Transcript Examining Pharmaceutical Claims of Unlimited Scope

Examining Pharmaceutical
Claims of Immense Scope
Gary L. Kunz
Supervisory Patent Examiner
Art Unit 1616
571-272-0887
Michael Woodward
Training Quality Assurance Specialist
571-272-8373
Examining Claims of Immense
Scope
– Biotech examiners have been making effective
scope of enablement rejections for many years
• Abundance of articles available which document the
high unpredictability of the effect of changing even
a single amino acid in a protein
-- Chemical examiners have not had the benefit
of a collection of articles establishing
unpredictability in traditional drug discovery
Fact Situation
• Claims are directed to an immense genus of
compounds defined around an active core
compound which is a methadone-like
derivative
• Specification discloses five specific
compounds which possess analgesic activity
The Problem
• How can we limit the scope of the allowed
genus of compounds so that it provides
reasonable protection for applicant’s
invention without giving applicant an
essentially unrestricted hunting license?
The Part of the Invention That is
Generally Enabled
• The part of the invention that is generally
enabled is a reasonable subgenus around the
exemplified active compounds wherein the
(1) total molecular size, (2) charge
distribution, (3) hydrophobicity, (4) polarity,
(5) hydrophilicity and (6) hydrogen bonding
are reasonably maintained.
The Part of the Invention That is
Generally NOT Enabled
• The part of the invention that is generally
not enabled is the scope of the genus claim
outside of a reasonable subgenus around the
exemplified active compounds.
– The scope of the non-enabled part of the
claimed genus vastly exceeds the scope of the
enabled subgenus and would require undue
experimentation to make and use.
Examiner Bears Burden
• To hold that a disclosure is not enabling, the
examiner must provide evidence or
technical reasoning substantiating those
doubts
• Without a reason to doubt the truth of the
statements made in the application, the
application must be considered enabling
In re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513, (Fed. Cir. 1992); In re
Marzocchi, 439 F.2d 220, 223, 169 USPQ 367, 369 (CCPA 1971)
In re Wands, 858 F .2d 731, 8
USPQ2d 1400 (Fed. Cir. 1988)
• The determination that “undue
experimentation would have been needed to
make and use the claimed invention is not a
single, simple factual determination.
Rather, it is a conclusion reached by
weighing all the relevant factual
considerations.
Wands Considerations
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The nature of the invention
The level of skill in the art
The state of the prior art
The predictability or lack thereof in the art
The amount of direction or guidance present
The presence or absence of working examples
The breadth of the claims
The quantity of experimentation needed
The nature of the invention
• Drug discovery is one of the most labor intensive
and expensive types of inventions; it can cost over
$500 million to bring a single new drug to market
• Drug discovery has become much more
sophisticated in the last 15 years:
– High throughput screening
– Recognition of cell surface receptors as key targets
– Rational drug design using x-ray crystallography data
for ligand binding site topography
– Combinatorial chemistry
The state of the prior art
• Highly sophisticated tools for rational drug
design still have not taken the
unpredictability out of this complex art; it
still requires trial and error experimentation.
• With the development of the understanding
of cell receptor and signal transduction
scientists are no longer shooting in the dark
but have their target clearly identified.
The predictability, or lack
thereof, found in the art
• Basis for unpredictability in drug discovery is the
exquisite stereospecificity between enzyme and
substrate and between receptor and ligand
**Amino acyl tRNA synthetases discriminate
between right and left-handed amino acids
substrates, acting only on L-amino acids.
**Amino acyl tRNA synthetases discriminate
between amino acids which are one carbon
homologs of each other (i.e., valine v. leucine,
serine v. threonine, glutamine v. asparagine, etc)
The predictability, or lack
thereof, found in the art (cont’d)
• In the last 20 years researchers have found that a
majority of key therapeutics act on a specific cell
surface receptor
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Dopaminergic receptors (migraine drugs)
Histamine receptors (allergy drugs)
Adrenergic receptors (asthma and BP drugs)
Serotonin receptors (anti-depressives, anti-anxiety, anticompulsive drug)
– GABA receptors (anti-anxiety drugs)
Unpredictability in Designing
Opioid Analgesics
• “Relative minor changes in the structure of an
opioid can convert a drug that is primarily an
agonist into one with antagonist actions at one or
more types of opioid receptors. The most
common such substitution is that of the large
moiety (e.g., an ally or methylcyclopropyl group)
for the N-methyl group that is typical of the uopioid agonists.” (Goodman & Gilman’s The Pharmacological Basis
of Therapeutics, Ninth Edition, McGraw-Hill, New York, 1996, page 549.)
Unpredictability in Designing
Opioid Analgesics
• Note that by substituting a methylcyclopropyl group for the N-methyl moiety, you
go from a delta-agonist to a delta-antagonist
Unpredictability of Designing
Opioid Analgesics
• If you substitute a fluorine atom for a hydrogen on
the phenyl ring near the indole nitrogen, you
change the activity from an antagonist to a partial
agonist, even though fluorine and hydrogen have
the same atomic radius.
• Finally, by selecting different stereoisomers of
TAN-67, you can change from (–)TAN-67 which
is a strong antinociceptive (analgesic) to (+)TAN67 which not only was not an analgesic, but
actually caused pain-like behavior (scratching,
biting, and licking)
Unpredictability in Designing
Opioid Analgesics
• Conclusion: small changes to opioid drugs can
create profound changes in biological activity.
This conclusion is not only relevant to opioid
receptors but is really representative of the
development of agonists and antagonists of all
receptors. (It is this exquisitely stereospecific
binding of ligand and receptor which in turn
requires that all therapeutic agonists or antagonists
be equally stereospecific.)
Unpredictability of Altering
Other Receptor Ligands
• Vertebrate growth hormone of 198 amino
acids becomes an antagonist instead of an
agonist when a single amino acid is
changed. (Kopchick et al. U. S. Patent
5,194,836)
Combinatorial Chemistry
Evidence of the Unpredictability
in Drug Discovery
• Combinatorial chemistry is a powerful tool
in the identification of small molecule
ligands for receptors and enzymes.
• In order to identify better inhibitors of
cathepsin D, an aspartyl protease combinatorial library was designed around a stable
mimetic of the the tetrahedral intermediate
of amide hydrolysis
Combinatorial Chemistry
Evidence of the Unpredictability
in Drug Discovery
• Two 1,000 member libraries were constructed, one
a diverse library and the other a design-directed
library
• Results: 2.7% of the diverse library were active
inhibitors of Cathepsin D and 6.7% of the directed
library were active inhibitors.
• Over 90% of the compounds were biologically
inactive.
• Kick et al. (1997) Chemistry and Biology 4(4):
297 – 307.
Combinatorial Chemistry as
Evidence of Unpredictability in
Drug Discovery
• Since more than 90% of the compounds generated in a
design-directed combinatorial library are likely to be
inactive, the person of skill in the art would have a sound
reason to doubt that even a simple majority of the
compounds defined by an unlimited genus claims would
possess biological activity.
• Such a high degree of unpredictability in the drug
discovery art places a greater burden on the applicant to
provide adequate guidance through this maze that would
be commensurate in scope with the claim(s).
Amount of Direction or Guidance
• The specification discloses five specific
compounds which have analgesic activity.
• The specification also provides an assay for
determining if a compound possesses the
claimed analgesic activity.
• However, this guidance is not commensurate with the full scope of the claim.
Working Examples
• The specification provides five working
examples of compounds which possess the
desired biological activity—analgesia.
Quantity of Experimentation
Required
• Because there is no way to predict a priori
which compounds will be active from the
specification or chemical structures alone,
an extraordinary amount of trial and error
experimentation is required to identify the
active compounds.
Breadth of the Claim
• The claim encompasses an immense
number of species. (Sometimes the number
of total variables within a single claim can
be 50 – 75 and the claim can range from 1
to 25 pages in length.)
CONCLUSION
• The evidence establishing a high degree of
unpredictability in the art of creating new opioid
analgesics combined with the expansive breadth of
the claim, the minimal guidance provided toward
the active species, and the relatively few working
examples leads to the conclusion that it would
require of undue experimentation for the person of
skill in the art to practice the full scope of the
claim.
Examples of Possible Ways to
Rebut this Scope Rejection
• Establish that the target of the drug does not
require such exquisite stereospecificity
• Provide additional data to show that a high
percentage of compounds in the genus, in
fact, are biologically active
Take Home Message
• When writing a specification in support of
claims of immense scope in the
pharmaceutical art, you should always
remember to provide support for a
reasonable subgenus around the disclosed
active compounds. This subgenus could be
a key to effectively responding to a scope of
enablement rejection.
ACKNOWLEDGEMENTS
Special thanks to Primary Examiner
Bob Landsman for providing the
opioid drug discovery data and to
Primary Examiner Mark Shibuya for
providing the combinatorial chemistry
information.
QUESTIONS?
THANK YOU