Jynarque® (tolvaptan)
Case Name: Otsuka Pharm. Co., Ltd. v. Lupin Ltd., Civ. No. 21-900-RGA, 2024 WL 3618123 (D. Del. July 31, 2024) (Andrews, J.)
Drug Product and Patent(s)-in-Suit: Jynarque® (tolvaptan); U.S. Patent Nos. 8,501,730 (“the ’730 patent”) and 8,273,735 (“the ’735 patent”)
Nature of the Case and Issue(s) Presented: Jynarque® is indicated to slow kidney function decline in adults at risk of rapidly progressing autosomal dominant polycystic kidney disease. The ’730 patent claims highly pure tolvaptan, while the ’735 patent claims a process for preparing tolvaptan. Prior to trial, the parties narrowed the issues to infringement, invalidity for obviousness, and unenforceability due to inequitable conduct. At trial, the court granted Otsuka’s motion for a Rule 52(c) judgment that the asserted patents were not unenforceable due to inequitable conduct, leaving only the issues of infringement and obviousness to be decided. The court’s trial opinion found that Lupin did not infringe the patents-in-suit, that the asserted claims of the ’735 patent were obvious, and that the asserted claims of the ’730 patent were not invalid.
Why Lupin Prevailed: Non-infringement. The parties disputed the interpretation of a claim term requiring reduction in the presence of a hydrogenating agent used in an amount of 0.25-1 mole per 1 mole of the ketone precursor. Otsuka argued that this claim language referred to the amount of hydrogenating agent added before the reduction reaction reaches “practical completion” or is “complete in a practical sense.” Conversely, Lupin argued that so long as unreacted ketone precursor and sodium borohydride are present, then the reaction is not complete. The court concluded that “absolute completion,” which is only a theoretical possibility, cannot define the endpoint of the claim. The court explained, however, that Otsuka failed to prove that Lupin’s process reached practical completion when 0.05 percent of the ketone precursor remains. In particular, the court noted that nothing in Lupin’s DMF demonstrated infringement and explained that Otsuka declined to recreate Lupin’s manufacturing method, meaning that Otsuka failed to meet its burden of proving infringement.
’735 patent obviousness. The parties agreed that the Kondo prior art reference disclosed each limitation of the asserted claims except for the claimed ranges of sodium borohydride added during the reduction stage. Otsuka, nevertheless, made several arguments as to non-obviousness. Otsuka first argued that a POSA would not have selected Kondo as a starting point because its process was for synthesizing small amounts of tolvaptan, and no aspect was appropriate for industrial-scale synthesis. The court rejected this argument, explaining that the asserted claims did not recite industrial-scale synthesis, and thus Lupin did not need to show that Kondo would have been appropriate for industrial-scale synthesis. Otsuka next argued that Lupin failed to explain why a POSA would have been motivated to modify the reduction step of the Kondo synthesis process, as opposed to one of the other process steps taught by Kondo. The court explained, however, that just because other steps in Kondo could also be improved does not mean that a POSA lacked the necessary motivation to modify Kondo to reach the claimed invention. The court subsequently adopted Lupin’s argument that a POSA would have been motivated to reduce the amount of sodium borohydride in Kondo in order to reduce costs, simplify post-processing, and improve overall safety of the manufacturing process. The court also agreed with Lupin’s argument that a POSA would have had a reasonable expectation of success in synthesizing tolvaptan by reducing the amount of sodium borohydride in Kondo’s reduction step. Finally, the court address Otsuka’s alleged secondary indicia of non-obviousness, including commercial success, long-felt need, and unexpected results. As to commercial success, the court found that Otsuka’s blocking patents deterred others’ investment in making the claimed invention. The court also found weak nexus, as the key driver in sales of Jynarque® were the API; not the claimed method. The court explained that there was no evidence of long-felt need or unexpected results. On balance, in light of minimal secondary indicia of non-obviousness, the court found that the ’735 patent was invalid as obvious.
’730 patent validity. The ’730 patent recited product-by-process claims. The parties disputed who bore the burden of proof of establishing structural and functional differences between the claimed product and the prior art. The court explained that it was Lupin’s burden, and therefore the patents were not invalid, as Lupin’s obviousness position rested on an argument that Otsuka’s expert presented no evidence in support of the non-obviousness of the ’730 patent.
