Prodrugs are inactive compounds designed to be converted into pharmaceutically active metabolites following delivery to a patient. Prodrugs have important pharmacokinetic advantages over traditional compounds, and a recent PTAB decision, Lupin Limited v. Vertex Pharmaceuticals Inc. (IPR2016-00558), illustrates how prodrugs can possess patent advantages as well. In its analysis of obviousness, the PTAB focuses on unpredictable results and whether a person of ordinary skill in the art has a reasonable expectation of success in view of the available art, as outlined in Procter & Gamble Co. v. Teva Pharm. USA, Inc., 566 F.3d 989 (Fed. Cir. 2009), frequently applied in pharmaceutical cases.
The PTAB’s decision concerned U.S. Patent No. 6,436,989 covering fosamprenavir, a prodrug of the active HIV protease inhibitor amprenavir (Lexiva ®). In advancing its case, the petitioner cited a patent teaching an oral formulation of amprenavir, and another patent publication teaching that protease inhibitors can generally be modified to improve properties, namely solubility and bioavailability. The petitioner cited an expert declaration to argue that the claimed invention was obvious in view of the two publications, asserting that a person of ordinary skill in the art would have sought to modify amprenavir to address its known solubility-related problems as disclosed in the first publication, using methods for improving the solubility of HIV protease inhibitors as disclosed in the second publication.
In contrast, the patent owner argued that the skilled person could not have had a reasonable expectation of success in combining the teachings of the two publications due to unpredictability in the art of prodrug development. In support, the patent owner provided evidence from two experts, showing that there can be significant variability in solubility and bioavailability properties among different prodrug designs, and furthermore, that the in vivo conversion of prodrugs in the gastrointestinal (GI) tract can be complex, particularly in certain patients (e.g., HIV patients) and in situations in which a prodrug must be converted in a particular way for optimal absorption of the active drug into the bloodstream.
In making its final determination on obviousness, the PTAB centered on the lack of predictability within HIV protease prodrugs, and concluded that the petitioner failed to satisfy its burden of demonstrating that the claimed prodrugs were obvious by a preponderance of the evidence. In its analysis, the PTAB found that the evidence of record supported the determination that there was no reasonable expectation that modifying amprenavir would result in a successful deliverable prodrug because of the complexities of in vivo conversion evidenced by the patent owner’s experts. Moreover, in the PTAB’s analysis of secondary considerations, the often unpredictable nature of prodrugs further pushed in favor of non-obviousness. The PTAB highlighted unexpected benefits of the claimed prodrug over the active drug – agreeing with the patent owner’s evidence showing that the prodrug shows decreased drug resistance and superior pharmacokinetics relative to the active drug, while avoiding certain GI side effects of the active drug. The PTAB agreed these results were unexpected, because the prodrug delivers the active drug. The PTAB found that these unexpected results with fosamprenavir tipped in favor of patentability.
This decision highlights that in an obviousness determination, the lack of a reasonable expectation of success by a person of ordinary skill in the art and unpredictable results are key in a finding of non-obviousness. In the context of patents concerning prodrugs, patent owners and challengers should pay careful attention to processes involved in converting the prodrugs to active compounds, particularly where such processes may be affected depending on the particular disease to be treated. As was the case in this IPR, patentability may turn on the extent to which such prodrug conversion processes yield predictable results.