Fulvestrant – Netherlands

Fulvestrant – Netherlands

On Nov 27, 2018, Court of Appeal reversed first instance decision (Court of Hague) & upheld the validity of AstraZeneca’s patents.

AstraZeneca markets FASLODEX® which is used for the treatment of oestrogen hormone dependent breast cancers. AstraZeneca is the proprietor of European patents, EP 1250138 & EP 2266573 (same family). Claims are related to use of fulvestrant in preparation of pharmaceutical formulation for breast cancer wherein formulation comprises excipients such as recinoleate vehicle, non-aqueous ester solvent, and alcohol to attain plasm concentration for at least 2 weeks.  District court previously found that patents lack inventive step based on some prior arts.  Specifically, district court held that the person skilled in the art knew that there had to be a formulation which showed the positive therapeutic effects, sustained release and few side effects disclosed in Howell, in which 250 mg of fulvestrant was dissolved in 5 ml of castor oil. According to the person skilled in the art, it was not possible to dissolve 250 mg of fulvestrant without excipients in 5 ml of castor oil. This provides an important motivation to search for a formulation containing 5 ml (this is the maximum amount that can be comfortably injected intramuscularly). In McLeskey a formulation is disclosed with three excipients (15% w / v BzBz, 10% w / v BzOH and 10% w / v EtOH) where fulvestrant is dissolved in the desired concentration in castor oil. In addition, it is stated in McLeskey that the solution in castor oil is pre-formulated ready for use. Thus person skilled in the art, starting from the objective technical problem and encountering the castor oil formulation of McLeskey, will examine the suitability of that formulation with standard tests with a reasonable expectation of success. In doing so, he will find that the formulation in in vivo animal testing on rabbits is appropriate for the treatment of breast cancer, does not precipitate and that there with a therapeutically significant plasma concentration is obtained for at least two weeks after administration of 5 ml by intramuscular injection, at least for five days in rabbits.

Court of appeal however, disagreed & said that the district court overlooked some important pointers. In summary, court of appeal said that prior art discloses 20% alcohol (10% benzyl alcohol and 10% ethanol) which is quite high when considering injectable preparations. It was not disputed that alcohol will diffuse rapidly from an injected site due to its volatile nature solution and so much of that alcohol diffuses away from that fulvestrant in the castor oil in a (supersaturated) concentration normally too high to be present as a solution, so that, normally spoken, fulvestrant precipitates. AstraZeneca has stated that the alcohol percentage of 20% is so high that the professional would definitely expect precipitation. The person skilled in the art would reasonably expect fulvestrant to crystallize and thus causing irritation. According to Sandoz’s claim, the percentage of 20% is true on the high side, but not in such a way that the professional would worry about it. Because the formulation is not a solution of fulvestrant in water where the alcohol is present freely and as a result dissipates fully in the tissue’, but a solution in oil, in which’ the alcohol is not present freely and will not dissipate fully and directly into the tissue. Court further said that the aforementioned Sandoz assertion – for which there is no specific evidence – remains unproven. Therefore, court sided with AstraZeneca that the alcohol percentage of 20% in prior art is so high that the skilled person would expect the occurrence of precipitation on the priority date. District court thus erred in its analysis & its judgment of invalidity is therefore reversed.

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