|European Case Law Identifier:||ECLI:EP:BA:2007:T098804.20070927|
|Date of decision:||27 September 2007|
|Case number:||T 0988/04|
|IPC class:||A61K 31/565|
|Language of proceedings:||EN|
|Download and more information:||
|Title of application:||Steroid 3-O-sulphamate derivatives as inhibitors of oestrone sulphatase|
|Applicant name:||Sterix Limited|
|Relevant legal provisions:||
|Keywords:||Auxiliary request "claim set A": admissibility (no)
Main request: added matter (yes), undisclosed combination of features
First auxiliary request: amended claims at appeal allowable
Summary of Facts and Submissions
I. European patent application No. 98 957 034.6 was filed as international application WO 99/27936 with nineteen claims.
The present appeal lies from the decision of the examining division refusing the patent application under Article 97(1) EPC, pursuant to the requirements of Articles 54, 56, 83 and 84 EPC.
The decision was based on the main and sole request, namely, claims 1 to 12 as originally filed and claims 13 to 16 filed with the letter of 6 June 2001.
Claim 1 of the main request, which was identical to claim 1 as originally filed, read as follows:
"1. A sulphamate compound suitable for use as an inhibitor of oestrone sulphatase (E.C. 126.96.36.199), wherein the compound is a polycyclic compound comprising at least two ring components, wherein the polycyclic compound comprises at least one sulphamate group attached to at least one of the ring components, and wherein at least one oxime group is attached to or is part of at least one of the ring components."
II. The following documents were cited inter alia during the proceedings:
(1) GB 1 398 026
(2) L. W. L. Woo, et al., Bioorg. Med. Chem. Letters, 1997, 7(24), 3075-3080
(3) WO 93/05064
(5) W. Elger et al., J. Steroid Biochem. Molec. Biol. 1995, 55(3-4), 395-403
(6) Copy of the declaration by M. J. Reed and B. V. L. Potter dated 6.2.2003, originally submitted in proceedings before the United States Patent and Trademark Office, and filed with the present grounds of appeal.
III. The examining division considered that the subject-matter of claim 1 of the main request lacked novelty with respect to the disclosure in document (1) of steroidal compounds of formula (III) comprising a sulphamate and an oxime group.
The examining division further considered that the subject-matter of claim 1 could not be regarded as being an inventive solution to the problem of providing inhibitors of oestrone sulphatase. In particular, inter alia document (3) taught that steroids having a sulphamate group in the 3-position were active inhibitors of oestrone sulphatase and that a range of substituents at position 17 were tolerated by the enzyme. Further incentive to introduce an oxime moiety at position 17 could be derived from document (1).
Furthermore, the examining division was of the opinion that the claims did not meet the requirements of Article 56 EPC "in conjunction with Article 83 EPC", since the single example did not adequately demonstrate that the problem had been solved over the whole scope claimed.
Finally, the examining division considered that dependent claims 3, 10 and 11 lacked clarity.
IV. The appellant (applicant) lodged an appeal against this decision, and filed new sets of claims with the grounds of appeal together with the declaration (6).
V. In a communication of 12 January 2007, the board expressed serious doubts as to whether the subject-matter of the requests on file were in conformity with the requirements of Article 84 EPC. In addition, the board stated that the novelty objection raised by the first instance with respect to document (1) did not appear to be maintainable, and discussed the issue of inventive step with reference to document (5), which had been cited in the international search report.
VI. With the letter of 12 March 2007, the appellant filed a main request to replace the previous requests on file and a further document.
Claim 1 of the main request read as follows:
VII. In response to the board's communication sent as an annex to the summons to oral proceedings, in which objections were raised to the main request with respect to Article 123(2) EPC, the appellant filed auxiliary requests 1 to 4 with the letter of 24 August 2007.
Claim 1 of the first auxiliary request read as follows:
VIII. Oral proceedings were held before the board on 27 September 2007.
IX. During oral proceedings, the appellant filed an auxiliary request as "claim set A" to be considered after the main request. The former differed from the latter in that "rings A, B and C may be substituted or unsubstituted" in claim 1 had been replaced by "rings A, B and C may be substituted or unsubstituted, saturated or unsaturated"; additionally, the double bonds in ring A in the formula of claim 1 were deleted.
X. The appellant's arguments, insofar as they are relevant to the present decision, can be summarised as follows:
With respect to the issue of admissibility of "claim set A", the appellant submitted that this request had been filed during oral proceedings as a direct response to issues raised for the first time during the discussion on whether the main request fulfilled the requirements of Article 123(2) EPC. Moreover, the appellant contended that only minor amendments had been made with respect to the main request in order to reflect the precise language used on page 7, lines 7 to 15, of the application as originally filed.
As regards the basis in the application as originally filed for claim 1 of the main request (Article 123(2) EPC), the appellant argued that, on reading the application as originally filed, the skilled person would readily identify the three core structural features of the present compounds, namely, the ring system, the sulphamate group and the oxime group, as well as the preferred scope of each of these features, namely:
(a) the ABCD´ central nucleus was disclosed at page 7, lines 7 to 15;
(b) the D´ ring structure including the oxime group was disclosed at page 7, lines 17 to 23, and the corresponding meanings of hydrocarbyl at page 5, lines 20 to 21; and
(c) the sulphamate group was disclosed at page 4, line 26 to page 5, line 4, in combination with the definitions of the R1 and R2 groups at page 6, lines 1 to 3, and its point of attachment at page 11, line 1.
With respect to the degree of saturation in the A-C ring system in the formula of claim 1 (i.e. A ring aromatic, B and C rings saturated), the appellant contended that the skilled person would understand this to be preferred, based on the reference on page 7, lines 13 to 15 to the fact that the rings A, B and C are "similar to those of a steroidal nucleus" in conjunction with the disclosure of the suitable rings A-C on page 9, line 1 to page 10, line 7.
The appellant submitted that, although these features were discussed individually in the specification as originally filed as being preferred, the skilled person would directly and unambiguously derive the combination thereof as claimed in claim 1 of the main request, making use of its common general knowledge.
Concerning the basis of the subject-matter of the first auxiliary request (Article 123(2) EPC), the appellant cited the following passages:
Claim 1: page 11, formula (III), whereby the oxime substituent had been corrected to be X (Rule 88 EPC; cf. page 8, lines 1 to 4), in conjunction with the passages cited above under (b) and (c) for the meanings of X, R1 and R2;
Claim 2: page 11, lines 11 to 12;
Claim 3: page 24, compound ;
Claim 4: claim 13 as originally filed;
Claim 5 to 8: page 4, lines 7 to 19; and
Claim 9: claim 18 as originally filed.
Regarding the requirements of Article 84 EPC, the appellant argued that the claimed subject-matter was clear. A considerably restricted and clearly defined formula had now been introduced into claim 1 of the first auxiliary request, whereby the substituent X had been defined to be H or particular hydrocarbyl groups which had the standard and well-recognised meanings in the art of organic chemistry, and the possible meanings of substituents R1 and R2 had been defined to be H or specific hydrocarbyl groups optionally containing one or more heteroatoms or groups. In contrast to claim 1 as originally filed, where the feature "suitable for use as an inhibitor of oestrone sulphatase (E.C. 188.8.131.52)" had provided a functional-like limitation to the broad structural requirements, said feature now merely described an inherent property of the compounds claimed.
Concerning the requirements of Article 83 EPC, the appellant emphasised that there could be no doubts concerning the possibility of synthesising the compounds encompassed by claim 1, having regard to the mode of synthesis disclosed in the description (page 12, line 29 to page 13, line 14 and example 2), as subsequently demonstrated in Appendix 2 of the declaration (6) and further confirmed for the sulphamoylation step in document (2) (see the variations for the sulphamate group X in Figure 2).
As regards the requirements of novelty, the appellant considered that they were clearly met by the subject-matter now claimed in the first auxiliary request.
In its analysis of inventive step, the appellant started from document (3) as closest prior art and defined the problem to be solved as lying in the provision of compounds exhibiting both oestrone sulphatase inhibitory activity and oestrogenicity.
The appellant emphasised that this formulation of the problem was not artificial but had practical implications since compounds having this dual activity would be useful not only as oestrogenic compounds in hormone replacement therapy and contraception, but also, for example, in circumstances where it might be desirable to inhibit oestrone sulphatase in tumour cells whilst maintaining systemic levels of oestrogen.
The appellant identified the solution to the above-mentioned problem as lying the provision of the sulphamate compounds as claimed in claim 1 of the first auxiliary request, which differed from the oestrone sulphamates disclosed in document (3) in that an oxime moiety was attached to position 17 of the steroid ring rather than an oxo group. Originally filed examples 3 and 4 and the additional data in the declaration (6) demonstrated that the problem had been solved.
Although document (3) generally disclosed that steroid derivatives bearing a sulphamate substituent at position 3 acted as steroid sulphatase inhibitors, the appellant argued that there was no hint in this document directing the skilled person to the claimed compounds as a solution to the above-mentioned problem. Moreover, the appellant considered that the solution proposed was not rendered obvious by document (1) since no specific therapeutic use was disclosed therein, and this document therefore offered no teaching as to how the presence of an oxime group would affect oestrone sulphatase inhibitory activity or oestrogenicity.
XI. The appellant requested that the decision under appeal be set aside and that a patent be granted on the basis of the main request filed with the letter of 12 March 2007, or on the basis of one of the auxiliary requests 1 to 4 filed with the letter of 24 August 2007.
Reasons for the Decision
1. The appeal is admissible.
2. Admissibility of late-filed requests
2.1 The admissibility of late-filed requests is at the board's discretion and depends upon the overall circumstances of the case under consideration, a general principle being that the later the requests are filed, the less likely they are to be held admissible. Moreover, account has to be taken, inter alia, of whether they could have been filed earlier and if so the reason why they were not, and of whether they immediately appear to fulfil the formal criterion for allowability.
2.2 The main request filed with the letter of 12 March 2007 is admissible since it was filed as a direct response to the board's substantive objections raised in the communication of 12 January 2007 (cf. "Summary of Facts and Submissions", points V and VI).
2.3 Auxiliary requests 1 to 4 filed with the letter of 24 August 2007 are also admissible since they were filed as a clear and direct response to the board's communication sent as an annex to the invitation to oral proceedings, and were clearly allowable with respect to Article 123(2) EPC (cf. "Summary of Facts and Submissions", point VII).
2.4 With respect to the admissibility of "claim set A" filed during the oral proceedings, the following has been considered:
This claim set was filed at a very late stage of the proceedings, after the appellant had already availed itself of the opportunity to overcome an objection with respect to Article 123(2) EPC raised in the communication sent as an annex to the summons to oral proceedings by filing four auxiliary requests.
During the oral proceedings, the appellant presented its case on Article 123(2) EPC, and the board raised some questions in order to clarify the appellant's position. Hence, the appellant's argument that "claim set A" was filed as a direct response to objections raised for the first time at oral proceedings is not correct, and the filing of this request at such a late stage in the appeal proceedings is not justified.
Additionally to the above reasons, the subject-matter of "claim set A" is not clearly allowable under Article 123(2) EPC, since, contrary to the appellant's submission, the wording of this set of claims has not been taken verbatim from page 7 of the description.
In view of the foregoing, the auxiliary request "claim set A" filed during oral proceedings is not admissible.
3. Main request - Article 123(2) EPC
3.1 Claim 1 of the main request relates to sulphamate compounds defined by means of a Markush formula followed by definitions of the groups and residues. Since the Markush formula appearing in claim 1 of the main request is not disclosed explicitly in the application as originally filed, the question arises whether such a sub-class of compounds is directly and unambiguously derivable from the application as originally filed.
In claim 1 as originally filed, the structural requirements are defined in a very broad manner in terms of three minimal structural fragments, namely, a polycyclic compound comprising at least two ring components, a sulphamate group and an oxime group. Additionally, it is required that the sulphamate group is attached to at least one of the ring components, and the oxime group is attached to or is part of at least one of the ring components.
Claim 4 as originally filed, which is dependent on claim 1 as originally filed, specifies that the "polycyclic compound has a steroidal structure". However, the requirement of "a steroidal structure" does not give any preference to a particular steroidal structure and gives no information about the presence and number of aromatic rings, or the presence and number of unsaturated bonds in the rings within the polycyclic structure. There is no reason to presuppose that an estra-1,3,5(10)-triene structure such as that in oestrone is preferred, or that the ring A is preferably aromatic and the other three rings are saturated.
Indeed, the term "steroidal structure" as used in originally filed claim 4 does not even presuppose a cyclopentanophenanthrene skeleton, as confirmed by the fact that, in the subclass of formula (a) as claimed in claim 8 as originally filed (worded as a dependent on claim 7, which is dependent on claim 6, which is in turn dependent on any of the previous claims), ring D (depicted as D**(1)) has not been defined as a cyclopentano ring. Furthermore, the position of the oxime in ring D**(1) is not specified. Moreover, even were formula (a) to be taken as a basis for defining a subclass of compounds, there is a further structural requirement which is not reflected by the formula appearing in claim 1 of the main request, namely, while formula (a) shows ring A as being aromatic, there is the additional compulsory structural requirement of a methyl group (in configuration "beta") at one of the fusion positions between rings C and D (D**(1)) (position 13).
Hence, the subclass of compounds depicted in claim 1 of the main request cannot be directly and unambiguously derived from the originally filed claims.
As regards the content of the description as originally filed, the appellant himself has acknowledged that the structure of the polycyclic core, the sulphamate group and the oxime group are separately and independently defined in the description of the application as originally filed. Hence, to arrive at the subclass appearing in claim 1 of the main request would require a combination of features not disclosed as such in the application as originally filed.
Thus, the sections dedicated to the "polycyclic compound", i.e. to the polycyclic skeleton and corresponding structural variations and substituents, start on page 6, lines 24 and 25, with a very broad definition, namely, "the polycyclic compound can comprise at least two ring components, or at least three ring components, or at least four ring components" and end with the restricted formulae (II) and (III) on pages 11 and 12, which are the basis for the subclass(es) appearing in the auxiliary requests.
As regards the possibility of deriving from the application as originally filed a broader subclass of compounds than those depicted by formulae (II) or (III), the following has been considered:
The description states on page 7, lines 1 to 2: "Preferred polycyclic compounds are those that are based on steroidal ring structures, that is to say a cyclopentanophenanthrene skeleton" (emphasis added). However, the next paragraph on page 7 makes it clear that ring "D" is not necessarily a five-membered ring since the polycyclic compound "has a structure similar to a steroidal structure but wherein an oxime group is attached to or is part of the D ring" (emphasis added), which means that a cyclohexano ring is also possible.
The structure of "the preferred polycyclic compound" of formula (i) on page 7 shows a phenanthrene skeleton with a fused moiety D**(1), whereby D**(1) is defined as "the combination of a ring and the oxime group (i.e. the oxime group is part of or is attached to the ring component)" and "the ring D**(1) may be substituted or unsubstituted, saturated or unsaturated" (emphasis added; cf. page 7, lines 11 to 13). Therefore, there is no indication in the definition of formula (i) appearing on page 7, lines 7 to 15, of the choice of a saturated cyclopentano ring with an oxyimino group attached thereto at the specific position now claimed (position 17 of the cyclopentanophenathrene) as the preferred definition for D**(1).
Moreover, in the compounds of formula (i) on page 7, the "rings A, B and C - which are similar to those of a steroidal nucleus - may be substituted or unsubstituted, saturated or unsaturated" (emphasis added; cf. page 7, lines 13 to 15). Hence, there is no disclosure either of a preference for the ring A being fully unsaturated (i.e. aromatic) in combination with the absence of further unsaturated bonds in the other rings. The "examples" of polycyclic skeleton appearing on page 9 (see particularly lines 1 to 3) confirm this point since oestrone and dehydroepiandrosterone (wherein ring A is saturated and ring B contains one unsaturated bond) are mentioned without giving any preference to one or the other.
Additionally, the information on page 11, line 1, of the description as originally filed that "preferably, the sulphamate group is attached to the 3 position of the A ring", without any reference to a particular generic formula or a specific ring A, cannot be combined with other pieces of information appearing in isolation elsewhere in the description without contravention of Article 123(2) EPC.
Therefore, in order to arrive at the generic formula appearing in claim 1 of the main request the skilled person either has to perform several unallowable selections in different directions, or to combine some specific meanings (claim 8 as originally filed) with more general definitions (page 7, formula (i)), by omitting compulsory structural requirements such as the methyl group in "beta" configuration, thus introducing unallowable generalisations.
Consequently, claim 1 of the main request does not meet the requirements of Article 123(2) EPC.
3.2 The appellant's argument that the combination now claimed did not give rise to added subject-matter cannot be accepted.
As already mentioned, the claimed preferred points of attachment of the oxime and sulphamate groups are each disclosed in separate passages of the description with reference to a broadly defined steroidal-like structure. No pointer can be found in the description directing the skilled person to the selection and combination of the structural features in the generic formula now appearing in claim 1 of the main request.
As explained under point 3.1, formula (i) appearing on page 7, lines 7 to 10, cannot be taken separately from the following definitions given in lines 11 to 15. The combination of this disclosure with the preferred ring D**(1) depicted on page 7, lines 16 to 23, yields a formula with a cyclopentanophenanthrene skeleton and an oxyimino substituent at position 17. However, in the resulting formula both the position of the sulphamate substituent and the degree of saturation in the ring system are not specified.
The only direct and unambiguous disclosure of the combination of an oxyimino substituent at position 17 and a sulphamate substituent at position 3 in the application as originally filed is in the form of formulae (II) and (III) (page 11) and in the form of compound  (page 24).
4. First auxiliary request
4.1 The amendments introduced into the first auxiliary request find their basis in the application as originally filed, in particular, formulae (II) and (III) on page 11, whereby an obvious error has been corrected, namely, the substituent at the oxime moiety erroneously designated as R has been corrected to be X (Rule 88 EPC, cf. preferred rings D**(1) depicted on page 8; see also passages cited under "Summary of Facts and Submissions", point X).
The subject-matter of the first auxiliary request therefore meets the requirements of Article 123(2) EPC.
4.2 The board sees no reason to differ from the appellant's reading of claim 1 of the first auxiliary request (see "Summary of Facts and Submissions", point X).
The claims against which clarity objections were raised by the examining division have been deleted in the first auxiliary request.
The requirements of Article 84 EPC are therefore considered to be satisfied.
4.3 In view of the content of the description as originally filed, the board is satisfied that the claimed oestrone oxime 3-O-sulphamate derivatives now claimed can be prepared (see in particular page 12, line 29 to page 13, line 14 and example 2), and that the subject-matter of the first auxiliary request is disclosed in a manner sufficiently clear and complete for it to be carried out by a person skilled in the art.
Therefore, the requirements of Article 83 EPC are met.
4.4 The only document cited by the examining division as being novelty-destroying is document (1).
The formula disclosed in claim 1 of the present first auxiliary request overlaps with formula (III) disclosed in document (1) (cf. page 1, lines 28 to 52). In order to arrive at the claimed compounds starting from said formula (III), R1 has to be selected as being a nitrogen-containing substituent, and R2 and R3 have to be selected such that they together represent an oximino group.
Nowhere in document (1) can a pointer to this particular combination be found, neither in the form of a general teaching nor based on the exemplified compounds. Thus, there is no direct and unambiguous disclosure in document (1) of compounds falling under the scope of present claim 1.
Consequently, the disclosure of document (1) is not prejudicial to the novelty of the subject-matter of the first auxiliary request.
Since none of the other cited prior art documents disclose oxime derivatives, the novelty of the subject-matter of the first auxiliary request can be acknowledged (Articles 52(1) and 54 EPC).
4.5 Inventive step
The subject-matter of present claim 1 relates to oestrone oxime 3-O-sulphamate derivatives. According to the description, these compounds are useful as oestrone sulphatase inhibitors and oestrogenic compounds (page 3, line 21 to page 4, line 19).
According to the established jurisprudence of the boards of appeal, the closest prior art is normally a document disclosing subject-matter aiming at the same objective as the claimed invention and having the most relevant technical features in common.
The board considers document (5) rather than document (3) to represent the closest prior art, since document (5) discloses the estrogenic activity of the compound oestrone sulphamate (emate) in addition to its sulphatase inhibitory activity (see page 397, Figure 1 and "Discussion" on pages 400 to 402, particularly last paragraph), whereas document (3) does not mention estrogenic activity of the oestrone sulphamate derivatives disclosed therein.
Hence, the problem to be solved lies in the provision of further compounds exhibiting both oestrone sulphatase inhibitory activity and estrogenicity.
The solution as defined in claim 1 relates to the derivatisation of the oxo group at position 17 of emate as an oxime moiety and the further derivatisation of the sulphamate group when R1 and R2 are other than H.
Although the application as originally filed discloses specific data for oestrone oxime 3-O-sulphamate (omate), which only differs from the closest prior art compound emate in the exchange of the oxo for a hydroxyimino group, it is noted that the additional compounds tested in declaration (6) no longer fall within the scope claimed. Nevertheless, the structural variations of the compounds tested, which include inter alia substitution at the oxime moiety, make it plausible that the desired activities are present for the scope claimed.
Having regard to the experimental results reported in examples 3 and 4 of the description of the application in suit and in the declaration (6) (see, inter alia, page 8, paragraph 14 and page 30, Appendix 3), the board is satisfied that the problem is plausibly solved by the claimed compounds.
It remains to be investigated whether the proposed solution is obvious to the skilled person in the light of the prior art.
The skilled person starting from emate disclosed in document (5) and being aware of its estrogenic and sulphatase inhibitory activities would look for further derivatives such as those depicted in Figure 1 of document (5). However, none of the remaining derivatives disclosed in document (5) contain an oxime group at position 17. Therefore, this document by itself cannot render the claimed subject-matter obvious.
It has not been disputed by the appellant that the skilled person was aware of document (3) dedicated to "steroid sulphatase inhibitors", which discloses, generically and specifically, 17-oxo-cyclopentanophenanthrene derivatives (see in particular formula (III) on page 6) bearing a sulphamate group at position 3 as inhibitors of enzymes having steroid sulphatase activity.
Thus, document (3) includes a broad general teaching that compounds of formula (i), in which a sulphamate substituent is attached to a polycycle, act as steroid sulphatase inhibitors (see page 2, line 20 to page 3, line 8). In the preferred compounds of formula (II) the sulphamate substituent is attached to position 17 of cyclopentanophenanthrene skeleton, whereby suitable steroid ring systems include oestrone and substituted oestrones (page 4, line 15 to page 5, line 11; see also page 6, formula (III)). It is disclosed that the steroid ring system ABCD may contain a variety of "non-interfering substituents", in particular, hydroxy, alkyl, alkoxy, alkinyl or halogen (page 5, lines 13 to 20).
However, document (3) does not provide any information on whether an oxime substituent would be considered to be "non-interfering" in terms of its impact on the steroid sulphatase inhibitory activity. Moreover, document (3) is completely silent on the subject of the estrogenicity of the compounds disclosed.
Therefore, document (3) also does not give the skilled person any incentive to derivatise the closest prior art compound, oestrone sulphamate (emate), by introduction of an oxime moiety as a solution to the problem defined above.
As regards the teaching which can be extracted by the skilled person from document (1), it is quite limited. Although oximino substituents appear among many other possible options for the residue at position 17 and sulphamate appears amongst other options for the group at position 3 in generic formula (III), document (1) only discloses these compounds as possible components in pharmaceutical compositions (page 2, lines 1 to 5). Document (1) is silent on any specific activity of these compounds and cannot therefore be viewed as providing any hint leading the skilled person to the selection of the presently claimed 17-oxime 3-O-sulphamate oestrone derivatives as a solution to the above-mentioned problem.
The further prior art documents cited in the procedure do not come closer to the claimed subject-matter than those addressed above. Hence, the subject-matter of claim 1 of the first auxiliary request involves an inventive step.
Having regard to the fact that claims 2 to 9 are dependent compound claims, or composition, use or process claims referring back to the preceding compound claims, it is concluded that the subject-matter of the first auxiliary request meets the requirements of Articles 52(1) and 56 EPC.
4.6 Since the first auxiliary request is considered to be allowable, it is not necessary to comment on the lower-ranking auxiliary requests.
For these reasons it is decided that:
1. The decision under appeal is set aside.
2. The case is remitted to the first instance with the order to grant a patent on the basis of the first auxiliary request filed with the letter of 24 August 2007 and a description to be adapted.