Eliquis®, the Bristol Myers Squibb (BMS) and Pfizer apixaban product, was recently ranked among the top five pharmaceutical products sold worldwide, with a significant increase in demand resulting from the Covid-19 pandemic. Enforceability of BMS and Pfizer’s patent portfolio will clearly be critical to the continued success of this blockbuster drug.
Following revocation proceedings brought by Sandoz and Teva Pharmaceutical Industries (Teva), earlier this year, the High Court of England and Wales invalidated the basic European (UK) apixaban patent and the supplementary protection certificate (SPC) from BMS, for lack of plausibility (i.e. Agrevo evidence and/or insufficiency).
Recently, the High Court also assessed the obviousness of four of BMS’s and Pfizer’s European (UK) patents relating to apixaban formulation patents, following new revocation proceedings initiated by Sandoz and Teva. The European patents belong to the same family and have all been recently revoked by the opposition division of the EPO. However, these decisions are either under appeal or pending appeal.
The main claim to be dealt with in the UK proceedings was claim 1 of EP3246021B (EP’021), in proposed amended form. This claim related to a tablet comprising up to 5 mg of apixaban crystalline particles having a specified particle size (D90
Based on this, the qualified team was taken to include a clinician, who would define the desired formulation; and a formulator, who would aim to prepare it.
As of the effective date, apixaban was well known to be a promising anticoagulant alternative to warfarin and had reached advanced stages of clinical trials.
The parties agreed that a review article regarding the development of apixaban would prompt the clinician to recommend the formulation of 2.5 and 5 mg immediate-release tablets, which had been used in the described clinical trials.
From the review article, the steps necessary for the claim were taken to be the choice of particle size and dissolution rate. The remaining features were not considered to contribute to inventive step.
For most drugs in tablet form to reach the systemic circulation, the tablet must first disintegrate in the stomach; then the active ingredient should dissolve in gastrointestinal fluids and penetrate through tissue membranes at the site of absorption from the gastrointestinal tract.
The parties agreed that at an early stage of development, the formulator would systematically assess the steady-state solubility of apixaban at recommended doses. As a result, they would consider apixaban a Class III drug (high solubility and low permeability) under the Biopharmaceutical Classification System (BCS).
Although equilibrium solubility tends to correlate with dissolution rate, they are different; sometimes a soluble drug is slow to dissolve, which may limit the absorption of the drug.
The BMS and Pfizer expert believed the qualified team would be so optimistic about the dissolution rate of a Class III drug that it would not be tested. However, Judge Meade disagreed. Given the complexity and cost of drug development, as well as the risks associated with future process changes and biological waivers, the judge ruled that the formulator would not leave poor bioavailability to chance. Instead, the formulator would aim to ensure a rapid dissolution rate (such as 85% dissolution in 15 or 30 minutes) at an early stage.
Although a problem with the dissolution rate could not be predicted, assuming the formulator had discovered a problem, the judge concluded that he would arrive at the claimed formulation based solely on his common general knowledge. The formulator would first check the decay rate and make any necessary improvements. An obvious way to ameliorate any remaining dissolution problems was to reduce particle size; and the claimed size (D90
Other obvious solutions were available, such as the optimization of excipients. However, this was not considered to make the claimed solution less obvious.
Conversely, if there was no dissolution rate problem, the receivable makes no technical contribution.
Therefore, Judge Meade held that the UK designations of the four European patents were invalid.
The judge was aware of the decisions of the opposition division. He acknowledged that different prior art had been considered at the EPO, but acknowledged that his reasoning was broadly consistent with that of the Opposition Division.