Late-stage functionalisation: a unique perspective from a research scientist turned patent attorney
Late-stage functionalisation – defined as “a desired chemoselective transformation on a complex molecule to provide at least one analog in sufficient quantity and purity for a given purpose without the necessity for installation of a functional group that exclusively serves the purpose to enable said transformation” [1] – has emerged as a valuable enabling tool within the arsenal of a medicinal chemist. As newer synthetic methods become developed for the generation of small molecules, so too has the chemical space that medicinal chemists will have access to.
Of course, these methods are valuable to the R&D team – but did you know that late-stage functionalisation will also likely have an impact on the IP profession? This perspective provides some insight into how late-stage functionalisation not only helps the chemists at the bench, but also the patent attorneys working in-house and within outside counsel who are very much off the bench.
The conventional approach to chemical synthesis – the “building block” route
Traditionally, the procedure for installing the required functionality in a small molecule typically involves utilising starting materials that already include such groups, or conducting one or more reactions that generate such groups – this stitching together of starting materials to generate the final product can be termed a “building block” approach.
The advent of late-stage functionalisation
The discovery and development of mild, chemoselective, site-selective and stereoselective reactions has fundamentally changed the way in which chemists think about synthetic chemistry. Reactions that were once considered fanciful decades ago are now enabled by recent advancements in transition metal catalysis, photoredox catalysis and the like.
For instance, it is now perfectly reasonable to think of various C-H groups as reactive handles at which functionality can be installed by C-H functionalisation [2].The medicinal chemist’s perspective
During the course of R&D, it is necessary to investigate structure-activity relationships (SAR). By investigating different types of substituents at various positions of a small molecule, the biological activity of the compound can be optimised.
The traditional “building block” approach can often conflict with the types of modifications desired when investigating SAR. Of course, it can be easier to investigate the effect of swapping out certain substituents if they were already introduced at a late stage of the synthetic route, illustrated schematically and with the example of imatinib below:
“wherein R1 is selected from hydrogen, halogen, OH, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted amino group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group”.
We have discussed in previous articles of our Data driven IP insights series that experimental evidence will be required showing how the invention can be reproduced by others (or, in legalese, by the notional “person having ordinary skill in the art” or “skilled person”). For a patent application relating to small molecules, this is typically achieved by providing synthetic procedures and characterisation data in the patent specification for a number of chemical compounds falling within the scope of such a Markush structure, much like the supplementary information section in a journal article.
The amount of experimental data required to “support” a claim to such a general chemical structure will very much depend on where you are pursuing patent protection.
Some jurisdictions may be relatively more lenient and will allow such claims to grant, even though not all substituent types have been exemplified by the experimental data of the patent specification (e.g. if an alkyl group has been exemplified in the examples for R1 in the Markush structure above, but not alkenyl or alkynyl groups).
However, other countries can be stricter, requiring that each substituent type be exemplified by at least one compound in the patent specification (e.g. if only an alkyl group has been exemplified in the examples for R1 in the Markush structure above, then the remaining substituents listed for R1 that are not exemplified may need to be deleted, before the patent office will allow the claim to grant). In such jurisdictions, the need to limit the scope of protection of the claims may be undesirable and can make it easier for third parties to work around the protection afforded by a granted patent.
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