Patenting Small Molecule Therapeutics:
From Target to Clinic
JUNE 7, 2012
© 2008 Venable LLP
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OUR GOAL
To provide a resource for inventors to recognize
patentable inventions and provide technical details
for strong applications to patent small molecule
therapeutics.
© 2012 Venable LLP
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Agenda

Why Patent Small Molecule Therapeutics?

Patent Basics
– Patentability
– Types of Applications
– Timelines

Target to Clinic – the Invention Story
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–
–
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Target
Assay
Screen
Compounds
Formulations
Patent Pitfalls
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Why Patent Small Molecule Therapeutics?
Target discovery/validation
Assay development
High-throughput screen
Lead Selection
Lead optimization/candidate selection
Preclinical Testing
Clinical Trials
Clinic
0
1
2
3
4
Years
5
6
7
10-15
• 1 in 5000-10000 compounds
• $800 million to $1 billion
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The Law
1. Patent-eligible subject matter
2. Written Description and Best Mode
3. Enablement
4. Novelty
5. Non-Obviousness
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The Patent Application
 Detailed sections


Claims
Description
 Optional, but detailed sections


Drawings/Figures
Description of Drawings
 Minimal sections


Abstract
Background
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What’s your invention?
Some Patent Eligible Inventions
 Chemical Compounds
–
–
Organic compounds (small molecules)
Peptides, Proteins, Oligonucleotides, Nucleic
Acids
 Chemical Compositions
–
Pharmaceutical Formulations
 Methods
–
–
–
Synthetic Methods
Assay Methods
Therapeutic Methods
 Genetically Modified Organisms
© 2012 Venable LLP
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8
1
Year
2.5
Years
International App.
U.S. and Foreign
National Apps.
U.S. and Foreign
Patents Issue
0
Provisional Appl.
Invention Disclosure
The Patent Timeline
4-6
Years
© 2012 Venable LLP
Patenting Small-Molecule Therapeutics
Target
Assay
Screen
Compounds
Formulations
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Target
 Discover a correlation between DNA
sequences/genes or proteins/enzymes and a
particular disease state.
 Important and valuable scientifically
 Difficult to Patent


“natural” DNA and proteins
“natural” phenomena
 Research tools, not as much commercial value
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Patenting Small-Molecule Therapeutics
Target
Assay
Screen
Compounds
Formulations
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Assay
 Develop and validate system to measure change
in target level or activity
 Assay method may be patent eligible (disputed)
–
Methods of measuring change in target
 Components, too
–
–
–
Compounds - enzyme substrates; chimeric
proteins, PCR probes, monoclonal
antibodies, cDNA
Chemical Compositions - growth or
expression media; assay kits (combinations
of ingredients)
Organisms - cell lines, transgenic/knockout
animals
 Research tools, but some commercial value
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Invention Disclosure – Assay
1. Use active verbs (mixing, incubating,
centrifuging)
2. Begin with the minimum essential steps
3. Include the minimum essential ingredients
4. List additional steps, and identify preferred or
optimized conditions and ingredients
5. Consider if there is a diagnostic application
6. List Alternatives such as:
–
–
–
–
–
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reagents/media
cells/expression systems
detection systems/equipment
reporter proteins/genes
times/temperatures/ranges
© 2012 Venable LLP
Patenting Small-Molecule Therapeutics
Target
Assay
Screen
Compounds
Formulations
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Screen for Therapeutic Compounds
 Discover compounds that modulate the target.
 Commercially valuable inventions:


Pharmaceutical compositions
Therapeutic Methods
 Methods of screening compounds may be patent
eligible

Method of identifying compounds that
modulate target
 Typically combined with assay description in one
application
 Can find new uses for known compounds
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Therapeutic Methods
New uses for old compounds and new compounds
too!
Example:
Method of treating Y comprising administering to a
subject in need of treatment an effective amount of a
compound of formula X.
Can be commercially valuable, especially with
previously approved drugs.
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Example – Same compound, two uses
Patent #1 (1993)
Patent #2 (2002)
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Pharmaceutical Compositions
Pharmaceutical Compositions
– Alternative invention if a compound is
known/commercially available but has no
previously-known biological activity
– Combine with therapeutic methods; include
with new compounds
– Combinations of active ingredients
Example:
A pharmaceutical composition comprising a
compound of formula X and a pharmaceutically
acceptable excipient
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Patenting Small-Molecule Therapeutics
Target
Assay
Screen
Compounds
Formulations
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Compounds
New compounds with therapeutic activity
 Commercially valuable, broadest scope of
protection, strongest claims.
 Protects compounds, regardless of how used; not
tied to particular therapeutic use.
 Include therapeutic methods and pharmaceutical
composition inventions too
Example:
A compound of formula X.
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Example
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Invention Disclosure – Compounds
Written
Description
• A structural class of compounds
• Structures of all compounds synthesized
Enablement
• General methods for synthesizing the
compounds in the class
• Synthesis and analytical details for all
compounds made
Patentability
• Biological activity results, including
inactives (supports non-obviousness)
• Details of biological activity assay for at
least one compound
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Structure Description
GOAL – Describe a generic structure encompassing
compounds with biological activity (measured and
predicted), but where no known compounds fall
within the generic structure
Step 0:
Library/on-line research to identify structurallyrelated compounds
– Give all references to OIP/Outside Counsel
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Step 1: Core Structure
Identify common structures:
1. Aromatic/Heteroaromatic structures
2. Non-aromatic ring structures
3. Saturated/Unsaturated chains
Identify variables:
1. Atom Substitutions
2. Connectors
3. Substituents
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Step 2: Identify the Variables
Atom substitutions: CN; OS; CSi, NO; etc.
1-atom Connections:
-C-; -N(R)-; -O-; -S-; -Si-; -C(O)-; -S(O)-; etc.
2-atom Connections:
-C-C-; -C=C-; -C-O-; -O-C-; -C(O)N(R)-; -N(R)C(O)-;
-OC(O)-; -C(O)O-; -N-O-; -N-N-; -N=N-; etc.
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Step 3: Substituents
Substituents

Hydrogen, Halogen, Nitro, Nitrile

Alkyl, alkenyl, alkynyl, linear, branched, cyclic, Haloalkyl

Aryl, heteroaryl, substituted aryl and heteroaryl

Hydroxy, Alkoxy, aryloxy, heteroaryloxy

Hydroxyalkyl, alkoxyalkyl, aryloxylalkyl, heteroaryloxyalkyl

Amino, alkylamino, arylamino, heteroarylamino

Aminoalkyl, alkylaminoalkyl, arylaminoalkyl, heteroarylaminoalkyl

Thiol, Alkylthio, arylthio, heteroarylthio, sulfone, sulfoxide

Thioalkyl, alkylthioalkyl, arylthioalkyl, heteroarylthioalkyl

Carbaldehyde, Acyl, O-acyl, N-Acyl, S-Acyl,
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C(O)OR, C(O)NHR, C(O)NR2, C(O)-S(alkyl)

Silane, alkylsilane, Arylsilane,
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Phosponate, phosphinate, phosphate
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Many, many more!
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Step 4: Create the Description
For each variable, create three lists.
1. All options
2. More favorable options selected from list 1
3. Best options selected from list 2.
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Include Multiple Inventions
Therapeutic Methods
 Uses of old and new compounds to treat disease
 Include with all new compound inventions
Pharmaceutical Compositions
 Mixtures of active compounds and
pharmaceutical excipients
 Include with all new compound inventions
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Invention Disclosure – Therapeutic
Methods
Written Description
• All diseases/
disorders associated
with target.
• Correlation between
compound activity
and disease/disorder
• Structures of all
active compounds
• Source for all active
compounds
• Commercial
source; Synthetic
Methods
Enablement
• Screening assay
details
• Screening assay
results of all active
compounds
• Biological activity
assay details
• Biological activity
assay results for all
active compounds
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Invention Disclosure – Therapeutic
Methods
Extras:
 Structures of known, but untested, structurally
related compounds expected to have similar
activity, with sources
 Structures and assay results for structurally
related compounds confirmed as inactive.
If available, include:
 Comparative data with known compounds used
to treat same diseases or disorders
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Describing Diseases/Disorders
Be Comprehensive
 International Classification of Diseases
 http://www.who.int/classifications/icd/en/
Target-based approach
 Combine with your library research on the target
protein
 Consider other targets with similar function
 Enzymes with the same function in different
pathogens
 Proteins that use similar substrates/co-factors,
if compounds mimic substrate/co-factor
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Invention Disclosure - Compositions
Definitely include:
 Everything from Therapeutic Methods
Also Include:
 Types of formulations and compatible excipients
–
Liquid Formulations
• Solutions/Suspensions
– Solid formulations - Additives
– Salts – Solubility Enhancers
 Any known or expected incompatible additives
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Patenting Small-Molecule Therapeutics
Target
Assay
Screen
Compounds
Formulations
© 2012 Venable LLP
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Clinical Formulations
For known compounds with known activity
 Combination of compound with an excipient or
delivery system to improve drug properties
 May be commercially valuable if new formulation
has improved properties.
 Usually pursued by pharmaceutical industry to
extend patent life, after compounds and
therapeutic methods have been patented.
Example:
A pharmaceutical formulation comprising a
compound of formula X and additional ingredient Y.
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Example – U.S. 5,686,104 (Nov. 11, 1997)
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Invention Disclosure - Formulation
Written Description
• Generic Compound Structures, with sources.
• Specific Compound Structures, with sources.
• Additives that produce enhanced properties, with sources.
• Include substitutions/equivalents.
• Minimum and maximum amounts for all additives
• Optional additives, if any.
• Minimum and maximum amounts for all optional additives.
Enablement
• Specific details of all formulations produced and tested.
• Details of tests used to measure formulation properties
• Results of tests showing improved properties
Non-Obviousness
• Comparison with formulations lacking additives and using other
additives
• Reasons why improved properties are important
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Patenting Small-Molecule Therapeutics
Compounds
Formulations
Pre-clinical
trials
Clinical Trials
Clinic
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Preclinic  Clinical Trials  Clinic

Fewer patentable inventions

Preclinical testing may inspire new patentable
formulations or dosage forms

Dosage/efficacy optimization not generally
sufficient for patentability
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Timing - Avoid the Patent Pitfalls
Experiment
Publication
Invention
Disclosure/
Provisional
Application
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Patent Pitfall #1 – The Unfinished
Experiment
 A research proposal as part of an invention
disclosure may not be patentable and may
foreclose a later patent. Why?
–
–
Enablement – if the provisional application is
not enabled, any non-provisional application
may not benefit
Provisional application becomes public after
a non-provisional application publishes. The
proposal may be accidentally disclosed.
 Remedy: include detailed prophetic examples of
viable experiments that can be completed within
one year
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Patent Pitfall #2 – The Accidental
Disclosure
 Disclosing the invention before the patent
application is filed may result in rejection. Why?
–
Novelty is destroyed by publication
 Common types of accidental disclosures
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–
–
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Poster and presentation abstracts
Conference presentations
Dissertations/Theses
Web publications!
 Remedy – File at least a Provisional Application
before any disclosure, but avoid Patent Pitfall #3
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Patent Pitfall #3 – The Last-minute
Provisional Application
T=0
Provisional
0<T<1Yr:
Disclosure
T=1Yr:
Non-Provisional
 Filing a “quickie” provisional application may limit
the scope of the patent. Why?
– Written Description & Novelty – claims must
have written description in the provisional
application. If not, any claims broader than
the provisional application may be rejected
based on the early publication
 Remedy: file a provisional application with full
description; Promptly file follow-on provisional
applications with more data
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Thank you!

Michael E. Nelson
[email protected]
202-344-4766
www.Venable.com
© 2011 Venable LLP
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contact information
YOUR VENABLE TEAM
Henry J. Daley, Ph.D.
[email protected]
t 202.344.4362
Michael A. Gollin
[email protected]
t 202.344.4072
Stefan J. Kirchanski, Ph.D.
[email protected]
t 310.229.9928
Lars H. Genieser, Ph.D.
[email protected]
t 202.344.8234
Devesh Srivastava, Ph.D.
[email protected]
t 202.344.4447
Nancy J. Axelrod, Ph.D.
[email protected]
t 202.344.8334
Michael E. Nelson, Ph.D.
[email protected]
t 202.344-4766
And the rest of the Venable
prosecution group…
www.Venable.com
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