Examining Pharmaceutical Claims of Immense Scope Gary L. Kunz Supervisory Patent Examiner Art Unit Michael Woodward Training Quality Assurance Specialist

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 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)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 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 –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)

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 & 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 methylcyclo- propyl 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 (+)TAN- 67 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 combina- torial 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 commen- surate 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