Jyothsna VenkatSupervisory Patent Examiner

Art Unit 1627(703) 308-2439

jyothsna.venkat@uspto.gov

Combinatorial TechnologyCombinatorial Technology

Art Unit 1627Art Unit 1627

• Bennett Celsa• Maurie Garcia• Grace Hsu • Padmashri Ponnaluri• Thomas Prasthofer• Theresa Wessendorf

The Evolution of Combinatorial The Evolution of Combinatorial TechnologyTechnology

Dates of appearance in the literature...• 1985 - Peptide & oligonucleotide libraries • 1992 - Small organic molecules• 1995 - Superconductors • 1997 - Luminescent compounds• 1998 - Catalysts• 20?? - Convergence with genomics

What Is What Is “Combinatorial” Chemistry?“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

What Is What Is “Combinatorial” Chemistry?“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

What IsWhat Is “Combinatorial” Chemistry? “Combinatorial” Chemistry?

“This field is so new that even the basic terminology is not defined”Lebl, M. J. Comb. Chem., 1999

What Is aWhat Is a“Combinatorial” Library?“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

““Combinatorial”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!

Terminology Used in Terminology Used in Combinatorial ChemistryCombinatorial 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!

Issues under 35 USC 112Issues under 35 USC 112

• As 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.

Issues under 35 USC 112Issues 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.

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.

• 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).

Issues under 35 USC 112Issues 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.

Issues under 35 USC 112Issues under 35 USC 112

Enablement Example 2Claim: A combinatorial library of dihydropyridine

compounds of formula (I):

NH

R2

R3

R1

(I)

wherein R1, R2 and R3 are independentlyselected from the group consisting of...

Claim: A combinatorial library of dihydropyridine compounds of formula (I):

• 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.

NH

R2

R3

R1

(I)

wherein R1, R2 and R3 are independently selected from the group consisting of...

Claim DependencyClaim Dependency

• Claim 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?

Claim DependencyClaim Dependency• Claim 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.

Another ScenarioAnother Scenario

• Claim 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

Utility - 35 USC 101Utility - 35 USC 101

A Library/Mixture/Collection must have a specific, substantial and credible utility

An 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.

Utility - 35 USC 101Utility - 35 USC 101

Utility ExampleConsider the previous claim...Claim: A combinatorial library of dihydropyridine

compounds of formula (I):

NH

R2

R3

R1

(I)

wherein R1, R2 and R3 are independentlyselected from the group consisting of...

Claim: A combinatorial library of dihydropyridine compounds of formula (I):

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 under 35 USC 101.

NH

R2

R3

R1

(I)

wherein R1, R2 and R3 are independently selected from the group consisting of...

Utility - 35 USC 101Utility - 35 USC 101

HOWEVERIf 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.

Clarity in Drafting the Disclosure and Claims is Essential!

Anticipation and ObviousnessAnticipation and Obviousness

AnticipationDo “art known” collections/compositions read on “combinatorial libraries”?

YESThe products/compositions are the same regardless of the manner in which they are prepared.

A case for prima facie A case for prima facie obviousnessobviousness

1. If the parent molecule in a series is known; and2. The substituents and the substitution pattern

claimed are established in the prior art, then

3. Motivation to make the library becomes the question.

MotivationMotivation

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

MotivationMotivationLibraries of inorganic compoundsThe 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

Thank YouThank You

Jyothsna VenkatSupervisory Patent Examiner

Art Unit 1627(703) 308-2439

jyothsna.venkat@uspto.gov

Combinatorial TechnologyCombinatorial Technology