Rivaroxaban - USA

On Jul 13, 2018, District court of Delaware found Xarelto compound patent valid in Hatch-Waxman litigation proceeding.

In a consolidated patent infringement action, plaintiffs, Bayer and Janssen alleged infringement of claim 16 of U.S. Patent No. 7,157,456, which claims the compound rivaroxaban. The parties concede infringement. Defendants, Mylan and Sigmapharm Laboratories submitted that the patent is invalid as obvious. Four-day bench trial was held beginning on March 5-9, 2018.

Rivaroxaban, a factor Xa inhibitor is an anticoagulant that prevents blood clot. Factor Xa inhibitors have two key binding sites: the S1 and S4 pockets. The conventional wisdom as of priority date in December of 1999 was that in order to be a potent factor Xa inhibitor a compound required a basic P1 group at S1 pocket and an aromatic or basic P4 group at S4 pocket. Defendants selected linezolid as lead compound for obviousness & asserted that POSA would have made changes to the S1 & S4 pockets to arrive at Rivaroxaban. Specifically, Defendants asserted that a POSA would have selected linezolid as a lead compound because (1) it was the most advanced oxazolidinone in Phase III clinical trials; (2) linezolid had an excellent pharmacokinetic profile and more specifically, 100% oral bioavailability; and (3) linezolid possesses structural motifs characteristic of existing factor Xa inhibitor.

Court however, disagreed & said that it is well established that a lead compound is “a compound in the prior art that would be the most promising to modify in order to improve upon its . . . activity and obtain a compound with better activity.” Therefore, POSA would not have selected a compound which is antibiotic as a lead compound for factor Xa inhibitors. Court agreed that the Linezolid was the most advanced oxazolidinone antibiotic and it was in Phase III trials for antibiotic indications. But the relevant issue here, however, was whether the prior art taught that oxazolidinones were useful in factor Xa inhibitors. It did not.

Defendants next asserted that a POSA would have selected linezolid because it had 100% oral bioavailability. Court said that this argument failed for several reasons. First, 100% oral bioavailability is meaningless without activity against factor Xa. Second, the prior art taught chemists to address bioavailability by incorporating less basic P1 replacements into factor Xa inhibitors to obtain “good” oral bioavailability. Conventional wisdom did not teach the use of compounds with no activity against the target and 100% oral bioavailability.

Defendants next argued that linezolid has structural motifs characteristic of factor Xa inhibitors. Court disagreed & said that Ewing II does not teach using an oxazolidinone or linezolid as a lead. What is more, Ewing provided no reason to use an oxazolidinone core instead of a pyrrolidinone. This argument is further weakened by the fact that Ewing actually discloses data for two pyrrolidinone core structures, and the one closer in structure to an oxazolidinone was 40-fold less potent. A POSA simply would not have selected linezolid as a lead based on this prior art. 

Court further said that even if any one of the three reasons set forth by defendants were supported by clear and convincing evidence, the fact remains that the prior art taught away from the selection of linezolid as a lead compound. First, linezolid is an antibiotic & not factor Xa inhibitor. Second, it had several side effects. Third, antibiotics such as linezolid is used for short term treatment whereas factor Xa inhibitors are used for long term. Thus, defendants failed to prove that POSA would have selected linezolid as lead compound.  

Court further said that even assuming the POSA would have selected linezolid as a lead compound, the POSA would have not made the modifications necessary to arrive at rivaroxaban. Specifically, court held that based on the evidence presented at trial, that the development of rivaroxaban from linezolid was not an obvious path because it did not involve a “finite number of identified, predictable solutions. Instead, “[e]ach layer of decision-making would have required a lengthy research and development process that would not have provided predictable results.” Moreover, secondary considerations put forth by plaintiffs weigh in favor of non-obviousness. Thus, the claim 16 of the ’456 patent is not invalid due to obviousness.