On Jul. 15, 2022, UK high court revoked four apixaban patents under obviousness over single prior art.
BMS/Pfizer markets apixaban under brand, ELIQUIS for treating thromboembolic disorders. This case concerned four patents relating to apixaban from same family (EP(UK) 3246021; EP(UK) 3017811; EP(UK) 3251660 and EP(UK) 3257500). Claim 1 of EP’021 is representative and reads:
(a) A tablet comprising up to 5 mg crystalline apixaban particles having
(b) a D90 less than 89µm as measured by laser light scattering and
(c) a pharmaceutically acceptable diluent or carrier, wherein
(d) the formulation exhibits dissolution properties such that an amount of the drug equivalent to at least 77% dissolves within 30 minutes, wherein
(e) the dissolution test is performed in an aqueous media buffered to a pH range 1 to 7.4 and controlled at 37° C, wherein
(f) the result is established as an average of 6 tablets, and wherein
(g) the dissolution test is performed in 900 mL of dissolution medium containing 0.05 M sodium phosphate at pH 6.8 with 0.05% SDS at 37 °C using USP Apparatus 2 (paddles) at a rotation speed of 75 rpm and the samples are analyzed for apixaban by HPLC at 280 nm.
Claimants (Teva/Sandoz) sought to revoke the patents over prior art, Carreiro (“Apixaban, an oral direct Factor Xa inhibitor: awaiting the verdict”, published in November 2008 in Expert Opinion on Investigational Drugs) and Common General Knowledge (CGK). The main issue was whether it was obvious to make an apixaban tablet of 2.5mg or 5mg with the particle size profile of feature (b) and the dissolution rate of feature (d).
Court said that there is no dispute that Carreiro would motivate the clinician to recommend the formulator to make immediate release tablets of apixaban in 2.5mg and 5mg doses. The question is whether specific particle size and dissolution are within the purview of one skilled in the art. These features would come from CGK as formulator knows how to perform pre-formulation and other studies to know appropriate particle size and dissolution. The formulator would come to it with the understanding that the task was a feasible one, since tablets of the relevant doses had been used in the clinical trials listed in Carreiro. Court agreed with claimants that the formulator would find that the aqueous solubility of apixaban is relatively low, at 40µg/mL. Formulator then regard the low aqueous solubility as a warning sign that apixaban might have a slow dissolution rate so as to cause a problem in vivo. Formulator would make prototype formulations and test them and it would have been obvious to settle on a target dissolution rate of 85% in 15 or 30 minutes. Next, and assuming that there was a problem concerning dissolution rate, the Claimants submitted that one CGK way to address it would be by reducing particle size. Court further said that it would be uninventive to address dissolution rate issues by choosing a more appropriate particle size and in dealing with CGK, the size specified by the claims of `021 is well within the CGK range. Court said that although the attack involves a number of sequential steps, they are the systematic sequence known to the CGK.
Thus, all the patents are invalid for obviousness over Carreiro.
Note: Previously, in a judgment of 7 April 2022, Court also held that a patent covering apixaban compound and its SPC invalid. You can read the decision summary “here“ on this blog.