Phone (610) 357-3281
`
`
`Ron Bihovsky, Ph.D.
`rbihovsky@keysynthesis.com
`
`
`
`
`804 Primrose Lane
`Wynnewood, PA 19096
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`Organic Chemistry and Medicinal Chemistry Expert with Laboratory. Specialist in pharmaceutical
`patent cases requiring laboratory investigation. Testifying experience. Extensive drug discovery and lead
`optimization accomplishments in the pharmaceutical industry. Discovered novel, potent heterocyclic and
`peptide mimetic enzyme inhibitors and receptor antagonists. Good working knowledge of biochemistry
`and pharmacology. Good communication and interpersonal skills. Strong patent and publication record.
`
`
`
` Expertise includes:
`
`• Structure-Activity Relationships
`• Molecular Modeling
`•
`Intellectual Property
`• Hatch-Waxman Patent Litigation
`
` •
`
` Medicinal Chemistry
`• Organic Synthesis
`• Drug Design
`• Lead Optimization
`
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` •
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`EXPERT WITNESS EXPERIENCE:
`
`2001-Present KEY SYNTHESIS LLC, Wynnewood, PA. President and Founder.
`• Organic chemistry and medicinal chemistry expert witness or fact witness in 20 Hatch-Waxman
`pharmaceutical patent litigation cases. Have been deposed and testified in three high-profile cases
`with favorable outcomes. Consult for intellectual property firms and perform experiments to establish
`the validity of patent claims. Perform custom organic synthesis. Specialize in pharmaceutical patent
`cases requiring laboratory investigation. Patent and literature searching capability. Wrote the genus
`and examples for my 15 granted US patents, and worked closely with patent attorneys and patent
`agents to construct the claims.
`
` Treasurer (2007-2008) and Chairman (2009-2012) of Chemical Consultants Network, a topical group of
`the American Chemical Society.
`
`RESEARCH EXPERIENCE AND ACCOMPLISHMENTS:
`
`2001-Present KEY SYNTHESIS LLC, Wynnewood, PA. President and Founder.
`
`
`Custom Organic Synthesis, Medicinal Chemistry, Expert Witness, Consultant.
`• Founded Key Synthesis LLC. Responsible for all aspects of the company: Located and equipped the
`laboratory, developed business strategy, attracted customers. Key Synthesis prepares compounds
`including enzyme inhibitors, receptor antagonists, enzyme substrates, and synthetic intermediates for
`the pharmaceutical and biotechnology industries. Pharmaceutical chemistry, biotechnology, and
`intellectual property consultant. .
`
`
`CEPHALON, INC., West Chester, PA. Principal Project Chemist and Senior Scientist,
`1992-2001
`Medicinal Chemistry. Treatment of Cerebral Ischemia, Cancer.
`
`• PARP Inhibitors - Principal Project Chemist: Designed novel, potent, selective heterocyclic inhibitors of
`poly(ADP-ribose) polymerase. Optimized potency and properties of screening hit to provide lead
`molecule. Lead compounds crossed blood-brain barrier, and reduced infarct volume in cerebral
`ischemia.
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`RS 1015 - 000001
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`• Calpain Inhibitors - Team Leader and Principal Project Chemist: Designed and synthesized novel
`peptide-mimetic and non-peptide cell-permeable calpain inhibitors with new enzyme-reactive groups for
`neurodegenerative therapy. Coordinated multidisciplinary team of 20 biochemists, pharmacologists, cell
`biologists and medicinal chemists. Supervised team of 7-10 medicinal chemists in calpain inhibitor
`program. Collaborated with directors of chemistry, biochemistry and pharmacology to evaluate
`hypotheses and plan new directions. Recruited the chemistry staff. Designed the laboratories.
`
`
`BERLEX LABORATORIES, Cedar Knolls, NJ. Scientist, Medicinal Chemistry.
`1987-1992
`Cardiovascular Research.
`
`• Project Leader - Directed group of medicinal chemists in synthesis of enzyme inhibitors and peptide
`mimetics. Represented medicinal chemistry on core team of biochemists and pharmacologists.
`• Designed and synthesized highly potent endothelin converting enzyme inhibitors.
`•
`Investigated mechanism of epoxysuccinate class of cysteine protease inhibitors.
`•
`Identified novel peptide-mimetic construct which was incorporated into angiotensin II.
`• Performed molecular modeling on peptides, peptide mimetics, and enzyme inhibitors.
`
`STATE UNIVERSITY OF NEW YORK, Stony Brook, NY. Assistant Professor
`1980-1987
`of Chemistry. Synthetic Organic and Bio-organic Chemistry.
`
`
`• Synthesized biologically significant natural products: biotin, oudenone, civet acid, C-glycoside
`antibiotics, lignans, tetrahydroisoquinolines.
`• Generation and utilization of α-halo ethers and oxonium ions in synthesis.
`• Regioselectivity of Pictet-Spengler reaction.
`• Determined structures of crown gall tumor metabolites.
`• Wrote computer software programs for literature reference retrieval and elemental analysis.
`• Supervised research of 2 Postdoctoral Fellows, 9 Graduate Students, and 20 Undergraduates.
`• Taught Graduate Synthetic Organic Chemistry and Undergraduate Organic Chemistry courses.
`
`UNIVERSITY OF WISCONSIN, Madison, WI. NIH Postdoctoral Fellow. Organic Synthesis
`1978-1980
`and Structure Elucidation.
`
`
`• Synthesized natural products; introduced chirality via microbial transformation. Isolated and elucidated
`structures of compounds with smooth muscle-contracting activity (Leukotriene and G-acid) from animal
`tissue; determined mechanism of action.
`• Performed smooth-muscle contractility assays.
`
`UNIVERSITY OF CALIFORNIA, Berkeley, CA. Graduate student, Organic Chemistry.
`1972-1978
`Organic Synthesis and Structure Elucidation.
`
`
`• Synthesized anatoxin-a via intramolecular cyclization of iminium ion.
`•
`Isolated and determined structure of saxitoxin, potent marine neurotoxin.
`• Developed sensitive oxidative fluorescence assay for saxitoxin.
`• Cultured microscopic marine algae, isolated toxins, performed bioassay, and determined structures.
`
`Additional Academic Experience:
`2001-2003
`Villanova University, Villanova, PA. Adjunct Professor of Chemistry.
`• Created and taught graduate Medicinal Chemistry course.
`
`Education:
`
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`Languages: Reading and Speaking – German
`Scientific Reading – French, Italian, Spanish
`
`
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`Computer
`Windows, UNIX, Fortran, Basic, ISIS Base, Beilstein, CAS-Scifinder,
`Experience: Excel, Word, Powerpoint, Netscape, Internet Explorer, etc.
`
`
`Ph.D. 1977, Organic Chemistry, University of California, Berkeley (Advisor: H. Rapoport)
`B.S. 1970, Chemistry, Magna cum laude, Honors in Chemistry,
`
`State University of New York, Stony Brook
`
`RS 1015 - 000002
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`

`
`(Note: Ron Bihovsky previously published under the name H. Bates)
`
`Publications:
`
`1. M. Tao,* C. H. Park, R. Bihovsky, G. J. Wells, J. Husten, M. A. Ator, R. L. Hudkins, "Synthesis and
`Structure-Activity Relationships of Novel Poly(ADP-ribose) Polymerase-1 Inhibitors."
`Bioorg. Med. Chem. Lett. 16, 938-942 (2006).
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`2.
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`3.
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`4.
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`5.
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`6.
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`7.
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`8.
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`G. W. Wells,* R. Bihovsky, R. L. Hudkins, M. A. Ator, and J. Husten, "Synthesis and Structure-
`Activity Relationships of Novel Pyrrolocarbazole Lactam Analogs as Potent and Cell-Permeable
`Inhibitors of Poly(ADP-ribose)polymerase-1 (PARP-1)." Bioorg. Med. Chem. Lett. 16, 1151-1155
`(2006).
`
`R. Bihovsky, M. Tao, J. P. Mallamo, and G. Wells,* "1,2-Benzothiazine 1,1-Dioxide α-Ketoamide
`Analogues as Potent Calpain I Inhibitors." Bioorg. Med. Chem. Lett. 14, 1035-1038 (2004).
`
`S. J. Miknyoczki, S. Jones-Bolin, S. Pritchard, K. Hunter, H. Zhao, W. Wan, M. Ator, R. Bihovsky, R.
`Hudkins, S. Chatterjee, A. Klein-Szanto, C. Dionne, and B. Ruggeri, "Chemopotentiation of
`temozolomide, irinotecan, and cisplatin activity by CEP-6800, a poly(ADP-ribose) polymerase
`inhibitor." Mol. Cancer Ther. 2, 371-382 (2003).
`
`G. J. Wells, M. Tao, K. A. Josef, and R. Bihovsky,* “1,2-Benzothiazine 1,1-dioxide P2 - P3 Peptide
`Mimetic Aldehyde Calpain I Inhibitors.” J. Med. Chem. 44, 3488-3503 (2001).
`
`K. A. Josef,* F. W. Kauer, and R. Bihovsky, “Potent α-Ketohydroxamate Inhibitors of Recombinant
`Human Calpain I.” Bioorg. Med. Chem. Lett. 11, 2615-2617 (2001).
`
`S. Chatterjee,* D. Dunn, M. Tao, G. Wells, Z.-Q. Gu, R. Bihovsky, M. A. Ator, R. Siman, and J. P.
`Mallamo, “P2-Achiral, P’-Extended α-Ketoamide Inhibitors of Calpain.” Bioorg. Med. Chem. Lett. 9,
`2371-2374 (1999).
`
`G. J. Wells* and R. Bihovsky, “Calpain Inhibitors as Potential Treatment for Stroke and Other
`Neurodegenerative Diseases. Recent Trends and Developments.” Expert Opin. Ther. Patents 8,
`1707-1727 (1998).
`
`
`9. M. Tao,* R. Bihovsky, G. J. Wells, and J. P. Mallamo, “Novel Peptidyl Phosphorous Derivatives as
`Inhibitors of Human Calpain I.” J. Med. Chem. 41, 3912-3916 (1998).
`
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`10. S. Chatterjee,* Z.-Q. Gu, D. Dunn, M. Tao, K. Josef, R. Tripathy, R. Bihovsky, S. E. Senadhi, T. M.
`O’Kane, B. A. McKenna, S. Mallya, M. A. Ator, D. Bozyczko-Coyne, R. Siman, and J. P. Mallamo,
`“D-Amino Acid Containing High Affinity Inhibitors of Recombinant Human Calpain I.” J. Med. Chem.
`41, 2663-2666 (1998).
`
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`11. S. Chatterjee,* M. A. Ator, D. Bozyczko-Coyne, K. Josef, G. Wells, R. Tripathy, M. Iqbal, R.
`Bihovsky, S. Mallya, S. E. Senadhi, T. M. O’Kane, B. A. McKenna, R. Siman, and J. P. Mallamo,
`“Synthesis and Biological Activity of a Series of Potent Fluoromethyl Ketone Inhibitors of
`Recombinant Human Calpain I.” J. Med. Chem. 40, 3820-3828 (1997).
`
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`12. R. Bihovsky* and M. A. Ator, “Calpains: Their Role in Pathology, and New Therapeutic
`Opportunities.” Investigational Drugs Weekly Highlights, 22-25, May, 1997.
`
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`13. M. Iqbal, P. Messina, B. Freed, M. Das, S. Chatterjee, R. Tripathy, M. Tao, K. A. Josef, B.
`Dembofsky, D. Dunn, E. Griffith, R. Siman, S. E. Senadhi, W. Biazzo, D. Bozyczko-Coyne, S. L.
`Meyer, M. A. Ator, and R. Bihovsky*, “Subsite Requirements for Peptide Aldehyde Inhibitors of
`human Calpain I.” Bioorg. Med. Chem. Lett., 7, 539-544 (1997).
`
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`14. M. Tao*, R. Bihovsky, and J. C. Kauer “Inhibition of Calpain by Peptidyl Heterocycles.” Bioorg. Med.
`Chem. Lett., 6, 3009-3012 (1996).
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`RS 1015 - 000003
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`15. R. Bihovsky*, and I. Pendrak, “Synthesis of Cystamidin A (Pyrrole-3-propanamide), a Reported
`Calpain Inhibitor.” Bioorg. Med. Chem. Lett., 6, 1541-1542 (1996).
`
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`16. S. Chatterjee*, K. Josef, G. Wells, M. Iqbal, R. Bihovsky, J. P. Mallamo, M. Ator, D. Bozyczko-
`Coyne, S. Mallya, S. Senadhi, and R. Siman “Potent Fluoromethyl Ketone Inhibitors of Recombinant
`Human Calpain I.” Bioorg. Med. Chem. Lett., 6, 1237-1240 (1996).
`
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`17. S. L. Meyer*, D. Bozyczko-Coyne, S. K. Mallya, C. M. Spais, R. Bihovsky, J. K. Kawooya, D. M.
`Lang, R. W. Scott, and R. Siman “Biologically Active Monomeric and Heterodimeric Recombinant
`Human Calpain I Produced Using the Baculovirus Expression System”. Biochem. J. 314, 511-519
`(1996).
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`18. R. Bihovsky*, B. Levinson, R. Loewi, P. W. Erhardt, and M. Polokoff, "Hydroxamic Acids as Potent
`inhibitors of Endothelin Converting Enzyme," J. Med. Chem. 38, 2119-2129 (1995).
`
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`19. R. Bihovsky*, J. C. Powers, C.-M. Kam, R. Walton, and R. Loewi, "Further Evidence for the
`Importance of Free Carboxylate in Epoxysuccinate Inhibitors of Thiol Proteases," J. Enzyme Inhib.
`7, 15-25 (1993).
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`20. R. Bihovsky*, "Reactions of α,ß-Epoxy Carbonyl Compounds with Methanethiolate: Regioselectivity
`and Rate," J. Org. Chem., 57, 1029-1031 (1992).
`
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`21. R. Bihovsky*, "Applications of Cyclic α-Haloethers and Unsaturated Oxonium Ions to Natural
`Product Synthesis: Carbon-Carbon Bond Formation," Trends in Organic Chemistry, 3, 1-6 (1992).
`
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`22. R. Mohan*, Y. L. Chou, R. Bihovsky, W. C. Lumma, Jr. P. Erhardt, and K. Shaw, "Synthesis and
`Biological Activity of Angiotensin II Analogs Containing a Val-His Replacement,
`ValΨ[CH(CONH2)NH]His," J. Med. Chem., 34, 2402-2410, (1991).
`
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`23. S. Rosenblum and R. Bihovsky*, "Synthesis of the Papulacandin C-Arylglucosylspiroketal Nucleus,"
`J. Amer. Chem. Soc., 112, 2746-2748 (1990).
`
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`24. R. Bihovsky* and V. Bodepudi, "Synthesis of (+)-Biotin: Efficient Resolution of Key Intermediates,"
`Tetrahedron, 46, 7667-7676, (1990).
`
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`25. R. Bihovsky*, M. U. Kumar, S. Ding, and A. Goyal, "Oxonium Ions in Organic Synthesis:
`Condensation of 2,3-Dihydrofuran and 3,4-Dihydro-2H-pyran with 1,3-Dicarbonyl Compounds," J.
`Org. Chem., 54, 4291-4293 (1989).
`
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`26. R. Bihovsky*, C. Selick, and I. Giusti, "Synthesis of C-Glucosides by Reactions of Glucosyl Halides
`with Oranocuprates," J. Org. Chem., 53, 4026-4031 (1988).
`
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`27. H. Bates*, K. Bagheri, and P. Vertino, "Effect of pH on the Regioselectivity of Pictet-Spengler
`Reactions of 3-Hydroxyphenethylamines with Formaldehyde and Acetaldehyde," J. Org. Chem. 51,
`3061-3063 (1986).
`
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`28. H. Bates*, J. Farina, and M. Tong, "An Approach to Pseudomonic Acids from Acetylenic Precursors:
`Synthesis of 2-(Hydroxymethyl)-3-butyn-1-ol," J. Org. Chem., 51, 2637-2641 (1986).
`
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`29. H. Bates* and S. Rosenblum, "Nucleophilic Displacements on an α-Chlorothioether by
`Organocuprates: A Novel Synthesis of Desoxybiotin," J. Org. Chem., 51, 3447-3451 (1986).
`
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`30. H. Bates, "Structure of Crown Gall Tumor Metabolites: Chemical Mediators of Parasitism," Anal.
`New York Acad. Sci., 471, 289-290 (1986).
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`RS 1015 - 000004
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`31. H. Bates*, N. Condulis, and N. Stein, "Reduction of Cyclic Ureas with Lithium Aluminum Hydride," J.
`Org. Chem., 51, 2228-2229 (1986).
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`32. H. Bates*, J. Magrath, and A. Kaushal, "A Direct Method for Assignment of Absolute Configurations
`in Crown Gall Metabolites: The Structure of Nopaline," J. Nat. Prod., 48, 598-601 (1985).
`
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`33. H. Bates* and J. Farina, "Oxonium Ion Electrophiles: Synthesis of the Hypotensive Oudenone," J.
`Org. Chem., 50, 3843-3845 (1985).
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`34. H. Bates* and S. Rosenblum, "300 MHz 1H NMR Spectra and Conformations of Biotin and Related
`Hexahydrothienoimidazolone Derivatives," Tetrahedron Lett., 41, 2331-2336 (1985).
`
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`35. H. Bates*, L. Smilowitz, and S. Rosenblum, "A Practical Stereospecific Synthesis of the Biotin
`Precursor (3aα,6aα)-1,3-Dibenzylhexahydro-1H-thieno[3,4-d]imidazol-2(3H)-one 1,1-Dioxide," J.
`Chem. Soc., Chem. Commun., 353-354 (1985).
`
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`36. H. Bates* and C. Selick, "Convenient Preparation of 2,3,4,6-Tetra-O-Methyl-α-D-Glucopyranosyl
`Bromide," J. Carbohydr. Chem., 4, 273-275 (1985).
`
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`37. H. Bates*, L. Smilowitz, and J. Lin, "Preparation of (3aα,6aα)-1,3-Dibenzylhexahydro-1H-
`thieno[3,4-d]imidazol-2(3H)-one: A Key Biotin Intermediate," J. Org. Chem., 50, 899-901 (1985).
`
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`38. H. Bates* and J. Garelick, "Synthesis of Tetrahydro-4,6,7-Isoquinolinetriols and Tetrahydro-4,7,8-
`isoquinolinetriols," J. Org. Chem., 49, 4552-4557 (1984).
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`39. H. Bates*, A. Kaushal, P. Deng, and D. Sciaky, "Structure and Synthesis of Histopine, a Histidine
`Derivative Produced by Crown Gall Tumors," Biochemistry, 23, 3287-3290 (1984).
`
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`40. H. Bates* and P. Deng, "Synthesis of the Civet Constituent cis-(6-Methyltetrahydropyran-2-yl)acetic
`Acid," J. Org. Chem., 48, 4479-4481 (1983).
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`41. H. Bates, "Characterization of Tetrahydroisoquinolines Produced by Pictet-Spengler Reactions of
`Norepinephrine with Formaldehyde and Acetaldehyde," J. Org. Chem., 48, 1932-1934 (1983).
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`42. H. Bates, "Decarbonylation of Tetrahydrofuran-2-carboxylic Acids and Tetrahydropyran-2-carboxylic
`Acids in Concentrated Sulfuric Acid: Formation of Oxonium Ions," J. Am. Chem. Soc., 104, 2490-
`2493 (1982).
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`43. H. Bates*, "Pictet-Spengler Reactions of Epinephrine with Formaldehyde," J. Org. Chem., 46, 4931-
`4935 (1981).
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`44. H. Bates and C. Sih*, "Arachidonic Acid is Responsible for the Smooth Muscle-Contracting Activity
`of G-Acid,” Proc. Nat. Acad. Sci., 76, 2712-2714 (1979).
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`45. H. Bates and H. Rapoport*, "Synthesis of Anatoxin a via Intramolecular Cyclization of Iminium
`Salts," J. Am. Chem. Soc., 101, 1259-1265 (1979).
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`46. H. Bates, R. Kostriken, and H. Rapoport*, "The Occurrence of Saxitoxin and Other Toxins in
`Various Dinoflagellates," Toxicon, 16, 595-601 (1978).
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`47. H. Bates, R. Kostriken, and H. Rapoport*, "A Chemical Assay for Saxitoxin: Improvements and
`Modifications," J. Agr. Food Chem., 26, 252-254 (1978).
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`48.
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`J. Bordner, W. Thiessen, H. Bates, and H. Rapoport*, "The Structure of a Crystalline Derivative of
`Saxitoxin. The Structure of Saxitoxin," J. Am. Chem. Soc., 97, 6008-6012 (1975).
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`RS 1015 - 000005
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`49. H. Bates and H. Rapoport*, "A Chemical Assay for Saxitoxin, the Paralytic Shellfish Poison," J. Agr.
`Food Chem., 23, 237-239 (1975).
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`50. H. Ruben, H. Bates, A. Zalkin*, and D. Templeton, "2,4,4-Triphenyl-1,2-diazetidine-3-one-1-
`carboxylic Acid, Ethyl Ester," Acta Cryst. B., 30, 1631-1633 (1974).
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`Patents:
`
`1.
`
`K. A. Josef, J. P. Mallamo, and R. Bihovsky, “Hydroxamate-Containing Cysteine and Serine
`Protease Inhibitors” US Patent 7,060,683 (2006).
`
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`2. M. Ator, R. Bihovsky, S. Chatterjee, D. Dunn, and R. Hudkins, “Multicyclic Compounds and the use
`thereof as Inhibitors of PARP, VEGFR2 and MLK3 Enzymes.” WO 01/85686 (2001), EP 1294725.
`(2003), US Patent 7,122,679 (2006).
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`3.
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`4.
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`5.
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`S. Chatterjee, J. P. Mallamo, R. Bihovsky, and G. Wells, “Peptide-Containing α-Ketoamide Cysteine
`and Serine Protease Inhibitors” US Patent 7,001,907 (2006).
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`S. Chatterjee, J. P. Mallamo, R. Bihovsky, and G. Wells, “Peptide-Containing α-Ketoamide Cysteine
`and Serine Protease Inhibitors” US Patent 6,703,368 (2004).
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`K. A. Josef, J. P. Mallamo, and R. Bihovsky, “Hydroxamate-Containing Cysteine and Serine
`Protease Inhibitors” WO 00/16767 (2001), EP 1115390 (2001), US Patent 6,686,335 (2004).
`
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`6. M. Tao and R. Bihovsky, “Peptidyl-2-Amino-1-hydroxyalkanesulfonic Acid Cysteine Protease
`Inhibitors” US Patent 6,500,802 (2002).
`
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`7. M. Tao and R. Bihovsky, “Peptidyl-2-Amino-1-hydroxyalkanesulfonic Acid Cysteine Protease
`Inhibitors” WO 98/47523 (1998); US Patent 6,348,448 (2002).
`
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`8.
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`9.
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`S. Chatterjee, J. P. Mallamo, R. Bihovsky, and G. Wells, “Peptide-Containing α-Ketoamide Cysteine
`and Serine Protease Inhibitors” US Patent 6,288,231 (2001).
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`S. Chatterjee, J. P. Mallamo, R. Bihovsky, and G. Wells, “Peptide-Containing α-Ketoamide Cysteine
`and Serine Protease Inhibitors” WO 99/17790 (1999); US Patent 6,150,378 (2000).
`
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`10. R. Bihovsky, G. Wells, and M. Tao, “Benzothiazo and Related Heterocyclic Group-Containing
`Cysteine and Serine Protease Inhibitors,” WO 98/21186 (1998); US Patent 5,952,328 (1999).
`
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`11.
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`12.
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`13.
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`J. P. Mallamo, R. Bihovsky, M. Tao, and G. Wells, “Phosphorous-Containing Cysteine and Serine
`Protease Inhibitors,” WO 97/03679 (1997); US Patent 5,639,732 (1997).
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`J. P. Mallamo, R. Bihovsky, S. Chatterjee, and R. Tripathy, “Cysteine Protease and Serine Protease
`Inhibitors,”US Patent 5,658,906 (1997).
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`J. P. Mallamo, R. Bihovsky, S. Chatterjee, and R. Tripathy, “Cysteine Protease and Serine Protease
`Inhibitors,” WO 96/14067 (1996); US Patent 5,498,616 (1996).
`
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`14. R. Bihovsky, P. Erhardt, J. Lampe, R. Mohan, and K. Shaw, "Inhibitors of the Conversion of Big
`Endothelin to Endothelin," WO 93/11154 (1993); US Patent 5,504,070 (1996).
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`15. H. Bates and S. Rosenblum, "Improved Synthesis of Biotin," US Patent 4,656,289 (1987).
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`RS 1015 - 000006