Agranat Israel, Marom Hili
Organic Chemistry, Institute of Chemistry, The Hebrew University of Jerusalem, Philadelphia Bldg. #212, Edmond J. Safra Campus, Jerusalem 9190401, Israel.
ACS Med Chem Lett. 2020 Feb 13;11(2):91-98. doi: 10.1021/acsmedchemlett.9b00497.
"An important objective of modern pharmaceutical research is the discovery of new medical uses for known molecules" (UKSC 2018), a component of secondary pharmaceuticals. This Viewpoint's focus is the defense of the vulnerable strategy of secondary pharmaceutical patents (SPPs). Typical claims thereof are new medical uses, dosage, selection, and enatiomer patents. The attacks on secondary pharmaceuticals, including chiral switches, use negative-connotation terms, such as "evergreening", "product hopping", and "pejorative". Most enantiomer patents, including the controversial Nexium patents, were challenged in courts worldwide yet validated. This Viewpoint considers the "teaching away" defense of nonobviousness of Nexium enantiomer patents due to "unexpected results", applying stereochemistry principles. Physical organic chemistry arguments and the prediction of lower energy barriers of epimerization/racemization of benzylic anions of esomeprazole and dexlansoprazole (compared with their uncharged enantiomers) are a basis of the "teaching away". This prediction is verified by DFT computations. "Obvious to try" of many SPPs should not prevail over "unexpected results". A generalized concern about "evergreening" drugs should not be a justification for comprehensive attacks on SPPs. Following UKSC Lyrica decision (2018), plausibility, a condition of patent validity, may enter the arena of enantiomer patents, claiming second medical uses. Secondary pharmaceutical dosage, selection, improvement, and enantiomer patents are not necessarily obvious.
“现代药物研究的一个重要目标是发现已知分子的新医学用途”（英国最高法院，2018年），这是二次制药的一个组成部分。本观点的重点是为二次制药专利（SPP）这一易受攻击的策略进行辩护。其典型的权利要求包括新医学用途、剂量、选择和对映体专利。对二次制药的攻击，包括手性转换，使用了“专利常青化”“产品跳跃”等带有负面含义的术语。大多数对映体专利，包括有争议的耐信专利，在全球范围内的法院都受到了质疑，但最终得到了验证。本观点考虑了耐信对映体专利因“意外结果”而具有的非显而易见性的“反向教导”抗辩，运用了立体化学原理。物理有机化学的论据以及对埃索美拉唑和右兰索拉唑苄基阴离子的差向异构化/外消旋化较低能垒的预测（与它们不带电荷的对映体相比）是“反向教导”的基础。这一预测通过密度泛函理论计算得到了验证。许多二次制药专利的“显而易见”不应胜过“意外结果”。对“专利常青化”药物的普遍担忧不应成为全面攻击二次制药专利的理由。继英国最高法院对乐瑞卡案的判决（2018年）之后，作为专利有效性条件的合理性可能会进入对映体专利领域，即主张第二医学用途。二次制药的剂量、选择、改进和对映体专利不一定是显而易见的。
