of a film or strip which had a suitable amount of apomorphine for treating the disorders defined in claims 12 and 13.
Inventive step
Document (3) differed in several aspects from the claimed subject-matter. It did not disclose a unit dosage form comprising a pH neutralising agent in a separate portion from the acid addition salt of apomorphine, and there was no disclosure of apomorphine particles. Since the application as filed indicated a prolongation of the stability of apomorphine (page 13, lines 19 to 21), the disclosure of document (41) had to be taken into account. The objective technical problem was thus the provision of an improved pharmaceutical apomorphine formulation which was safe and reliable and which could be used by, for instance, Parkinson's disease patients as a rescue medication to treat "off" states. In particular, the pharmaceutical composition should have an improved shelf life. The claimed subject-matter was not obvious. Document (23) referred to a treatment method via inhalation. Document (2) contained an embodiment in the form of dry powders or suspensions intended to be diluted at the point of use. In view of the fact that neither document (23) nor document (2) related to a pharmaceutical composition having the form described in the closest prior-art document (3) (i.e. a flat, foil-, paper- or wafer-like form), the person skilled in the art would neither have turned to these documents nor would have had any motivation to incorporate apomorphine in the form of particles when trying to improve the pharmaceutical composition of document (3).
IX. The final requests of the parties were as follows.
The appellant requested in its written submissions that the decision under appeal be set aside and that the patent be revoked.
The respondent requested that the decision under appeal be set aside and that the patent be maintained on the basis of the main request filed as auxiliary request 2 with the reply to the grounds of appeal or on the basis of auxiliary request 1 filed with the reply to the grounds of appeal or, further alternatively, that the appeal be dismissed or that the decision be set aside and that the patent be maintained on the basis of any of auxiliary requests 3 to 8 filed with the reply to the grounds of appeal or any of auxiliary requests 9 to 26 filed with the letter of 14 October 2021.
Opponent 2 made no requests in appeal.
1. The appeal is admissible.
2. Oral proceedings before the board took place in the absence of both opponents, which had been duly summoned but had chosen not to attend. In accordance with Rule 115(2) EPC and Article 15(3) RPBA, the board was not obliged to delay any step in the proceedings, including its decision, by reason only of the absence at the oral proceedings of any party duly summoned, which was treated as relying only on its written case. Hence, the board was in a position to announce a decision at the conclusion of the oral proceedings, as provided for by Article 15(6) RPBA.
3. Main request - amendments
Claim 8 as filed defines a pharmaceutical composition of claim 1, which is a film or a strip having a first portion in the form of a first layer which is acidic and comprises an acid addition salt of apomorphine and a second portion in the form of a second layer comprising a pH neutralising agent. Claim 1 defines, inter alia, that the pharmaceutical composition is in unit dosage form.
Claim 1 of the main request differs from claim 8 as filed in that apomorphine is present in the form of apomorphine particles.
This technical feature can, however, be directly and unambiguously derived from the application as filed by making a single selection since apomorphine particles are generally disclosed on page 6, lines 14 to 16 of the description as filed.
The subject-matter of claim 1 of the main request fulfils the requirements of Article 123(2) EPC.
4. Main request - sufficiency of disclosure
The use of apomorphine as an active agent in the treatment of conditions related to Parkinson's disease or sexual dysfunction is well known in the art (see documents (2) and (3)). The person skilled in the art is thus aware of the amount of drug to be formulated in a unit dose. Such amounts are furthermore taught in the application as filed (page 7, lines 24 to page 8, line 2). Films containing up to 40 mg apomorphine hydrochloride as a unit dose are described in the examples. These amounts are in line with the unit doses of document (2) (page 10, lines 23 and 25). The dimensions of the film or strip are directly correlated with the concentration of the active agent in the matrix. It is thus immediately evident to the person skilled in the art how to select the appropriate dimensions or, alternatively, when aiming at a unit dosage form having a certain dimension, how to select the appropriate concentration of the active agent.
The claimed subject-matter is sufficiently disclosed (Article 83 EPC).
5. Main request - inventive step
5.1 The patent in suit relates to compositions comprising apomorphine formulated for sublingual administration and the use of such compositions in the treatment of Parkinson's disease and sexual dysfunction (paragraphs [0001] and [0012]). The composition is in unit dosage form, in the form of a film or strip, having a first layer which is acidic and includes an acid addition salt of apomorphine and a second layer including a pH neutralising agent (paragraphs [0013] and [0016]). According to claim 1 of the main request, the apomorphine addition salt is in the form of particles. The sublingual formulations according to the invention can increase the bioavailability of apomorphine, prolong the stability of apomorphine, and/or improve the safety and efficacy of apomorphine therapy. The formulations can produce a rapid uptake of apomorphine into the subject, allowing dyskinesia episodes to be self-treated. Furthermore, the convenience with which the sublingual formulations can be self-administered provides a significant advantage to severely ill patients, such as those with middle or late stage Parkinson's disease (paragraph [0051]).
5.2 The appellant considers, in line with the decision under appeal, document (3) as the closest prior art.
Document (3) defines a composition in the form of a film ("mit flacher, folien-, papier- oder oblatenförmiger Darreichungsform") for use in the oral cavity comprising apomorphine or a salt of it (claim 1). This composition is to be used in the treatment of Parkinson's disease (page 4, paragraph 4). Preferred excipients have mucoadhesive properties. When mucoadhesive excipients are used, the composition may have two or more layers (page 8, second paragraph, claims 2 and 3). The two examples disclose single layer compositions comprising apomorphine hydrochloride.
5.3 The difference between the subject-matter of claim 1 and the disclosure of document (3) is the presence of the acid addition salt of apomorphine in the form of apomorphine particles and the addition of a neutralising agent in a second layer of the film or strip.
5.4 The technical problem may be seen as the provision of an alternative pharmaceutical composition suitable for sublingual administration of apomorphine.
The problem has been solved. This has not been contested.
5.5 It remains to be determined whether the claimed solution is obvious.
The appellant has referred to documents (2) and (23) as rendering the claimed subject-matter obvious.
Document (2) defines a kit comprising, in separate compartments of a container, a component (a) comprising apomorphine or an addition salt of it and an excipient and a component (b) comprising a solution including a pH modifying agent (claim 1). Component (a) may be in particulate form, for example in the form of dry powder or dry granules, or in the form of a suspension of powder or granules in an appropriate medium (or in other liquid forms requiring dissolution of apomorphine) (page 6, lines 1 to 7). The two components are to be mixed together at the time of use, and the resulting formulation is administered immediately after the mixing has been effected (page 8, lines 17 to 22). The system of document (2) thus differs considerably from the system of document (3). Instead of a flat, foil-, paper- or wafer-like form, a kit consisting of either a first powdery/granular or liquid (suspension of particles or solution) component and a liquid second component and requiring a mixing step immediately prior to use is taught. A person skilled in the art, aiming to provide an alternative composition starting from the film of document (3), would not have considered singling out one of the technical features of the first component (i.e. the particular form of the active agent), incorporating it into the film or strip of the closest prior art and, furthermore, modifying the second component to be suitable to act as a second portion in the form of a layer of a pharmaceutical composition in the form of a film or strip. There is no pointer anywhere in the prior art at hand that would have motivated the person skilled in the art to combine and additionally modify the technical features of documents (3) and (2).
Document (23) relates to the treatment of sexual dysfunction via inhalation therapy (paragraph [0011]). A skilled person would not have considered directly transferring characteristics of a composition formulated for inhalation to a film or strip for sublingual administration.
5.6 Consequently, the claimed subject-matter is not obvious when considering the prior art invoked by the appellant. An inventive step is thus acknowledged (Article 56 EPC).
5.7 Having come to this conclusion, it is not necessary to discuss a technical problem which takes stability effects into account.
For these reasons it is decided that:
- The decision is set aside.
- The case is remitted to the opposition division with the order to maintain the patent on the basis of the following documents:
(i) claim 1 to claim 13 of the main request (filed as auxiliary 2 with the reply to the grounds of appeal)
(ii) a description possibly to be adapted thereto.