Fulvestrant – Netherlands

Fulvestrant – Netherlands

On Apr. 11, 2018, District Court The Hague handed down its decision in FASLODEX® & revoked formulation patents for lack of inventive step in a revocation proceeding initiated by Sandoz.

AstraZeneca is the holder of the European patents EP 1250138 B2 and EP 2266573 B1. The patents belong to the same patent family, both bear the title ” Fulvestrant formulation.” Court considered “Howell” as closest prior art, which shows results from Phase II clinical studies with fulvestrant for the treatment of estrogen-dependent breast cancer. It discloses formulation of fulvestrant in castor oil containing 250 mg / ml fulvestrant is administered intramuscularly to patients with breast cancer. It is also shown in Howell that the blood plasma concentration of fulvestrant remains at a therapeutically relevant value for a month.
Based on the foregoing, the objective technical problem can, in the opinion of the District Court, be further specified as follows: “the provision of a fulvestrant formulation in which 250 mg of fulvestrant is dissolved in 5 ml of castor oil and the formulation (i) is suitable for treatment. of breast cancer, (ii) does not precipitate and (iii) with sustained release, in that a therapeutically significant plasma concentration is obtained for at least two weeks after administration 5 ml by intramuscular injection”.

Court further said that in the search for a solution to the problem, the person skilled in the art would primarily look for known castor oil formulations of fulvestrant. Applying a previously disclosed formulation is after all the simplest solution to the problem. The court agreed with Sandoz that the expert will encounter “McLeskey” in the same field – research into the treatment of breast cancer – and was public. In McLeskey, moreover, reference is made to Howell. In McLeskey two different formulations of fulvestrant are disclosed, both with a concentration of 50 mg fulvestrant / ml, as shown by the description of the drugs used. In McLeskey, therefore, one skilled in the art will find a preformulated solution of fulvestrant in castor oil with exactly the target concentration (50 mg / ml corresponds to 250 mg in 5 ml, as used in Howell, sub-features 30.5 and 30.6).
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. He also knew by the clinical research published in Howell, but also by publications of (the predecessor of) AstraZeneca , that fulvestrant was promising for the second-line treatment (after tamoxifen) of (estrogen-dependent) breast cancer in humans. 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. The excipients that are disclosed in McLeskey are therefore excipients that are suitable for and not unusual in medicines. This fact will put the person skilled in the art on the trail that there may be a suitable formulation, and in any case the used expedients will not prevent him from doing research.
Court further held that the relevant 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 vivoanimal 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. He thus comes to the invention claimed in claim 30 without creative thinking. This implies that conclusion 30 in combination with claims 1 and 29 of EP 138 is null and void due to lack of inventiveness.
EP 573 is a (small) daughter of EP 138. EP 573 discloses the specific formulation of (claim 30 of EP 138), which has previously been found invalid. Neither has it been established nor revealed that EP 573 discloses other sub-features which make it inventive. The same applies to the sub claims. All this implies that EP 573 on the same grounds as considered with regard to EP 138 is not inventive based on Howell in combination with general knowledge and McLeskey, so that the Dutch part of this patent will also be destroyed. 
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