T 0239/16 - Clinical trial document kills patent

Key points

• The Board decides that a patent for a second medical use lacks inventive step over D55, the patient consent form of the clinical trial.
• " In view of the fact that D55 was handed out to people who were encouraged to discuss its contents with anyone, the board comes to the conclusion that the contents of D55 have been made available to persons neither being bound by any confidentiality agreement nor being in a special relationship to the study sponsor who are thus to be classified as members of the public." The physician involved with the trial had declared that he hald told the patients " that, before signing the form, they should openly discuss the treatment referred to in the document with anyone, including their family and family doctor. " (document D57, filed by Opponent 5 on 01.06.2015,  from litigation in Australia).
• D55 discloses all features of claim 1, except the feature that the treatment is effective. However, that feature does not provide for inventive step.
• " The set-up of the clinical study of D55 thus creates an expectation of success for the treatment of osteoporosis with zoledronic acid administered once yearly. That expectation is not diminished by any disclosure of the prior art [the Board reviewed the cited documents in its decision]. A person skilled in the art would therefore follow a dosage regimen as disclosed in D55 for the once-yearly study arm when aiming at an effective treatment of osteoporosis and would thus arrive at the subject-matter of the independent claims of the main request." 
• In the preliminary opinion, also priority was discussed, and the Rapporteur had raised the issue whether the EPO is competent to examine the validity of transfer of priority. This was followed by submissions of the party about priority, including a legal opinion of Prof. Strauss. This issue is not discussed anymore in the present decision. 
• The parent patent EP1296689 has been subject of the NL Supreme Court decision ECLI:NL:HR:2017:692. The patent familiy was subject of litigation in numerous countries.

EPO T 0239/16 -  link

4. Public availability of document (55)

It was disputed amongst the parties whether document (55) formed part of the state of the art pursuant to Article 54(2) EPC.

Document (55) is entitled "Information for the patient concerning the study 42446 02 041". It consists of six pages numbered 1/6 to 6/6. In the introductory lines the following is stated: "Dear Madam, We would like to ask you to read the following information so that you understand the study you are asked to participate in and so that you may decide whether or not to participate... You were diagnosed with a reduced density of the bone. The medical term for this is Osteoporosis." Pages 1/6 to 3/6 give information about the objective of the study, explain the set-up of the study including details of the treatment to be given, provide information on possible benefits, risks and discomforts, and discuss contra-indications. Page 4/6 relates to other, alternative treatments, insurance conditions and confidentiality arrangements concerning patients' medical data. In the last paragraph of page 4/6 actual participation in the study is addressed. Page 5/6 relates to the information provided to the patient's general physician. The last paragraph on page 5/6 reads: "Thereafter, you must decide whether or not you would like to participate in the study. If you decide to participate, you shall be asked to sign the next page. You shall receive a photocopy of this or a second, signed copy." Finally, page 6/6 can be summarised as representing the patient consent form, comprising statements of the patient and the physician and their signatures.

From the information that is directly obtainable from document (55) it can thus be derived that it was addressed to a number of patients suffering from osteoporosis who were asked to participate in study 42446 02 041.

Document (57) is an affidavit signed by Prof. Verbruggen. On page 2, in points 2 and 3, Prof. Verbruggen indicates that he was a clinical investigator for Novartis study 42446 02 041 and that he supervised about five patients from start to finish on the basis of a fully prepared protocol provided by the Novartis study. In point 4 he confirms that a copy of the document labelled "LV-1" annexed to his affidavit (see part of document (57) corresponding to document (55)), had been handed out to his patients. He also provided one signed version of page 6/6, with the name of the patient redacted and her signature partly removed (part of document (57), labelled "LV-2"; see point 5).

Thus, document (55) was received by patients, i.e. women suffering from osteoporosis, in the context of their participation in the study. This was not contested by the appellant-proprietors.

The essential question to be answered is therefore whether the recipients of document (55) are to be considered members of the public within the meaning of Article 54(2) EPC.

It has not been argued by the appellant-proprietors that there was an explicit confidentiality agreement between the study sponsor and these patients or an obligation to maintain confidentiality (under national law). It remains to be seen whether there existed a special situation or some special relationship between the sponsor of the study and the patients having the consequence that the patients, as recipients of the information provided in document (55), cannot be considered members of the public due to an implied obligation to maintain confidentiality.

Of particular importance in this context is Prof. Verbruggen's affidavit (document (57)). In point 6, he stated that he had explained the contents of LV-1 to his patients and told them that, before signing the form, they should openly discuss the treatment referred to in the document with anyone, including their family and family doctor. Then he stated: "Indeed, I encouraged my patients to do so. That is without any obligation of confidentiality."

The facts given in Prof. Verbruggen's affidavit were not disputed by the appellant-proprietors, and the board sees no reason to question them. Thus, from the information that can be gained from the affidavit it is clear that his patients participating in the study were actively encouraged to discuss the contents of document (55) with "anyone".

The term "anyone" includes people who cannot be considered to be in a special relationship with the patient, let alone with the study sponsor, such as friends and other patients suffering from the same or similar conditions, as submitted by the appellant-opponents. There is thus no pointer to a special situation that would lead to the conclusion that the patients were under an implied obligation to keep the information contained in document (55) secret. Quite to the contrary, the recipients of the information were given the impression by its donor, i.e. the study sponsor via Prof. Verbruggen, that they were free to disseminate it further without restriction. Nor was this in conflict with the information that they could derive from document (55), since the section relating to confidentiality on page 4 addressed a different issue, namely the protection of the patients' data, and there is nothing else in document (55) to suggest that particular information contained therein should be kept secret.

The decisions cited in this context by the appellant-proprietors do not further support their case. The board agrees with the principle that information cannot be regarded as made available to the public for the purpose of Article 54(2) EPC and that the recipient of that information cannot be regarded as a member of the public if at the time of receipt of the information he is in some special relationship to the donor of the information (cf. T 1081/01, Reasons 7, and T 1057/09, Reasons 5.13). However, each case has to be assessed on its own facts, and in the circumstances of the present case the board does not acknowledge the existence of such a special relationship.

It is established case law that if a single member of the public who is not under an obligation to maintain secrecy has the possibility to access particular information, this information is considered as being available to the public within the meaning of Article 54(2) EPC. In view of the fact that document (55) (or its respective country/language version, see "LV1" of document (57)) was handed out to people who were encouraged to discuss its contents with anyone, the board comes to the conclusion that the contents of document (55) have been made available to persons neither being bound by any confidentiality agreement nor being in a special relationship to the study sponsor who are thus to be classified as members of the public.

5. Novelty

5.1 Document (6) [...]

5.2 Document (55)

In document (55), after an introduction identifying the disease as osteoporosis and the active agent as "Zoledronate", the objective of the study is set out: "The objective of this study is to check if Zoledronate is an effective product in the prevention of bone loss in patients with post-menopausal Osteoporosis. Five different doses of Zoledronate shall be compared and it shall be determined what dose delivers the best result" (page 1/6, "Objective of the study"). The study is performed double-blindly, including a placebo arm in addition to the five study arms. From page 2/6 it can be derived that the five study arms include three arms in which different doses of zoledronate are administered at intervals of three months, one arm in which 2 mg zoledronate is administered at an interval of six months and one arm in which 4 mg zoledronate is administered at an interval of one year. The medication is injected intravenously.

The appellant-proprietors argued that the skilled person would not have expected any effective therapeutic treatment with the last study arm, i.e. the arm concerning once-yearly administration. That arm could have been included in the study for determining other effects, such as the point in time when the biomarkers start to drop. It is thus necessary for the board to carefully study document (55) to see if a conclusion can be drawn on the study sponsor's aim in including the five study arms discussed above.

In document (55) the five study arms are presented in exactly the same manner, being listed under five bullet points (page 2/6). This section of document (55) is followed, without a bullet point and thus clearly separated from said presentation, by a statement concerning the administration of the placebo. The five study arms are designed in a way that allows for data on efficacy to be obtained for different doses and for different dosing intervals. There are three study arms with different doses and three-monthly intervals, varying the dose while keeping the interval constant. The two further arms are also logically placed within the set-up of the study. Following the study arm relating to 1 mg zoledronate every three months, there is a study arm for 2 mg zoledronate every six months and a study arm for 4 mg zoledronate once a year. These arms keep the total dose administered per year constant and vary the administration frequency. From the information and the way the information is presented in document (55) the board cannot conclude that the study sponsor included any of the five arms for reasons other than studying the effectiveness of the treatment. Also, there is no indication that one study arm was considered from the outset to be unlikely to lead to a successful therapeutic treatment. The possible and probably also actual wish of the study sponsor to observe the occurrence of certain biomarkers over time is not contradictory to this conclusion. Similar considerations apply to the post-study treatment scheme: The fact that a post-study treatment scheme comprising administration of zoledronate every three months is offered does not provide an indication that the study sponsor considered that the study arms for twice-yearly and yearly administration would fail. Each of the five study arms is equally presented and consequently seriously contemplated by the study sponsors of document (55).

In summary, it can be concluded that document (55) relates to the treatment of post-menopausal osteoporosis in human females, using, inter alia, 4 mg zoledronate, and administering said dose by single intravenous injection once-yearly (at the beginning of the study running for one year). There is however no disclosure of any effect, i.e. the effective treatment of osteoporosis, in document (55) itself.

In the present case the next step involves analysing whether the effect discussed above would arise with certainty from the treatment as described in document (55), i.e. whether the disclosure of document (55) has to be read as an implicit disclosure of the effective treatment of osteoporosis.

To provide support for the notion of an implicit disclosure the appellant-opponents have referred to documents (89), (11), (19), (20), (30) and (31).

Document (89) explains in the context of pharmaceutical aspects of clinical studies that administration of a new drug to humans is preceded by extensive pre-clinical testing both in vitro and in animals (page 342, right column, paragraph 2).

Document (11) is a textbook dealing with bisphosphonates in bone disease. The actions of the bisphosphonates as a class of compounds, especially their physico-chemical and biological effects, are described on pages 34 to 51 in the context of the pre-clinical assessment of bisphosphonates. In normal animals zoledronate has been shown to have a positive effect on mechanical characteristics in various experimental osteoporosis models (page 39, first paragraph). Zoledronate is described as being among the most potent bisphosphonates (page 40 in figure 2.3-9).

Document (19) relates to the pre-clinical pharmacology of zoledronate. Zoledronate is identified as a highly potent inhibitor of bone resorption in vitro (page 16, left column, last paragraph). Results obtained from an animal model provide a basis for speculation ("may") as to the effectiveness of zoledronate in the treatment of human post-menopausal osteoporosis (page 17, left column, paragraph 2).

Document (20) discusses the effects of zoledronate on bone loss in rat models of osteopenia. A treatment time of up to 30 days was chosen ("2.3 Experimental protocol"). In the discussion part it is stated, with reference to a prior publication, that the "particular pharmacokinetic behaviour justifies intermittent administration with prolonged treatment-free intervals" (page 85, right column, paragraph 1).

Document (30) discloses substituted bisphosphonates as active agents in the treatment of, inter alia, diseases linked to disorders in calcium metabolism, e.g. osteoporosis (claim 1, page 3, lines 21-31). Zoledronic acid is listed, among other bisphosphonates, in claim 8.

Document (31), starting on page 30, gives an update on bisphosphonates in the context of osteoporosis. On page 31 (paragraph bridging the left column and the middle column), it is suggested that high doses of a potent bisphosphonate should be given once or twice a year.

The documents cited by the appellant-opponents in this context provide no information on the use of zoledronate in humans for the treatment of osteoporosis. There is no explicit or implicit indication in any of these documents that effects of animal models or of other bisphosphonates can be directly transferred to the treatment as disclosed in document (55), i.e. to the particular dose of 4 mg, to the yearly dosing interval and to human females having post-menopausal osteoporosis. There remains a certain residual doubt that the effect, i.e. the treatment of post-menopausal osteoporosis in human females getting an intravenous dosage of 4 mg zoledronic acid once a year, is/will be achieved. Consequently, document (55) does not directly and unambiguously disclose the effective treatment of osteoporosis as defined in the independent claims of the main request.

5.3 The subject-matter of the claims of the main request is thus novel.

In the light of this conclusion it is not necessary to discuss T 2506/12, T 1859/08 and T 158/96 in this context.

6. Inventive step

6.1 The subject of the patent in suit is the therapeutic treatment of conditions of abnormally increased bone turnover, such as osteoporosis, with bisphosphonates (paragraph [0001]). The patent in suit aims at providing a convenient medicament for the treatment of osteoporosis. For this purpose the administration of a very potent N-bisphosphonate, i.e. zoledronic acid, at a very long dosing interval ([0005] and [0006]) is taught.

6.2 A possible starting point for the assessment of inventive step is document (55). The content of document (55) is discussed in detail in point 5.2 above. The five study arms are presented in the same manner. Each can be seen as a valid starting point. In the present case, the board considers the last study arm pertaining to once-yearly administration as the most promising starting point for the assessment of inventive step.

6.3 As can be seen from the discussion under point 5.2 above, the difference between the disclosure of document (55) and the subject-matter of claims 1 and 2 of the main request lies in the failure of document (55) to directly and unambiguously disclose the effective treatment of osteoporosis.

Consequently, the technical problem to be solved in view of the once-yearly arm as starting point in document (55) is the provision of an effective treatment of osteoporosis.

6.4 The board considers that the data presented in example 5 of the patent in suit provides evidence that the problem has been solved, at least for post-menopausal osteoporosis. This has not been contested by the appellant-opponents.

6.5 Obviousness

As already stated under point 5.2 with regard to the content of document (55) in the context of novelty, a certain doubt remains as to whether the yearly treatment arm leads to an effective treatment of osteoporosis. The question to be answered is thus whether this doubt would diminish the skilled person's expectation of success for this yearly treatment arm.

The board considers that the mere fact that an active agent selected from the group of bisphosphonates is being tested in a clinical study for the treatment of osteoporosis (as disclosed in document (55)) leads to an expectation of success, due to the fact that clinical studies are based on data obtained by pre-clinical testing both in vitro and in animals and require authority approval which takes ethical considerations into account. This means in the present case that the skilled person would expect all study arms to treat osteoporosis effectively, unless he was dissuaded from this by the prior art

Several documents have been invoked by the parties in this context. It is necessary to establish whether any of the documents cited by the parties would lead the skilled person to expect the once-yearly study arm to fail.

The contents of documents (6), (11), (19), (20), (30) and (31) have been discussed under point 5. Document (6) does not deal with the treatment of osteoporosis. The skilled person would understand from the disclosure of document (11) that the various bisphosphonates cannot be directly compared and that the results obtained with one bisphosphonate cannot be directly extrapolated to another bisphosphonate. However, the skilled person would also learn from document (11) that zoledronate is expected to act generally as a member of the group of bisphosphonates, i.e. like all other bisphosphonates zoledronate is expected to be effective in the treatment of osteoporosis. This is in line with general expectations raised by the pre-clinical studies and the studies on animal models in documents (19) and (20). Documents (30) and (31) are very general in their disclosure. However, they do not contain any indication that zoledronate would not be useful for once-yearly administration in the treatment of osteoporosis.

A brief analysis of some of the further documents needs to be carried out:

[...]

To summarise, several documents assess the efficacy of therapeutic treatment with bisphosphonates, in one form or another, by assessing either biomarkers or BMD, after several months of dosing. There is no indication whatsoever in the prior art suggesting that zoledronic acid would behave differently in principle than the tested bisphosphonates. While there is no teaching in the prior art that clearly indicates that zoledronic acid is effective in the treatment of osteoporosis when given once yearly, there is on the other hand no indication either that such treatment would fail. It might even be said that in general for bisphosphonates, which also include zoledronic acid, there was speculation about persistent effects lasting at least 12 months.

The set-up of the clinical study of document (55) thus creates an expectation of success for the treatment of osteoporosis with zoledronic acid administered once yearly. That expectation is not diminished by any disclosure of the prior art. A person skilled in the art would therefore follow a dosage regimen as disclosed in document (55) for the once-yearly study arm when aiming at an effective treatment of osteoporosis and would thus arrive at the subject-matter of the independent claims of the main request.

Consequently, the subject-matter of the independent claims of the main request does not involve an inventive step (Article 56 EPC).

6.6 Further arguments

The board agrees with the appellant-proprietors that the mere fact that a clinical study is performed does not as a rule mean that the particular therapeutic effect is always achieved, in line with decision T 158/96. That decision, however, addresses novelty rather than inventive step. For the assessment of inventive step, certainty as to the outcome of a clinical study is not necessary.

The appellant-proprietors invoked decision T 293/07 in support of their argument that tests on humans are not routine approaches. The present situation, however, cannot be compared with the situation arising in case T 293/07, since document (55) already relates to human testing, whereas in T 293/07 the closest prior art relied on animal tests where ischemic incidents were produced in mice by suppressing blood flow to the brain. Also, the mode of administration varied between the claimed subject-matter (peripherally) and the closest prior art (direct administration intraventricularly). In the present case no modifications to the teaching of the closest prior art necessitating further routine tests leading to a "try-and-see" approach are required. Unlike the situation underlying decision T 293/07, the only remaining question relates to the residual doubt as to the outcome of the clinical study of document (55).

The present situation furthermore differs from the one underlying decision T 715/03, also cited by the appellant-proprietors, in that, unlike the situation in T 715/03, animal models for osteoporosis exist and in that zoledronic acid has been successfully tested in those animal models (see document (20)). Furthermore, again unlike the situation in T 715/03, zoledronic acid belongs to the chemical class of substituted bisphosphonates, which are established drugs in the treatment of osteoporosis (see documents discussed above), whereas in T 715/03 the active agent had a chemical structure and belonged to an activity class that was remote from the active agents known to treat the disease under consideration.

The appellant-proprietors argued that, unlike the situation in case T 2506/12, in the present case there was only pre-clinical evidence that the active agent, zoledronic acid, could be effective in the treatment of osteoporosis.

The board refers to point 5.2 above, in which the fact that zoledronic acid has not yet been shown to be effective in humans is exhaustively discussed. The board holds that there remained a residual doubt that the desired treatment would be obtained, which however did not diminish the prospects of success to such an extent that the reasonable expectation turned into a mere "hope to succeed". Clinical trials in humans are planned scientific investigations. They require authority approval, which is only given after a risk/benefit evaluation. For ethical (but also economic) reasons it has to be ensured that research risks are minimised and are reasonable in relation to any potential benefits. Ethical and economical considerations require that the "benefit" will arise with reasonable certainty and will not only "be hoped for". This has to be taken into consideration as part of the technical circumstances when assessing the level of confidence of the skilled person in making rational predictions about achieving the envisaged treatment. Consequently, even though the circumstances are different from those of case T 2506/12, that does not automatically mean that an inventive step is to be acknowledged.

The appellant-proprietors pointed to the importance of assessing biomarkers. They explained that BMD and fracture incidences would only become of serious interest once an effective treatment had been established. The board cannot accept this argument. The three parameters under consideration, i.e. biomarkers, BMD and fracture incidences, show the effect at different levels, i.e. at the biochemical level of bone formation and resorption, at the physiological level representing the results of the biochemical processes, and finally at the clinical level corresponding to the practical aim of the treatment. Effective therapeutic treatment can be and is assessed at all three levels, as argued by the opponents and evidenced inter alia by documents (9), (10), (20), (27), (31) and (46). The board has thus taken all three parameters into account.

7. Auxiliary request 1

Claim 1 of auxiliary request 1 is identical to claim 1 of the main request. The same conclusions as for claim 1 of the main request apply. The subject-matter of claim 1 of auxiliary request 1 is novel but does not involve an inventive step.

Order

For these reasons it is decided that:

1. The decision under appeal is set aside.

2. The patent is revoked.