T 1075/09 (Treatment of anovulatory women/LABORATOIRES SERONO SA) 21-10-2013

Main request

Amendments to claim 1 - Article 123(2) EPC

1. The claims as granted related to the treatment of anovulatory women in general. During the opposition proceedings the claims were restricted to the treatment of WHO Group II anovulatory women only. In the decision under appeal the opposition division has held that this amendment found a basis in the application as filed on page 1, lines 8 and 9 and in example 1.

2. Page 1, lines 8 to 9 form part of the introductory part of the description relating to the prior art treatment of women with WHO Group II and WHO Group I anovulation using hMG (human menopausal gonadotrophin) or u-FSH (urinary human follicle stimulating hormone) for the induction of folliculogenesis and hCG (human chorionic gonadotrophin) for the induction of ovulation. This passage does not disclose the use of luteinising hormone (LH) for the induction of pauci- or unifolliculogenesis let alone the use of such a treatment in WHO Group II women. Accordingly, this passage cannot provide a basis for the amendment in claim 1.

3. The only other reference to WHO Group II anovulation in the application as filed is found in the context of example 1 in which the effect of LH, when administered after FSH stimulation, was assessed in WHO Group II anovulatory women. The patients underwent routine ovulation induction with FSH until there were 4 or more follicles in the range of from 8 to 13 mm in diameter, no larger follicles and an endometrium of 8 mm or more thickness. Then, FSH treatment was stopped and LH administration started with two different LH doses,

225 IU/day of r-hLH and 450 IU/day of r-hLH and a placebo as control (see page 10, line 18 to page 11, line 9 of the application as filed).

4. The subject-matter of present claim 1 differs from the disclosure in example 1 at least in that (i) it does not require that the FSH treatment be stopped when LH administration starts, (ii) the LH treatment starts in the mid- to late-follicular phase, and (iii) LH is used at a higher daily dose, namely in the range of from

100 to 1500 IU. The patient subgroup - WHO Group II anovulatory women - is therefore extracted from the specific combination of features disclosed in

example 1.

5. According to established jurisprudence of the Boards of Appeal if a claim is restricted to a preferred embodiment it is normally not admissible under

Article 123(2) EPC to extract isolated features from a set of features which have originally been disclosed in combination for that embodiment. An amendment of this nature is only justified in the absence of any clearly recognisable functional or structural relationship among said features (Case Law of the Boards of Appeal of the European Patent Office, 6th edition 2010, section III.A.2). The issue to be decided in the present case is thus whether or not there exists a functional or structural relationship between the patient sub-group, i.e. WHO Group II anovulatory women, and the other features disclosed in example 1, in particular the timing of the FSH and LH administration and the daily dose of LH used.

6. At the priority date of the application it belonged to the common general knowledge of the person skilled in the art that, based on their distinct clinical conditions, anovulatory women are classified into three groups termed WHO Group I to III anovulation (see document (D8), page 7 to 8). While WHO Group I anovulation is characterised by reduced hypothalamic or pituitary activity and resulting in abnormally low serum FSH and LH levels and negligible estrogen activity, WHO Group II anovulation is characterised by distinct estrogen activity and normal but fluctuating gonadotrophins. Finally, WHO Group III anovulation is characterised by low endogenous estrogen activity and pathologically elevated serum and urinary gonadotrophins. The women belonging to the different groups are thus characterised by different endogenous hormonal levels.

7. The application as filed discloses on page 6, lines 22 to 24 that "LH can be administered only once the required stage of follicular development has been reached. In this case, the administration of FSH can be discontinued altogether or can be continued at the same dose as before, or at a lower or higher dose." This disclosure concerns recommendations for dosing and timing of the administration of the gonadotrophins, but there is no reference to any patient group, let alone the WHO Group II specifically. Hence this passage provides no information at all as to whether FSH treatment should be stopped or can be continued once a specific patient group is selected for treatment.

8. It would not escape the skilled person that the examples disclose different points in time to administer LH (or finish FSH administration), depending on the anovulatory patient subgroup to be treated. Thus, while in WHO Group II anovulatory women FSH treatment is stopped and LH administration started when there were 4 or more follicles in the range of from

8 to 13 mm in diameter, no larger follicles and an endometrium of 8 mm or more thickness (see example 1, page 11, lines 5 to 9 of the application as filed), in WHO Group I anovulatory women LH and FSH are administered in the late follicular phase which is defined to begin when at least one follicle with a mean diameter in the range of from 10 to 13 mm is present (see example 2, page 13, line 23 to page 15, line 11 of the application as filed). Bearing in mind that the application as filed (see page 6, lines 22 to 23) also emphasises that "LH can be administered only when the required stage of follicular development has been reached" the skilled person would, in the board's judgement, conclude that a distinct functional relationship exists between the subgroup of patients, the administration of FSH and the point in time of LH administration, which point is defined in the examples on the basis of the number and size of follicles present.

9. The application as filed also discloses (see page 3, lines 14 to 23) that "there is evidence that excessive exposure to LH will trigger follicular atresia and suppress granulosa proliferation. Developing follicles appear thus to have finite requirements for stimulation by LH, beyond which normal follicular development ceases. This is the "LH ceiling" concept." It would not escape the skilled person that in example 1 of the application as filed a LH dose of 450 IU/day results in all follicles becoming atretic in one out of eight patients (see Table 2). Therefore the skilled person would have also concluded that a distinct functional relationship existed between the subgroup of patients treated and the dose of LH administered.

10. The board concludes that the patient subgroup - WHO Group II anovulatory women - is inextricably linked to the other features disclosed in combination in example 1, in particular the stopping of the FHS treatment, the starting point of the LH treatment and the daily dose of LH administered. Accordingly, claim 1 presents the skilled person with technical information which is not directly and unambiguously disclosed in the application as filed.

11. The respondent submits that claim 1 does not contain added matter because the application teaches the absence of a functional and structural relationship between the patient sub-group and the remaining features of example 1. The respondent relies in particular on page 5, lines 8 to 12 and on page 6, lines 9 to 14 and lines 22 to 26 of the application as filed.

12. The board notes that the passage on page 5, lines 8 to 12 discloses that a LH dose of 100 to 1500 IU/day has been found by the inventors to promote paucifollicular development in patients undergoing follicular induction. However, there is no reference to any particular patient subgroup. Hence this passage provides no information whether the daily dose of LH disclosed in example 1 for the treatment of WHO group II anovulatory women, i.e. 225 or 450 IU, can be altered and in particular exceeded threefold.

13. The passage on page 6, lines 9 to 14 merely indicates various points in time as reflected by the number of follicles having a certain size. These various definitions do not synonymously define the same time point. For example, the occurrence of a "single follicle having a mean diameter of 8 mm" necessarily takes place earlier in time than the occurrence of a follicle that has "a mean diameter in the range of

10 to 15 mm". Therefore this paragraph merely illustrates the actual bandwidth of the term mid- to late-follicular phase. It does not provide, however, any teaching that the beginning of LH administration is not inextricably linked with the patient group so that it could be singled out of the context of example 1.

14. The disclosure on page 6, lines 22 to 24 concerns recommendations for dosing and timing of administration of the gonadotrophins, but there is no reference to any patient subgroup. Hence this passage provides no information at all as to whether FSH treatment should be stopped or can be continued once a specific patient group is selected for ovulation induction.

15. The board concludes from the above that the passages referred to by the respondent provide no basis in the application as filed for isolating the patient subgroup from the context in which it is disclosed in example 1 and then combining it with the remaining features defined in claim 1.

16. For these reasons, the subject-matter of claim 1 extends beyond the content of the application as filed and the main request is accordingly not allowable (Article 123(2) EPC).

Objection under Article 123(3) EPC - admissibility

17. In its letter of 14 May 2013 the appellant raised for the first time an objection under Article 123(3) EPC contending that deletion of the alternative "LH and/or a biologically-active analogue thereof" from claim 1 as granted extended the scope of protection. The respondent requested not to admit the objection in the appeal proceedings because it had been raised late.

18. The board notes that the objection under Article

123(3) EPC arises from an amendment made by the proprietor-respondent during the opposition proceedings before the department of first instance. Accordingly, any objection under Article 123(3) EPC could and thus should have been raised before the department of first instance. The objection has however been raised at a late stage in the appeal proceedings. Thus its admission in the appeal proceedings is at the discretion of the board (Article 13(1) RPBA). The appellant justified the lateness of the submission by arguing that the objection could not have been raised earlier as it was based on recent case law

(see decisions T 2017/07 of 26 November 2009 and decision T 9/10 of 16 November 2011).

19. The board notes that the decisions on which the appellant's argumentation under Article 123(3) EPC is based have issued after the time limit for filing the statement of grounds of appeal in the present case expired. Accordingly this case law was not available at the time of filing the statement of grounds of appeal and a fortiori not during the proceedings before the department of first instance. Thus, under the present circumstances, the board accepts that the objection, in this form, could not have been raised earlier. Being satisfied that the explanation provided by the appellant justifies the late raising of the objection under Article 123(3) EPC in the appeal proceedings the board decides in the exercise of its discretion to admit the objection in the appeal proceedings (Article 13(1) RPBA).

Amendments to claim 1 - Article 123(3) EPC

20. Pursuant to Article 123(3) EPC the European patent may not be amended in such a way as to extend the protection it confers. In order to decide whether or not an amendment of the granted patent satisfies that requirement, it is necessary to compare the protection conferred by the claims as granted with that of the claims as amended.

21. Claim 1 as granted concerned the use of LH and/or a biologically-active analogue thereof in the production of a medicament for inducing paucifolliculogenesis or unifolliculogenesis in anovulatory women at a daily dose in the range of from 100 to 1500 IU. This is understood by the board to mean inter alia that the daily dose of LH - if used alone - must not exceed

100 to 1500 IU.

22. Claim 1 as amended is directed to the use of LH at a daily dose in the range of from 100 to 1500 IU and is thus limited to one of the three alternative embodiments of claim 1 as granted. The daily dose of LH used alone must not exceed 100 to 1500 IU which corresponds exactly to - and does not exceed - the daily dose of LH according to one of the embodiments of claim 1 as granted.

23. The appellant submitted that claim 1 as amended confined the maximum daily dose of LH to a range of from 100 to 1500 IU. Due to the term "comprising" in claim 1, however, the presence of additional LH analogues was not excluded. In analogy to the cases underlying decisions T 9/10, supra, and T 2017/07, supra, this might result in a combined LH activity of more than the originally granted upper limit of 1500 IU and thus in a broadening of scope.

24. The board does not consider this line of reasoning persuasive. The wording of claim 1 of the main request does in fact not contain the term "comprising" but relates to "the use of LH in the production of a medicament" (see section IV above, for the complete wording of the claim) and the argumentation of the appellant fails for this reason alone.

25. If, for the sake of argument only, the board were however to accept the interpretation advanced by the appellant, then that same interpretation would of course also have to apply to claim 1 as granted which encompassed as one of the three alternative embodiments the use of LH (alone). In other words, the embodiment of claim 1 as granted directed to the use of LH would not have excluded the presence of any other compound -for example LH analogues - in any amount, also resulting in a combined LH activity of more than 1500 IU. The board would like to emphasise that the mere deletion of two alternative embodiments from claim 1 as granted cannot justify a different interpretation of the term "LH" in the context of claim 1 as granted vis- à-vis claim 1 as amended. In summary, the board is not persuaded that claim 1 as amended covers any use that was not covered by claim 1 as granted.

26. Finally, the board is not persuaded that the case law relied on by the appellant (decisions T 9/10 and

T 2017/07, supra) is at all relevant to the present situation for the following reasons.

27. In the case underlying decision T 2017/07, supra,

claim 1 as granted related to a composition openly defined as comprising inter alia a class of compounds (alkylene carbonate having 3 to 5 carbon atoms) in an amount which was defined by a numerical range and therefore excluded the presence of that component in an amount outside of that range. In claim 1 as amended the class of compounds had been restricted to a single species (propylene carbonate). The competent board decided that this amendment violated Article 123(3) EPC because other alkylene carbonates having 3 to 5 carbon atoms might be present in any amount due to the open language of the claim. Decision T 9/10, supra, dealt with an analogous situation and reached a similar conclusion.

28. The present situation is different from that decided in decision T 2017/07, supra, at least because in the present case the claim as granted was not directed to a composition specified to comprise LH, i.e. openly defined, but was directed to the use of LH as one of three possible alternative embodiments. Nor has the claim been amended to restrict the breadth of the component from a generic class to a specific component within that class. Rather, in the present case, two out of three embodiments were deleted. For these reasons the findings of decision T 2017/07, supra, are not relevant to the present case. For the same reasons the findings of decision T 9/10, supra, are also irrelevant.

29. The board concludes that the scope of protection conferred by present claim 1 has not been extended vis-à-vis that of claim 1 as granted, such that the requirements of Article 123(3) EPC are satisfied.

Article 53(c) EPC - claim 1

30. Claim 1 as granted has been amended during the proceedings before the opposition division by including the feature relating to the administration of FSH. In its letter of 14 May 2013 the appellant raised for the first time an objection under Article 53(c) EPC against claim 1. The board notes that this objection also arises out of an amendment made by the respondent during the proceedings before the opposition division and has also been raised late in the appeal proceedings. The respondent did not object to the admission of this objection in the appeal proceedings. The board considers the objection prima facie of high relevance and therefore decides to admit it in the appeal proceedings in the exercise of its discretion under Article 13(1) RPBA.

31. Present claim 1 concerns two different therapeutic methods, namely (i) the administration of FSH for the induction of folliculogenesis and (ii) the administration of LH for inducing paucifolliculogenesis or unifolliculogenesis in WHO Group II anovulatory women (see section IV, above for the complete wording of the claim). The board notes that claim 1 is worded such that the purpose defined in the Swiss-type format is restricted to the administration of LH only while the administration of FSH is not covered by the Swiss-type format. Therefore claim 1 teaches the direct administration of FSH to the patient for inducing folliculogenesis which feature constitutes a method of treatment of the human body by therapy involving a direct physical intervention on the human body. The Enlarged Board has held in decision G 2/08 (see OJ EPO, 2010, page 456, reasons, point 5.6) that it is established case law "(…) that any method claim containing even a single step pertaining by nature to a treatment by therapy is not allowable." The board concludes that claim 1 can be read as a sequence of two separate activities, the induction of folliculogenesis by the administration of FSH which is not drafted in Swiss-type format followed by the administration of LH drafted in the Swiss-type format and is therefore excluded from patentability pursuant to Article 53(c) EPC.

32. The respondent submitted that the feature "and wherein folliculogenesis is induced by the administration of FSH" was part of the definition of the patient group to be treated by the medicament of claim 1 and could not be considered to be a claimed therapeutic method involving a direct physical intervention on the human body.

33. The board does not consider this argument persuasive. The patient group is clearly indicated as being the WHO Group II anovulatory women and in the judgement of the board the wording of the feature "and wherein folliculogenesis is induced by the administration of FSH" leaves no doubt that the administration of FSH for the induction of folliculogenesis is carried out as an active step as part of the treatment of these WHO Group II anovulatory women.

34. For the above reasons the board decides that the main request is excluded from patentability pursuant to Article 53(c) EPC and hence unallowable.

Auxiliary requests 1, 2, and 3

Amendments (Article 123(2) EPC) and Article 53(c) EPC

35. The respondent submitted no further arguments for these requests and conceded that the objections that applied to the main request also applied to these requests.

36. The point in time for administration of LH and the daily dose of LH as defined in claim 1 of these requests do not correspond to the point in time and the daily dose disclosed in example 1. Accordingly, all these requests also fail the requirements of Article 123(2) EPC for the same reasons as set out above for the main request.

37. Moreover, claim 1 of all of these requests encompasses the step relating to the induction of folliculogenesis by the administration of FSH and therefore all requests are excluded from patentability pursuant to

Article 53(c) EPC for the same reasons as set out above for the main request.

Auxiliary request 4

Admissibility

38. Auxiliary request 4 was filed during the oral proceedings before the board. The appellant submitted that this request not only failed to address all objections raised so far but also lead to new objections. Accordingly it requested that it should not be admitted in the proceedings.

39. The board considers that auxiliary request 4 constitutes a fair attempt to address the objections raised with regard to the higher ranking requests. The amendments made in this request are straightforward and do not lead to any surprising turn of events. Under these circumstances the board decides to admit this request into the proceedings in the exercise of its discretion under Article 13(1) RPBA.

Amendments (Article 123(2) EPC) - claims 1, 3, and 4

40. The respondent indicated example 1 as a basis for the amendments carried out in claim 1.

41. Pursuant to example 1, LH administration starts when there are 4 or more follicles in the range of from 8 to 13 mm in diameter, no larger follicles and an endometrium of 8 mm or more thickness while according to present claim 1, LH administration starts when there are more than 3 follicles with a mean diameter in the range of from 8 to 13 mm and no larger follicles and when the endometrium thickness is 8 mm or more. The diameter and the mean diameter are different parameters and the number and size of the follicles and hence the timepoints defined by the expressions used in example 1 and claim 1, respectively, are therefore different. The timepoint defined in present claim 1 has therefore no basis in example 1 and extends beyond the content of the application as filed. This was not disputed by the respondent.

42. Claim 1 defines the daily dose of LH as 225 IU or

450 IU. Claims 3 and 4 depend on claim 1 and specify the IU ratio of LH to FSH as being in the range of from 1.5:1 to 20:1 and from 1.5:1 to 10:1, respectively, thus defining possible ranges of amounts for FSH (see section XI above for the complete wording of the claims). Example 1, which forms the basis of claim 1, does disclose the amount of LH used (225 IU/day or 450 IU/day) but does not disclose the amount of FSH being used. The combinations of features arising from the combination of present claim 1 and claims 3 or 4, in other words the specific ratios of LH to FSH, have not been disclosed in example 1 or anywhere else in the application as filed. Therefore, the subject-matter of claims 3 and 4 extends beyond the content of the application as filed.

43. The respondent submitted that claims corresponding to claims 3 and 4 were present in the set of claims as granted and accordingly no objection could be raised under Article 123(2) EPC. The board understand this argument as relying implicitly on the absence of any objection under Article 100(c) EPC against the claims as granted (see section III, above).

44. The board is not persuaded. It is correct that the wording of claims 7 and 8 as granted corresponds to the wording of present claims 3 and 4. In the set of claims as granted, claims 7 and 8 were dependent on claim 1 which related to a daily dose of LH in the range of from 100 to 1500 IU while present claim 1, on which claims 3 and 4 depend, relates to a daily LH dose of 225 IU or 450 IU. Thus, although claims corresponding to present claims 3 and 4 were present in the set of claims as granted, the combination of features covered by present claims 3 and 4 was not. That no objection under Article 100(c) EPC has been raised against the claims as granted is therefore irrelevant.

45. For these reasons auxiliary request 4 is not allowable under Article 123(2) EPC.

Auxiliary request 5

Admissibility

46. The appellant has not contested the admissibility of this request and the board is satisfied that the amendments made in the request are straightforward and do not lead to any surprising turn of events. Under these circumstances the board decides to admit this request into the proceedings in the exercise of its discretion under Article 13(1) RPBA.

Amendments (Article 123(2) EPC)

47. The request consists of claims 1 and 2. The respondent indicated example 1 as a basis for the amendments carried out in claim 1 and submitted that claim 2 corresponded to claim 3 as granted.

48. The appellant observed that according to example 1 the patients underwent routine ovulation induction with FSH whereas claim 1 did not specify that the ovulation induction was routine. In its view therefore claim 1 violated Article 123(2) EPC.

49. According to established case law of the Boards of Appeal (Case Law of the Boards of Appeal of the European Patent Office, 6th edition 2010, section II.B.5.3.3) terms used in patent documents should be given their normal meaning in the relevant art. In the board's judgement, in the absence of any information in the claim as regards the procedure to be followed when using FSH for inducing folliculogenesis, the skilled person giving the terms their normal meaning in the relevant art would understand that the protocol to be followed for the induction of folliculogenesis with FSH is the protocol normally, i.e. routinely, used. Therefore, in the board's judgement, the fact that the claim does not refer to "routine" in the context of induction of folliculogenesis does not result in the skilled person being presented with information which was not clearly and unambiguously set out in the application as filed.

50. For these reasons auxiliary request 5 complies with the requirements of Article 123(2) EPC.

Article 84 EPC

51. The appellant objected to claim 1 because it referred to both "inducing folliculogenesis" and "inducing paucifolliculogenesis or unifolliculogenesis". In its view these two terms were mutually exclusive and

claim 1 was thus unclear.

52. Claim 1 relates to the treatment of anovulatory women. While in a first step of the treatment administration of FSH induces folliculogenesis, in a second step administration of LH reduces the number of preovulatory follicles per treatment cycle, i.e. promotes paucifolliculogenesis or even unifolliculogenesis. In other words, the induction of folliculogenesis is a necessary prerequisite for the subsequent induction of of paucifolliculogenesis or unifolliculogenesis. In the board's judgement claim 1 is thus clear.

Amendments (Article 123(3) EPC)

53. The appellant has not raised any objections under Article 123(3) EPC. Since the board has no objections either, the amendments introduced in the claims are regarded as fulfilling the requirements of Article 123(3) EPC.

Article 53(c) EPC

54. The appellant has not raised any objections under Article 53(c) EPC and the board is satisfied that the requirements of Article 53(c) EPC are fulfilled.

Article 83 EPC

55. The appellant has not raised any objections under Article 83 EPC and the board is satisfied that the requirements of Article 83 EPC are fulfilled.

Article 56 EPC

Closest prior art

56. The patent in suit concerns the use of LH for promoting paucifollicular and unifollicular development, when inducing ovulation in anovulatory women. It is common ground between the parties that document (D5) represents the closest prior art. The board sees no reason to disagree.

56.1 Document (D5), a review article, summarises the relative contributions of FSH and LH to folliculogenesis in spontaneous menstrual cycles. According to the last sentence of the abstract the development-related response to LH shown by the pre-ovulatory follicle raises the possibility that exogenous LH might be used as an adjunct to therapy with exogenous FSH in clinical ovulation induction regimes where the aim is to induce monovulation.

56.2 In particular, document (D5) explains the FSH threshold hypothesis and the LH ceiling hypothesis (Figure 1, Table I, Table II). According to the FSH threshold hypothesis ovarian follicles have development-related requirements for stimulation by FSH. Beyond a certain "threshold" level, FSH stimulates granulosa proliferation and functional maturation (including expression of aromatase and the LH receptor). As follicles mature they become increasingly sensitive to FSH. According to this hypothesis, the FSH dose should exceed the threshold of the most mature follicle during ovulation induction.

56.3 By mid-follicular phase, the dominant follicle is recognizable as the largest healthy follicle in either ovary. Maintenance of its status as the dominant follicle becomes increasingly dependent on LH. According to the LH ceiling hypothesis ovarian follicles also have development-related requirements for stimulation by LH. Beyond a certain ceiling level, LH suppresses granulosa proliferation and initiates atresia. Mature follicles are more resistant to LH than immature follicles. According to this hypothesis, the LH dose should not exceed the ceiling of the most mature follicle during ovulation induction.

56.4 As regards the clinical implications of these hypotheses, document (D5) proposes that FSH and LH can be used to develop improved clinical strategies for stimulating ovarian function. According to document (D5) it is desirable to stimulate monovulation in women receiving treatment for ovulatory dysfunction and the challenge is to tailor therapy with FSH and LH, individually or combined, based on the principles put forward.

56.5 Finally, document (D5) proposes (page 191, left hand column, last paragraph) that "Pure LH may be of particular use in treatment regimes that aim to achieve monovulation for conception in vivo. Once an appropriate (i.e. LH-responsive) stage of follicular development has been achieved in response to treatment with FSH, there are theoretical grounds for reducing or completely withdrawing FSH and maintaining tonic (subceiling) stimulation of the dominant follicle with exogenous LH. Such a low-dose LH "coast", for no more than 1 or 2 days, could have the dual advantage of promoting the terminal maturation of a single pre-ovulatory follicle and simultaneously arresting the development of multiple less mature follicles that would otherwise occur in response to treatment with FSH (Hillier 1993)" (emphasis added). Document (D5) concludes with stating that "Controlled clinical trials are required to evaluate these possibilities".

56.6 The parties disagree on the interpretation of the feature "withdrawing FSH and maintaining tonic (subceiling) stimulation of the dominant follicle with exogenous LH", see sections XIV and XV above.

56.7 The board notes that document (D5) discloses to maintain - not to start - tonic stimulation with exogenous LH. The term "maintaining" in this passage of document (D5) clearly implies that exogenous LH is already present before FSH is withdrawn. In the board's judgment, further evidence that this interpretation is correct can be found in document (D10) which is the document "(Hillier 1993)" to which document (D5) explicitly refers at the end of the passage under dispute. Accordingly, document (D10) can be consulted when assessing the teaching of document (D5). Document (D10) is by the same author as document (D5) and proposes that the availability of pure LH could be particularly beneficial to patients with forms of anovulation amenable to gonadotropin therapy in which the object is to stimulate the development of a single ovulatory follicle so that conception might occur in vivo (see page 44, last paragraph). According to the last sentence on page 44 of document (D10): "The strategy involving pure LH would be that once a preovulatory follicle had begun to develop in response to a suprathreshold dose of FSH (given in combination with a tonic amount of LH), treatment with FSH could be gradually withdrawn while tonic stimulation with LH was maintained." This passage therefore explicitly teaches that LH is given at a tonic amount concurrently with FSH. Under the heading "conclusions", document (D10) discloses on page 46, last paragraph, that: "Pure LH could be of particular use in stimulation regimens aiming to achieve mono-ovulation and for conception in vivo. Once the appropriate (i.e. LH-responsive) stage of preovulatory development has been achieved in response to treatment with FSH, it would seem rational to withdraw FSH and maintain tonic (subceiling) stimulation with LH." This passage corresponds almost verbatim to the passage in question of document (D5). In the light of the passages on pages 44 and 46 of document (D10) the board is satisfied that "maintaining" tonic (subceiling) stimulation with LH means that exogenous LH is given concurrently with FSH and is continued after FSH is withdrawn.

56.8 In this regard, the board also notes that document (D5) discloses on page 190, left hand column, third paragraph that: "LH receptors are constitutively present on thecal cells and appear on granulosa cells that have been adequately stimulated by FSH. Tonic exposure to LH facilitates the inductive function of FSH during follicular selection." Document (D5) thus discloses explicitly the simultaneous presence of LH and FSH and its advantages. Accordingly, the board is not persuaded by appellant's argument that the skilled person, when considering the whole content of document (D5), would have understood that document (D5) suggested a regime where follicular stimulation was started with FSH alone during the early follicular phase.

56.9 The board concludes that document (D5) proposes on page 191, left hand column, last paragraph, a treatment regimen that aims to achieve monovulation for conception in vivo which involves continuous stimulation with LH at a subceiling dose while FSH is withdrawn once an appropriate (i.e. LH-responsive) stage of follicular development has been achieved.

The technical problem to be solved

57. The board considers that the subject-matter of claim 1 differs from the teaching of document (D5) in i) that it relates to the treatment of WHO group II patients, (ii) the daily dose of LH administered and iii) the time point of the administration of LH. Table 3 of the patent in suit shows that this treatment results in less follicles with a diameter equal or larger than 14 mm.

58. The problem to be solved is therefore defined as the induction of uni-or paucifolliculogenesis in WHO group II anovulatory women. The solution consists in the treatment according to claim 1.

59. The claim under consideration is drawn up in the Swiss-type format and the statement of purpose thus limits the claim such that the whole subject-matter is to be regarded as a solution to the problem (see e.g. decision T 1031/06 of 9 April 2009, reasons, point 23). The board is thus satisfied that the problem is plausibly solved by the subject-matter of claim 1.

60. The appellant submitted that document (D5) disclosed the principle of the claimed invention but not the amount of LH recited in the claim, the patient subgroup and the exact time point for the administration of LH. However, the limitation to WHO group II anovulatory women and the exact time point for the administration of LH were arbitrary and did not contribute to the technical effect. The objective technical problem over document (D5) was regarded as defining an appropriate LH dosage in a treatment protocol wherein "exogenous LH was used as an adjunct to therapy with exogenous FSH in clinical ovulation induction regimes where the aim was to induce monovulation".

61. In the board's judgement this argumentation fails because it has been established that i) document (D5) does not disclose the principle of the claimed invention (see points 56.1 to 56.9 above) and ii) that a distinct functional relationship exists between the sub-group of patients, the administration of FSH, the time point of LH administration and the daily dose of LH administered (see points 1 to 16 above). These features are thus not arbitrarily chosen but contribute to the claimed technical effect.

Obviousness

62. It remains to be answered whether the skilled person, when faced with the technical problem defined in point 58 above, would have modified the teaching in the closest prior art document (D5) - possibly in the light of other teachings in the prior art - so as to arrive at the claimed invention in an obvious manner.

63. Document (D5) discloses LH administration throughout and does not disclose or suggest the administration of LH only at a later point during follicular development, in particular during the mid- to late-follicular phase. Moreover, document (D5) does not mention any suitable daily dose of LH. Accordingly, the claimed solution is not obvious from document (D5) alone.

64. Document (D1) studies the ovarian response to r-hFSH and r-hLH in women that have been rendered artificially anovulatory. Document (D1) discloses in the paragraph bridging pages 231 and 232 that: "Defining a cut-off point below which LH or hCG will not maintain follicular growth could be helpful to control the number of preovulatory follicles in ovulation induction protocols. Theoretically, a sequential FSH and LH ovarian stimulation protocol could be used to limit follicular recruitment, thereby reducing the complications now associated with ovulation induction protocols." (emphasis added). Document (D1) thus proposes a protocol which involves sequential FSH and LH ovarian stimulation to limit follicular recruitment.

65. The first question to be answered is whether the skilled person, when faced with the technical problem formulated above, would even consider document (D1). The women treated in this document have no ovarian dysfunction but are rendered artificially anovulatory by administration of leuprolide acetate to minimize endogenous gonadotropin secretion (see page 229, left hand column, fourth paragraph). In contrast thereto WHO Group II anovulatory women have normal and fluctuating levels of serum FSH and LH. In that regard, the board is not persuaded by appellant's argument that document (D19) equates the patient group disclosed in document (D1) to those patients belonging to WHO group II anovulatory women. Document (D19) merely discloses that in WHO group II anovulatory women or in women treated with analogues of gonadotrophin releasing hormone, pure FSH can stimulate the follicular development (see page 3, right hand column, fourth paragraph). Accordingly, the patients of document (D1) are not WHO group II anovulatory women and can not be equated to WHO group II anovulatory women either.

66. Assuming, for the sake of the argument, that the skilled person would consider document (D1), when faced with the technical problem formulated above, the board notes that document (D1) fails to disclose or suggest the point in time when FSH should be stopped and administration of LH started according to claim 1. Thus, document (D1) discloses in the right hand column of page 231, last paragraph, that: "Although our data show that LH is capable of maintaining the maturation of follicles with diameters of 14 mm, the actual stage of follicular development when LH can sustain follicular development in the presence of declining serum FSH concentrations is not known." In the same paragraph, further down, document (D1) discloses that "FSH treatment was arbitrarily discontinued when one or more follicles reached a diameter of 14 mm." Finally, in the paragraph bridging pages 231 and 232 document (D1) states that: "Although studies in human have indicated that LH receptors are present on the granulosa cells by the midfollicular phase (day 7) and increased throughout the late follicular phase, the exact size at which a follicle becomes LH responsive is not known". The board concludes from the above that, even if the skilled person could have considered the teaching of document (D1), it is not established that he would have arrived at the appropriate time point for the administration of LH in WHO group II anovulatory women with a reasonable expectation of success.

67. Document (D19) discloses that FSH can be used to stimulate folliculogenesis in WHO Group II patients (see page 3, right hand column, fourth paragraph).

Document (D19) moreover teaches that high levels of LH at the start of stimulation are undesirable (see page 3, left hand column, first paragraph). Document (D19) does however not disclose or suggest that LH should be administered starting in the mid- to late-follicular phase in WHO group II anovulatory women. Accordingly, the skilled person would not have arrived at the claimed solution by combining the teaching of documents (D5) and (D19).

68. Document (D2) relates to a dose finding study on rLH to support rFSH induced follicular development in LH-FSH-deficient anovulatory women, i.e. in women belonging to WHO group I anovulatory women. Document (D2) discloses administration of LH together with FSH from the beginning of the treatment of WHO Group I anovulatory women (see abstract). Therefore, the skilled person would not obtain any hint from document (D2) to start the administration of LH only in the mid- to late-follicular phase in WHO group II anovulatory women.

69. The appellant submitted that document (D2) also suggested that LH at higher concentrations could be used to achieve folliculogenesis of fewer follicles (page 1512, left hand column, second full paragraph). However the board notes that document (D2) also discloses that this is a hypothesis which requires further investigation (ibid.). Under these circumstances, even if it might have been obvious to try in the light of document (D2), to use LH to reduce the number of growing follicles - no case has been made out that the skilled person had also a reasonable expectation of success.

70. In summary, the board concludes that none of the documents relied on by the appellant suggests that LH should not be administered in WHO group II anovulatory women until the mid- to late-follicular phase was reached. Already for this reason alone, none of the documents provides any hint that would have motivated the skilled person to modify the teaching in the closest prior art document (D5) so as to arrive at the claimed invention in an obvious manner. The above considerations in respect of claim 1 apply also to the subject-mater of claim 2 which is dependent on claim 1. For these reasons auxiliary request 5 complies with the requirements of Article 56 EPC.