T 0940/02 (Use of a peptide/NOVO NORDISK A/S) 05-07-2004

1. The appeal is admissible.

Main Request Article 123(3) EPC

2. The respondent argues that granted claim 1 (c.f. "... GLP-1(7-37), GLP-1(7-36)amide or a pharmaceutically acceptable peptide containing a fragment of the GLP-l(7-37) sequence, or an analogue or a functional derivative of such a peptide...") only covered the use of analogues of fragments of GLP-1(7-37) and GLP-1(7-36)amide for the preparation of a medicament and that the scope of claim 1 of this request (c.f. the wording "...or an analogue of such a peptide...") has been extended to also cover analogues of GLP-1(7-37) and GLP-1(7-36)amide.

3. However, the wording "...or an analogue or a functional derivative of such a peptide..." in granted claim 1 relates not only to "...a pharmaceutically acceptable peptide containing a fragment of the GLP-1(7-37) sequence..." but also to the peptides GLP-l(7-37) and GLP-1(7-36)amide, wherein the acronym "GLP" means glucagon-like peptide. Therefore, the analogues of GLP-l(7-37) and GLP-1(7-36)amide were already covered by granted claim 1. This interpretation is corroborated by paragraph [0026] of the description, giving the definition of the wording "analogues of GLP-l(7-37) and GLP-1(7-36)amide". In conclusion, the board sees no offence against the requirements of Article 123(3) EPC.

Article 83 EPC

4. The board sees the possible relevance of the objections raised by the respondent under this Article. However, in view of the board's negative conclusions on the fulfilment of the requirements of Article 56 EPC (see point 10 infra), the board finds it superfluous to deal with this issue. Detailed reasons for claims being regarded as allowable under Article 83 EPC will be given (see Auxiliary Request 3, point 21 infra).

Inventive step (Article 56 EPC)

Closest prior art

5. The appellants consider document (D7) as representing the closest prior art for the determination of inventive step. However, the board does not share this view and favours document (D3) for this purpose. This is because document (D3) relates to both components (GLP-1(7-37) and glibenclamide) of the binary combination referred to in claim 1, unlike document (D7), which discloses only one, (GLP-1(7-37)), of the two. The "monotherapy theory" is also not convincing (see point 12 infra).

The problem to be solved

6. The problem to be solved is the provision of a further therapy for diabetes type 2. The proposed solution is the combination of a GLP-l peptide and an oral hypoglycaemic agent which is a blocker of the ATP-dependent potassium channel on Beta-cells. The examples in the patent in suit show that such a combination can be used successfully to treat type 2 diabetes patients.

7. The relevant question is whether it was obvious or not for the skilled person to arrive at the use of claim 1, characterized by the treatment of type 2 diabetes with the above combination.

8. Document (D3) is concerned with experiments regarding the mechanisms of action of GLP-1(7-37) and glibenclamide in rat pancreatic islets and HIT cells. It is stated in this abstract that: "...islets were perifused with ...a maximally-effective dose of GLP- 1(7-37) (10 nM) or glibenclamide (10 µM)..." and "GLP-1(7-37) (10 nM), when added to islets statically incubated with 8 mM glucose plus a maximally effective dose of glibenclamide (10 µM), caused a further increase in insulin secretion (1.44 ± 0.21 fmol/islet/min to 2.89 ± 0.28 fmol/islet/min, P < 0.05" (emphasis by the board).

9. As highlighted above, the tests described in document (D3) were performed with maximally effective doses of GLP-1(7-37) (10 nM) and glibenclamide (10 µM). This means that e.g. 10 µM glibenclamide provided the highest insulin release that could be obtained when glibenclamide was used alone, i.e. adding a higher concentration of this compound would not cause additional insulin secretion from the islets' Beta-cells. In spite of that, the authors of document (D3) found that adding GLP-1(7-37) (10 nM) to this 10 µM glibenclamide "caused a further increase in insulin secretion" and concluded that a different mechanism of action underlay insulin release by GLP-1(7-37) and glibenclamide from the islets' Beta-cells.

10. In the board's judgement, there was thus an incentive at the priority date of the patent in suit to use GLP-1(7-37) in combination with glibenclamide, the latter being "an oral hypoglycaemic agent which is a blocker of the ATP-dependent potassium channel on Beta-cells" (see claim 1), since the skilled person was taught that a combination of GLP-1(7-37) and glibenclamide provided a greater insulin release than glibenclamide alone. The skilled reader of document (D3) would have appreciated that even an additive response would be clinically worthwhile, in view of the expectation of an improved treatment, irrespective of any synergy (see points 28 and 29 infra) which might be observed when GLP-1(7-37) and glibenclamide were used together. Therefore claim 1 of the main request lacks an inventive step and this request is refused.

11. To the several further arguments submitted to argue inventive step, the board observes the following:

Relying on documents (D17)) and (D3B), the appellants maintain that the considerable risk of hypoglycaemia arising from the presence of a sulfonylurea represented a strong prejudice against trying to use a combination of a sulfonylurea with GLP-1 peptides, all the more so as document (D7) (see page 275) presented GLP-1(7-37) as a hypoglycaemia-free alternative to the use of sulfonylureas.

12. However, on page 275, r-h column of document (D7) it is stated that the administration of insulin also carries a risk of hypoglycaemia. Nevertheless, this risk was not such as to dissuade diabetics from using insulin either alone or in conjunction with sulfonylureas, as disclosed, for example in documents (D1) and (D2). A proper control of diabetes involves striking a balance between hypo- on the one hand and hyperglycaemia on the other. In conclusion, there is no convincing evidence before the board that in the present case a prejudice existed in the state of the art which would have diverted the skilled person away from the simultaneous administration of a sulfonylurea with a GLP-1 peptide.

13. It is further argued by the appellants that, owing to the scientific flaws (i) to (iii) below in the design of the experiments conducted according to document (D3), the skilled person could not draw any conclusions about what effects, additive or otherwise, the combination of GLP-1 and glibenclamide might have on insulin secretion from Beta-cells in vitro, let alone in vivo:

(i) The effect of GLP-1(7-37) on its own (ie, without glibenclamide) in the static incubation system has not been measured (see document (D14), section 11 and document (D15), section II(ii)).

(ii) GLP-1(7-37) and glibenclamide had been tested at less than maximal doses (see legend to Fig. 5 of document (D3A)).

(iii) In vitro tests cannot be extrapolated to the in vivo situation (see document (D15), section II(ii): "toxicity problems cannot be ruled out").

14. As for scientific flaw (i), Figure 5 of document (D3A), namely the "poster" presented to the public at the 14th International Diabetes Federation Conference (23 to 28. June 1991) and underlying later published abstract (D3) shows that the effect of GLP-1(7-37)on its own has also been measured by the authors of documents (D3) and (D3A).

As for flaw (ii), the wording "less than maximally" (see legend to Figure 5 of document (D3A)) rather relates to the glucose concentration, not to that of GLP-1(7-37) and glibenclamide, which have indeed been tested at their maximally effective doses of 10 nM and 10 µM, respectively (see ibidem, Fig. 3a and 3b: "the maximum stimulation").

As regards deficiency (iii), it is true that the investigations on the combination GLP-1 peptide/sulfonylurea according to documents (D3) and (D3A) have been performed in vitro on islets. However, the single components were already known to the skilled person to be active and to lack toxicity in vivo on their own (for GLP-1(7- 37): see document (D7); for sulfonylureas: see document (D17), page 277, r-h column). Neither did the appellants provide any evidence in support of the assertion that the in vivo effectiveness of the GLP-1 peptide could be reduced by the concurrent administration of a sulfonylurea, or that simultaneous administration of the two components could bear some risk due to potential interactions between the two drugs. Therefore this appellants' argument is also not convincing.

15. None of the above appellants' arguments are thus susceptible to alter the view the board has come to (see point 10 supra) that document (D3) provided an incentive to use GLP-1(7-37) in combination with glibenclamide, the latter being an "oral hypoglycaemic agent which is a blocker of the ATP-dependent potassium channel on Beta-cells".

Auxiliary Requests 1 and 2

Article 123(2) EPC

16. Insert (i) "...the treatment of type 2 diabetes is in a type 2 diabetic patient in whom sulphonylurea administration alone does not suffice to normalise blood sugar levels" and insert (ii) "...the treatment of type 2 diabetes is in a type 2 diabetic patient with secondary failure to sulphonylurea treatment in whom sulphonylurea administration alone no longer normalises blood sugar levels" in claim 1 of both requests (see Section IV supra) find a basis on page 2, lines 8-18 and Example 2 (c.f. "patients with secondary failure to sulfonylureas") of the published application WO 93/18786 as filed.

Article 83 EPC

17. In view of the board's negative conclusions on the fulfilment of the requirements of Article 56 EPC (see point 19 infra), the board will not deal with this issue.

Article 56 EPC

18. According to claim 1 of these requests the patient suffering from type 2 diabetes being treated may be, inter alia, "a type 2 diabetic patient in whom sulphonylurea administration alone does not suffice to normalise blood sugar levels". According to paragraph [003] of the patent in suit, the majority of patients suffering from diabetes type 2 (NIDDM) were still treated with agents that stimulated the Beta-cell function, the latter being not completely unreactive to the stimulating action of sulfonylureas, which still sensitised Beta-cells, although normal blood sugar levels were not achieved.

Closest prior art and problem to be solved

19. For the reasons emphasized under point 5 supra, the closest prior art is represented by document (D3). The problem to be solved is the provision of a further therapy for a diabetes type 2 patient in whom sulphonylurea administration alone does not suffice to normalise blood sugar levels. The proposed solution is the combination of a GLP-l peptide and an oral hypoglycaemic agent which is a blocker of the ATP-dependent potassium channel on Beta-cells.

20. Document (D3), in the board's opinion, provided an incentive to use sulfonylureas in combination with GLP-1 peptides to treat the above category of patients. This is because the skilled person was taught by this document that a combination of the above ingredients provided a greater Beta-cells stimulation, and hence insulin release, than a sulfonylurea alone, in these patients whose Beta-cells could still be sensitised, although normal blood sugar levels were not achieved. The skilled reader of document (D3) would have appreciated that even an additive response would be clinically worthwhile, in view of the expectation of an improved treatment vis-à-vis the treatment with a sulfonylurea alone, irrespective of any synergy which might be observed. Therefore, claim 1 of the auxiliary requests 1 and 2 lacks an inventive step and these requests are refused.

Auxiliary request 3

Article 123(2) EPC

21. The wording "...the treatment of type 2 diabetes is in a type 2 diabetic patient with secondary failure to sulphonylurea" in claim 1 of this request finds a basis in Example 2 of the published WO 93/18786 application.

Article 83 EPC

22. The respondent argues that the patent imposes an undue burden on the skilled person to identify all the synergistic combinations covered by claim 1 and that the patent in suit does not teach the reader how to obtain a synergistic response when the combination is administered by alternative routes.

23. However, claim 1 of this request is restricted to a medical use involving a combination of GLP-1(7-37) or GLP-1(7-36)amide with a sulfonylurea. The number of possible combinations to be tested is thus limited and the insulinotropic activity can easily be tested by the skilled person, unlike in the situation dealt with in decision T 923/92 (OJ EPO 1996, 564, see point 27), where the board found insufficiency of disclosure. Moreover, no substantiation by way of verifiable facts has been provided by the respondent against the claimed "sulfonylurea" generalisation.

24. As for synergy, the board accepts that Example 2 of the patent in suit demonstrates synergy between GLP-1(7-37)amide and the sulfonylurea glibenclamide. Further, the board accepts that post published document (D11), taken as expert opinion, shows that combinations of GLP-1(7-36)amide with glibenclamide or tolbutamide, i.e. two different sulfonylureas, exhibit synergism. In the board's view, it is reasonable to conclude from the results of Example 2 (GLP-1(7-37)amide + glibenclamide) and from those of document (D11) (GLP-1(7-36)amide + glibenclamide or tolbutamide) that similar results will be obtained with other sulfonylureas, having in common the same mechanism of action and a similar chemical structure (see e.g. document (D3B), Diabeta® leaflet, third paragraph), the latters being decisive synergy factors prevailing, in the board's opinion, over e.g. the mode of administration.

25. In conclusion there is no basis for a finding of insufficiency of disclosure.

Article 56 EPC

26. Claim 1 of this request is now limited such that the patient suffering from type 2 diabetes is characterized as "...a type 2 diabetic patient with secondary failure to sulphonylurea treatment", namely a patient who has been treated with sulfonylureas and got a failure due to Beta-cells' exhaustion, which, accordingly, are no longer able to produce and excrete insulin upon glucose stimulation.

27. The respondent maintains that Table 3 on page 6 of the patent ("glibenclamide = 10.6"; "control 1.6") shows that the patients still respond to sulfonylurea. However, these results relating to the insulinogenic indices (integrated insulin/integrated glucose) have to be balanced with those of Table 2 ("glibenclamide = 6.0; "control 6.0"), showing that glibenclamide does not achieve any increase in the concentration of blood glucose over the control. The board is therefore convinced that these patients do not react to a treatment with sulfonylurea.

Closest prior art and problem to be solved

28. The closest prior art is represented by document (D3) (see point 5 supra). The problem to be solved is the provision of a further therapy for a diabetes type 2 patient with secondary failure to sulfonylurea treatment. The proposed solution is the combination of GLP-1(7-37) or GLP-l(7-36) amide and a sulfonylurea.

29. The appellants maintain that at the priority date of the patent in suit, the skilled person would not expect any therapeutic advantage by administrating to a patient suffering from a secondary failure to sulfonylurea treatment with a further sulfonylurea or another agent stimulating the Beta-cell function, or with a combination of these agents. It was thus unexpected, in the appellants' view, that such a patient could still be treated with the claimed combination of GLP-1(7-37) or GLP-1(7-36)amide and a sulfonylurea, owing to the surprising synergistic effect arising in such a combination (see also paragraphs [0027] and [0028] of the patent in suit).

The claimed subject matter would, in the board's view, be considered not obvious if an unexpected synergistic effect took place. In fact, since document (D3) does suggest an additive effect (see the term "additivity" at the end of document (D3)) and thus while this technical teaching was an incentive for the skilled to arrive at the subject matter of the main request and auxiliary requests 1 and 2 (see points 10 and 20 supra), the board accepts that the situation for the above identified subject matter is different, as the skilled person would not expect any therapeutic advantage by administrating the combination disclosed in document (D3) to a patient who has been treated with sulfonylureas and got a secondary failure to sulfonylurea treatment due to Beta-cells' exhaustion.

The relevant issue is thus to establish whether a combination of GLP-1(7-37) or GLP-1(7-36)amide with a sulfonylurea exhibits the synergistic effect maintained by the appellants, but which the respondent denies.

Synergy

30. The patent in suit (see Tables 1, 2 and 3) and post- published documents (D8) and (D11) show a synergistic insulinotropic effect upon concomitant administration of GLP-1(7-37)amide and glibenclamide or tolbutamide. Furthermore, Figure 2 of test report (D9) by Dr. Sturis shows a greater than additive effect for GLP-1(7-37)and glipizide. The data points for GLP-1(7-37) are above the dotted line which is the threshold above which a synergistic effect takes place. Dr. Sturis used as a control/baseline level of insulin secretion the worst possible approach for a demonstration of synergy, i.e. the peak insulin level observed during the 7 minute period preceding glipizide stimulation instead of a mean insulin value during this pre-incubation time lag.

Dr. Sturis obtained further confirmatory data in a second series of experiments (see document (D16)), wherein four treatment groups were included: controls, glipizide only, GLP-l only, or a combination of glipizide with GLP-1 administered concomitantly to pancreas tissue. The figure under "Results" shows a marked and statistically significant synergistic effect on insulin secretion when a combination of glipizide and GLP-1 is used. This experiment also addresses the criticism raised by the respondent that in the experiment of document (D9), GLP-1(7-37) and glipizide were not administered concomitantly.

31. In view of the foregoing, the board is satisfied that a combination referred to in the use of claims 1 and 2, of GLP-1(7-37) or GLP-1(7-36)amide with a sulfonylurea exhibits an unexpected synergistic effect.

32. The respondent points to an inconsistency between the tests carried out according to document (D9) (7.5 nM glucose and 30 pM GLP-1(7-37)) and document (D16) (8 nM glucose, 56 pM GLP-1). However, the board finds this difference in the concentration of one component (glipizide being 30 nM in both experiments) not fundamental as long as synergy is shown. If anything it shows that synergy is not confined to a punctual value.

33. The respondent questions the statistics underlying test report (D16) (see declaration (D19), which extends this criticism to documents (D9) and (Dl1)), by arguing that the reliance on a t-test to argue synergy requires that the data have to be consistent with a normal distribution and that this is not the case with the bar chart in document (D16), wherein the variability (ie standard deviations) is a function of the mean response.

However, the board observes that a respondent's expert (see Declaration (D21)) already considered the t-test as appropriate for evaluating the statistics underlying both Example 2 of the patent in suit and post-published document (D8), wherein the situation was the same as in test report (D16). Moreover, Dr. Sturis (see document (D16)), also used the Satterthwaite's approximation for the degrees of freedom, thus taking into account the different variances. In any case, the criticism raised in declaration (D19) has to be balanced with declaration (D18), which confirms that the statistical approach taken by Dr. Sturis in test report (D16) is reliable and valid and that the data support synergism.

34. Finally the respondent argues that test report (D16) at most demonstrates synergy in vitro between GLP-l and glipizide without any implication regarding a possible effect in vivo.

However, the investigations described in document (D16) are ex vivo data in that the experimental set-up exploits whole organs removed from a body, not just cell-lines kept in suspension in a tube. As such, the set-up used by Dr. Sturis is highly representative of the in vivo situation. Furthermore, the single components were already known to the skilled person to be active and to lack toxicity in vivo on their own (for GLP-1(7-37): see document (D7); for sulfonylureas: see document (D17), page 277, r-h column). Neither did the respondent provide any evidence in support of the assertion that the in vivo effectiveness of the GLP-1 peptide could be reduced by the concurrent administration of a sulfonylurea, or that simultaneous administration of the two components could bear some risk due to potential interactions between the two drugs. Therefore this respondent's argument is also not convincing.

35. Thus the claims of this request also satisfy the requirements of Article 56 EPC.