3The Evolution of Combinatorial Technology Dates of appearance in the literature...Peptide & oligonucleotide librariesSmall organic moleculesSuperconductorsLuminescent compoundsCatalysts20?? - Convergence with genomics
4What Is “Combinatorial” Chemistry? “The chemical or enzymatic synthesis of a very large number of different molecules coupled with a screening technique…”Ecker et al. US 5,474,253, 1995“Methods for the efficient synthesis and screening of libraries of related compounds with well defined levels of diversity”Ellman et al. PNAS, 1997
5What Is “Combinatorial” Chemistry? “A new subfield of chemistry with the goal of synthesizing very large numbers of chemical entities by condensing a small number of reagents together in all combinations defined by a given reaction sequence”Czarnik and DeWittA Practical Guide to Combinatorial Chemistry, 1997
6What Is “Combinatorial” Chemistry? “This field is so new that even the basic terminology is not defined”Lebl, M. J. Comb. Chem., 1999
7What Is a “Combinatorial” Library? “An intentionally created collection of differing molecules which can be prepared either synthetically or biosynthetically” Gallop et al. J. Med. Chem., 1994“A combinatorial library can be defined as any ensemble of molecules” Janda, K. D. PNAS, 1994
8“Combinatorial”Absent evidence to the contrary, it is merely a process limitation similar to the term “recombinant”.Clarity in drafting the specification and claims is essential!
9Terminology Used in Combinatorial Chemistry In combinatorial technology there is no good set of terms that can cover every scenario.Commonly seen terminology: “combinatorial”, “library”, “collection”, “plurality”, “array”, “linker”, “resin”, “bead”, “diversity”, “tag”, “solid support/supported”, “high-throughput”, “iterative”, “deconvolution” this is by no means an exhaustive list!
10Issues under 35 USC 112As a library is a collection of components, it is therefore distinguished from a traditional Markush group.Amendments canceling library components may lead to new matter rejections, unless there is original support for the collection as amended.
11Issues under 35 USC 112 Enablement Example 1 Claim: A combinatorial library of compounds of formula Q-R in which R is a ligand that inhibits a target receptor and Q is a functional group.
12Claim: A combinatorial library of compounds of formula Q-R in which R is a ligand that inhibits a target receptor and Q is a functional group.Specification teaches only libraries with specific R moieties having binding properties to a particular receptor and specific Q moieties.Will probably result in rejection under 35 USC 112, first paragraph for scope of enablement (applicant enabled for specific moieties taught above).
13Issues under 35 USC 112 Important Points Specification must set forth the “core” on which a library is built.The core structure of the library that is described must bear some reasonable correlation to the scope of the claims.
14Issues under 35 USC 112 Enablement Example 2 Claim: A combinatorial library of dihydropyridine compounds of formula (I):wherein R1, R2 and R3 are independentlyselected from the group consisting of...
15Claim: A combinatorial library of dihydropyridine compounds of formula (I): wherein R1, R2 and R3 are independently selected from the group consisting of...Specification teaches libraries containing various functionalized compounds of formula (I) that are inhibitors of a particular receptor.Will probably NOT result in rejection under 35 USC 112, first paragraph.
16Is Claim 3 Properly Dependent? Claim DependencyClaim 1. A compound of formula x-a, wherein a is selected from the group consisting of . . .Claim 2. A combinatorial library comprising two or more compounds of formula x-a as set forth in claim 1.Claim 3. A compound of formula x-a as set forth in claim 1, which is a combinatorial library.Is Claim 3 Properly Dependent?
17Claim DependencyClaim 1 is a short hand of claiming a number of variations of a single compound of formula x-a.Claim 3 is a short hand way of claiming a collection of compounds en masse or as an ensemble and is NOT properly dependent.
18Another ScenarioClaim 1. A combinatorial library comprising two or more compounds of formula x-a.Claim 2. A compound of formula x-a selected from the library of claim 1.Is Claim 2 Properly Dependent?Most Likely
19Utility - 35 USC 101A Library/Mixture/Collection must have a specific, substantial and credible utilityAn example, covering the scope of the invention, goes a long way in avoiding potential utility problems.According to case law and current USPTO utility guidelines...basic research such as using a material in a method for studying the properties of the material itself or the mechanisms in which the material is involved, is not a specific and substantial utility.
20Utility - 35 USC 101 Utility Example Consider the previous claim... Claim: A combinatorial library of dihydropyridine compounds of formula (I):wherein R1, R2 and R3 are independentlyselected from the group consisting of...
21Assuming no well-established utility exists for such compounds then… Claim: A combinatorial library of dihydropyridine compounds of formula (I):wherein R1, R2 and R3 are independently selected from the group consisting of...Specification teaches libraries of compounds of formula (I) can be screened for biological activity.Assuming no well-established utility exists for such compounds then…Will probably result in rejection under35 USC 101.
22Utility - 35 USC 101HOWEVERIf specification teaches libraries of compounds of formula (I) can be screened for a specific activity and/or provides an example of screening the libraries and identifying a compound having a particular activity...Will probably NOT result in rejection under 35 USC 101.
23Clarity in Drafting the Disclosure and Claims is Essential!
24Anticipation and Obviousness Do “art known” collections/compositions read on “combinatorial libraries”?YESThe products/compositions are the same regardless of the manner in which they are prepared.
25A case for prima facie obviousness 1. If the parent molecule in a series is known; and2. The substituents and the substitution pattern claimed are established in the prior art, then3. Motivation to make the library becomes the question.
26Motivation Libraries of (bio)chemical entities “The goals of combinatorial organic synthesis are to create populations of molecular structures” in order to search them for more potent derivatives of known pharmacophores Gordon et al. J. Med. Chem., 1994
27Motivation Libraries of inorganic compounds The fact that properties rely on a number of variables “precludes the truly rational design…and provides a clear invitation to use the power of combinatorial chemistry to accelerate discovery”.Francis et al. “Combinatorial libraries of transition-metal complexes, catalysts and materials”, Cur. Opin. Chem. Biol., 1998