In Defense of Secondary Pharmaceutical Patents in Drug Discovery and Development

Abstract

“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.

Nonsteroidal Anti-Inflammatory Drugs–1-Phenylethylamine Diastereomeric Salts: A Systematic Solid-State Investigation

“…The development of a single-enantiomer drug starting from the corresponding chiral one, previously developed as a racemic mixture, is referred to as a “chiral switch”. The change in the status of the drug chirality, i.e., the chiral switch, also implies patent issues, e.g., enantiomer patents, a kind of secondary pharmaceutical patent, which claims a single enantiomer of a chiral drug previously claimed as a racemate. , Ibuprofen was the first NSAID to be switched to the single-enantiomer formulation, followed by ketoprofen four years later (1998), and their S enantiomers are also marketed in several fixed-dose combination drugs, as well as ( S )-naproxen.…”

Synthesis and Enantioselective Pharmacokinetic/Pharmacodynamic Analysis of New CNS-Active Sulfamoylphenyl Carbamate Derivatives

“…In this document, the FDA recommends the evaluation of therapeutic utility and/or toxicological effects of each stereoisomer for chiral drug candidates [ 18 ]. Thus, there is an incentive to develop a chiral drug as a single individual enantiomer even if it is marketed first as a racemate [ 12 , 15 ]. In addition, a chiral switch from a racemate to one of its individual enantiomers is utilized to extend the period of patent exclusivity, since secondary pharmaceutical patents protect a range of aspects other than the active pharmaceutical ingredient (API-protected by the primary pharmaceutical patent) [ 15 ].…”

“…Thus, there is an incentive to develop a chiral drug as a single individual enantiomer even if it is marketed first as a racemate [ 12 , 15 ]. In addition, a chiral switch from a racemate to one of its individual enantiomers is utilized to extend the period of patent exclusivity, since secondary pharmaceutical patents protect a range of aspects other than the active pharmaceutical ingredient (API-protected by the primary pharmaceutical patent) [ 15 ]. The term “chiral switch”, which is a component of secondary pharmaceutical patents, refers to the development of a single enantiomer from a chiral drug that was developed or marketed previously as a racemate.…”

“…It also demonstrates that a whole-body (in vivo) PD measure such as MBPC-MES-ED 50 is enantioselective as an MBPC-specific PD measure, such as a CA inhibition K I or the primary PK parameter clearance, which, in the case of MBPC, is mainly metabolic. The better anticonvulsant activity of (S)-MBPC is an incentive that it will be developed as a single individual enantiomer [ 12 , 15 ]. Nevertheless, this needs to be confirmed by other anticonvulsant models and does not rule out the possibility that both MBPC individual enantiomers might be candidates for further evaluation as potential new AEDs.…”

“…Indeed, drug chirality is a major issue in the design and development of new active pharmacological entities, since stereoisomers that possess the same chemical formula but different 3D conformations generally produce diverse pharmacological responses [ 11 , 12 , 13 , 14 , 15 ]. Many new chiral small molecule drugs were recently approved by the US Food and Drug Administration (FDA) as a single stereoisomer [ 13 , 16 , 17 ].…”