Examining Pharmaceutical Claims of Immense Scope

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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

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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

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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

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The Problem

• How can we limit the scope of the allowed genus
  of compounds so that it provides reasonable
  protection for applicants invention without
  giving applicant an essentially unrestricted
  hunting license?

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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.

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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.

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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)

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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.

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Wands Considerations

• 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

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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

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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.

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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)

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The predictability, or lack thereof, found in the
art (contd)

• In the last 20 years researchers have found that
  a majority of key therapeutics act on a specific
  cell surface receptor
• Dopaminergic receptors (migraine drugs)
• Histamine receptors (allergy drugs)
• Adrenergic receptors (asthma and BP drugs)
• Serotonin receptors (anti-depressives,
  anti-anxiety, anti-compulsive drug)
• GABA receptors (anti-anxiety drugs)

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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
  u-opioid agonists. (Goodman Gilmans The
  Pharmacological Basis of Therapeutics, Ninth
  Edition, McGraw-Hill, New York, 1996, page 549.)

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Unpredictability in Designing Opioid Analgesics

• Note that by substituting a methylcyclo-propyl
  group for the N-methyl moiety, you go from a
  delta-agonist to a delta-antagonist

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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 ()TAN-67
  which not only was not an analgesic, but actually
  caused pain-like behavior (scratching, biting,
  and licking)

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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.)

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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)

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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 combina-torial
  library was designed around a stable mimetic of
  the the tetrahedral intermediate of amide
  hydrolysis

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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.

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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).

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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 commen-surate with
  the full scope of the claim.

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Working Examples

• The specification provides five working examples
  of compounds which possess the desired biological
  activityanalgesia.

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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.

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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.)

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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.

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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

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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.

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• 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.

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QUESTIONS?
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THANK YOU