Patent Landscape Report on Ritonavir - WIPO

several different ways. This particular area has seen a lot of patenting activity since Abbottdiscovered the issue of heat instability of crystalline Ritonavir in its solid dosage forms in thelate 1990’s. The innovation track is particularly note worthy because the documents in latergenerations can be important in the innovation tracks related to both liquid and solid dosageforms.The first generation patent application WO1994014436, assigned to Abbott Laboratories, isthe first disclosure of Ritonavir. The ‘436 document claims a broad Markush structure describingRitonavir. This initial document only claims a retroviral protease inhibitor and doesnot describe structural considerations or conformational polymorphs of Ritonavir.The second generation contains two documents, WO1996039398 and WO1995009614,both assigned to Abbott. The ‘398 document family claims a method of preparing an HIVprotease inhibiting compound. This also describes preparing an acid addition salt of thecompound. The Markush group prepared broadly covers Ritonavir because the Markushstructure is very general. The addition salt allows for this compound to be considered acrystalline solid. This document does not specifically disclose the crystalline conformation.The second second-generation document ‘614 family, claims a solid pharmaceutical compositioncomprising Ritonavir. This document does not disclose Ritonavir as crystalline. Thisdocument was included because it is one of the first patents to describe a solid pharmaceuticalcomposition comprising Ritonavir. The ‘614 document is also present in the next innovationtrack.The third generation documents claim a version of Ritonavir polymorphs. WO200004016(Abbott) and its published patent EP1097148 describe a crystalline polymorph of Ritonavirand methods of its use and preparation. These documents claim X-ray diffraction patterns ofa polymorph. As will be described in subsequent generations, the actual crystal form is notspecifically described because this is the first X-ray characterization. These claims leave potentialfor patenting around the crystal structure of Ritonavir.The fourth generation contains three patent families including US2004024031 (TransformPharm), US20050009756 (Abbott) and US20050203152 (Abbott). US2004024031 cites theAbbott PCT ‘016 and further describes polymorphs, solvates and compositions. The ‘031document claims five specific forms of Ritonavir with unique melting points and X-ray diffractionpatterns. The document also claims specific methods for preparing each form of Ritonavir.The preparation methods do not describe reaction conditions, but do generally describe“a solvent system comprised of formamide and an immiscible or partially miscible solventto provide a mixture, and reducing the solubility of Ritonavir”. These reaction conditionsare general in their description, but this document contains five lengthy independent claims.This application has since been granted as US7205413. The second document in the fourthgeneration, US20050203152, claims a pure amorphous form of Ritonavir with a specificglass transition temperature. This document is important because a pure compound with aglass transition temperature below room temperature would need to be stored in refrigerationto prevent conformational polymorphism. The third document in the fourth generation,US20050009756, describes the similar claims and has the same priority data asEP1097148. The ‘031 document describes the same crystal structure as the EP1097148document but also includes an independent claim describing substantially pure amorphousRitonavir.