T 0145/22 (Oral azacytidine/CELGENE) 26-07-2024

1. Admittance of new evidence

Document A51, a textbook reference, as well as documents A52-A54 were cited by the proprietor to support the argument that contrary to the finding in the decision under appeal enteric coated compositions may pass through the stomach within 0.5 hour and that the pharmacokinetic data in document D9 were therefore not indicative for an immediate release composition.

Document A51 was further cited by the proprietor as evidence of common general knowledge that absorption is a two-step process and dissolution is often the rate-limiting step in absorption. Contrary to the finding in the decision under appeal the suggestion in document D9 regarding a delay in absorption due to the coating would therefore not refer to an effect of the coating occurring only after the dissolution.

The Board considers the filing of documents D51-D54, justified as a response by the patent proprietor to considerations in the decision under appeal, which were according to the patent proprietor not in line with the skilled person's common general knowledge. No objections against the admittance of these documents were upheld by the opponents and the filing of documents A51-A54 raises no new issues. The Board has therefore admitted documents A51-D54 into the appeal proceedings under Article 12(4) RPBA.

Main request (patent as granted)

2. Basis for the amendments

The application as filed describes from paragraph [00108] onwards under the heading "C. Pharmaceutical Formulations" embodiments relating to pharmaceutical formulations comprising a cytidine analog such as 5-azacytidine which are prepared for oral administration, preferably for release in the stomach. In paragraph [00110] under the sub-heading "Performance of Certain Dosage Forms Provided Herein" the application as filed specifically describes that in certain embodiments the formulations comprising a cytidine analog such as 5-azacytidine are orally administered compositions for immediate release without specific reference to the release in the stomach. In paragraph [00137] the application as filed describes that in certain embodiments the composition may be a sublingual tablet for absorption through the oral mucosa, which may dissolve promptly and provide rapid release of the drug.

The application as filed furthermore specifically highlights the treatment of acute myelogenous leukemia (AML) as particular embodiment of the disorder associated with abnormal cell proliferation to be treated in accordance with the claimed invention (see paragraph [00183]).

In addition, the application as filed provides in independent claim 71 in connection with its dependent claims 72 and 74 a clear pointer to the combination of features involving immediate release of 5-azacytidine from orally administered formulations and the treatment of AML, be it with the specification in claim 71 that the active agent is released substantially in the stomach.

According to G 2/10 the assessment whether the patent comprises subject-matter extending beyond the content of the application as filed is based on what the skilled person would derive directly and unambiguously from the whole of the application as originally filed. As pointed out by the opponents all the independent claims as originally filed indeed included the feature of the release substantially in the stomach. The application as filed stated accordingly in paragraph [00015] under the heading "Summary" that pharmaceutical compositions comprising cytidine analogs are provided, wherein the compositions release the API substantially in the stomach upon oral administration. It is however evident from the embodiments mentioned in paragraphs [00108], [00110] and [00137] that the original disclosure as a whole is not restricted to the originally claimed compositions which released the active agent substantially in the stomach and expressly includes orally administered immediate release compositions comprising 5-azacytidine without the requirement regarding the release in the stomach as an alternative embodiment.

The Board therefore considers that the subject-matter of claim 1 as granted does not involve a new combination of features selected from multiple lists or otherwise results from an impermissible generalization by omission of a crucial feature, but rather reflects the limitation to an embodiment which had been highlighted in the application as originally filed, namely the treatment of AML, by the administration a specifically disclosed composition comprising 5-azacytidine, namely by oral administration of an immediate release composition.

Accordingly, the Board concludes that the subject-matter of claim 1 as granted is directly and unambiguously derivable from the original disclosure and that the patent therefore complies with the requirement of Article 123(2) EPC.

3. Priority

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

4. Novelty

4.1 Effective treatment of AML

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 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. In this context the patent explains that oral administration of immediate release formulations comprising 5-azacytidine in doses up to 1200 mg allows to achieve an exposure indicative for effective treatment from single or multiple daily dosing of 5-azacytidine based on the results in examples 4-6 (see paragraphs [00190]-[00209]).

Document D9 describes a pilot study of oral azacytidine reporting the pharmacokinetics and tolerability of single oral doses of 5-azacytidine up to 80 mg in the form of film coated tablets. Document D9 concludes that the single doses are bioavailable, safe and well tolerated. However, document D9 does not explicitly report any therapeutic efficacy from administration of the single doses and specifically states in this context (see D9, page 1683, left column): "However, high oral doses may be required to overcome potential absorptive limitations of gastrointestinal administration and reach a clinically significant therapeutic effect."

No effective therapy is implicitly derivable from the plasma levels described in document D9. The plasma levels from the oral administration (PO) reported in document D9 are substantially below the level resulting from the subcutaneous (SC) dose of 135 mg that was known to be effective (see D9, Figure 1). Document D43 only confirms on pages 2 and 12 the subcutaneous administration of 135 mg as the recommended starting dose and mentions lower doses of 67,5 and 45 mg expressly only in the context of an example of how to calculate individual doses.

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

4.2 Immediate release

Claim 1 as granted relates to a composition for the defined use, wherein the composition is defined as an immediate release composition for oral administration of 5-azacytidine. Document D17, which was relied upon by the opponents, 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 for 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.

The initial observed plasma levels after about 30 minutes following administration as reported in document D9 (see page 1682, Figure 1) do not implicitly indicate that the tablets of document D9 were immediate release compositions, because even enteric coated tablets may well pass through the stomach into the intestine within 30 minutes to give rise to initial plasma levels as reported in document D9 (see A51, page 132, lines 5-6).

Document D9 actually mentions an observed delay in absorption which it attributes to the coating of the tablets (see page 1683, left column). The plasma profiles reported in document D9 (see Figure 1) reaching peak levels between 1-2 hours following administration indeed suggest a delayed release with respect to the plasma profiles presented in the patent (see Figure 11) for the exemplified immediate release compositions F3 and F6 reaching peak levels an hour after administration. As the absorption of a solid drug is a two step process involving dissolution and actual uptake by the body (see A51, page 128) the delay in absorption as observed in document D9 is indicative for a delayed release composition rather than an immediate release composition.

The Board therefore considers that document D9 does not disclose an immediate release composition.

4.3 Accordingly, the Board concludes that the subject-matter of claim 1 as granted is new in view of document D9 and that the patent thus complies with the requirement of Article 54 EPC.

5. No remittal

In view of the Board's conclusions concerning the basis for the amendments and compliance with the requirement of novelty in relation to claim 1 of the patent as granted the decision under appeal is to be set aside.

The opponents have specifically requested the Board not to remit the case to the first instance. The patent proprietor has not requested a remittal either. Moreover, the patent proprietor and the opponents have provided their arguments regarding the ground of opposition concerning inventive step. The opponents have furthermore during the appeal proceedings not maintained that the patent lacks sufficient disclosure of the claimed invention.

In view of these circumstances the Board considers that the lack of a finding in the decision under appeal on the issues of inventive step and sufficiency of disclosure does not represent in the present case 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 ground of opposition which concerns the requirement of inventive step.

6. Inventive step

6.1 Starting point in the prior art

Examples 4-6 of the patent (see paragraphs [00190]-[00209]) report that oral administration of immediate release formulations comprising 5-azacytidine allows to achieve an exposure indicative for effective treatment from single or multiple daily dosing of 5-azacytidine.

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 4 above) document D1 describes the oral administration of a therapeutically effective amount of 5-azacytidine in 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 teaching of document D1 differs from the subject-matter of claim 1 as granted in that it relates to oral administration of delayed release compositions.

6.2 Objective technical problem

In view of the results reported in examples 4-6, 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. The opponents have questioned whether on the basis of the provided experimental data an oral formulation for immediate release in the form of a sublingual tablet could also be regarded as a solution to the mentioned objective technical problem. However, the Board finds no basis to doubt that given the demonstrated effectiveness of conventionally prepared immediate release tablets a promptly dissolving sublingual tablet intended for absorption through the oral mucosa as mentioned in paragraph [00137] should lack such effectiveness.

6.3 Assessment of the solution

6.3.1 The Board observes that document D1 itself (see pages 2-3, paragraphs [0007]-[0012]) reports that in general oral delivery of the class of cytidine analogs, including in particular 5-azacytidine, has proven difficult due to the combinations 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. This teaching in document D1 is in line with document D30 (see page 8, right column), document D41 (page 8, right column) as well as document D4 (under "Abstract", lines 8-12) and document D9 (see page 1680, Abstract and Introduction), which refer to 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 analog, 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 with the aim 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 T2201/10 (see reasons 5.1.3) not seem obvious to the skilled person to arrive at an orally administered immediate release composition, because such a solution deviates in light of the aim pursued diametrically from what was the essence of the disclosure in document D1, namely the delayed release of the 5-azacytidine disclosure to enhance its otherwise problematic systemic delivery.

6.3.2 The opponents 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 D2, D3, D4 and D9.

The Board does not consider this argument persuasive.

As explained section 4.2 above the Board is not convinced that document D9 relates to an immediate release formulation for oral administration of 5-azacytidine. 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 under "Abstract", lines 8-16). Document D4 does therefore also not dismiss but confirm the difficulty of oral administration of 5-azacytidine addressed in document D1.

Document D3 also refers to the rapid absorption with high bioavailability of 5-azacytidine following oral administration in dogs and reports that based on preclinical studies a single-treatment study of oral azacytidine is underway in subjects with MDS, AML or solid tumors to assess the safety, tolerability and pharmacokinetics of escalating single doses of orally administered 5-azacytidine. However, document D3 does not mention the actual nature of the oral administration form under investigation. Document D3 is therefore also not suitable to dismiss the difficulty of oral administration of 5-azacytidine addressed in document D1.

Document D2 envisages in a generic manner that solid state forms of 5-azacytidine may be formulated in oral administration forms such as tablets and in parenteral administration forms such as solutions for injections, and that the compound be formulated to achieve quick or delayed release (see D2, paragraphs [0048]-[0049]). However, without any further substantiation, for instance in the form of tested examples, this mere generic reference to envisaged administration forms in document D2 cannot be considered to dismiss the difficulty of oral administration of 5-azacytidine addressed in document D1.

6.4 As explained in section 6.1 above the Board considers document D9 a less suitable starting point in the prior art than document D1, because document D9 does not even describe effective treatment of a disease with abnormal cell proliferation such as AML.

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 6.3.2 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 6.3.1 when starting from document D1 would therefore anyway apply, in case the skilled person should attempt to adjust the dose for the formulation described in document D9 in order to achieve effective treatment. The subject-matter of claim 1 as granted would thus also not be obvious to the skilled person when starting from document D9 as closest prior art.

6.5 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.