Bayer Intellectual Prop. GmbH v. Aurobindo Pharma Ltd.

Case Name: Bayer Intellectual Prop. GmbH v. Aurobindo Pharma Ltd., No. 15-902, 2018 U.S. Dist. LEXIS 116931 (D. Del. July 13, 2018) (Stengel, C.J.)

Drug Product and Patent(s)-in-Suit: Xarelto® (rivaroxaban); U.S. Patent No. 7,157,456 (“the ’456 patent”)

Nature of the case and Issue(s) Presented: Xarelto is a factor Xa inhibitor that is used to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation, to treat deep vein thrombosis (DVT) and pulmonary embolism (PE), and to prevent DVT and PE in patients undergoing knee or hip replacement surgery. Bayer and Janssen sued various generic manufacturers alleging infringement of the ’456 patent based on the generics’ filing of ANDAs. The generics stipulated to infringement but went to trial on the issue of obviousness. The only claim at issue at trial was claim 16, which is directed to the compound rivaroxiban.

The court’s decision turned on whether a POSA would have been motivated to choose linezolid, an oxazolidinone compound that at the time of the invention was in clinical trials for antibiotic indications, as a lead compound for developing a factor Xa inhibitor. In addition, if so, whether a POSA would have been motivated to modify the lead compound to make rivaroxiban with a reasonable expectation of success. After a bench trial, the court concluded that the asserted claim was not invalid as obvious.

Why Bayer Prevailed: Defendants argued that a POSA would have selected linezolid as a lead compound because: (i) it was the most advanced oxazolidinone in Phase III clinical trials; (ii) linezolid had an excellent pharmacokinetic profile, specifically 100% bioavailability; and (iii) linezolid possessed structural motifs characteristic of existing factor Xa inhibitors. The court found at the outset that there were seven promising lead compounds in the factor Xa field at the time of the invention, of which linezolid was not one. The court also found that a POSA would have been motivated to choose one of the seven with known factor Xa activity, and would not have been motivated to choose linezolid. But the court noted that even if there were no attractive lead compounds known, defendants still failed to prove by clear and convincing evidence that a POSA would have chosen linezolid.

The court found that Defendants’ first argument was a “red herring,” explaining that linezolid was in clinical trials for antibiotic indications rather than factor Xa indications. The court further found that there was no evidence in the prior art that oxazolidinones were useful as factor Xa inhibitors.

Next, the court found that 100% bioavailability, by itself, was an insufficient reason to choose linezolid as a lead compound. The court explained that 100% bioavailability was meaningless without known activity against factor Xa, and concluded that a POSA would not choose such a compound as a lead compound. Additionally, the court found that 100% bioavailability was not necessary for a lead compound as the prior art taught that 20% bioavailability was enough. Indeed there were compounds in the art with known factor Xa activity that had at least 20% bioavailability.

With respect to Defendants’ third argument, the court found that linezolid did not have structural motifs characteristic of factor Xa inhibitors. First, the court found that the prior art taught using a pyrrolidinone scaffold rather than an oxazolidinone scaffold, and provided no reason to use an oxazolidinone instead of a pyrrolidinone. Further, the art showed a pyrrolidinone example that was structurally similar to an oxazolidinone, which was forty times less potent than pyrrolidinones that were less structurally similar. Next, the court addressed defendants’ argument that the prior art taught factor Xa inhibitors with six-membered rings, like linezolid, would be effective. The court found that the prior art did not support that proposition. Instead, the prior art taught that aromatic rings were effective, and that the aromatic rings in the prior art just happened to be six-membered. The court went on to explain that the prior art taught away from the selection of linezolid as the lead compound. For one thing, it was undisputed that linezolid has no activity against factor Xa. Next, linezolid had several adverse effects. Linezolid had a potent antibacterial effect, which would have promoted antibiotic resistance. It also had several toxicities. Based on all of the foregoing analysis, the court found that a POSA would not have chosen linezolid as a lead compound.

The court then addressed the second prong of the lead-compound analysis, finding that even if a POSA would have been motivated to choose linezolid as a lead compound, POSA would not have made the modifications necessary to arrive at rivaroxaban. First, the court found that a POSA would have been motivated to modify linezolid’s oxazolidinone core by replacing it with a known factor Xa inhibitor. The POSA would have been motivated at least in part by the need to eliminate linezolid’s antibacterial activity. If POSA had modified the core, she wouldn’t have arrived at rivaroxaban. Next, the court found that a POSA would not have made two other structural modifications to arrive at rivaroxaban, finding that those structural modifications found no support in the prior art and went against conventional wisdom.

Finally, the court addressed secondary considerations of non-obviousness. The court found that rivaroxaban satisfied a long-felt but unmet need as evidenced by the eighteen pharmaceutical companies and hundreds of scientists looking for a factor Xa inhibitor. The court found that rivaroxaban had success where others failed, received industry praise, had industry skepticism, has been accepted by the medical community, demonstrated unexpected properties, and is a “blockbuster commercial success.” The court also found a nexus between the secondary considerations and the claimed invention because the asserted claim covers rivaroxaban, the sole active ingredient that makes Xarelto an effective drug. And nexus is presumed where “the asserted objective evidence is tied to a specific product and that product is the invention disclosed and claimed in the patent.”