European patent 2101731 was granted on the basis of eleven claims. The first claim of the granted patent was directed towards 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. The OD decided to revoke the patent for lacking novelty. In particular, it was considered that two cited prior art documents already reported the effect of endoxifen on the proliferation of breast cancer cells, meaning that no new technical teaching with respect to the claimed medical use was presented.
The decision of the OD to revoke the patent was appealed by the P. Together with the statement of grounds of appeal the P filed a new main request. 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.”
According to the P, claim 1 of the main request was novel over the cited prior art because it related to the actual use of endoxifen in the treatment or prevention of cancer by the oral mode of administration.
Starting from this specific form of administration as the identified difference, the P subsequently formulated the objective technical problem as the provision of an advantageous administration form for effective cancer treatment with endoxifen. The P argued that the skilled person would not have arrived at claim 1 of the main request because they would have had to overcome a technical prejudice against the oral administration of endoxifen. This prejudice was explained in an expert declaration presented to the OD, and was allegedly supported by other documents as filed before the OD. The P believed that, altogether, these documents:
As such, the P reasoned that claim 1 of the main request was also inventive in view of the prior art.
The question to be addressed at hand was therefore whether a relevant prejudice against the oral administration of endoxifen was convincingly demonstrated by the P.
The Board ruled that P did not convincingly substantiate the existence of a relevant prejudice against oral administration of endoxifen. Specifically, the Board observed that the unsuitability of the tamoxifen metabolite 4-OH-Tam for effective oral administration may support the prejudice against oral administration of 4-OH-Tam, but did not necessarily demonstrate the existence of a similar prejudice with respect to endoxifen.
The Board acknowledged that 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 P with reference to the expert declaration, the skilled person may have expected based on the structural similarity between 4-OH-Tam and endoxifen that the bioavailability of endoxifen following oral administration would also be affected by inactivation and elimination by the liver.
However, the related agents raloxifene and droloxifene, which were also prone to deactivating glucuronidation of their phenolic hydroxy group, had nevertheless been reported in the prior art as effectively administered in oral dosage forms. As pointed out in the decision under appeal, oral administration of raloxifen was effective in spite of its reduced (2%) bioavailability, whilst the development of droloxifene was not stopped in view of its inadequate bioavailability, but due to inferior effectiveness with respect to tamoxifen.
In view of the above, the Board ruled that neither the structural similarity of endoxifen with 4-OH-Tam, nor the hepatic inactivation of both 4-OH-Tam and endoxifen by glucuronidation, nor the more hydrophilic character of endoxifen with respect to tamoxifen, convincingly substantiated the existence of a relevant prejudice against the suitability of endoxifen for oral administration. As a result, claim 1 of the main request was deemed to lack an inventive step. Further auxiliary requests submitted by the P were also considered to lack an inventive step. The appealed decision was therefore dismissed, and the patent remained revoked.
Summary written by the NLO EPO Case Law Team