Key points
- Claim 1 of the main request reads: "Claim 1 of the main request defined: "A composition comprising an effective amount of a complex comprising synthetic endoxifen, wherein said endoxifen is a free base or is in the form of a salt for use in the treatment or prevention of cancer by the oral mode of administration."
- "Document E1 reports results of in vitro assays for estrogen receptor binding, inhibition of estrogen stimulated breast cancer cell proliferation and regulation of estrogen responsive genes indicating that endoxifen has equivalent activity to 4-OH-Tam, which is known as a potent active tamoxifen metabolite [i.e. is a metabolite of tamoxifen, and is potent and active]."
- The abstract of E1, from 2004, can be found here; the authors are not the inventors of the patent: https://link.springer.com/article/10.1023/B:BREA.0000025406.31193.e8.
- The abstract includes: "We demonstrate that endoxifen has essentially equivalent activity to the potent metabolite 4-hydroxy tamoxifen (4-OH-tam) often described as the active metabolite of this drug [tamoxifen]. "
- "Tamoxifen is a nonsteroidal antiestrogen that has found successful applications for each stage of breast cancer in the treatment of selected patients. " (link, from 1992)
- The Board: "Document E1 does not describe a composition for use in the treatment or prevention of cancer by the oral mode of administration as defined in claim 1 of the main request."
- As a comment, it is unclear to me if the Board considers that E1 does not describe endoxifen for use in the treatment or prevention of cancer, or only fails to teach the oral administration.
" the patent presents in example 10 results of in vitro experiments which are in line with the results from the experiments already described in document E1. In example 9 the patent further reports that mice can survive exposure to certain doses of intravenously administered endoxifen, whilst examples 11-15 relate to protocols for testing the effects of endoxifen following oral administration without presentation of any actual results."
- "In view of document E1 and having regard to the teaching in the patent the Board considers the objective technical problem as the provision of an effective and convenient administration form for endoxifen in the treatment of cancer."
- Note, the formulated problem does not refer to safety, so the additional example 9 regarding mice safety is not apparently considered. Hence, possibly, providing in vitro results that are "in line" with the in vitro results of E1, is seen as solving the problem of "the provision of an effective ... administration form", or the protocols that are presented without results, or some information added in the general part of the description (which uses claim-like language instead of the language used in the scientific paper E1).
- Note, apparently, the presented in vitro results are considered to be sufficient proof that an effective administration form for endoxifen in the treatment of cancer is provided (together with any other technical information in the patent); though it must be borne in mind that the Board found the claimed subject-matter not inventive even when seen as solving this problem..
The Board: " In view of the pharmacological activity of endoxifen as known from document E1 and taking account of the well known convenience of oral administration the Board considers that the skilled person would, in the absence of any prejudice against oral administration of endoxifen, regard the claimed subject-matter an obvious solution for providing a convenient and effective mode of administration for endoxifen in the treatment of cancer."
A detailed discussion follows whether there was a technical prejudice "against effective oral administration of endoxifen." The Board considers such prejudice not proven after a detailed review of the (technical) evidence.
The appeal of the proprietor is dismissed, and the patent remains revoked.
As it stands, the Board does not need to comment on the holding of G 2/21 (which was issued a few days before the present decision was taken) that for second medical use claims, "it is necessary that the patent at the date of its filing renders it credible that the known therapeutic agent, i.e. the product, is suitable for the claimed therapeutic application".
Of course, whether the in vitro assay results are sufficient for meeting that requirement of G 2/21 can be a matter of debate requiring great expertise in the technical field at issue.
EPO
Reasons for the Decision
1. Main request - inventive step
1.1 Closest prior art
Document E1 reports results of in vitro assays for estrogen receptor binding, inhibition of estrogen stimulated breast cancer cell proliferation and regulation of estrogen responsive genes indicating that endoxifen has equivalent activity to 4-OH-Tam, which is known as a potent active tamoxifen metabolite (see E1, abstract and pages 155-156, figure 3).
The identification of document E1 as an appropriate starting point in the prior art was not in dispute.
1.2 Problem to be solved
Document E1 does not describe a composition for use in the treatment or prevention of cancer by the oral mode of administration as defined in claim 1 of the main request.
As pointed out in the decision under appeal (see page 10, section 2.3.3.1) the patent presents in example 10 results of in vitro experiments which are in line with the results from the experiments already described in document E1. In example 9 the patent further reports that mice can survive exposure to certain doses of intravenously administered endoxifen, whilst examples 11-15 relate to protocols for testing the effects of endoxifen following oral administration without presentation of any actual results.
In view of document E1 and having regard to the teaching in the patent the Board considers the objective technical problem as the provision of an effective and convenient administration form for endoxifen in the treatment of cancer.
1.3 Assessment of the solution
1.3.1 In view of the pharmacological activity of endoxifen as known from document E1 and taking account of the well known convenience of oral administration the Board considers that the skilled person would, in the absence of any prejudice against oral administration of endoxifen, regard the claimed subject-matter an obvious solution for providing a convenient and effective mode of administration for endoxifen in the treatment of cancer.
In this context the Board observes that endoxifen represents one of various known metabolites of tamoxifen. In view of the required metabolism for its generation following the oral administration of tamoxifen it is not at all surprising that a different endoxifen exposure profile, including a faster onset of the Cmax , results from the oral administration of endoxifen itself as compared to the oral administration of tamoxifen. Accordingly, the difference in endoxifen exposure profile from oral administration of endoxifen itself as compared to tamoxifen as reported in document E23 does not affect the assessment of the solution.
1.3.2 In accordance with the established jurisprudence a technical prejudice concerns an opinion or preconceived idea widely or universally held by experts in the relevant field. The existence of a prejudice relied upon for meeting the requirement of inventive step needs to be convincingly demonstrated by the proprietor, typically by reference to the literature or to encyclopedias published before the relevant filing date (see Case law of the Boards of Appeal of the European Patent Office, 10th edition, 2022, section I.D.10.2).
1.3.3 The appellant relied with reference to the declaration in document E26 on the existence of a prejudice against effective oral administration of endoxifen. In view of the common knowledge presented in document E27 (see paragraph "Passage diffusion" on page 1) the skilled person would already expect reduced absorption for endoxifen as compared to the more lipophile tamoxifen. The prejudice would in particular follow from the known unsuitability for oral administration of the closely related tamoxifen metabolite 4-OH-Tam due to its inactivation by the liver as described in documents E8 and E30, the structural similarity between 4-OH-Tam and endoxifen and the known inactivation of 4-OH-Tam and endoxifen by glucuronidation as described in document E31 and cited in the review on first-pass glucuronidation of phenolics as a barrier to oral bioavailability of phenolics in document E28.
The Board observes, however, that the unsuitability of the tamoxifen metabolite 4-OH-Tam for effective oral administration due to extensive hepatic inactivation and elimination as reported in documents E8 (see page 497, left column, third full paragraph) and E30 (see page 1525, left column, last paragraph) may support support the prejudice against oral administration of 4-OH-Tam, but does not necessarily demonstrate the existence of a similar prejudice with respect to endoxifen.
The structures of 4-OH-Tam share a phenolic hydroxy group and only differ in the demethylated amino group in endoxifen. As argued by the appellant with reference to document E26, the skilled person may on the basis of the structural similarity between 4-OH-Tam and endoxifen, have expected that the bioavailability of endoxifen following oral administration is also affected by inactivation and elimination by the liver. Document E31, which relates to a research article published in 2007, the year of filing for the present patent, indeed confirms that endoxifen is glucuronidated and indicates that the glucuronidates of 4-OH-Tamoxifen and endoxifen are inactive at relevant doses (see E31, page 1943, Figure 1 and page 1946, right column). However, the related agents raloxifene and droloxifene, which are also prone to deactivating glucuronidation of their phenolic hydroxy-group, have nevertheless been reported in the prior art as effectively administered in oral dosage forms (see E29, page 694, left column, paragraph 1; see E32 and E33, abstracts). As pointed out in the decision under appeal (see page 14, paragraph 5) oral administration of raloxifen is effective in spite of its reduced (2%) bioavailability (see E29, supra), whilst the development of droloxifene was not stopped in view of inadequate bioavailability, but due to its inferior effectiveness with respect to tamoxifen (see E33, "Results" and "Conclusion"). The Board therefore considers that neither the structural similarity of endoxifen with 4-OH-Tam, nor the hepatic inactivation of endoxifen by glucuronidation, nor the more hydrophilic character of endoxifen with respect to tamoxifen convincingly substantiate the existence of a relevant prejudice against the suitability of endoxifen for oral administration.
The review in document E28 indicates that extensive glucuronidation can be a barrier to oral availability of an active agent (see E28, abstract) and confirms with references to document E31 and a further document published in 2007 (E52 as cited by the appellant) that endoxifen is mainly cleared via glucuronidation (see E28, pages 13-14, section 10.7.3). The Board takes the view that document E28 thereby merely indicates that the endoxifen will show a reduced bioavailability after oral administration. Apart from the circumstance that docent E28 was published after the filing for the patent (2011), the Board considers that document E28 does therefore not demonstrate the existence of any relevant prejudice against the oral administration of endoxifen either.
1.3.4 The appellant filed documents E39-E52 with the statement of grounds of appeal. The filing of these documents represents an amendment to the appellant's case under Articles 12(4) RPBA.
The additional documents E53-E62 were filed with the appellant's letter of 26 May 2021. The filing of these documents represents an amendment to the appellant's appeal case under Articles 13(1) RPBA.
Document E39 merely indicates that it is possible that tamoxifen metabolites are rapidly conjugated and excreted via the bile duct (see page 134, left column) and may therefore not enter the systemic circulation at a detectable concentration without any reference to endoxifen.
Documents E40-E51 were relied upon by the appellant to confirm that 4-OH-Tam was widely known to be metabolically inactivated following oral administration and that 4-OH-Tam had been successfully developed in a different direction, namely for transcutaneous administration. Document E54 and the post-published document E55 also focus on the administration of 4-OH-Tam. As explained above in section 1.3.3 in relation to documents E8 and E30, the Board does not consider that the unsuitability of 4-OH-Tam for oral administration demonstrates the existence of a prejudice against oral administration of endoxifen.
Document E52 confirms the susceptibility of endoxifen to glucuronidation by liver enzymes (see page 2013, right column, last paragraph). However, as explained above in section 1.3.3 in relation to document E31 the Board does not consider that the susceptibility of endoxifen to glucuronidation demonstrates a prejudice against its suitability for oral administration.
The passages from document E53 (pages 52, 54, 60 and 80) relied upon by the appellant in the letter of 26 May 2021 relate to droloxifene, raloxifene and 4-OH-Tam without specific reference to endoxifen. Moreover, document E53 was published in 2013, which is well after the filing date for the patent.
Document E56 (see abstract) discusses differences in the metabolic sulfation of raloxifene and 4-OH-Tam without reference to endoxifen.
Documents E57 and E58 (see abstracts) discuss the consequences of enterohepatic recirculation (EHC) on the exposure to drugs without reference to endoxifen. Moreover, these documents were published after the filing date for the patent.
Documents E59 and E60 (see abstracts) report on the influence of the position of the hydroxyl groups on the glucuronidation of flavones without reference to endoxifen. Moreover, document E60 was published after the filing date for the patent.
Document E61 reports the more rapid elimination of droloxifene as compared to tamoxifen without reference to endoxifen.
Document E62 was cited by the appellant to merely point out that tamoxifen is glucuronidated after its conversion to endoxifen.
The Board therefore considers that documents E39-E62 are not suitable to address the issues that lead to the decision under appeal. The Board therefore decided not to admit documents E39-E52 under Article 12(4) RPBA and not to admit documents E53-E62 under Article 13(1) RPBA.
1.3.5 Accordingly, the Board concludes that the subject-matter of claim 1 of the main request does not involve an inventive step.
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