Summary :
- EP 1,427,415 was assigned to BMS and is set to expire on September 17, 2022. On May 19, 2026, the corresponding SPC (SPC/GB11/042) would expire.
- The patent claims are for apixaban, a factor Xa inhibitor supplied by BMS under the brand name ELIQUIS and used to treat thromboembolic diseases.
- Sandoz and Teva, the claimants, admitted infringement but asked for the patent to be revoked due to a lack of plausibility.
Sandoz and Teva Invalidate Patent and SPC of Blockbuster Apixaban
Sandoz and Teva bring claims
Teva filed a lawsuit in January 2021, and Sandoz filed a claim in November 2020. Following a case management conference in March 2021, Sandoz and Teva agreed to work together to manage the issue. The move might pave the way for the corporations to develop their own generic version of one of the most profitable anticoagulant medications on the market. Due to increased demand for anticoagulant medications during the global coronavirus epidemic, its market share has recently surged.
EP 14 27 415 and a supplementary protection certificate pertaining to it are owned by Bristol Myers Squibb and are valid until 2026. These relate to the apixaban chemical, which the business sells under the brand name Eliquis. The medicine, which thins the blood, can help treat thromboembolic problems such blood clots, especially after hip or knee surgery.
Applying for Amendments
Sandoz and Teva filed suit against Bristol Myers Squibb, contending that EP 415 was invalid. According to the judgment, the parties claim that the patent does not plausibly suggest that apixaban has a useful factor Xa inhibitory effect or would be useful in therapeutic settings. Also, according to the parties, physicians could not use the patented drug for other purposes. Since the success of apixabans depends on the use of an Xa inhibitor, the court examined the question of plausibility in order to find nullity. BMS also filed a counterclaim for infringement, which both plaintiffs admitted if the court found the patent valid.
The US company also applied to amend the EP-415 claims. Ultimately, however, the court declared the patent and corresponding protection certificates invalid for lack of plausibility due to inadequacy. The court recognized the amendments but did not formally admit them as it would not cure the invalidity [of the patents].
Protection across the Pond
In separate but related US proceedings, Bristol Myer Squibb fared better. In 2020, the US District Court for the District of Delaware upheld US patent 6,967,208 and formulation patent US 9,326,945. Following appeals by generics companies Sigmapharm, Sunshine Lake Pharma, Hec Pharm and Uniche, the US Court of Appeals for the Federal Circuit upheld the first-instance decision. Now, no generic drugs can enter the US market until the patents expire in 2028.
The dispute is also not yet over in the UK, as Sandoz and Teva also brought claims against five formulation patents (case numbers: HP-2020-000048; HP-2021-000009).
Sandoz has since cleared the validity and infringement of four patents, EP 25 38 925, EP 30 17 811, EP 32 57 500 and EP 32 51 660, while the lawsuit is over claims one through seven of the remaining patent EP 32 46 021 . Tevas’ actions were also fully pending for all five patents, although the EPO’s Technical Boards of Appeal have now revoked EP 925.
The UK High Court is due to consider the remaining four patents in a two-week trial commencing 28 April 2022.
Court Evaluation
Court said that the statements about lower Ki for preferred/more preferred/still more preferred compounds are aspirational targets only. There is no indication in this text itself of which or how many compounds were tested or with what specific result, and there is no reference to apixaban.
Court evaluated plausibility into 2 steps:
- Plausibility of factor Xa binding and Plausibility of therapy. BMS argued that only first point is sufficient and `652 makes it plausible that apixaban is an effective factor Xa inhibitor. Claimants disputed and argued that even if the specification of `652 made it plausible that apixaban had been tested and found to have a Ki of the order of 10 µM, that was inadequate for therapeutic use. C
- ourt agreed with claimants and said that BMS seeks to read far too much into the above sentence of page 170. There is no way from this sentence alone to draw any sort of inference about any individual compound, be it apixaban or any other. There is simply no information, and given Counsel for BMS’s acceptance that some compounds might also have failed, there is no way for the reader to know of any particular compound whether it was good or bad. Court thus finally concluded that the `652 application does not make it plausible that apixaban would have factor Xa binding of the level of 10 µM as referred to on page 170, or any useful degree of binding.
With respect to second point, (plausibility of therapy) court said that even if `652 had made it plausible that apixaban had the degree of binding indicated on page 170 (10 µM), it would not make it plausible that it would be useful in therapy, because nanomolar potencies were needed for that.
Conclusion
Court thus concluded that EP 1,427,415 B1 is invalid by reason of lack of plausibility. Because the patent is invalid, so is SPC/GB11/042.
About Apixaban
Apixaban Structure
- Apixaban, sold under the brand name Eliquis, is an anticoagulant medication used to treat and prevent blood clots and to prevent stroke in people with nonvalvular atrial fibrillation through directly inhibiting factor Xa.
- Apixaban is a pyrazolopyridine that is 7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide substituted at position 1 by a 4-methoxyphenyl group and at position 6 by a 4-(2-oxopiperidin-1-yl)phenyl group
- It is used for the prevention and treatment of thromboembolic diseases.
Medical Use –
- To lower the risk of stroke and embolism in people with nonvalvular atrial fibrillation.
- Deep vein thrombosis (DVT) prevention. DVTs may lead to pulmonary embolism (PE) in knee or hip replacement surgery patients.
- Treatment of both DVT and PE.
- To reduce the risk of recurring DVT and PE after initial therapy.
Mechanism of action
Apixaban is a highly selective, orally bioavailable, and reversible direct inhibitor of free and clot-bound factor Xa. Factor Xa catalyzes the conversion of prothrombin to thrombin, the final enzyme in the coagulation cascade that is responsible for fibrin clot formation. Apixaban has no direct effect on platelet aggregation, but by inhibiting factor Xa, it indirectly decreases clot formation induced by thrombin
Apixaban MOA
Pharmacodynamics
Apixaban selectively inhibits factor Xa in its free and bound forms, independant of antithrombin III Apixaban also inhibits prothrominase . These effects prevent the formation of a thrombus
Protein binding :92-94%