T 1680/17 - Fulvestrant formulation

Key points

• In this opposition appeal (whith parallel national litigation), claim 1 is for a second medical use of fulvestrant for the treatment of breast cancer with intra-muscular injection with distinguishing feature over D4 that fulvestrant is formulated with ehtanol, benzyl alcohol, benzyl benzoate, and castor oil. The gist is that this combination of solvents allows for a high concentration of fulvestrant and hence a small volume for injection. D4 is silent about the cosolvents in the "castor oil-based vehicle" used therein. 
• D1 is a scientific article using in one of the examples the precise formulation of fulvestrant according to claim 1. D1 " aims to elucidate mechanisms underlying an acquired tamoxifen resistance in the therapy for estrogen receptor-positive breast cancer". 
• The objective technical problem in view of D4 is therefore, according to the Board: "The technical problem is the provision of a castor oil-based vehicle for a fulvestrant containing composition allowing for treatment of breast cancer by intramuscular injection." 
• The Board finds that the use of the formulation of D1 is not obvious. " However, the purpose of [D1] is the elucidation of a biochemical mechanism. [D1]  does not aim at the provision of a therapy." 
• " Firstly, [D1] is a scientific paper dealing with basic research. The board considers that the skilled person would not have turned to formulations used in basic research when aiming at providing a formulation for therapeutic treatment. The requirements of a formulation to be used in basic research are fundamentally different from the requirements of a formulation to be administered to a patient. While in basic research merely the availability of the active at the test site is of relevance, in a clinical situation aspects such as safety/tolerability and bioavailability over the treatment period are decisive factors." 

EPO T 1680/17 -  link

II. Independent claim 1 of the patent in suit as granted reads as follows:

"1. A pharmaceutical formulation for use in the treatment of breast cancer by intra-muscular injection,
wherein the pharmaceutical formulation comprises fulvestrant,
a pharmaceutically-acceptable alcohol being a mixture of 10 % weight of ethanol per volume of formulation and 10 % weight of benzyl alcohol per volume of formulation,
and the formulation contains 15 % weight of benzyl benzoate per volume of formulation
and a sufficient amount of a ricinoleate vehicle so as to prepare a formulation of at least 45 mgml**(-l)of fulvestrant,
wherein the ricinoleate vehicle is castor oil, and wherein the total volume of the formulation is 6 ml or less."

Reasons for the Decision

4. Novelty (Article 100(a) and Article 54(1) EPC)

Document (1) [McLeskey et al.,] does not provide a direct and unambiguous disclosure of the feature of intramuscular injection and is thus not novelty-destroying for the subject-matter of claim 1.

Respondent 1 has argued that the skilled person would have understood the disclosure of document (1) as referring to intramuscular administration. The board cannot accept this line of argument since document (1) discloses the formulation under consideration solely for animal studies. In animal studies a subcutaneous administration is a common mode of administration which is, however, distinct from intramuscular administration. Therefore, intramuscular administration is not directly and unambiguously disclosed.

The board notes that document (1) does not disclose any concrete formulations in the context of the therapeutic treatments discussed in the passages of the "introduction" (page 697, right column, first paragraph to page 698, left column, first paragraph).

The ground for opposition under Article 100(a) and Article 54 EPC does therefore not prejudice the maintenance of the patent.

5. Inventive step (Article 100(a) and Article 56 EPC)

5.1 Preliminary remarks

The boards of appeal of the European Patent Office generally apply the problem-solution approach to assess inventive step. In accordance with the problem-solution approach, it is first necessary to identify the closest prior art, then to determine in the light of the disclosure of the closest prior art 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. The problem-solution approach was developed to ensure an objective assessment of inventive step and to avoid ex post facto analysis of the prior art (see "Case Law of the Boards of Appeal of the EPO", 8th edition 2016, I.D.2).

5.2 Closest prior art

5.2.1 The decision under appeal relies on document (4) [Howell et al.] as the closest prior art. Furthermore, all respondents have chosen document (4) as the closest prior art. Document (4) is thus the only document that has been invoked as the starting point for the assessment of inventive step in the appeal proceedings.

The patent in suit is based on the premise that oestrogen deprivation is fundamental to the treatment of many benign and malignant diseases of the breast and reproductive tract (paragraph [0002]) and consequently provides a sustained release pharmaceutical formulation comprising fulvestrant for the treatment of breast cancer (paragraph [0001]). Document (4) relates to the same problem.

5.2.2 Document (4) concerns the pharmacokinetics, pharmacological and anti-tumour effects of the specific anti-oestrogen ICI 182780 in women with advanced breast cancer (title). ICI 182780 is fulvestrant. The agent was administered as a monthly depot intramuscular injection. Out of the 19 patients participating in the study, 13 responded, seven of which had partial responses while the other six had "no change" responses (abstract). No serious drug-related adverse events were reported. The formulation was well tolerated locally at the site of injection (page 303, "Side-effects"). Of the 19 patients treated, five patients were still in remission and continued treatment after 30-33 months (page 304, "Response"). There was evidence of drug accumulation after multiple dosing, such that after 6 months of treatment, there was an 80% increase in mean end of month drug levels and a 50% increase in the AUC compared with data from month 1. These data were interpreted as suggesting that lower doses of drug may be effective in maintaining therapeutic serum drug levels (page 305, left column, paragraph 3). In the section "Study design", on page 301, right column, first paragraph, information relating to the administration of fulvestrant can be found. It is stated that "ICI 182780 was administered as a long-acting formulation contained in a castor oil-based vehicle by monthly i.m. injection (5 ml) into the buttock. For appraisal of drug safety, the first four patients received escalating doses of ICI 182780, starting with 100 mg in the first month and increasing to 250 mg i.m. from the second month onwards, following confirmation of lack of local or systemic drug toxicity at the 100 mg dose". This passage provides information on the administration mode, i.e. intramuscular, the administered volume, i.e. 5 ml, the amount of active, i.e. 250 mg, and gives an indication that the vehicle comprises castor oil. No further information is given on other excipients.

In document (4), there is thus no disclosure of the complete formulation used in the clinical study. Information on further excipients is not provided, i.e. is not been made available to the public.

5.2.3 Next, the consequences of the missing information must be assessed.

In the absence of a disclosure of the complete formulation used in the study, the study cannot be directly reworked, i.e. reproduced. The question to be answered in the context of the problem-solution approach is: What exactly had been made accessible to the skilled person?

To answer this question, the link between formulation and effects must be examined. The literature cited in this respect mainly relates to the side effects due to the presence of excipients. Of particular relevance is document (9). Entitled "Castor Oil as a Vehicle for Parenteral Administration of Steroid Hormones", document (9) discusses the use of co-solvents to render castor oil-based steroid formulations suitable and acceptable for parenteral administration.

The initial consideration to be made according to document (9) is the solubility of the active in the vehicle. The high concentrations of active in solution sought by the clinicians required the addition of co-solvents to castor oil (abstract, paragraph bridging pages 893 and 894). The skilled person would thus have been aware that the physical state of a formulation, i.e. the form of solution or suspension, was linked to the amount of active and the specific solvents/co-solvents used. Furthermore, it was common general knowledge that the physical state of a formulation had an influence on the bioavailability of active agents.

The authors of document (9) then point to the fact that the presence of side effects is linked to the specific formulation. On page 894, left column, second paragraph, it is stated that the irritative response depended on the particular hormone, its concentration in the formulations, and/or the composition of the vehicle. As can be seen in the data presented in tables V and VI, different vehicles were acceptable for 17-hydroxyprogesterone caproate and for estradiol valerate. While a vehicle comprising 58% castor oil, 40% benzyl benzoate and 2% benzyl alcohol was accepted for estradiol valerate (adverse reactions in 2.67%), the same vehicle was rejected for 17-hydroxyprogesterone caproate (adverse reactions in 23.2%).

The skilled person would thus have been aware, when reading in document (4), page 303, right column, second paragraph, that the formulation of fulvestrant used appeared well tolerated locally at the site of injection and that such a good tolerance was not to be expected for any castor oil-based fulvestrant formulation. Or, put another way, the skilled person would have had in mind that the lack of side effects would have been due to a particular formulation, including a certain amount of a certain active in combination with certain excipients in certain concentrations. In sum, there is strong evidence in the literature that side effects are linked to specific formulations. There is no reason to believe that other effects, e.g. effects in the context of efficacy of treatment, would not be similarly linked.

This finding must be reflected in the assessment of the overall information obtainable from document (4). Based on the foregoing, the disclosure of document (4) would have told the skilled person that:

- Fulvestrant was a potent agent in the treatment of breast cancer.

- Intramuscular administration was a suitable mode of administration.

- A vehicle of choice would contain castor oil.

When using document (4) as the starting point in the assessment of inventive step, i.e. as the closest prior art, the next steps of the problem-solution approach must therefore be based only on the disclosure as set out above.

5.2.4 The fact that the missing information does not concern only the formulation as such but also the achievability of the effects described in document (4) has direct consequences on the correct formulation of the technical problem.

5.3 Technical problem

5.3.1 The following technical problems have been formulated by the parties:

Appellant [proprietor]:

The problem is to provide a fulvestrant formulation - for the first time - that is suitable for treating breast cancer, i.e. that is effective and safe and shows an even release of therapeutically significant fulvestrant levels over a prolonged period of time following intramuscular injection.

Respondent 1:

The problem resides only in the provision of a castor oil-based fulvestrant injection formulation allowing solubilisation of a higher concentration of fulvestrant for a complete monthly dose of around 250 mg to be solubilised in the recommended injection volume for intramuscular administration of no more than 5 ml in a single injection.

Respondents 2 and 5:

The problem is to provide a fulvestrant formulation based on castor oil, containing fulvestrant in a concentration of 50 mg/ml and being suitable for intramuscular administration.

Respondent 3:

The problem is to provide an exact formulation based on castor oil and having 50 mg/ml fulvestrant.

Respondent 4:

The problem resides in the provision of a castor oil-based formulation suitable for administration of 250 mg fulvestrant by intramuscular administration of 5 ml.

5.3.2 For the following reasons, the board cannot adopt any of these wordings.

The board concurs with the respondents that the inclusion of the terms "safe and effective" for characterising the treatment of breast cancer is meaningless in the absence of a certain "level" or "benchmark" qualifying these terms. The terms "treatment of breast cancer" are taken to imply that patients with breast cancer benefit from the administration of the formulation under consideration, i.e. that the administration of the formulation has a positive influence on their condition in the absence of intolerable side effects.

However, having come to the conclusion that the achievement of effects is linked to the actual formulation (see point 5.2.3 above), the therapeutic indication as such must be part of the technical problem.

Document (4), on two occasions (first on page 305, left column, third paragraph, and second in the concluding remarks on page 306, right column, last paragraph) discloses that drug accumulation has been observed in the patients. Drug accumulation is generally not considered favourable by the skilled person. It is thus questionable whether the skilled person would have limited themselves exclusively to formulations comprising 50 mg/ml or 250 mg total dose when starting from document (4) as the closest prior art. Consequently, the concentration or dose of fulvestrant must not be included in the formulation of the technical problem.

5.3.3 The technical problem is thus as follows:

The technical problem is the provision of a castor oil-based vehicle for a fulvestrant containing composition allowing for treatment of breast cancer by intramuscular injection.

5.4 Solution of the technical problem

The patent specification provides the information that the claimed fulvestrant composition, upon intramuscular administration, leads to plasma levels which are considered effective (see figure 1 of the patent in suit). In paragraph [0049] it is stated that there was no evidence of precipitation of fulvestrant at the injection site. It is thus plausible that the claimed formulation leads to the treatment of breast cancer. This has not been contested by the respondents.

5.5 Obviousness

In the following it will be examined whether the solution as defined in claim 1 of the main request was obvious. One point arising in this context is the skilled person's expectation of success. It will thus be examined, inter alia, whether the skilled person, in the expectation of solving the technical problem, would have arrived at the claimed subject-matter, in particular, at the claimed fulvestrant formulation.

5.5.1 Two approaches will be analysed in detail. The first approach focuses on the knowledge of the skilled person in view of the preparation of a castor oil-based intramuscular formulation containing a steroid as an active agent. The second approach considers the state of the art concerning the formulation of the active agent under consideration, i.e. fulvestrant. Document (7), fulfilling both criteria, will be addressed in the second approach.

5.5.2 Various documents deal with castor oil as solvent for steroids in the context of parenteral administration, some also explicitly in the context of intramuscular administration.

Documents (9) and (63) have extensively been discussed by the parties in this context. Document (9) is silent on fulvestrant. It relates to castor oil-based vehicles for parenteral administration of steroid hormones (title). Castor oil is combined either with benzyl alcohol at 2 to 5%, benzyl benzoate at 20 to 50% or with both. Tables V and VI show that different vehicles were acceptable for 17-hydroxyprogesterone caproate and for estradiol valerate. While a vehicle comprising 58% castor oil, 40% benzyl benzoate and 2% benzyl alcohol was accepted for estradiol valerate, the same vehicle was rejected for 17-hydroxyprogesterone caproate.

The respondents have furthermore invoked Appendix A of document (63) listing several commercially available oil-based solutions for parenteral administration.

Document (45), a textbook on pharmaceutical technology, discusses solvents and dispersing aids in parenteral formulations. It lists solvents, including castor oil, ethanol, benzyl benzoate and benzyl alcohol, for parenteral formulations and provides indications for their concentrations, including, however, both hydrophilic and lipophilic vehicles (table 5.22). Although combinations of alcohols are suggested, no details on such combinations are disclosed (page 552, last paragraph).

Document (47) lists solvents for peroral, parenteral and cutaneous administration. This list includes, inter alia, ethanol, said to be suitable in concentrations up to 30% for all three modes of administration; castor oil, also suitable for all three modes of administration; and benzyl benzoate, listed only for parenteral administration without any indication as to its concentration. Ethanol is listed as being miscible with castor oil, benzyl benzoate is to be used exclusively in mixture with an oil, especially in mixture with sesame oil (table on pages 83 and 84). No concrete formulation is disclosed.

Document (48), comprising entries in the Martindale Pharmacopoeia, provides excerpts on various drugs. It shows that intramuscular formulations may contain one or more of the excipients under consideration. No formulation comprising a combination of castor oil, ethanol, benzyl benzoate and benzyl alcohol is disclosed.

Document (65), a textbook entitled "Injectable Drug Development", discusses various aspects of co-solvents. A list of co-solvent compositions for various formulations is shown in table 11-1. It can be seen that mixtures of ethanol and benzyl alcohol are mainly used in aqueous-based formulations for intravenous administration. The importance of the selection of appropriate co-solvents is stressed. On the one hand co-solvents are considered powerful tools for providing the required solubility (page 217, first and third paragraph). On the other hand, they may cause side effects (page 245, second paragraph and page 414, second paragraph).

It is, however, not clear to what extent these passages can be applied to fulvestrant. As acknowledged by all parties, fulvestrant is difficult to formulate. Not all general guidelines for steroids can be applied directly to fulvestrant. Document (21), for example, teaches to add benzyl benzoate to castor oil to increase the solubility of the active agent in the form of a steroid (page 192, paragraph 4, last three lines), and document (15) provides guidance to generally use benzyl benzoate in formulations for intramuscular administration at concentrations of 0.01 to 46.0% (page 38, left column, middle paragraph). Fulvestrant is however less soluble in benzyl benzoate than in castor oil. A skilled person would have had no incentive to add a worse solvent to increase solubility.

Furthermore, the documents relied upon by the parties in this context do not suggest using a combination of the three co-solvents/excipients ethanol, benzyl benzoate and benzyl alcohol.

In sum, the documents considered above do not point towards a formulation for intramuscular administration of a steroid having the claimed combination of excipients in the required concentrations. Such a combination would thus not have been rendered obvious by common general knowledge.

5.5.3 Several documents refer to fulvestrant formulations. However, only two of these documents disclose complete formulations. While documents (5) ("castor oil based vehicle"), (10) (ethanol spiked into peanut oil), (11) (no information on vehicle) and (14) (propylene based vehicle) mention fulvestrant formulations, they do not disclose a complete castor oil-based formulation. Complete castor oil-based fulvestrant formulations are disclosed in documents (1) and (7).

Document (7) deals with various steroids. Example 3 relates to a formulation of fulvestrant for intramuscular administration. The formulation comprises fulvestrant, benzyl alcohol and castor oil in certain concentrations. Although breast cancer is not mentioned in document (7), the document relies on the anti-estrogenic effects of its actives. This can also be seen from example 3, which describes that the/a "uterus test" is carried out. In sum, document (7) discloses a formulation that could have been adopted by the skilled person. The formulation was, however, rejected by the inventors of the patent in suit (see paragraph [0014] of the patent in suit relating to the US family member of document (7)).

The only other concrete composition comprising fulvestrant to be found in the cited documents is described in document (1), which is a scientific paper. Document (1) is titled: "Tamoxifen-resistant Fibroblast Growth Factor-transfected MCF-7 Cells Are Cross-Resistant in Vivo to the Antiestrogen ICI 182,780 and Two Aromatase Inhibitors". It aims to elucidate mechanisms underlying an acquired tamoxifen resistance in the therapy for estrogen receptor-positive breast cancer (abstract). To find information underlying the mechanism(s) or tamoxifen resistance, FGF-transfected MCF-7 cells were used. Such cells do not rely on an estrogen receptor based mechanism and thus allow for the examination of other pathways. There is no doubt that treatment, or rather the failure of treatment, of breast cancer by tamoxifen, is the cause of the experiments on which document (1) is based. However, the purpose of document (1) is the elucidation of a biochemical mechanism. Document (1) does not aim at the provision of a therapy.

In the context of these mechanistic studies, four drugs, ICI 182,780 (fulvestrant), 4-OHA (4-hydroxyandrostenedione), letrozole and tamoxifen, were used in 5 different vehicles. Fulvestrant was used in two different vehicles. Firstly, powdered fulvestrant was dissolved in ethanol and spiked into peanut oil. Secondly, preformulated drug in a vehicle of 10% ethanol, 15% benzyl benzoate, 10% benzyl alcohol, brought to volume with castor oil was used. The latter formulation is said to have been provided by "B. M. Vose (Zeneca Pharmaceuticals)". The two fulvestrant formulations were administered subcutaneously at a dose of 5 mg in 0.1 ml of vehicle every week. For the experiments depicted in figure 1, the first formulation was used, while for the experiments used in figure 1, B and C, the second formulation was used. For other experiments, such as the "uterus test", which of the two fulvestrant formulations was used is not disclosed (page 698, right column, paragraph 3).

Thus, there is no doubt that document (1) discloses the use of, inter alia, a fulvestrant formulation that has the same excipients as defined in claim 1 of the main request.

5.5.4 To determine whether the claimed invention, starting from the closest prior art and the technical problem formulated above (see point 5.3.3 above) would have been obvious to the skilled person, it must be determined whether the skilled person would have used the fulvestrant formulation of document (1) which is described as "preformulated drug in a vehicle of 10% ethanol, 15% benzyl benzoate, 10% benzyl alcohol, brought to volume with castor oil". The skilled person would have used this formulation, if they had a reasonable expectation of success that it would solve the problem defined above.

5.5.5 Therefore, it is now necessary to have a closer look at the context and the detailed disclosure of document (1).

Document (1) is a scientific research paper. It pertains to the domain of basic research. References to therapeutic applications are made merely to put the basic research into context. The document aims at elucidating a mechanism of tamoxifen resistance on the level of molecular pathways, in particular, looking at whether estrogen receptor pathways are implicated. Experiments in basic research are done with formulations that primarily aim at ensuring that the compound tested will be present at the location where it was hypothesised to exert its activity. This is supported by the disclosure of document (1). After negative results were obtained for the hypothesised mechanism, the authors of document (1) went on to carry out the "uterus test" to verify whether the compounds tested (fulvestrant, 4-hydroxyandrostenedione and letrozole) could exert their activity in the test system. A formulation in basic research is thus geared to ensure that a high concentration will reach the required location. Such research requires no considerations on the pharmacologically suitable concentration, the safety and tolerability, or the suitability for administration in a clinical setting are necessary. Thus, a skilled person would have had no incentive to turn to document (1), a scientific paper dealing with basic research, to provide a formulation for administration in a clinical situation.

The respondents have pointed to the fact that document (1) cites document (4). Document (1), on page 698, left column, line 5, cites 8 references (references 13-20) relating to the response of tamoxifen-resistant patients to subsequent fulvestrant or aromatase inhibitor therapy. One of these 8 references is document (4). These references are cited in the context of considerations relating to mechanisms of tamoxifen resistance. Formulations are not even mentioned. The fact that document (4) is cited would have thus not caused the skilled person to assess the formulations of document (1) in a different way.

It has been argued that the relevant formulation of document (1) has been highlighted by three facts: Firstly, the skilled person would have considered the combination of a solvent (castor oil) with three co-solvents to be "sophisticated". Secondly, the skilled person would have been made aware that the formulation was the result of a targeted development process due to the term "preformulated". Finally, the skilled person would pay special attention to a complete formulation obtained by "Zeneca", which was known to develop a fulvestrant based medicament.

The formulation of document (1) contains three co-solvents in addition to the base oil. Commercially available steroid formulations for parenteral administration usually contain one or two co-solvents, the exception being "Syncortyl**(®)", which contains three further excipients in the form of cholesterol, benzyl alcohol and ethanol (Appendix A of document (63)). Cholesterol, having a melting point of 148°C, is not a classical "co-solvent". The commercially available compositions listed in table 1 of the patent include, at most, two further solvents (note that the two last entries of table 1 contain errors, two columns being shifted). Document (65) states on page 217, first paragraph, that co-solvents are powerful tools to reduce irritation and have advantages over other techniques for solubilisation of water-insoluble compounds. The document goes on to teach that the solubility of a compound should be maximised to lower the total amount of solvents needed and thus to reduce potential side effects (page 217, third paragraph). Reduction of pain and irritation at the injection site can be obtained by using appropriate co-solvents (page 245, second paragraph). Document (46) describes an ideal formulation as containing no excipients at all. It is however acknowledged that excipients are necessary to preserve potency, elegancy and safety. Nevertheless, extreme caution should be used in selecting proper excipients (page 462, last paragraph). Having in mind these statements, the skilled person would have had certain reservations against the use of the formulation of document (1) in a clinical setting.

The respondents have argued that the term "preformulated" would have directed the skilled person towards this composition since they would assume that this composition was the result of extensive development. This is mere speculation. The term "preformulated" in the context of document (1) simply refers to the fact that an active has been provided to the researchers in dissolved form. The reason for the provision of fulvestrant in a solvent mix, in contrast to the second part of fulvestrant used in document (1), which was obtained as a powder, is not known. Several different explanations are possible.

It does not come as a surprise that the "preformulated" formulation, as well as the powdered fulvestrant, was obtained from "Zeneca". Given the history of fulvestrant, to which the respondents have pointed several times, the obtaining of the compound from Zeneca was to be expected, since Zeneca was the company in possession of fulvestrant (after the transfer of, inter alia, the pharmaceutical sector of ICI in 1993 (AstraZeneca only being founded in 1999)). Thus, no pointer can be derived from the fact that fulvestrant was obtained from Zeneca. This view is supported by expert declaration (23) stating that active ingredients were usually obtained from the producer of the active ingredient (page 4, last paragraph).

5.5.6 Thus, having analysed document (1) in detail, a conclusion must be reached whether the skilled person, having in mind the problem defined above (see point 5.3.3), would have considered the disclosure of document (1) and adopted one of the fulvestrant formulations disclosed in it with a reasonable expectation of success of solving the problem.

The respondents have asserted that a person skilled would not have required certainty of success to adopt a certain route. The board agrees with this statement. However, in the present case, no expectation of success can be admitted by the board when assessing the approach proposed by the respondents. This absence of an expectation of success is due to the following reasons:

Firstly, document (1) is a scientific paper dealing with basic research. The board considers that the skilled person would not have turned to formulations used in basic research when aiming at providing a formulation for therapeutic treatment. The requirements of a formulation to be used in basic research are fundamentally different from the requirements of a formulation to be administered to a patient. While in basic research merely the availability of the active at the test site is of relevance, in a clinical situation aspects such as safety/tolerability and bioavailability over the treatment period are decisive factors.

Secondly, even if the skilled person would have paid particular attention to the formulations used in document (1), they would have had reservations about using a formulation having a combination of an unusually high number of excipients in unusual concentrations in a clinical trial.

Thirdly, the formulation under consideration of document (1) is not particularly preferred. This can be seen in that it was not used in all the experiments carried out in document (1).

Consequently, the skilled person would have had no reasonable expectation of success when using the formulation of document (1) in the treatment of breast cancer. Such a use would thus not have been obvious.

5.5.7 Further arguments

(a) It has been argued that the skilled person was a team of a pharmacologist and a formulator. The pharmacologist would have studied the introductory parts of document (1) and concluded that it concerns certain aspects of breast cancer. Having been pointed to document (1), the formulator would have immediately spotted the formulation under consideration for the reasons set out above.

The board cannot accept this argument. The skilled person may well be a team of specialists of neighbouring technical fields. However, in the present case, considering a pharmacologist and a formulator as suggested by the respondents, the proper "work sharing" of the team would be for the pharmacologist to identify document (4) as a promising springboard and for the formulator to look for a formulation allowing the carrying out of a therapeutic treatment. The approach adopted by the respondents can either be seen as an ex post facto analysis or as an approach taken by researchers of inventive skill.

(b) The respondents have argued that the skilled person, being aware that the formulation of document (1) had anti-estrogenic properties as shown by the "uterus test", would have had a high expectation of success when using this formulation for solving the technical problem. The anti-estrogenic properties are the properties of fulvestrant that underlie its anti-breast cancer effect.

However, document (1) discloses not one but two fulvestrant formulations. Which of the two fulvestrant formulations was used in the "uterus test" is not disclosed. Furthermore, the simple fact that an active agent has been shown to retain its known activity under animal test conditions in a mechanistic study cannot be seen as an incentive for the skilled person to use such a formulation in a clinical setting.

(c) The respondents have argued that it was usual to use similar or closely related formulations in animal studies and in clinical studies. This argument is pertinent when considering preclinical animal studies carried out to assess the treatment of a disease by a certain active. However, in the present case, the situation is different since document (1) pertains to the domain of basic research far removed from preclinical situations.

In this context, it is important to stress that the absence of an expectation of success by the skilled person is (at least in part, see above) due to the fact that document (1) is a scientific paper relating to basic research. The mere fact that animal models are used cannot be seen as a deterrent for a skilled person to consider a document in the context of therapeutic treatments, such as the animal studies mentioned in document (69). The animal studies referred to in document (69), page 58, paragraph bridging the columns, relate to pharmacological effects and anti-tumour acting in animal models, i.e. clearly to preclinical studies. However, this passage merely reports that "a variety of oil-based formulations" of fulvestrant were used.

(d) Castor oil-based fulvestrant formulations have been identified as being "prototypic" of long-acting formulations for intramuscular injection (document (34), page 245, left column). This statement is in line with the fact that document (4), i.e. the closest prior art, relies on castor oil-based fulvestrant formulations. However, no further information or pointer can be gained from the qualification of castor oil-based formulations as being "prototypic".

(e) The argument that the "The skilled person would use the formulation, because it is there" amounts to an ex post facto analysis. Although it sounds like a compelling and simple approach when having in mind the claimed formulation, it attains these attributes only with the knowledge of the claimed solution. According to established case law, it is necessary to identify objective factors which would have motivated the skilled person to combine the teaching of documents. Such a pointer cannot be seen in the fact that a formulation was merely disclosed.

5.6 The subject-matter of claim 1 of the patent in suit involves an inventive step and, therefore, the ground for opposition under Article 100(a) and Article 56 EPC does not prejudice the maintenance of the patent.

Order

For these reasons it is decided that:

1. The decision under appeal is set aside.

2. The oppositions are rejected.