I might be giving away my age, but I remember the early 90’s, and the revolution we saw in chiral purification techniques at that time. Sepracor even made a successful business of it, by taking old molecules that had been approved as racemates, and developing the active stereoisomer for FDA approval. You may remember the “chiral switch” of such famous brands as Prilosec® (omeprazole) to Nexium® (esomeprazole), or Celexa® (citalopram) to Lexapro® (escitalopram).
Our patent system successfully encouraged these advances in chemistry, with safer and more effective drug products as a consequence. I did an assignee search in the U.S. patent database, and learned that Sepracor received 322 United States patents as a result of its innovation. What a great client that would have been!
At the time I wondered how, if it was known that a compound exists as only two stereoisomers, either of the stereoisomers could be patentable. How could it not be obvious to separate the stereoisomers, and figure out which one is active. And make no mistake about it; a chemist can determine whether a molecule exists in more than one optical state simply by looking at the structure of the molecule on a piece of paper.
I happened to be working with some great chemists who were developing new nucleosides to combat viral diseases such as HIV, HBV, HCV, etc. Biologists had discovered that you could fool these viruses into incorporating the wrong stereoisomer of a nucleoside into a nucleotide as it was being transcribed and that once this stereoisomer was plugged in, transcription would come to a grinding halt. Chemists were then tasked with synthesizing nucleosides with the appropriate chiral activity. Chiral chromatography was not what it is today, and they had to develop new chemical schemes for synthesizing and purifying these unnatural stereo-specific nucleosides.
The patents that these chemists were awarded, however, were not limited to chemical schemes that they had developed. They also secured patents that claimed the stereospecific molecules themselves. The Patent Office awarded these patents because, until the chemists developed these new synthetic schemes, a method was not known for isolating the optically pure compound. An inventor of a chemical compound is entitled to a patent if someone of ordinary skill in the art would not have been able to make the compound without undue experimentation. See Forest Labs., Inc. v. Ivax Pharm., Inc., 2007 WL 2482122 (Fed. Cir. Sept. 5, 2007) (no anticipation because paper did “not enable the preparation of the (+)-enantiomer of citalopram.”); In re Wiggins, 488 F.2d 538, 542-43 (C.C.P.A. 1973) (prior art reference naming of compounds “whose syntheses were unsuccessfully attempted” did not anticipate later claim to compounds).
With time, however, reagent manufacturers began developing new materials for use in HPLC columns that could separate molecules based on their stereochemistry. Which raised the question: could a method that was patentable 20 years ago suddenly become non-patentable based on subsequent scientific developments? In Ex parte Eugene, 2018, Pat. App. LEXIS 3698 (P.T.A.B. May 15, 2018) (“Ex Parte Eugene”), the PTAB hit this issue head-on.
In Ex Parte Eugene, the applicant was attempting to claim an enantiomerically enriched genus of diacylhydrazines. The Examiner cited a trade publication from a company whose business is to perform chiral separations on a contract basis. According to the PTAB, this publication described "dramatic advances in the chiral stationary phases (CSPs) that have made HPLC and SFC indispensable techniques for drug discovery." Further:
Zhang discloses that 1300 CSPs (columns to separate enantiomers) have been prepared and that over 200 are commercially available. Further, Chiral Technologies is a product and services catalog describing a large number of different commercially available CSP columns and commercial separation services. Thus, at the time of the invention, technology was widely available to achieve enantiomer separation.
The Applicant attempted to turn this disclosure around by calculating 21,600 experiments that could be performed following Zhang’s teachings to find the right chiral reagents and conditions, but the PTAB was not persuaded. According to the PTAB:
we consider whether the claimed invention would have been arrived at by following a routine and predictable path described in the prior art.
The PTAB rejected the applicant’s 21,600 experiment argument because:
it has not been persuasively demonstrated that enantiomeric separation of the identified compound required anything more than routine experimentation using the conventional technology available to one of ordinary skill in the art at the time of the invention. Indeed, the evidence from two companies offering services in enantiomeric separation, PDR-Chiral and Chiral Technologies, suggest that enantiomeric separation technology was well developed and routine.
Which leaves us with one burning question. Will it ever be possible again to patent a molecule based on its stereochemistry? The PTAB’s rationale Ex Parte Eugene certainly seems to leave little room for argument.
But perhaps there is still some hope. I am reminded of a stereoisomer strategy that the Europeans employ, which effectively extends their patent term for new stereoisomers by 18 months. They claim a racemic mixture in their first application for a new compound and then, 18 months later, before the racemic patent application is published, they file a second application that claims the purified stereoisomer. Even if the stereoisomer is obvious based on the racemate, it is still novel and, under European examination guidelines, the application for the compound cannot render the stereoisomer obvious until after it is published.
