T 0056/24 (Oral azacytidine III/CELGENE) 22-07-2025

1. Admittance of document A67

In its communication pursuant to Article 15(1) RPBA the Board indicated that it intended not to admit document A67, because it should have been filed during the first instance proceedings and did not seem to address the issue that led to the decision under appeal. The patent proprietor had already argued in its response to the oppositions that the skilled person would not formulate 5-azacytidine for immediate release in view of its known instability. Moreover, the Board did not recognize how the reference to A67 by opponent 2 addressed that argument.

No substantive arguments were submitted by the opponents in response to the preliminary opinion expressed by the Board in its communication.

The Board has therefore confirmed the opinion expressed in the communication pursuant to Article 15(1) RPBA and has not admitted A67 into the appeal proceedings under Article 12(4) and 12(6) RPBA.

Main request (patent as granted)

2. Novelty

2.1 Document D9

2.1.1 The finding in the decision under appeal that the subject-matter of claim 1 as granted does not enjoy the priority of 15 May 2008 was not in dispute. Document D9 therefore represents prior art under Article 54(2) EPC.

2.1.2 Effective amount / treatment

The Board considers that the utility defined in claim 1 as granted, which is formally directed to the use of the defined composition in a method of treating a subject having acute myelogenous leukemia (AML) with an effective amount of 5-azacytidine, will be understood by the skilled reader as directed to the effective treatment of AML in the defined subject.

Document D9 describes a pilot study concerning the oral administration of azacytidine. The document reports the pharmacokinetic profile and tolerability of single oral doses of 5-azacytidine up to 80 mg in the form of film-coated tablets administered to cancer patients, including one patient with AML (see D9, Abstract). Document D9 concludes that the single doses are bioavailable, safe and well tolerated (see D9, page 1683, left column).

However, document D9 does not explicitly report any therapeutic efficacy from the administration of the single doses. To the contrary, document D9 explicitly observes: "However, high oral doses may be required to overcome potential absorptive limitations of gastrointestinal administration and reach a clinically significant therapeutic effect" (page 1683, left column).

The plasma levels from oral administration (PO) reported in document D9 remain substantially below the levels resulting from the subcutaneous (SC) dose of 135 mg that was known to be effective in the treatment of AML (see D9, page 1682, Figure 1). Whilst document D56 mentions that the generally recommended subcutaneous dose of 135 mg (75 mg/m²) may be reduced to 50% or 33% thereof for a particular sub-group of patients experiencing certain side effects (see D56, page 3), the relative bioavailability of 24.5% for the oral administration in the patient with AML compared to a 135 mg subcutaneous dose reported in document D9 (see page 1682, Table 3, patient 3) still remains substantially below the dose reductions of 50% and 33% recommended in document D56 for a particular sub-group of patients. Any effective therapy is therefore also not implicitly derivable from the plasma profiles and the relative bioavailability described in document D9 for the orally administered doses of 5-azacytidine.

The Board distinguishes the situation in the present case, in which document D9 does not disclose any therapeutic effect, from the situation in T 230/18, in which the credibility of a disclosed therapeutic effect was addressed.

The Board therefore considers that document D9 does not disclose the utility of the described tablets for effective treatment of AML.

2.1.3 Immediate release / release substantially in the stomach

Claim 1 as granted defines an immediate release composition which releases the 5-azacytidine substantially in the stomach following oral administration. Paragraph [0043] of the patent explains that the immediate release feature means that the composition does not comprise any component, including a coating, which delays the release of some or all of the active compound beyond the stomach. Paragraph [0045] of the patent defines the release substantially in the stomach independently from the immediate release feature as requiring that at least 10% of the 5-azacytidine is released in the stomach. The definition of the feature of the release substantially in the stomach therefore only restricts the definition of the immediate release compositions in claim 1 as granted.

Document D17 confirms that immediate release tablets are intended to release the drug rapidly directly after administration, which distinguishes immediate release tablets from prolonged and delayed release tablets, which are formulated to provide the release of the drug over an extended period of time or only after a delay (see D17, page 454 right column to page 455 left column).

Document D9 does not explicitly describe the investigated tablets as immediate release formulations, nor does it explicitly describe the release of the 5-azacytidine in the stomach.

As indicated by documents D61-D64, enteric coated compositions may pass through the stomach within 0.5 hours (see D61, page 132; D62, page 1; D63, page 666, Table 1; D64, page 274, Table 1). Document D29 confirms that gastric residence times may vary from as short as 5 minutes up to 2 hours. The release from an enteric formulation after 2 hours, as suggested in document D41, thus corresponds to the longer transit times within that range. However, in view of the possible shorter transit times the initial plasma values reported 30 minutes after administration for the tablets in document D9 do not exclude that the administered tablets still comprised an enteric coating preventing the release in the stomach. Moreover, document D9 explicitly points out that a delay in absorption was observed, which it attributed to the coating of the tablets (see D9, page 1683, left column). The plasma profiles in Figure 1 of document D9 indeed appear to imply a delay when compared to the plasma profiles of the exemplified immediate release compositions presented in Figure 11 of the patent. Notably, the plasma profiles described in document D9 correspond to those reported in a similar study in document D1 for tablets with an enteric coating (see D1, Example 3 paragraph [00130]; Example 5, paragraphs [0142]-[0163]; Figure 5).

The Board thus concludes that it cannot be derived from document D9 that the tablets described in this document are immediate release compositions, nor that these tablets release the 5-azacytidine substantially in the stomach as defined in claim 1 as granted.

2.2 Document D1

Document D1 relates to controlled release compositions for oral administration of a cytidine analogue which release the agent primarily in the large intestine (see D1, paragraphs [0020]). The compositions typically comprise an enteric coating which allows them to pass the stomach intact (see D1, paragraph [0043]). As mentioned in section 2.1.3 above document D1 describes in Example 3 tablets containing 5-azacytidine provided with such an enteric coating which demonstrated a similar bioavailability profile as the tablets of document D9. In view of the purpose of controlled release of the compositions in document D1 the Board is not convinced that the tablets of example 3 of document D1 comprised a "leaky" coating as mentioned for "Formulation 1" in the patent (see paragraph [0167]).

The Board therefore considers that document D1 does not describe immediate release compositions for oral administration of 5-azacytidine as defined in claim 1 as granted.

2.3 Accordingly, the Board concludes that the patent as granted complies with the requirement of novelty (Article 54 EPC).

3. No remittal

In view of the Board's conclusions concerning the novelty of claim 1 of the patent as granted the decision under appeal is to be set aside.

The decision under appeal does not deal with the raised grounds of opposition regarding the basis for the amendments, inventive step and sufficiency of disclosure. However, the patent proprietor has addressed these issues in its statement of grounds of appeal and the opponents have responded by at least providing their replies with respect to the issue of inventive step. Notably, no party to the appeal proceedings has requested the Board to remit the case to the first instance.

In view of these circumstances the Board considers that in the present case the fact that the decision under appeal did not deal with the issues of the basis for the amendments, inventive step and sufficiency of disclosure does not represent a special reason justifying remittal under Article 11 RPBA. The Board has therefore decided to continue the procedure in accordance with Article 111 EPC to reach a conclusion on the only remaining grounds of opposition.

4. Basis for the amendments / Sufficiency

The Board expressed in the communication pursuant to Article 15(1) RPBA the preliminary opinion that claim 1 as granted was, for instance, adequately based on claims 71, 72 and 74 of the original PCT application which defined the use of 5-azacytidine in a composition intended for release substantially in the stomach for treating a disease associated with abnormal cell proliferation, specifying AML as the disease to be treated and characterizing the composition as prepared for immediate release.

The Board further expressed the preliminary opinion that the patent credibly disclosed the suitability of the claimed composition for the treatment of AML in view of the oral bioavailability of the exemplified immediate release compositions reported in the patent and that the opponents had not raised any serious doubts to substantiate their objection.

Notably, it was not in dispute that adequate exposure to 5-azacytidine following subcutaneous administration is effective in treatment of AML. Moreover, no evidence suggests that the exemplified formulations did not release the 5-azacytidine substantially in the stomach, or that the skilled person would face undue burden when formulating oral immediate release formulations for the release the 5-azacytidine substantially in the stomach.

No substantive arguments were submitted by the opponents in response to the preliminary opinion expressed by the Board in its communication.

Accordingly, the Board has confirmed the preliminary opinion that the patent as granted does not comprise subject-matter extending beyond the original disclosure (Articles 76(1) and 123(2) EPC) and sufficiently describes the claimed invention (Article 83 EPC).

5. Inventive step

5.1 Starting point in the prior art

Examples 4-6 of the patent (see paragraphs [00190]-[00198] and Figures 10-20) report that the oral administration of immediate release formulations comprising 5-azacytidine allows for achieving a similar exposure as that achieved with the recommended dose for subcutaneous administration, which is indicative of effective treatment of AML.

The Board considers document D1 to represent a more suitable starting point in the prior art than document D9, because in contrast to document D9 (see section 2 above) document D1 describes the oral administration of a therapeutically effective amount of 5-azacytidine in the treatment of a disease with abnormal cell proliferation such as AML (see D1, paragraphs [0020], [0023], [0082], [0094], [0142] and [00191]) and claim 1). The subject-matter of claim 1 as granted differs from the teaching of document D1 in that it relates to an immediate release composition for oral administration instead of a controlled release composition (see D1, paragraph [0020]).

Document D32 describes salt formation of cytidine analogues such as azacytidine to overcome the difficulties associated with the development of this type of drugs (see D32, page 6, lines 28-36). This document therefore represents a less suitable starting point in the prior art than document D1.

5.2 Objective technical problem

In view of the results reported in examples 4-6 of the patent, in which conventionally prepared immediate release tablets comprising 5-azacytidine were used, the Board is satisfied that the claimed subject-matter may be considered to represent at least a solution to the objective technical problem of providing an alternative formulation for the oral administration of 5-azacytidine for use in the treatment of AML.

5.3 Assessment of the solution

5.3.1 The Board observes that document D1 itself (see pages 2-3, paragraphs [0007]-[0012]) reports that in general the oral delivery of the class of cytidine analogs, including in particular 5-azacytidine, has proven to be difficult due to a combination of chemical instability, enzymatic instability, and/or poor tissue permeability, and that various strategies have been proposed to improve the oral bioavailability of this class of drugs. Documents D4 ("Abstract", lines 8-12), document D9 (see page 1680, Abstract and Introduction), and document D32 (see page 6, lines 28-34) confirm the problematic stability of 5-azacytidine and the challenge this represents for the formulation of effective oral dosage forms. It is in this context that document D1 presents a controlled release pharmaceutical composition for oral administration to provide enhanced systemic delivery of a cytidine analogue, in particular 5-azacytidine, to achieve effective therapy (see D1, paragraph [0020]).

The Board is of the opinion that starting from document D1 as closest prior art and aiming at a solution to the problem of providing an alternative formulation for the oral administration of 5-azacytidine for effective use in the treatment of AML, it would in line with the considerations in T 2201/10 (see reasons 5.1.3) and T 145/22 (see reasons 6.3.1) not seem obvious to the skilled person to arrive at an orally administered immediate release composition, because such a solution deviates diametrically from what was the essence of the disclosure in document D1, namely the delayed release of the 5-azacytidine intended to enhance its otherwise problematic systemic delivery.

The Board distinguishes the situation in the present case, in which the closest prior art specifically teaches away from the claimed immediate release compositions for oral administration, from the situation in T 237/15, in which the skilled person had a reasonable expectation of the effective oral administration of an agent based on its known oral bioavailability demonstrated in animal studies and its known efficacy human treatment when introduced directly into the blood stream (see T 237/15, reasons 4.6.1).

5.3.2 The opponents argued that document D1 did not teach away from the claimed subject-matter, because, unlike the claims evaluated in T 145/22, claim 1 as granted defined the feature of the release substantially in the stomach. According to the description of the patent this feature required the release of at least 10% in the stomach. This permitted in their view for the claimed composition the release of similar relative amounts of 5-azacytidine beyond the stomach as described for the compositions of document D1.

However, as explained in section 2.1.3 above, the feature of the release substantially in the stomach only further limits the immediate release compositions as defined claim 1 as granted. Claim 1 as granted therefore excludes, in the same manner as the claims evaluated in T 145/22, any component serving to delay the release beyond the stomach. In contrast, document D1 specifically requires controlled release to achieve release of the 5-azacytidine primarily in the large intestine, for instance by including an enteric coating (see D1, paragraphs [0020] and [0043]). The release of at least 10% in the stomach, as specified in paragraph [0045] of the patent, does in any case not suggest that the claimed immediate release composition may realistically release a similar amount of 20% or more of its 5-azacytidine in the large intestine, as described for the controlled release compositions of document D1 (see D1, paragraph [0031]).

The Board therefore considers the opponents' argument not convincing.

5.3.3 The opponents further argued that no general prejudice or other consideration preventing the skilled person from providing oral administration of immediate release formulations of 5-azacytidine could be considered to have persisted following the publication of documents D4 and D9.

The Board also considers this argument not persuasive.

As explained in section 2.1.3 above the Board is not convinced that document D9 relates to an immediate release formulation for oral administration of 5-azacytidine releasing the 5-azacytidine substantially in the stomach. In fact, document D9 specifically refers to the development of a film-coated formulation to circumvent the difficulty of rapid enzymatic catabolism and hydrolysis of 5-azacytidine in aqueous environments (see D9, page 1680, Abstract). Document D9 does therefore not dismiss, but confirm the difficulty of oral administration of 5-azacytidine addressed in document D1 and proposes a similar solution.

Document D4 mentions a study in which orally administered 5-azacytidine was absorbed rapidly with high bioavailability in dogs (see D4, Abstract, lines 22-24). However, document D4 further confirms the challenges that are associated with oral administration of 5-azacytidine and explicitly states that non-clinical testing is hampered by the difficulty of inappropriate animal models for representing human gastrointestinal tract conditions reported in document D4 (see D4, Abstract, lines 8-16). Document D4 does therefore also not dismiss, but confirms the difficulty of oral administration of 5-azacytidine addressed in document D1.

5.4 As explained in section 5.1 above the Board considers documents D9 and D32 less suitable starting points in the prior art than document D1, because document D9 does not describe effective treatment of a disease with abnormal cell proliferation such as AML and because document D32 relates to salts of cytidine analogues.

The opponents have argued that the skilled person would in view of the results reported in document D9 as a matter of obviousness increase the dose to achieve effective concentrations.

However, as mentioned in section 5.3.2 above document D9 specifically refers to the development of a film-coated formulation to circumvent the difficulty of rapid enzymatic catabolism and hydrolysis of 5-azacytidine in aqueous environments (see D9, page 1680, Abstract). Document D9 thus refers to the same difficulty of oral administration of 5-azacytidine as addressed in document D1 and suggests a similar solution. The very same considerations as set out in section 5.3.1 when starting from document D1 would therefore still apply if the skilled person were to attempt to adjust the dose for the formulation described in document D9 in order to achieve effective treatment.

The opponents have further argued that the skilled person would in view of the reference in document D32 to liquid pharmaceutical compositions for oral administration as a matter of obviousness arrive at the claimed immediate release compositions for use in the treatment of AML.

However, the compositions of document D32 are for salts of cytidine analogues to overcome the hydrolytic degradation, low solubility and minimal oral bioavailability otherwise associated with this type of drug (see D32, page 6, lines 28-36). This document thus also teaches away from the claimed immediate release composition for treatment of AML as defined in granted claim 1.

The subject-matter of claim 1 as granted would thus also not be obvious to the skilled person when starting from document D9 or document D32.

5.5 Accordingly, the Board concludes that the subject-matter of claim 1 as granted involves an inventive step and that the patent thus complies with the requirement of Article 56 EPC.