T 1378/11 (Tramadol dosage/EURO-CELTIQUE) 16-09-2015

Reasons for the Decision

1. The appeal is admissible.

2. The alleged violation of the appellant's right to be heard by the opposition division.

2.1 Article 113(1) EPC states that the decisions of the EPO may only be based on grounds or evidence on which the parties concerned have had an opportunity to present their comments. This implies that a party may not be taken by surprise by the reasons of a decision, referring to unknown grounds or evidence (R 3/13 of 30 January 2014, point 2.2 of the Reasons). If a party was aware, or could have been aware, of the ground or evidence on which the assessment or reasoning of a decision was based, and had an opportunity to comment thereon, it cannot be taken by surprise. It must also be added that the right to comment does not extend to every possible assessment or reasoning in a decision (R 2/13, point 2.1.3 of the Reasons). No provision of the EPC requires the deciding body to provide a party in advance with all foreseeable reasons in favour or against a request (R 1/08 of 15 July 2008, point 3.1 of the Reasons).

The alleged new ground is to be found in the first paragraph of point 4.4.5.3 on page 15 of the contested decision. It concerns the opposition division's analysis of the data of the clinical study (pages 20 to 23 of the application as filed; paragraphs [0099] to [0107] of the patent) with respect to the issue, whether these data demonstrate a technical effect linked to the differences of the claimed subject-matter with the dosage regimen of the closest prior art document (D1). The opposition division had raised this issue in its communication of 20 September 2010 (see point 6.4.1) and the appellant commented thereon in its letter of 22 February 2011 (see pages 14-20) and filed additional documents (D18) to (D20) in support. The issue was also discussed at the oral proceedings (see page 8 of the minutes). In its decision, the opposition division dealt with the appellant's submissions regarding this issue and found the clinical data of the patent to be inconclusive. This evaluation of the appellant's evidence did not introduce any change to the factual or legal framework of the debate. It does not constitute a new ground within the meaning of Article 113(1) EPC either, since it is part of the opposition division's detailed assessment and reasoning relating to the grounds and evidence which have been put forward by the parties (as to the distinction between new grounds and reasons see R 2/13, point 2.1.3 of the Reasons). The opposition division has to evaluate the evidence before it, even in the absence of any objections from the adverse party. Such lack of objections raised cannot render the evidence conclusive.

The appellant relied on decision R 16/13 of 8 December 2014. It appears from points 5.2 to 5.4 of the reasons of said decision that the Enlarged Board of Appeal considered that the technical board had ignored the petitioner's argument that the reference to the micronisate of the invention in the comparative data provided by the petitioner implied that the respective samples had the parameters as claimed by the product claim of the main request, and that, as a consequence, the petitioner could not have been expected to have anticipated the board's view that the comparative data were deficient to show the alleged advantage. In view of the specific circumstances and the further jurisprudence of the Enlarged Board of Appeal in review cases, decision R 16/13 cannot, in the board's judgment, be understood to have given the parties the right to find out from the deciding body how it assesses the facts and arguments on which its decision will likely be based. The decision has rather to be seen in connection with the reference in decision R 3/13 of 30 January 2014 (point 2.6 of the Reasons) to the jurisprudence of the Federal Court of Justice, according to which the obligation to inform the parties only exists under German law if the parties, despite conducting the proceedings with all due care, could not foresee the legal considerations on which the court's decision might ultimately be based. This is, however, not the situation in the present case. It is established jurisprudence that, if comparative tests are chosen to demonstrate an inventive step on the basis of an advantageous effect, the nature of the comparison with the closest state of the art must be such that the alleged advantageous effect is convincingly shown to have its origin in the distinguishing feature of the invention compared with the closest state of the art, and that alleged but unsupported advantages cannot be taken into consideration in respect of the determination of the problem underlying the invention (see Case Law of the Boards of Appeal, 7th edition 2013, I.D.10.9). Since the appellant could have been expected to know this jurisprudence and since it relied on its own data, the opposition division had no obligation to warn it of deficiencies within its own responsibility. In so far as the appellant alleges that the opposition division evaluated the clinical data of the patent incorrectly, this amounts to an error in judgment only, which is open to review in appeal, and cannot be characterised as a procedural violation, let alone a substantial one.

For the above reasons, the appellant could not, on an objective basis, have been surprised by the decision in the sense that it discovered a ground for the first time in the written decision.

2.2 With respect to the alleged error in the determination of the burden of proof, the Board notes that, as a matter of principle, the legal burden of proof lies with the party who makes the assertion. The legal burden of proof that the patent is lacking inventive step thus lies on the opponent. The opponent has to show that, in the light of the state of the art it has put forward, the skilled person would arrive at the claimed invention without inventive skills. However, if the patentee relies on an improvement, the burden is on the patentee to prove that, compared with the closest prior art, there is an improvement. The mere assertion that an improvement exists is not sufficient to discharge the burden of proof. There must be at least a single experimental result showing the alleged improvement. The experimental evidence should show that the improvement is attributable to the claimed difference vis-à-vis the closest state of the art. The opponent can challenge such experimental evidence either by saying the experimental result reported is not correct, or by showing that equally valid experimental comparisons do not confirm the improvement. However, the opponent does not, as alleged by the appellant, bear the burden of proof that there is no improvement.

Since the opposition division allocated the burden of proof in accordance with the principles set out above, it did not contravene Article 113(1) EPC.

2.3 The appellant did not raise any further objections under Article 113(1) EPC. Consequently, there is no reason to conclude that the opposition division did not respect the patent proprietor's right to be heard.

3. Admission of documents (D23) to (D25)

3.1 Article 12(4) of the Rules of Procedure of the Boards of Appeal (RPBA) states that the board has the power to hold inadmissible those facts and evidence "which could have been presented ... in the first instance proceedings" (see Supplementary Publication of OJ EPO 1/2015, 41-50).

3.2 Documents (D23) to (D25) were enclosed with the statement setting out the grounds of appeal dated 22 August 2011.

3.2.1 Document (D23)

This document was used by the appellant as evidence in support of its argument that document (D1) could not be the closest prior art. It merely supplements the information of the press release (D1) and thus does not introduce facts which change the factual framework of the first instance proceedings. Hence, the board decided to admit document (D23) into the proceedings.

3.2.2 Document (D24)

During the oral proceedings before the board, the appellant declared that he would not rely on this document. Hence, there was no reason to decide on the admission of this document into the appeal proceedings.

3.2.3 Document (D25)

Document (D25) is a "Memo of the Proprietor concerning the oral proceedings before the Opposition Division on March 22, 2011". As it relates to the final step in the opposition procedure, it could not have been presented before the opposition division. Moreover, it related to the procedural issues raised in the statement of grounds of appeal. Hence, the conditions under Article 12(4) RPBA for not admitting this document were not met. Therefore, document (D25) was admitted into the proceedings.

Main Request

4. Article 100(c) EPC

The feature "moderate to severe pain"

4.1 This feature is disclosed in the application as filed in the section "BACKGROUND OF THE INVENTION" on page 1, line 19. Furthermore, the appellant pointed out that the use of tramadol for the treatment of moderate to severe pain was generally known from document (D15).

In contrast to this, the formulations in example 1 of the application as filed "were developed for the relief of mild to moderate pain" (see page 18, lines 5-6). This leads to the conclusion that the dose of tramadol in this example was lowered to such a degree that only mild to moderate pain, and not severe pain, could be alleviated to an acceptable level. Such a lowering of the dose whenever possible is clearly linked to the object of the invention to reduce "the occurrence of and concomitant severity of adverse tramadol elicited side effects" (see page 2, lines 1-6, of the application as filed).

The dosage forms disclosed in example 1 of the application as filed comprise those containing 100 mg, 200 mg and 300 mg of tramadol HCl (see page 19, line 19; page 18, line 10; page 20, line 4). This corresponds to the dosing regimen defined in claim 1 as originally filed, in which the three steps of 75 to 125 mg, 175 to 225 mg and 275 mg to 325 mg are to be used.

4.2 Hence, the person skilled in the art would have derived directly and unambiguously from the application as filed that the aim of the dosage regimen claimed therein was to alleviate "mild to moderate pain" as disclosed in its example 1, but not "moderate to severe pain" as stated in the background section.

4.3 The fact that document (D15) recommends a maximum dose of 400 mg per day of tramadol HCl for the treatment of moderate to severe pain does not mean that a dose of 275 to 325 mg is generally sufficient to treat severe pain. This is all the more so the case as (D15) allows for higher daily doses for the treatment of pain caused by tumours.

4.4 Consequently, grounds under Article 100(c) EPC prejudice the maintenance of the patent on the basis of the claims as granted (main request). Hence, the main request was refused.

First Auxiliary Request

5. Article 123(2) EPC

In the claims of the first auxiliary request, the expression "moderate to severe pain", which gave rise to the rejection of the main request, was deleted.

For the reasons given under point 4 above, the insertion of the expression "mild to moderate pain" does not contravene the requirements of Article 123(2) EPC.

6. Novelty

6.1 The respondent considered the subject-matter claimed to

lack novelty in view of document (D1) or (D13).

6.2 Document (D1) reports on a 12-week placebo controlled double blind study with 300 mg or 200 mg tramadol extended release formulations with patients suffering from low back pain. Said extended release formulations are "once-daily" formulations (see page 2, line 2).

During a three-week run-in period patients were

- initiated on 100 mg per day for at least three days,

- permitted to increase to 200 mg QD based upon the tolerability of the side effects on days 4-7,

- maintained at 200 mg per day and titrated upward to 300 mg QD depending on the tolerability of the side effects during week 2,

- escalated to 300 mg at the beginning of the third week and maintained at this dose for one week, and, if the patient was responsive and the side effects were acceptable, for the remainder of the twelve weeks (see the third paragraph on page 2).

6.3 There is no direct and unambiguous disclosure in (D1) that some patients moved to 200 mg on any of days 5, 6 or 7. Even if one were to concur with the respondent in this respect, document (D1) does not disclose in a clear and unambiguous manner that those patients who moved to 200 mg on any of days 5, 6, or 7 maintained a dose of 200 mg for at least four consecutive days.

6.4 The same applies to the corresponding information in document (D13) (see example 11 on page 67, lines 6-13).

6.5 Therefore, neither document (D1) nor document (D13) disclose all the features of present claim 1.

Hence, the board considers the subject-matter claimed to be novel.

7. Inventive step

7.1 Closest prior art

7.1.1 Whereas the respondent considered document (D1) to represent the closest prior art, the appellant argued that document (D1) was not the closest prior art as it did not focus on improving the titration phase to reduce the drop-out rate. Therefore, it held that document (D21) was closer (see points VIII and IX above).

7.1.2 The closest state of the art is normally a prior art document disclosing subject-matter conceived for the same purpose or aiming at the same objectives as the claimed invention and having the most relevant technical features in common. A further criterion for the selection of the most promising starting point is the similarity of the technical problem (see T 1634/06 of 4 March 2011, point 2.2.1 of the reasons).

7.1.3 It is clear from the foregoing that the "objectives" and the "technical problem" are not considered to be identical. The objective of the patent in suit is defined in paragraph [0002]:

" 2. FIELD OF THE INVENTION

[0002] This invention relates to a titration dosing regimen for the administration of controlled release dosage forms of tramadol to patients."

7.1.4 Document (D1) reports on the results of a phase III study for the treatment of low back pain with extended release (once-daily) tramadol (see the title and the first sentence of the second page). During a three week run-in period, the patients were titrated from 100 mg QD to 200 mg and finally to 300 mg QD. "Patients with pain unresponsive to appropriate dosage adjustments or with unacceptable side effects were dropped from the study" (see the third paragraph on the second page).

7.1.5 Document (D21) "relates to a dosing regimen for the administration of the analgesic tramadol. The dosing regimen achieves the desired analgesic effect while reducing or delaying the on-set of the side effects generally associated with the administration of tramadol." (see page 1, lines 8-12). The aim is to minimise side effects commonly associated with discontinuation of the treatment (see page 3, lines 26-32). Document (D21) does not relate to extended release tramadol.

7.1.6 Hence, a dosing regimen for extended-release tramadol is disclosed in document (D1); it is not disclosed in (D21), as the latter does not concern a controlled release dosage form. Consequently, this is an indication that the person skilled in the art would have used the teaching of document (D1) rather than that of (D21) as a starting point for the invention claimed in the patent in suit. Indeed, the person skilled in the art who is wishing to provide a titration dosing regimen for the administration of controlled release dosage forms of tramadol to patients would use a controlled release dosage form of this drug as the starting point, and not an immediate release form.

7.1.7 As mentioned above, a further criterion for the selection of the most promising starting point is the similarity of the technical problem. The technical problem of the closest prior art should be similar to the one of the claimed invention. That does not mean that the technical problems must be identical, as the appellant seemed to imply.

7.1.8 The problem addressed in the patent in suit is the provision of "an advantageous dosing regimen for a controlled release dosage form of tramadol. More specifically, ... a dosage regimen for a controlled release tramadol which significantly reduces the occurrence of and concomitant severity of adverse tramadol elicited side effects, and thus, reduces potential discontinuation by patients due to these effects and increases the number of patients who may successfully be treated" (see paragraph [0010] on page 3; see page 2, lines 1-6, of the application as filed).

7.1.9 The technical problem to be solved in document (D1) was "to evaluate the efficacy and safety of Biovail's extended release tramadol (once-daily) formulation in the treatment of chronic low back pain" (see the first sentence of the second page).

7.1.10 It is evident that the safety of the formulation addressed in document (D1) is linked to the severity of its adverse side effects as referred to in the patent in suit. Furthermore, the final titration step up to 300 mg QD (see document (D1), third paragraph on page 2) is based on the tolerability of the side effects, which is a further indication that the avoidance or reduction of side effects is an issue in document (1).

Therefore, the problem addressed in document (D1) and the one defined in the patent in suit are similar.

7.1.11 In view of this similarity, the fact that patients were taken out of the study would not have dissuaded the skilled person, trying to solve the problem defined in point 7.1.8 above, from taking the teaching of document (D1) into consideration, as was alleged by the appellant. In this context, it is noted that 100% success rates are hardly ever achieved with medicaments.

The appellant gave no reasons for its allegation that the person skilled in the art would be more likely to use a patent application as the starting point than a press release such as document (D1); due to the detailed disclosure of the test in document (D1), the board has no doubt that the person skilled in the art would consider its disclosure to be credible and useful.

7.1.12 For these reasons, document (D1) (rather than (D21)) is considered to represent the closest prior art.

7.2 The problem to be solved

The appellant and patent proprietor defined the problem to be solved as providing a dosing regimen for extended release formulations of tramadol that reduced adverse side effects and thus reduced the number of patients who discontinued treatment. This definition is in accordance with page 2, lines 2 to 6, of the application as filed. The appellant did, however, concede that he could not present data showing that this problem was solved in view of document (D1). As is evident from point 2.4 above, the burden of proof that the problem set out in the patent in suit is solved in view of the closest prior art lies with the patent proprietor. Hence, there is no evidence that the problem mentioned above was solved. Consequently, the problem to be solved can only be considered as the provision of an alternative dosing regimen for extended release formulations of tramadol with low adverse side effects.

7.3 Example 1 of the patent in suit shows that this problem was indeed solved.

7.4 The appellant argued with reference to the declaration (D18) that it was essential that each of the two lower doses according to claim 1 (75 to 125 mg and 175 to 225 mg) had to be taken for a minimum period of four days.

7.4.1 Points 10 and 11 of the declaration (D18) state that the tramadol hydrochloride controlled release formulation (THCR)

"has a half-life of approximately 10 hours. One typically assumes that it would take 5 to 6 half-lives until steady state is reached during continuous oral administration. In the case of tramadol, one can thus assume that steady state is reached after approximately 2 - 3 days. Occurrence of adverse events, however, does not only depend exclusively on blood plasma concentration values but is also influenced by other factors. Clinically relevant effects such as an adverse event may therefore appear not only some time after the steady state has been reached but also during the time period leading to steady state.

11. It is my experience that for tramadol a minimum period of four days will be sufficient to reliably link clinically relevant effects (i.e. efficacy and safety) with an administered dose."

7.4.2 Hence, this declaration extrapolates from the half-life of THCR, using several assumptions, that a minimum of four days is sufficient for the given purpose. Such an extrapolation does not rule out a minimum period of less than four days also being sufficient. Therefore, in the absence of more reliable data, the minimum period of four days indicated in claim 1 of the first auxiliary request is considered to be arbitrary.

7.4.3 During the three-week run-in period reported in document (D1) patients were

- initiated on 100 mg QD for at least three days,

- permitted to increase to 200 mg QD based upon the tolerability of the side effects on days 4-7,

- maintained at 200 mg QD and titrated upward to 300 mg QD depending on the tolerability of the side effects during week 2, and

- escalated to 300 mg at the beginning of the third week (see the third paragraph on page 2).

7.4.4 Therefore, document (D1) requires the patients to maintain

- a daily dose of 100 mg for at least three days and up to a maximum of seven days, and

- a daily dose of 200 mg for up to a maximum of eleven days (week 2 and days 4 to 7 of week 1).

Consequently, the teaching of document (D1) encompasses completely the subject-matter of claim 1 of the first auxiliary request. As mentioned under point 7.4.2 above, the selection of the minimum number of four days is considered to be arbitrary and thus cannot contribute to the presence of an inventive step.

In this context, it is irrelevant that the FDA approved the dosing regimen of document (D20), which recommends increasing the dose every five days by an increment of 100 mg, up to a maximum dose of 300 mg per day (see the first paragraph on page 17).

7.4.5 For these reasons, the subject-matter of claim 1 of the first auxiliary request 1 does not involve an inventive step. Hence, the first auxiliary request was also refused.

Second Auxiliary Request

8. Claim 1 of this request differs from claim 1 of the first auxiliary request in that the former specifies that each of the daily doses of 100 mg and 200 mg are to be maintained for a week and that the final dose is 300 mg per day (see above under point VII c)).

The conclusions drawn above under point 7, that the requirement to maintain the lower doses for a minimum of four days cannot contribute to the presence of an inventive step, apply mutatis mutandis to the requirement to maintain them for a week.

Therefore, the subject-matter of claim 1 of the second auxiliary request does not involve an inventive step either. Hence, the second auxiliary request was refused.

9. The main request was refused because grounds under Article 100(c) EPC prejudice the maintenance of the patent as granted. The first and second auxiliary requests were refused as the subject-matter of their claims 1 does not involve an inventive step. The appellant did not file any further auxiliary requests. Hence, the appeal had to be dismissed.