T 0970/12 (Inhalation formulations of hypertonic solution containing hyaluronic acid/CHIESI FARMACEUTICI) 22-07-2015

1. Re-establishment of rights and admissibility of the appeal

1.1 The time limit for filing the notice of appeal under consideration expired on 27 February 2012. On 13 March 2012, that is 14 days after the expiry of the time limit for filing the notice of appeal, the representative's attention was drawn to the fact that no appeal had been filed. Thereby the cause of non-compliance with the time limits for filing an appeal was removed. The request for re-establishment was filed on 6 April 2012, that is less than two months after discovery of the omission and of the expiry of the time limit for filing the appeal. Therefore, the time limits pursuant to Rule 136(1) EPC have been observed. The board is also satisfied that the other conditions for admissibility of the request for re-establishment are fulfilled.

1.2 Pursuant to Article 122(1) EPC a request may be granted if the time limit has been missed in spite of all due care required by the circumstances having been taken.

1.3 In the board's judgement, the circumstances leading to the omission were exceptional and the appellant's representative found himself in an extraordinary situation that hindered him on his return to the office on 30 December 2011 and after his leave beginning on 2 January 2012 from paying attention to the notification of the contested decision on 27 December 2011. As a consequence, he was unaware of the time limits for the appeal and unable to make arrangements for meeting them (cf. decision T 387/11 of 6 July 2012).

1.4 In the light of the evidence provided it is credible that the appellant's representative suffered considerable psychological stress at the end of December 2011 and in January 2012, subsequent to the sudden death of his mother. Moreover, on the day of notification of the contested decision, that is on 27 December 2011, the representative left the office in the morning since he had been informed that his mother's health had suddenly deteriorated. The experienced assistant previously in charge of monitoring dates and time limits had retired early and was no longer at the office at that time. The new assistant was still in the training period. She could not seek advice from any of the four other professional representatives of the association because they were on leave in keeping with the turns of work planned for the Christmas and New Year holiday. The assistant erroneously believed that the sub-authorised professional representative, who had represented the appellant at the oral proceedings before the examining division, was in charge of monitoring the time limit for appeal. The circumstances were thus exceptional: No professional representative was present and the newly appointed assistant had no experience in handling incoming notifications of decisions, even though she had worked for some time at the office in another function. Moreover, it was not apparent to her from the file who had the responsibility for the appeal, since the sub-authorisation that had been given to the professional representative in Munich was not expressly limited to the representation at the oral proceedings before the examining division and there was no information in the verbal arrangement between the two representatives involved that the sub-authorisation was not intended to change responsibility for the appeal. In view of the considerable psychological stress due to his sudden bereavement, the appellant's representative could not be reasonably expected to become aware of the notification of the contested decision during his short presence at the office on 30 December 2011 and immediately after his return from leave in January 2012. In the board's judgment, this extraordinary situation persisted, so the appellant's representative could not have been expected to note the omission before receipt of an email on 13 March 2012 from the sub-authorised professional representative drawing his attention to the missing notice of appeal.

1.5 For the above reasons, the board allowed the request for re-establishment of rights.

2. Main request

2.1 Added subject-matter

2.1.1 The present application is a divisional application and therefore the provisions expressed in Article 76(1) EPC in relation to the content of the earlier application (parent application as filed) have to be examined.

2.1.2 Claim 1 of the main request is a product claim, which relates to:

(i) inhalation formulations

(ii) in sterile monodose ampoules of 5-7% hypertonic solution containing

(iii) hyaluronic acid or a salt or ester thereof with low molecular weight or an intermediate molecular weight at a concentration of between 0.01% to 1%.

2.1.3 A verbatim basis for claim 1 of the main request can be found on page 6, first paragraph, of the parent application as filed, with the exception of the expression "inhalation" before the term "formulations".

Hence, it has to be investigated whether or not the above-mentioned passage on page 6 of the parent application as filed refers to inhalation formulations, i.e. to formulations suitable for inhalation.

The generic disclosure in the parent application as filed refers to the administration of several formulations containing inter alia hyaluronic acid as being "by inhalation (nasal administration or administration in the upper airways) or bronchial administration" (page 4, lines 19 to 21). Furthermore, the parent application as filed specifies that "The invention also allows treatment of patients who have to discontinue antibiotic treatment of the lower airways by inhalation due to bronchial intolerance" (page 4, lines 27-28 and page 5, line 1). This disclosure is immediately followed on page 5 by the following: "It has also been found that the administration of a hypertonic solution, associated with hyaluronic acid or its salts, leads to better tolerability, with a reduction in the inflammatory component affecting the mucosa of the airways, a lower risk of discontinuance of the treatment, and better compliance by patients" (page 5, lines 2 to 6). Therefore, the administration mentioned in this passage is to be understood within the context of the description, so that the hypertonic solutions containing hyaluronic acid according to the "invention" have to be suitable for administration by inhalation. This teaching directly and unambiguously applies to the formulations explicitly disclosed in the first paragraph of page 6, which also mentions esters of hyaluronic acid in addition to salts thereof. Moreover, the second and fifth paragraphs on page 6, which explicitly mention that the formulations are rendered suitable for administration by aerosols, confirm that the formulations in the first paragraph on page 6 which are suitable for inhalation are disclosed in the parent application as filed.

That the whole parent application describes inhalation formulations (i.e. suitable for inhalation), irrespective of whether or not they also contain an antibiotic, is also supported by the examples of the parent application as filed. In fact, the parent application as filed does not disclose other kinds of formulations such as injection formulations or oral liquid formulations.

Examples 16 and 17 of the parent application as filed illustrate inhalation formulations in disposable ampoules of hypertonic solutions of hyaluronic acid without antibiotics as those generically disclosed in the first paragraph on page 6. The description of the specific products in examples 16 and 17 is not restricted to their use in a kit-of-parts mode as in example 18, but corresponds to the sterile monodose ampoules of the first paragraph on page 6 of the parent application as filed and of claim 1 of the main request.

The parent application as filed describes two different aspects of the "invention", the first one relating to inhalation formulations comprising a hypertonic solution, hyaluronic acid and an antibiotic (page 4, lines 18 to 23) and the second to inhalation formulations comprising a hypertonic solution and hyaluronic acid (page 4, line 27 to page 5, line 6). The technical teaching on pages 5, 6 and examples 16 and 17 is not restricted to the use of the formulations with an antibiotic in the form of a kit-of-parts product, but it provides an allowable basis for a separate product claim such as claim 1 of the main request.

2.1.4 Therefore, claim 1 of the main request does not contain added subject-matter. Additionally, dependent claim 2 relates to the preferred mode defined on page 6, lines 4 and 5 of the parent application as filed, and the nasal route is also mentioned in the parent application as filed as the administration route for the upper airways.

2.1.5 Page 4 of the description has been amended in order to acknowledge the prior art which was generally cited as background (Rule 42(1(b)) EPC). Additionally, deletion of the redundant word "patient" has also been undertaken in line 23.

2.1.6 The amendments undertaken on page 5 of the description were introduced as a direct reply to an objection of lack of consistency between the claims and the description raised by the board under Article 84 EPC. These amendments do not introduce added subject-matter, since they merely delete definitions concerning some "preferred" ranges for the molecular weight of hyaluronic acid. Additionally, the specification of the units as Da on page 5 derives directly and unambiguously from the content of page 6 of the parent application as filed. The board accepts the appellant's submission that the terms "low molecular weight" and "intermediate molecular weight" are employed in claim 1 in relation to the well-known hyaluronic acid (HA) and should thus be given their ordinary meaning in the art. The broad ranges for the molecular weight of HA defined in the description encompass both alternatives.

2.1.7 Consequently, the main request does not contain added subject-matter (Article 76(1) EPC).

2.2 Novelty

2.2.1 Document D1 discloses saline solutions containing hyaluronic acid (page 6, line 1 to page 7, line 22), which may be administered in the form of an aerosol. Document D1 does not explicitly disclose whether the saline solutions are isotonic, hypotonic or hypertonic. The skilled person would not have concluded without any mention of the saline concentration in document D1 that the saline solutions in said document are hypertonic, since he knew from his common general knowledge that hypertonic saline solutions caused local irritation.

Thus, document D1 does not disclose inhalation compositions according to claim 1 of the main request.

2.2.2 Document D2 discloses inhalation solutions containing hyaluronic acid with a molecular weight of 400 to 4000 kilodaltons suitable for aerolisation (page 167, right-hand column, last paragraph to page 168, left-hand column, first paragraph). Document D2 discloses colloidal preparations of hyaluronic acid (HA) in saline (page 168, right-hand column, under heading "exercise test") which are administered by aerosol. However, document D2 does not disclose whether these preparations are isotonic, hypotonic or hypertonic. Therefore, document D2 fails to disclose 5-7% hypertonic saline solutions containing hyaluronic acid as defined in claim 1 of the main request.

2.2.3 Consequently, the subject-matter of claim 1 of the main request is novel vis-à-vis documents D1 and D2 (Articles 52(1) and 54(2) EPC).

2.3 Inventive step

2.3.1 Document D6, which discloses inhalation formulations in the form of monodose ampoules of 7% hypertonic saline solution further containing quinine sulfate as taste-masking agent (page 230, right-hand column, last paragraph), represents the closest prior art. Moreover, it further discloses that "inhaled hypertonic saline acutely increases mucociliary clearance and, in short-term trials, improves lung function in people with cystic fibrosis" and that "long-term safety and efficacy of inhaled hypertonic saline in a long-term trial was tested" (abstract). The treatment in document D6 with the hypertonic saline solutions improved lung function and reduced the frequency of exacerbations, whereas the most frequent treatment-related adverse reactions were cough, chest tightness and pharyngitis (Table 3 on page 239).

The technical problem to be solved lies in the provision of alternative inhalation formulations of hypertonic saline solutions exhibiting good patient compliance.

The solution lies in the addition of hyaluronic acid or a salt or ester thereof with a low molecular weight or an intermediate molecular weight at a concentration of between 0.01% and 1%, instead of quinine sulfate.

The problem is plausibly solved in the light of the content of the patent application, which states that: "it has been found that the administration of a hypertonic solution, associated with hyaluronic acid or its salts, leads to better local tolerability, with a reduction in the inflammatory component affecting the mucosa of the airways, a lower risk of discontinuance of the treatment, and better compliance by patients affected by cystic fibrosis" (page 4 under the heading "Description of the invention").

Moreover, the appellant filed during appeal proceedings the post-published document D9 in order to show that the underlying problem has actually been solved by the claimed invention. Document D9 states that: "The inhaled solution of 0.1% hyaluronic acid and hypertonic saline significantly improved tolerability and pleasantness compared to hypertonic saline alone" (page 1, right-hand column, lines 5 to 8).

Hence, the remaining question is whether or not the proposed solution was obvious to the skilled person.

Since neither document D1 nor document D2 disclose inhalation formulations of hypertonic saline solutions, the problem of patient compliance caused by inhalation with the 5-7% hypertonic solution does not arise. Therefore, the skilled person has no hint in documents D1 or D2 to add hyaluronic acid as a solution to the stated problem.

The fact that document D1 discloses inhalation compositions containing hyaluronic acid in saline solutions for the treatment of respiratory disorders, especially emphysema (page 3, lines 1 to 21), does not teach the skilled person what to do when looking for an alternative to the 7% hypertonic saline solutions disclosed in document D6. Documents D1 and D2 do not teach the skilled person that adding hyaluronic acid to inhalation hypertonic saline solutions would allow the achievement of good patient compliance.

None of the other documents available on file suggests the obviousness of the proposed solution to the technical problem defined above.

Consequently, the main request complies with the requirements of Article 56 EPC.