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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