T 0676/01 (Treatment of inflammation/SONORAN DESERT CHEMICALS LLC) 09-05-2005

The "Chapman appeal"

1. Referring to decision J 0001/92 (supra) appellant I maintains that the appeal lodged on 5 July 2001 had been made in the name of the representative, Mr Chapman, rather than in the name opponent 03, and thus it had to be rejected as being inadmissible. However, the board holds the view that this notice of appeal was filed in the name and on behalf of opponent 03 because Mr Chapman signed the notice as authorised representative (c.f. "Chapman Paul William, Authorized Representative") and the heading to his letter referred to opponent 03 (c.f. "Opposition Thereto by Bayer"), whom he already represented during the opposition proceedings. The present appeal language thus differs from that dealt with in decision J 0001/92 (supra), including a statement (see Section IV) "I, (followed by the name of the representative and his address) file herewith an appeal against the decision of EPO dated September 18, 1991. The appeal is lodged in my own name...". Therefore the board judges that the appeal filed on 5 July 2001 has been made in the name of opponent 03 and is admissible.

Main Request

Article 123(2) EPC

2. Claim 1 relates to a medical use, namely the topical treatment of skin diseases or asthma implicated by mast cells and their mediators by means of serine protease inhibitors. Insofar as claim 1 relates to the treatment of asthma, a basis can be found in the WO application on page 10, line 5, in Example VIII, taken in combination with claim 10.

3. Insofar as claim 1 relates to the treatment of skin diseases, this medical use can be derived from the combination of claims 1, 2 and 3, all of the published WO application.

4. A critical issue has been the question of whether or not the wording in claim 1 "if the disease is a skin disease, then a single serine protease inhibitor is present in the composition" can be derived directly and unambiguously from the application as filed.

5. Appellants II and III maintain that no basis can be found in the application as filed for the treatment of a skin disease with a single serine protease inhibitor. However, already the combination of claims 1, 2 and 3 of the WO application provides a basis, but in any case, the expression "when topically applied, a serine protease inhibitor such as...is useful in the treatment of...inflammatory skin diseases" (see page 9, penultimate paragraph) provides an explicit basis for the above wording in present claim 1, i.e., for the treatment of a skin disease with a single serine protease inhibitor. A further basis can be found in claim 14 as filed relating to "at least one serine protease inhibitor"; in Example II on page 12, last paragraph, wherein the use of AAT as the sole active principle is clearly presented as an alternative to the use of a combination of AAT and ACT; in page 11, first full paragraph ("alone or in combination"); in page 4, line 29 ("alone or in combination") and in page 8, last sentence, wherein the "preferable" use of ACT with the AAT shows that it is optional, in the sense that AAT can also be used alone.

6. Appellants II and III argue that the expression "a single protease inhibitor is present" in claim 1 is broader than the list of protease inhibitors of said claim (alpha-1-antitrypsin, secretory leucocyte protease inhibitor, C-reactive protein, serum amyloid A protein and/or alpha-2-macroglobulin). However, owing to the wording of the claim, "a single protease inhibitor" must of necessity be selected from the list of the above five protease inhibitors. Therefore, the wording "a single protease inhibitor" cannot go beyond this list, although there is a basis for serine proteinase inhibitors in general in claim 1, in page 9, penultimate paragraph and in page 11, last paragraph of the WO application.

7. As for the contention by appellants II and III that the application as filed provides a basis only for AAT to be used alone in skin diseases, the combination of claims 1, 2 and 3 of the WO application provides a basis for any protease inhibitor used alone in the treatment of a skin disease.

8. Appellants II and III question the expression "to the site" in present claim 1 as finding no basis in the application as filed, especially when taken in combination with the treatment of asthma. However this expression finds a basis on page 7, lines 3-4 ("when administered to the site of inflammation") and in claim 1 of the WO application. Administration by inhalation (see ibidem, page 10, first paragraph) is an administration to the site of inflammation of an asthmatic patient.

9. It is argued by appellants II and III that the "disclaimer" excluded more than it was necessary, as document E7 merely dealt with binary composition comprising AAT and ACT. However, the board does not view the wording "if the disease is a skin disease, then a single serine protease inhibitor is present in the composition" as a "disclaimer", but merely as a limitation to one of the many embodiments covered by claim 1, which embodiment is expressed as a positive correlation that a single protease inhibitor is used for the treatment of skin diseases. The relevant question is whether there is a basis in the application as filed for the embodiment "single protease inhibitor for the treatment of skin diseases" (the answer is in the affirmative, see points 5 and 6 supra), not whether it excludes more or less than not (or no longer) relevant documents.

10. Since document E7 is prior art under Article 54(3) EPC (see point 21 infra), the contention by appellants II and III that the "disclaimer" in claim 1 is not allowable under Article 123(2) EPC in view of document E7 being full prior art under Article 54(2) EPC, must fail.

11. Finally, appellants II and III argued that a consequence of the "disclaimer" in claim 1 being not allowable under Article 123(2) EPC was that document E7 switches from a status of a document under 54(3) EPC to that of a document pursuant to 54(2) EPC, depending on whether Article 87(4) EPC is applied ante or post. However, since the embodiment that a single protease inhibitor should be used for the treatment of skin diseases finds a basis in the application as filed, this issue needs not be dealt with further.

12. In conclusion, the subject-matter of claim 1 and dependent claims satisfies the requirements of Article 123(2) EPC.

Article 84 EPC

13. The only objection raised by appellants II and III under this Article is that the medical use of claim 1 in its present wording is not sufficiently delimited over known medical uses involving AAT-deficient patients. However, to the board this issue is more adequately dealt with in the context of novelty and inventive step (see points 21 onwards).

Priority rights (Article 87(4) EPC)

14. Insofar as claim 1 at issue relates to the treatment of asthma, the parties and the board agree that this subject-matter cannot validly claim any of the priorities and thus the relevant date for establishing the prior art is the filing date of patent application.

15. Insofar as claim 1 at issue relates to the treatment of skin diseases, the topical treatment of skin diseases implicated by mast cells and their mediators by means of serine protease inhibitors is disclosed on page 5, lines 3-5 from the bottom, on page 8, second paragraph in combination with page 9, third paragraph and claim 1 of priority document P2, and illustrated by Examples I, II, III and IV of priority document P2. The five protease inhibitors referred to in claim 1 are listed on page 6, last paragraph of priority document P2.

16. A critical issue is the question of whether or not the wording in claim 1 "if the disease is a skin disease, then a single serine protease inhibitor is present in the composition", i.e., the treatment of a skin disease with a single serine protease inhibitor can be directly and unambiguously derived from priority document P2.

17. The above wording finds a basis in priority document P2 as follows: Claim 1: "at least one human serine protease"; Example II on page 11, wherein the use of AAT as the sole active principle is clearly presented as an alternative to the use of a combination of AAT and ACT; page 9, line 7 from the bottom and third paragraph: "alone or in combination"; page 8, third full paragraph: AAT is "preferably used in combination with the ACT" (it is optional to use it alone or in combination); and page 5, line 1: "alone or in combination". The wording on page 6, second paragraph "when topically applied, a serine protease inhibitor such as...is useful in the treatment of...inflammatory skin diseases" provides a further explicit basis for the treatment of a skin disease with a single serine protease inhibitor, according to the above wording in present claim 1.

18. Appellants II and III argue that document E21 represents an earlier filing of the same invention and that thus none of priority documents P1 to P3 is the first application for this invention, since the first application US 445005 had not been withdrawn, abandoned or refused leaving no right outstanding (the corresponding US patent, namely document E21, has been granted). As a consequence of this loss of priority rights, document E7 switches from a status of a document under Article 54(3) EPC to a document pursuant to Article 54(2) EPC, with the further consequence that the disclaimer introduced in claim 1 for excluding the disclosure of document E7 infringes Article 123(2) EPC.

19. However, document E21 (and application US 445005) discloses ACT-containing compositions for treating skin diseases by inhibition of mast cell chymase (see column 2, lines 46-51). But ACT is not among the list of serine protease inhibitors in present claim 1. The document also does not disclose AAT of its own nor any serine protease inhibitor (other than ACT) alone. In column 6, lines 23-26, it is merely stated that AAT may be used together with ACT. However, the wording in claim 1 at issue "if the disease is a skin disease, then only a single serine protease inhibitor is present in the composition" is effective in excluding the disclosure of E21.

20. In conclusion, since the claimed subject-matter can be found neither in document E21 nor in the priority document underlying it (US 445005), the subject-matter of claim 1, insofar as it relates to skin disease, can validly rely on the filing date of priority document P2 (18 January 1991) for the purpose of establishing the state of the art.

Novelty

Document E7

21. As far as the treatment of skin diseases is concerned, document (E7) is thus part of the state of the art under Article 54(3) EPC. It discloses ACT-containing compositions for treating skin diseases by inhibition of mast cell chymase (see page 3, lines 7-9). But ACT is not among the list of serine protease inhibitors in present claim 1. It does not disclose AAT of its own nor any serine protease inhibitor other than ACT alone. On page 3, lines 27-28 and page 5, lines 49-50, it is stated that AAT may be the "other serine protease inhibitor" to be used together with ACT. However, the wording in claim 1 at issue "if the disease is a skin disease, then only a single serine protease inhibitor is present in the composition" is effective in excluding the disclosure of E7. The claim is therefore novel over document E7.

Document E15

22. Claim 1 of this request is drafted as referring to a second/further medical use, the diseases to be treated being skin diseases implicated by mast cells and their mediators, while the active principle is one serine protease inhibitor selected from alpha-1-antitrypsin, secretory leucocyte protease inhibitor, C-reactive protein, serum amyloid A protein or alpha-2-macroglobulin.

23. Document E15 discloses the use of AAT or alpha-2-macroglobulin and topical creams containing them in the treatment of inflammatory skin diseases. The relevant issue to be decided is thus whether or not the medical use according to claim 1 represents a distinct (further) medical use vis-à-vis the therapeutic use disclosed in document E15.

24. The skin disease dealt with in document E15 is e.g., periproctitis (see page 3, line 4 from the bottom of the translation) and the proteases to be inhibited are SH-proteases (ibidem, page 2, third paragraph) of plasma or the digestive tract (ibidem, page 1, lines 43-44). These mediators to be inhibited thus differ from the serine protease present in mast cells (see claim 1) fixed in tissues, from which the associated proteases and other mediators are not released into the serum/plasma.

25. Furthermore, there are a great many aetiologies of inflammation, not necessarily mast-cell-mediated, each of which identifies a different clinical situation/disease and hence a new sub-group of subjects being treated, e.g., histamine-induced inflammation (see document E80), neutrophil-mediated inflammation (see document E24), leukocyte protease-mediated inflammation (see document B4, page 309, introduction), neutrophil serine collagenase-mediated inflammation (ibidem, page 318) and inflammation of the fat (panniculitis) (see document E64, page 303, bottom of r-h column). Finally, post-published document E65, taken as expert opinion, illustrates in Fig. 4, page 412, other possible mechanisms of inflammation involving T-cells, neutrophils and their mediators. Document E23 lists on pages 342-343 representative mediators of inflammation.

26. Appellants II and III argue that the inflammatory skin diseases dealt with in document E15 are caused by bacterial infections (see page 3, under "Working/Effect"), possibly involving mast cells. However, it can neither be derived from document E15, nor is there any evidence before the board that skin inflammation caused by bacterial infections is mast-cell-mediated, as is required by claim 1 at issue. In any case, eczema and psoriasis (see present claim 5) and atopic dermatitis (see document E65) falling under the category of such mast-cell-mediated skin diseases are distinct from periproctitis caused by bacterial infections.

27. In view of the foregoing, the board concludes that the feature in claim 1 that the skin disease should be implicated by mast cells and their mediators identifies a new clinical/pathophysiological situation vis-à-vis the SH-protease-mediated skin diseases disclosed in document E15. The above technical feature is not a mere explanation of how the protease inhibitors listed in claim 1 heal the skin diseases since it identifies a new pattern of skin inflammations having mast cells and their mediators as common denominator, and it is only when the skin disease results in the involvement of said mast cells and their mediators that AAT exerts a beneficial role. Therefore, the medical use according to claim 1 represents a distinct (further) medical use vis-à-vis the therapeutic use disclosed in document E15.

Document E2

28. Appellant II and III maintain that the treatment of asthma with AAT is disclosed in a novelty-destroying manner in document E2. However, this document discloses AAT for treating emphysema (see column 2, line 48) by inhibiting elastase (see column 4, bottom). It is true that the document refers to asthma (see column 3, line 9), however, this occurs in the context of the diseases (see column 3, lines 9-11: "...asthma, adult or infant respiratory distress syndrome, emphysema, lung cancer, etc") which can be treated with high mw proteins such as interferons, immunoglobulins, lipocortin, etc, as set out at column 3, lines 2-5. Therefore, the conclusion cannot be drawn that document E2 discloses the specific combination "AAT" for treating "asthma", let alone asthma implicated by mast cells and their mediators, as required by claim 1 at issue.

29. In conclusion, the subject-matter of claim 1 and dependent claims satisfies the requirements of Article 54 EPC.

Inventive step

Asthma

Closest prior art and problem to be solved

30. Appellants II and III depart from document E2 or E16 as closest prior art. Both documents relate to AAT and its known therapeutic uses. Document E2 discusses the use of AAT for treating emphysema, a pulmonary inflammation (see column 2, lines 25-29 and column 4, lines 62-65) by inhibition of elastase (column 2, line 46). Document E16 suggests a list of diseases related to AAT-deficiency to be treated with AAT, including chronic obstructive pulmonary disease (see page 7, line 29 to page 8, line 11). The problem to be solved starting from either documents, according to all appellants, is the provision of a further and distinct medical use of AAT, namely the treatment of asthma implicated by mast cells and their mediators by administration of the medicament to the site of the disease (see point 27 supra).

31. It is argued by appellants II and III that departing from document E2 or E16, teaching that AAT was useful in treating inflammatory conditions in general, it was obvious to move to the treatment of another pulmonary inflammation condition, asthma, using AAT.

32. However, the current dogma before the filing date of the patent in suit was that severe AAT genetic deficiency was linked to emphysema, whereas only a mild degree of AAT genetic deficiency was linked to asthma (see document E77, under "Introduction"). It was only this severe AAT deficiency which could be treated with AAT in a replacement therapy by iv injections. This dogma finds further support in document E4 (see page 2, column 2, second paragraph), stating that "a strong consensus emerged from all conference participants for recommending that replacement therapy be reserved for only those persons with severe, inherited deficiency of alpha-1-antitrypsin".

33. Therefore, in the board's judgement, the skilled person had prima facie no reasons to use AAT replacement therapy in the mild genetic deficiency associated with some form of asthma, in breach of the current dogma at that time.

34. Moreover, it did not seem to make sense to treat the above genetic deficiency of AAT at the site of the disease, since the skilled person would aim at re-establishing the protease/anti-protease balance in blood by iv injections.

35. As regards the inflammation conditions underlying emphysema, which appellants II and III argue to be common to any inflammatory conditions, including asthma (hence a similar treatment for both diseases), the following should be noted. Firstly, it has already been emphasized under point 25 supra that inflammation is merely a symptom of a great many different underlying pathophysiologic events and/or biochemical mechanisms, each of which identifies a different clinical situation/disease, the successful treatment of which requires an understanding of these pathophysiologic events (see e.g., document E78, page 519, r-h column, last paragraph). Secondly, the skilled person is taught by documents E2 and E16 that the biochemical mechanism underlying the healing the emphysema-associated inflammation is the inhibition of elastase (document E2) and that the inflammation (if any) accompanying the chronic obstructive pulmonary disease, caused by AAT-deficiency could be healed by re-establishing the protease/anti-protease balance in blood by iv injections of AAT (document E16), i.e., two mechanisms of action very remote from healing mast cell-mediated asthma by switching off the inflammation cascade produced by mast-cells and their mediators with AAT applied topically at the site of the disease (see claim 1). Therefore, the board must conclude that the skilled person departing from this prior art alone had no reasonable expectation of success in treating mast cell-mediated asthma with the same medicament (AAT) used for treating other inflammatory diseases such as emphysema.

36. In conclusion, the argument by appellant II and III that the use of AAT to treat an inflammatory disease such as emphysema, disclosed by documents E2 and E16, rendered obvious to the skilled person to use AAT to treat mast cell-mediated asthma, is not convincing.

37. Appellants II and III further argue lack of inventive step of the subject-matter of claim 1 in view of the combination of documents E2 or E16 with one or more of documents E77, E27, E78, E79 and E80.

38. As for the combination of document E2 or E16 with document E77, the asthma patients referred to in the latter document suffer from a genetic deficiency of AAT (see page 363, under "Introduction"). Therefore, the conclusion arrived at by the board under points 33 and 34 supra also apply to document E77, namely that the skilled person would not use AAT replacement therapy in the mild genetic deficiency associated with this form of asthma, in breach of the current dogma (and there is no suggestion either in document E77 to treat asthma caused by AAT-deficiency with AAT), and that administration of AAT to the site of the disease is not contemplated.

39. Moreover, although the aetiology of asthma is not fundamentally linked to a genetic deficiency of AAT, the above AAT-deficient asthma patients represent 1-2 % of all asthma patients (see post published document E39 cited as expert opinion, page 156, l-h column, last paragraph). These AAT-deficient patients have a predisposition to have asthma (c.f. the expression "hyperactive airways" on page 365, line 5 of document E77) and tend to have a more severe disease characterized by a less response to steroids, which is the medicament of choice (see document E4, page 365, lines 1-7 and document E39, r-h column, last paragraph). Appellant I has cited post published document E39 as expert opinion for showing that asthma in AAT-deficient patients is a disease different from that referred to in claim 1 at issue since the former does not involve mast cells (see page 155, Fig. 1), and it is treated with steroids. The board agrees that asthma linked to a genetic deficiency of AAT is a pathological situation distinct from the disease to be treated according to claim 1 at issue, namely asthma implicated by mast cells and their mediators. Therefore, in the board's judgement, even if the skilled person departing from document E2 or E16 taken in combination with document E77, decided nevertheless to treat the AAT-deficient asthma patients dealt with in document E77 by application of AAT to the site of the disease (which is not the view taken by the board), he/she would not arrive at the distinct medical use stated in claim 1.

40. As regards the combination of document E2 or E16 with document E27, the latter represents a summary of the knowledge at that time about the role of mast cell-mediated inflammation in asthma (see the title). It can be derived from this document that the biology of mast cells and their mediators was very complex (see page 546, middle column, first full) and that the role of mast cells and their mediators in asthma was not understood (see page 547, l-h column, second full paragraph; page 548 central column, under the heading "Enzymatic Mediators": "...The function of these enzymes in the disease is uncertain"). Moreover, it is stated on page 548, r-h column that tryptase is not inhibited by circulating plasma antiproteases. Therefore, the skilled person departing from documents E2 or E16 and coming across document E77 would not arrive at the medical use of claim 1, relying on the blockage of the inflammation cascade produced by mast-cells and their mediators with AAT applied topically at the site of the disease.

41. Furthermore, document E2 (see column 2, line 46 and column 4, bottom) taught that AAT had to inhibit elastase (produced by neutrophils; see patent in suit, page 2, line 41), in order to protect against inflammation, while document E27 relating to mast cell-mediated inflammation did not mention elastase. Hence, the skilled person would not combine these documents.

42. Appellants II and III rely on document E26 (see page 21308, last full paragraph) for maintaining that the mechanism regulating neutrophil serine proteases such as elastase is the same as that regulating mast cell serine proteases. However, the authors of document E26 merely say that these two mechanisms "may" be the same in the context of "host defence", not inflammation, without providing any proof. Therefore, this unproven hypothesis would further increase the skilled person's uncertainty.

43. As for the combination of document E2 or E16 with document E78/E79, appellants II and III argue that document E78 taught the skilled person that IgE-mediated mast cell degranulation was a critical factor in the pathogenesis of asthma, as further shown by document E79, demonstrating that in human lung mast cells, activation by IgE-induced Ca++ uptake and release of histamine (degranulation).

44. However, IgE is merely presented in document E78 as one of the many possible factors that can cause mast cell degranulation (see Fig. 1). Moreover document E78 lists all the possible mediators (see Table III) and mast cell mediators (Table II) involved in asthma, or causes of asthma (Table I). Even if the skilled person turned by "lucky guess" to tryptase or chymotryptic proteinase (Table II), the only proteases among this plethora of potential targets (AAT is not mentioned), the skilled person is taught by document E27 (see page 548, r-h column) that these proteases might not be inhibited by circulating plasma antiproteases and hence by AAT. Given the above uncertainty as to the pathophysiologic events underlying asthma, the author of document D78 refrains from proposing any possible treatment for asthma, let alone an AAT-based treatment (see page 519, r-h column, last paragraph). In conclusion, the combination of document E2 or E16 with documents E78 and/or D79 does not render obvious the medical use of claim 1, relying on the blockage of the inflammation cascade produced by mast-cells and their mediators with AAT applied topically at the site of the disease.

45. As for document E80, appellants II and III maintain that this document taught the skilled person that local addition of AAT to IgE-stimulated human mast cells inhibited histamine release (degranulation) in a dose-dependent manner and that the authors of this paper concluded that in inflammatory conditions, such as bronchial asthma, AAT controlled histamine release from stimulated human mast cells. Therefore, the skilled person, when considering the closest prior art, i.e. documents E2 or E16, would inevitably proceed to utilise AAT in the treatment of asthma, with the expectation of success.

46. However, the board firstly observes that at the publication date of document E80 (June 1985), IgE-stimulated histamine release from mast cells was merely one of the many possible factors, cells, aetiologies and mediators possibly underlying the pathophysiology of asthma (see Fig. 1 of document E78, published more than four years later than document E80), i.e., the skilled person was still uncertain as to the decisive inflammatory cascade underlying asthma and did not consider that IgE-mediated mast cell degranulation was the critical event in the pathogenesis of asthma. Secondly, document E80 (see last sentence of the abstract and page 6, third paragraph) reports that severe attacks of bronchial asthma were associated with raised levels of AAT in the blood or in local lesions. This finding was thus no incentive for the skilled person to supply further AAT, either by iv injection or by local application to a patient suffering from such an attack of bronchial asthma. Finally, it has not been disputed by appellants II and III that standard antihistamine medicaments were known to be ineffective for treating asthma, suggesting that inhibition of histamine release was not the target to be aimed at in the treatment of asthma. Therefore, the combination of document E2 or E16 with documents E80 does not render obvious the medical use of claim 1, either.

47. Appellants II and III depart from document E2 or E16 as closest prior art (see point 30 supra), relating to the use of AAT for treating emphysema (document E2) or chronic obstructive pulmonary disease (document E16). However, in accordance with the problem and solution approach, the Boards of Appeal have developed in their case law certain criteria for identifying the closest prior art which provides the best starting point for assessing inventive step. It has been repeatedly pointed out that this should be prior art relating to subject-matter conceived for the same purpose or aiming at the same objective as the claimed invention and having the most relevant technical features in common, i.e. requiring the minimum of structural modifications (c.f. Case Law of the Boards of Appeal of the European Patent Office, 4th Edition 2001, chapter I.D.3).

48. The invention according to claim 1 serves the purpose to provide a medicament for treating asthma. In the light of the criteria elaborated by the Boards of Appeal for identifying the closest prior art, the most appropriate starting point for the objective assessment of an inventive step following the problem and solution approach is in the present case considered to be document E77, aiming at the same purpose as the present application, i.e. the treatment of asthma.

49. Document E77 indeed refers to asthma patients suffering from a genetic deficiency of AAT (see page 363, under "Introduction"). These AAT-deficient asthma patients have a predisposition to have asthma (c.f. the expression "hyperactive airways" on page 365, line 5 of document E77) and tend to have a more severe disease characterized by a less response to steroids, which is the medicament of choice (see document E4, page 365, lines 1-7 and document E39, r-h column, last paragraph).

50. The problem to be solved departing from this closest prior art is thus to find an alternative treatment to asthma. The proposed solution stated in claim 1 at issue is the topical treatment of asthma by means of one or more serine protease inhibitors. In view of post-published document E60, showing the effectiveness of local administration (inhaled aerosol) of AAT in treating asthma, the board is satisfied that the above problem has been solved.

51. The relevant question is whether or not the above alternative treatment of asthma follows in an obvious manner from document E77, taken alone or in combination with other prior art documents. The board already decided (see points 33 and 34 supra) that the skilled person departing from document E77 would not use topical AAT therapy in the mild genetic deficiency associated with this form of asthma disclosed in this document because (i) this would represent a breach of the current dogma at that time, (ii) there was no suggestion in document E77 to treat this form of asthma with AAT and (iii) administration of AAT to the site of the disease was not contemplated. In the board's judgement, reasons (i) to (iii) above would also dissuade the skilled person from using topical AAT therapy in asthma implicated by mast cells and their mediators according to claim 1 at issue.

Skin diseases

52. Insofar as claim 1 relates to skin diseases, the board agrees that documents E81, E82 and E83, dealing with the treatment of psoriasis, represent the closest prior art. Appellants II and III maintain that claim 1 lacks an inventive step in view of this prior art. However, these documents merely disclose that there is a link between AAT deficiency and the manifestation of an inflammatory skin disease, namely psoriasis, and that increased AAT activity was a characteristic of symptom-free psoriasis. It can also be derived from these documents that neutrophils and one of their mediators, elastase, were the main group of cells and mediators involved in psoriasis. Therefore, the skilled person departing from documents E81, E82 and E83 taken alone or in combination would not arrive at the medical use of claim 1, relying on the blockage of the inflammation cascade produced by mast-cells and their mediators with AAT applied topically at the site of the skin diseases.

53. In conclusion, the subject-matter of claim 1 and dependent claims also satisfies the requirements of Article 56 EPC.