T 1872/14 - Allowable disclaimer for A54(2)

Key points

• Opposition was filed against a patent with an undisclosed disclaimer in the claims as granted. The Board finds that the disclaimer is allowable. 
• Moreover, the document D1 of which the example was disclaimed, was an application of the same applicant, and would therefore be a first filing for the now claimed subject matter without the disclaimer. The disclaimer therefore also restores validity of the claimed priority (and renders D1 a prior right and not Article 54(2)  EPC prior art). The Board deems this allowable. The remark in G 1/03, that introducing a valid disclaimer, does not affect priority, can not be understood the other way around.
• " Therefore, on a objective reading, said passage [ in G 1/03] cannot be said to advocate that the entitlement to priority is to be evaluated based on the subject-matter claimed prior to the introduction of the disclaimer; rather, the subject-matter actually claimed is to be taken as the starting point and compared with the content of the priority document, in order to establish whether the introduction of the disclaimer changes the identity of what is claimed, in analogy to the criteria set out in decision G 2/10"
• The Board hence does not follow T 1222/11, wherein the Board expressly rejected the use of a disclaimer, because the earlier filing in that case was Article 54(2) EPC prior art for the claim without disclaimer. 
• The Board further explains that " contrary to the submission of the appellant opponents, the problem-solution approach was not merely developed as an exercise in time saving, but rather in order to ensure an objective assessment of inventive step and avoid ex post facto analysis of the prior art" 

EPO T 1872/14 - link (online 27.07.2016)

Summary of Facts and Submissions

I. European patent No. 1 920 764 was filed as patent application No. 08 100 474.9 (document (34)). It is a divisional application of the parent application No. 04 077 870.6, which in turn is a divisional application of the root application No. 94 305 752.1 (document (35)), filed on 3 August 1994 and claiming priority of 3 August 1993 from the US patent application No. 08/101,598 (document (36)).

II. Independent claim 1 of the patent in suit as granted reads as follows (emphasis added):

"1. A topical ophthalmic composition for use in the treatment of glaucoma and ocular hypertension comprising a therapeutically effective amount of fluprostenol isopropyl ester,
with the proviso that the composition does not include the following composition: compound (F) 0.0001 wt%, fluprostenol isopropyl ester 0.001 wt%, benzalkonium chloride 0.01 wt%, dextran 70 0.1 wt%, disodium edetate 0.05 wt%, potassium chloride 0.12 wt%, sodium chloride 0.77 wt%, hydroxypropyl methyl cellulose 0.3 wt%, HCl and/or NaOH to adjust pH, and purified water q.s. to 100%, wherein compound (F) has the following formula: FORMULA/TABLE/GRAPHIC"

Reasons for the Decision

. Main request, Article 100(c) EPC

5.1 Objections were raised by the appellant opponents owing to the fact that document (35), which is the root application as originally filed (cf. above point I), does not disclose the disclaimer now appearing in claims 1 and 2 of the main request. Hence, the question to be addressed in this context is whether the introduction of the undisclosed disclaimer based on document (1) gives rise to subject-matter extending beyond the content of this earlier application as filed, based on the criteria laid down in decision G 1/03 (see Order, point 2). Accordingly, it will have to be examined whether, for the subject-matter now claimed, document (1) qualifies as state of the art under Article 54(3) EPC and Article 54(4) EPC 1973, and whether the disclaimer has been properly drafted to fulfil its purpose of restoring novelty, as set out in points 2.1, item 1, and 2.2 and 2.3 of said Order. It is noted that the issue of conformity with Article 84 EPC, in accordance with point 2.4 of the Order, has already been addressed above in point 3.3.

In addition, as further elaborated in Enlarged Board of Appeal decision G 2/10 (OJ EPO 2012, 376) with reference to decision G 1/03, the subject-matter remaining in the claim after the introduction of the disclaimer should not present the skilled person with technical information which he would not derive directly and unambiguously from the application as filed; the same standard is to be applied when assessing entitlement to priority (see, in particular, G 2/10, Reasons, point 4.4; points 4.5.1, 4.5.2 and 4.5.4; point 4.6).

5.2 Scope of disclaimer based on document (1)

5.2.1 Document (1) is a European patent application filed and published between the present priority and publication dates. The fact that document (1) validly claims an earlier priority date from document (1a) was not disputed by the appellant patentee. Moreover, the same contracting states are designated in document (1) as in the patent in suit. Accordingly, the content of the former must indeed be considered as being comprised in the state of the art for the latter, at least for the purposes of novelty (for status of document (1) under Article 54 EPC, see point 5.4 below, first sentence, and preceding analysis in point 5.3).

5.2.2 Document (1) relates to topical ophthalmic compositions for the treatment of glaucoma and ocular hypertension, comprising combinations of prostaglandins of formula (I) and (II) (cf. claim 1). The representative examples include the composition of Example E, which comprises a compound of formula (I) designated as "Compound 4, isopropyl ester" (page 8, lines 1 to 15), whereby Compound 4, as defined in Table 1 (page 4), is fluprostenol having the same absolute configuration as that specified for FIE in the present claims. In other words, composition E comprises (+)-FIE. In the following, for the sake of conciseness, this compound will simply be referred to as FIE.

In composition E, FIE is present in combination with a specific prostaglandin (compound (F) in present disclaimer), together with a number of specific excipients and solvents, in defined percentages by weight. This is the only disclosure of FIE to be found in document (1).

In the summary of the invention, it is emphasised that "an optimum combination of a compound of formula (I) and a compound of formula (II) will allow a more potent reduction of intraocular pressure without the side-effects produced by treatment with an adequate dose of a single component" (see page 2, lines 52 to 54). The skilled person would recognise from this disclosure that each individual exemplified combination is characteristic, in the sense that the two active compounds are specifically chosen in order to obtain optimum results, and closely linked to the other characteristics of the composition, most notably the concentrations of said components. This is confirmed by the fact that Examples A to J according to document (1) each relate to different individualised combinations in individually adapted concentrations.

Contrary to the appellant opponents' submissions, it cannot be accepted that the composition of Example E is open to generalisation on the basis of further passages of document (1). As explained above, FIE is locked into a specific combination of functionally related features. There is no direct and unambiguous disclosure of this compound as being a representative, preferred compound of formula (I) in the context of the more general disclosure. The appellant opponents sought to establish such a link by reference to the paragraph introducing the examples (cf. page 6, lines 25 to 27). However, the examples are designated therein as "representative pharmaceutical compositions of the invention" (emphasis added), and not in terms of their separate components. Moreover, no such link can be derived from the reference to Table 1 in said paragraph, since this is merely mentioned in the context of providing a key to the numbers used in defining the compounds of formula (I) within the exemplified compositions. In Table 1 itself and in the remaining passages of document (1), fluprostenol is listed amongst the preferred compounds, but not FIE (see page 3, line 31 to page 4, line 55; claims 2 and 3).

Consequently, the board concludes that FIE is only disclosed in document (1) in combination with the particular features of Example E.

5.2.3 Monotherapy with FIE is also not disclosed in document (1).

The paragraph on page 2 cited by the appellant opponents in this respect reads as follows (see lines 34 to 39, emphasis added; note: IOP stands for intraocular pressure):

"It has been unexpectedly discovered that co-administration of an E series prostaglandin and an F series prostaglandin in combination produces a greater reduction of IOP than the same dose of either type of compound given separately. In fact, as described in greater detail below, representative mixtures of the prostaglandins of the present invention produce a profound and long lasting IOP decrease. Administration of both types of prostaglandins in combination is apparently necessary to produce the desired IOP lowering effect for glaucoma therapy, while decreasing the likelihood of systemic side effects."

It is noted that the statements in this paragraph are rather general, with an emphasis on the "type of compound". This is is also echoed in the following two paragraphs on page 2 (lines 40 to 54), and the corresponding paragraph on page 5 (lines 40 to 43), in which trends are disclosed with general reference to compounds of formulae (I) and (II). Therefore, it cannot directly and unambiguously be derived therefrom that the reported observations are based on a separate and combined testing of each and every one of the active ingredients appearing in the examples.

The further submission in this respect, which relied on modifying the doses disclosed in Example E by reference to selected ratios and doses appearing elsewhere in different paragraphs on page 5 of the description, clearly falls short of the standards required for a direct and unambiguous disclosure.

5.2.4 From points 5.2.2 and 5.2.3 above, it follows that the relevant disclosure in document (1) with respect to FIE is restricted to the specific composition E and its use in the treatment of the conditions indicated.

In this respect, the appellant opponents additionally argued that, in the absence of a specific range assigned to the pH, the disclaimer was broader than the corresponding disclosure of Example E in document (1). However, in said example, there is also no pH value specified. Therefore, the skilled person would read this parameter in context, as only being limited in so far as the values encompassed should be compatible with the defined composition and use. Contrary to the submission of the appellant opponents, the passage of document (1) on page 5, lines 50, 51, does not support a more specific limitation, since it is merely stated therein that "the mixtures are generally formulated ... at a pH between 4.5 to 8.0" (emphasis added). Moreover, since the use defined in the present claims is the same as that disclosed in document (1), a technically meaningful reading of the disclaimer in context imposes a corresponding functional limitation on the pH of the disclaimed composition. It follows that the subject-matter of Example E in document (1) and of the present disclaimer are identical in scope.

The appellant opponents' further line of argument, according to which the disclaimer was narrower than the corresponding disclosure of Example E in document (1), must also fail. This submission relied on the description of the patent in suit to justify a reading of the disclaimer as being limited to the pH range of 7.3 to 7.4, as disclosed in the only specific composition comprising FIE, namely, Formulation 4. However, in view of the claim construction set out in the previous paragraph, it is evident that no recourse to the description is required in order to understand the disclaimed subject-matter within the context of the claims. Furthermore, it is noted that Formulation 4 differs in several aspects from that disclaimed, and there would therefore be no reason to apply the pH values of the former to the latter.

5.2.5 In view of the above considerations, it is concluded the disclaimer introduced in claims 1 and 2 of the main request (cf. proviso in above point II, combined with the definition of FIE reproduced in point VI) removes that which is necessary to restore novelty over the disclosure of document (1).

5.3 Entitlement of claimed subject-matter to priority from document (36)

5.3.1 Document (36) generally discloses compounds of formula (I) and corresponding topical ophthalmic compositions, as well as their use in the treatment of glaucoma and ocular hypertension (see e.g. claims 1 and 9; see also page 1, lines 4 to 7; page 5, lines 12 to 25; page 6, lines 15 to 17, and 23 to 30). With reference to Table 1, it is further disclosed that five specific compounds were tested, "two of which are compounds of the present invention" (page 4, line 26 to page 5, line 3). From a comparison of formula (I) and the structures depicted in Table 1, the two compounds of the invention are readily identifiable, namely, cloprostenol isopropyl ester (compound A) and FIE (compound B), whereby the structure of the latter is identical to that defined in claims 1 and 2 of the main request. Therefore, in order to arrive at the features defined in positive terms in the main request, only a single, allowable selection within the disclosure of document (36) is required, namely, of FIE from a list of two specifically named compounds.

5.3.2 The appellant opponents further argued that document (36) insufficiently disclosed the claimed invention, such that no priority right could be validly claimed. However, the board cannot concur with this line of argumentation for the reasons given below in points 6.2 and 6.3 (in particular, last paragraphs of points 6.2 and 6.3.1; Article 100(b) EPC).

5.3.3 Finally, the introduction of the disclaimer is not considered to lead to a loss of priority in the present case:

As a result of the exclusion of an isolated specific embodiment, the technical information presented to the skilled person has not been modified, in the sense that the disclaimer does not result in a singling out a novel subgroup in the subject-matter remaining in the claim (cf. G 2/10, Reasons, point 4.5.4, and reference therein to G 1/03, Reasons, point 2.1.3, second paragraph; see also G 2/10, Reasons, point 2.3, third paragraph). Since the identity of the claimed subject-matter has not been changed by said amendment, it does not affect the right to priority (cf. G 1/03, Reasons, point 4).

Moreover, since the disclaimer appropriately delimits the claimed subject-matter with respect to the disclosure of document (1), as set out above in point 5.2, it is considered that document (36) represents the first application, in the sense of Article 87(1) EPC, for the subject-matter remaining in the claims, and priority can be validly claimed therefrom.

5.3.4 It is therefore concluded that the main request is entitled to the priority date claimed from document (36), in accordance with Article 89 EPC.

5.4 Allowability of claim amendments by way of disclaimer

A consequence of the finding on priority in above point 5.3 is that document (1) constitutes prior art under Article 54(3) EPC and Article 54(4) EPC 1973.

The present disclaimer serves the purpose of restoring novelty over the relevant disclosure of this document (cf. above point 5.2).

Moreover, applying the same considerations as those set out in the second paragraph of above point 5.3.3, it is concluded that the skilled person is not presented with new technical information as a result of the introduction of the disclaimer.

Consequently, the claim amendment by way of disclaimer is considered to be allowable, pursuant to Article 100(c) EPC, in agreement with the criteria set out above in point 5.1.

5.5 The present board does not consider that the approach proposed by the appellant opponents for evaluating the allowability of the present disclaimer, based on that adopted in decision T 1222/11, is in accordance with Enlarged Board of Appeal decision G 2/98, G 1/03 and G 2/10 for the following reasons:

The decisive element in the reasoning of the appellant opponents was that the correct point of departure for assessing the entitlement to priority was the subject-matter claimed prior to the introduction of the disclaimer. In support of their position, the appellant opponents relied on decision G 1/03, and in particular the highlighted phrase from the following passage (see Reasons, point 4):

"In order to avoid any inconsistencies, the disclosure as the basis for the right to priority under Article 87(1) EPC and as the basis for amendments in an application under Article 123(2) EPC has to be interpreted in the same way. This means that a disclaimer, not providing a technical contribution as outlined above, which is allowable during the prosecution of a European patent application does not change the identity of the invention within the meaning of Article 87(1) EPC. Therefore, its introduction is allowable also when drafting and filing the European patent application without affecting the right to priority from the first application, which does not contain the disclaimer."

The board cannot concur with the appellant opponents' reading of this paragraph:

In the first sentence reproduced above it is reiterated that "the concept of disclosure must be the same for the purposes of Articles ... 87 and 123 EPC" (see Reasons, point 2.2.2, last paragraph; cf. also G 2/10, Reasons, point 4.6). In the second sentence, the phrase "not providing a technical contribution as outlined above" has been neglected in the appellant opponents' analysis. This refers back to previous sections of decision G 1/03, such as points 2.1.3 and 2.2.1, according to which disclaimers excluding state of the art under Article 54(3) EPC or an accidental anticipation, respectively, having no bearing on the technical information in the application, are not in contradiction to Article 123(2) EPC (see also analysis in decision G 2/10, Reasons, point 4.4). In the final sentence of the above paragraph, it is concluded that, by the same token, the introduction of such a disclaimer does not change the identity of the invention and would not affect the right to priority.

Therefore, on a objective reading, said passage cannot be said to advocate that the entitlement to priority is to be evaluated based on the subject-matter claimed prior to the introduction of the disclaimer; rather, the subject-matter actually claimed is to be taken as the starting point and compared with the content of the priority document, in order to establish whether the introduction of the disclaimer changes the identity of what is claimed, in analogy to the criteria set out in decision G 2/10 (see Reasons, points 4.5.1, 4.5.2 and 4.5.4). This is also consistent with Enlarged Board of Appeal decision G 2/98 (OJ EPO 2001, 413, see Reasons, point 6.2), according to which, "pursuant to Article 84 EPC, the claims of the European patent application define the matter for which protection is sought and, hence, determine the matter for which priority may be claimed".

In the present case, as explained above in point 5.3, regardless of whether document (1) is to be classified as a document under Article 54(2) or 54(3) EPC with respect to a notional claim not containing the disclaimer, the fact remains that, once the novelty destroying subject-matter disclosed in document (1) had been disclaimed, for the remaining claimed subject-matter, the priority date is then valid, and document (1) is prior art in the sense of Article 54(3) EPC. The introduction of such a disclaimer only serves the purpose for which it was intended, and does not represent an arbitrary reshaping of the claims, in keeping with the rationale underlying decision G 1/03 (see Reasons, point 2.6.5, and point 3, second paragraph).

Differing views were presented by the parties as to the fairness of allowing an applicant to disclaim its own prior art. However, the board cannot recognise anything in the reasoning or conclusions of decision G 1/03 from which it could be derived that such a possibility was to be excluded. It is noted that the situations listed in point 2.1 of the Order are not confined to ones of which an applicant could not have been aware at the time of filing. Moreover, in view of the fact that the relevant subject-matter has been disclaimed, the board cannot agree that there has been an extension of priority right for this subject-matter beyond the prescribed twelve-month time limit. Therefore, the cited purpose of Article 87(1) EPC, with reference to document (112) (see page 36, section (d)), namely, "to avoid a chain of successive claims of priority for the same subject", has not been undermined.

5.6 The board therefore concludes that the disclaimer of claims 1 and 2 of the main request does not result in subject-matter extending beyond the content of the root application as originally filed (document (35)).

[...]

8. Main request, Inventive step (Articles 52(1) and 56 EPC)

8.1 In accordance with the problem-solution approach applied by the boards of appeal to assess inventive step, it is first necessary to identify the closest prior art, then to determine in the light thereof the technical problem which the claimed invention addresses and successfully solves, and finally to examine whether or not the claimed solution to this problem is obvious for the skilled person in view of the state of the art.

Contrary to the submission of the appellant opponents, the problem-solution approach was not merely developed as an exercise in time saving, but rather in order to ensure an objective assessment of inventive step and avoid ex post facto analysis of the prior art (cf. "Case Law of the Boards of Appeal of the EPO", 7th edition 2013, chapter I, section D, point 2).

Accordingly, regarding the first step of choosing the closest prior art, care must be taken to identify a starting point which the skilled person would have realistically taken under the circumstances of the claimed invention. Therefore, the first consideration in this selection is whether a prior art document discloses subject-matter conceived for the same purpose or aiming at the same objective as the claimed invention. A further consideration is the structural similarity with the claimed invention, in terms of common relevant technical features. In cases of doubt, before an inventive step can be acknowledged, the problem-solution approach should be repeated taking possible alternative starting points (Case Law, supra, I.D.3; cf. also T 1760/11, point 10.1, and T 967/97, point 3.2).

8.2 The patent in suit relates to the treatment of glaucoma and ocular hypertension by means of prostaglandin analogues (e.g. paragraph [0001]). It is further elaborated therein that, although naturally-occurring prostaglandins are known to lower IOP after topical application, they generally cause inflammation and conjunctival hyperemia, and that these side effects have been observed to persist in many synthetic prostaglandins (paragraph [0004]).

In this context, document (3) is then discussed in some detail, as disclosing esterified PGF2alpha analogues, synthetically modified to include a phenyl ring, and retaining the potent IOP-lowering effect of the parent PGF2alpha isopropyl ester (IE), while decreasing the degree of conjunctival hyperemia. The subclass of 17-phenyl- 18,19,20-trinor analogues is disclosed as being preferred and, most particularly, the 13,14-dihydro derivative (latanoprost). In contrast, 16-phenoxy-17,18,19,20-tetranor-PGF2alpha-IE (i.e. compound 4 of document (3), designated as compound C in the patent in suit) is reported to still display unacceptable hyperemia (cf. patent in suit, paragraphs [0005], [0006]).

In the section "Summary of the Invention", the patent in suit highlights that "the addition of a trifluoro­methyl group to the meta position on the phenoxy ring at the end of the omega chain provides a compound having excellent IOP reduction without the significant side effects found with other, closely related compounds" (paragraph [0010]).

Form the foregoing, the board concludes that the patent in suit relates to the field of topical ophthalmic prostaglandin analogues for the treatment of glaucoma and ocular hypertension, and aims at providing treatments having an improved therapeutic profile.

8.3 The appellant opponents did not dispute that document (3) constitutes a suitable closest prior art. However, they maintained that document (4) represented at least an equally suitable starting point for the assessment of inventive step. The board does not agree:

8.3.1 Document (4) is directed to investigation into the receptors involved in the ocular hypotensive activity of PGE2 and PGF2alpha, and in particular into the postulate that the EP2, EP3 and FP receptor subtypes are discrete entities in this context (see page 545, 546, Summary and Introduction). To this end, a number of selective ligands, including the two FP-receptor agonists 17-phenyl PGF2alpha and fluprostenol were investigated for the effect of single doses on IOP in dogs and monkeys (cf. Tables 1 and 2). Three ligands were then selected, including 17-phenyl PGF2alpha, for further studies in monkeys using a 5-day, b.i.d. dosing regimen (Figures 1 to 3). Finally, radioligand binding studies were performed with a diverse variety of prostanoids, including, 17-phenyl PGF2alpha and fluprostenol (Figures 4 to 6). Based on these studies, it was concluded: "These findings also suggest that the decrease in intraocular pressure produced by EP3- and FP-receptor agonists is indeed mediated by different receptor subtypes" (see page 552, last sentence, and page 546, last sentence of Summary).

8.3.2 Thus, as outlined above in point 8.3.1, document (4) relates to a mechanistic investigation into receptor pharmacology underlying the ocular hypotensive activity of prostanoid analogues. The structurally diverse range of ligands are selected and classified in this study according to their selectivity for the specific receptor subtypes of interest. No information is provided with respect to the side effects of the compounds tested.

However, as set out in the patent in suit, and in document (3) cited therein, the problem of side effects was known to be a serious liability, potentially limiting the practical usefulness of prostaglandins and their analogues as drugs for the treatment of glaucoma and ocular hypertension (cf. document (3), page 2, line 45 to page 3, line 3). This is also confirmed by a number of further cited prior art documents (cf. e.g. documents (14), page 241, first paragraph; (18), page 456, "Summary and Conclusions"; (20), page 510, sentence bridging left- and right-hand columns; (23), page 692, left-hand column; (27), page 243, left-hand column, third paragraph; (30), page 535, lines 10, 11; (31), page 7, "Prostaglandine", first paragraph).

8.3.3 In view of the exclusive focus of document (4) on mechanistic aspects of IOP reduction, and complete absence of any discussion of utility in glaucoma treatment, or the critical issue of side effects, it is concluded that this document cannot be considered as being a suitable candidate as closest prior art.

8.4 In contrast, as summarised above in point 8.2, document (3) discloses the use in the treatment of ocular hypertension and glaucoma of a class of phenyl-substituted prostaglandin esters, and addresses both the issues of maintaining IOP reduction and decreasing side effects. It is therefore concerned with the same field and purpose as the patent in suit, and discloses structurally closely related compounds. The fact that it can be seen as a realistic starting point for further development in the field is confirmed by the above-referenced documents (14), (23), (27), (30) and (31), which all report research into the class of compounds first disclosed in document (3).

8.5 The further arguments of the appellant opponents in favour of document (4) as closest prior art are not considered to be convincing for the following reasons:

8.5.1 With reference to documents (71), (73) and (74), the appellant opponents argued that IOP-lowering activity alone, that is, without reference to side-effect profile, was recognised as the gold standard for establishing utility in the treatment of glaucoma and ocular hypertension. However, the board does not consider that the cited documents provide support for this submission:

Document (71) relates to a comparative review with respect to the responses of eyes of different species to topically applied prostaglandins (PGs), in terms of both hypotensive effect and side effects (see page 349, title; page 362, first sentence; page 363, Table 1). The skilled reader would also be aware of the significance of the latter from a further chapter from the same book, cited in the present proceedings as document (18) and referred to above in point 8.3.2. It is therefore in this context that the skilled person would read document (71) and the concluding paragraph cited by the appellant opponents (page 364). This is also consistent with the tentative quality of the statement therein, according to which "PGs or related eicosanoids, especially their more potent esterified prodrugs, represent a new class of ocular hypotensive agents that may prove useful in the therapeutic control of glaucoma" (emphasis added).

Document (74), which was published in the same year as document (71) (1989), is similarly cautious in its concluding statements (see page 74, last paragraph), and the issue of side effects is repeatedly mentioned therein, also in the context of the topical application of PGF2alpha-IE (see page 65, left-hand column, first paragraph, and also page 74, sentence bridging, left- and right-hand columns).

Finally, the appellant opponents referred to the following statement in document (73): "many prostaglandin derivatives are capable to decrease intraocular tension when used topically, i.e. they are useful for the treatment of glaucoma". However, this sentence is embedded in a single introductory paragraph of a patent document relating to the development of a novel process for the preparation of 13,14-dihydro-15(R)-17-phenyl-18,19,20-trinor-PGF2alpha esters, as disclosed in document (46) (page 1, lines 15 to 24), which is a family member of document (3). The skilled person would therefore read said statement, in the context of the prior art cited (cf. above point 8.2), as representing an oversimplification in the interest of brevity.

Consequently, these documents cannot support the appellant opponents' contention that the issue of side effects was a secondary consideration that should be disregarded in choosing the closest prior art.

8.5.2 In terms of structure, FIE is distinguished from the closest compounds of documents (3) and (4) by a single feature, namely, in the meta-CF3 substituent and an isopropyl ester group, respectively. Therefore, considerations of structural proximity cannot override the primary criterion of identity of purpose and objective, as outlined above in points 8.1 to 8.4. In this context, the appellant opponents emphasised the relationship of fluprostenol and FIE as parent and prodrug, with reference to document (15). However, the evaluation of obviousness of structural modifications undertaken with reference to further prior art documents is a matter to be considered in the last rather than the first step of the problem-solution approach, as set out above in point 8.1.

8.5.3 Finally, the board cannot agree that the fact that document (4) is authored by employees of a pharmaceutical company is relevant in the present context. Whatever the ultimate aim of the research published might be, the skilled person would nevertheless assess the content of this document at face value, based on the information actually disclosed therein.

8.6 In view of the above, the board concludes that document (3) is a suitable closest prior art document, in accordance with the problem-solution approach, and that the skilled person would not have considered document (4) for this purpose.

Since the board does not regard document (4) to be a realistic starting point for the assessment of inventive step, the rationale behind decision T 967/97, cited by the appellant opponents, is not applicable to the present case (cf. also T 1760/11, Reasons, point 10.3.7).

Consequently, the board sees no reason to deviate from the starting point indicated in the patent in suit for the assessment of inventive step. Document (3) is therefore considered to represent the closest state of the art.

8.7 According to the problem-solution approach, it is now necessary to determine the problem which the claimed invention addresses and successfully solves in the light of document (3).

The appellant patentee defined the problem to be solved as lying in the provision of a treatment of glaucoma and ocular hypertension with an efficacious IOP reduction, and reduced incidence of conjunctival hyperemia.

The solution as defined in the claims relates to the use of FIE, which differs from the structurally closest compound 4 of document (3), which is designated as compound C in the patent in suit, in the meta-CF3 substituent at the 16-phenoxy group.

8.8 As a next step, it must be established whether it has been rendered plausible that the problem defined under point 8.6 has been successfully solved over the whole scope claimed.

With respect to the aspect of reduction in hyperemia, the appellant patentee relied on the data provided in Table 3 of the patent in suit (page 17), and in the graphic presentation thereof in Figure 1. The two curves of interest in the latter are those designated "16-phenoxy-PGF2alpha" and "fluprostenol", which correspond to the results in Table 3 for comparative compound C and for FIE (compound B), respectively. It can be seen that there is a higher incidence of conjunctival hyperemia for compound C than for FIE, but that the separation of curves is less marked at lower doses, and that no difference in this respect is observed at a dose of 0.03 µg per eye.

The appellant patentee argued that the failure to detect a difference was due to limitations in the biological model employed. However, the board notes that said model is the one chosen by the appellant patentee in order to substantiate the alleged improvement. As explained in the previous paragraph, the absence of a difference in hyperemia at lower doses is also consistent with the general trends in Figure 1, and this result cannot therefore be assumed to be a mere artefact. This situation is to be distinguished from that underlying decision T 1850/10, cited by the appellant patentee, wherein an isolated deviation was observed in an otherwise consistent array of results (see Reasons 4.3).

Moreover, the relevant question is not whether the skilled person would be "particularly interested in what was happening at the extremities of the dose-response curves", but rather whether such doses can be regarded as being suitable doses, encompassed within the terms of the claimed applications. In this regard, it is noted that the dose of 0.03 µg per eye is well within the range of 0.01 to 100, indicated as being preferred in the patent in suit (paragraph [0016]). In addition, according to the appellant patentee's own submission with respect to auxiliary request 1, documents (58) and (59) provide evidence for an IOP-lowering effect at such levels (see document (58), Table 4 and associated text on page 427; document (59), Figures 1 and 4 (note: 0.0001% = dose of 0.03 µg for a drop size of 30 µL; cf. page 32, right-hand column, line 15), and page 34, left-hand column, third full paragraph).

Consequently, the data provided in Table 3 of the patent in suit cannot support a lower propensity for FIE to cause conjunctival hyperemia over the full scope claimed.

8.9 The problem to be solved must therefore be reformulated in a less ambitious manner, as lying in the provision of alternative treatment of glaucoma and ocular hypertension.

Having regard to the data provided in the patent in suit, in Examples 5 and 6, and corresponding Figures 1 and 2, the board is satisfied that this problem has been solved.

8.10 It remains to be investigated whether the proposed solution would have been obvious to the skilled person in the light of the prior art.

As becomes evident from the summary in point 8.2 above, document (3) is focused on prostaglandin derivatives in which the omega chain has been modified to contain a ring structure, for the topical treatment of glaucoma or ocular hypertension (page 2, lines 1 to 4; claims 1, 12, 23). This group of compounds is disclosed as exhibiting the unique property of causing insignificant ocular side effects while retaining the IOP lowering effect (page 11, lines 29 to 31). The structures envisaged are disclosed in more detail on page 3, line 7 to page 4, line 30. In all the exemplified compounds (see Table 1, and page 4, lines 8 to 20), the alpha chain is an isopropyl ester, and said ring structure in the omega chain is a phenyl group (cf. also e.g. page 3, lines 30 to 40, and page 4, line 3). One of the compounds listed is compound 4, which only differs from FIE in the lack of the meta-CF3 substituent at the phenyl ring (cf. above point 8.7).

Amongst the further structural modifications contemplated in document (3) is the present substitution of the phenyl ring, and the trifluoromethyl group is specifically listed as a suitable substituent (see page 4, lines 3 to 5; claim 6). Therefore, in seeking a solution to the problem defined in point 8.9 above, it would have been obvious for the skilled person to have considered the corresponding modification of compound 4, thereby arriving at the claimed subject-matter. In other words, the skilled person would not require any inventive skill to select a compound within the general teaching of document (3) and use it in the manner suggested therein.

8.11 The appellant patentee submitted that, based on the teachings of prior art documents (3), (4) and (23), the skilled person would have expected the meta-CF3 substitution of compound 4 to have a detrimental effect on IOP reduction; the comparable efficacy demonstrated in Example 6 and Figure 2 of the patent in suit would therefore establish an inventive step.

The appellant patentee firstly referred to the data for compounds 1 and 8 in Table V of document (3) as demonstrating that substitution with a para-OMe group led to a decrease in efficacy. However, in document (3) itself these results are commented as follows (page 11, lines 5 to 8; emphasis added): "substituting a hydrogen on the ring structure of 16-phenyl-17,18,19,20-tetranor-PGF2alpha-IE with a methoxy group eliminated much of the ocular irritating effect preserving most of the intraocular pressure lowering effect". Moreover, regardless how the significance of this effect is to be assessed, the board sees no logical reason why a skilled person should extrapolate a specific observation relating to substitution at a different structure, bearing a methylene group rather than an oxygen atom adjacent to the phenyl ring (i.e. phenyl vs. phenoxy), with a different substituent type (-OMe vs. -CF3), at a different position of the ring (para vs. meta).

The same applies to document (23) (see page 701, "Structure-activity relationships"), in which the effects of substitution at the phenyl ring in 17-phenyl-18,19,20-trinor-PGF2alpha-IE are reported (designated as compound 2 in document (3)). Again, in view of the differences in structure, and nature and/or position of the substituents, no sound conclusion can be drawn as to the expected effect of meta-CF3 substitution at the present 16-phenoxy-17,18,19,20-tetranor-PGF2alpha-IE structure.

Finally, the appellant patentee pointed to document (4) as disclosing modest efficacy for fluprostenol (page 548, Table 2 and following paragraph); it was further argued, with reference to document (15), that no improvement in this respect would be expected on esterification. The board cannot accept this line of reasoning: In document (4), fluprostenol is disclosed as being a "potent ocular hypotensive" (see page 545, Abstract; page 551, "Discussion", first sentence). Based on the teaching of document (15), according to which ester derivatives of prostaglandins act as prodrugs increasing efficacy of delivery to intraocular tissues (see page 185, second complete paragraph), the skilled person would expect this activity to at least be maintained on esterification. Moreover, the skilled person would not exclude the possibility that an increase in IOP lowering activity might be observed on esterification, in the case of free acids exhibiting poor ocular delivery. It is therefore concluded that the skilled person would not derive any clear teaching from documents (4) and (15) with respect to the expected efficacy of FIE.

8.12 Consequently, the main request is rejected for lack of inventive step.