IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF DELAWARE
`
`ASTRAZENECA AB,
`
`Plaintiff,
`
`v.
`
`AUROBINDO PHARMA LTD. and
`AUROBINDO PHARMA U.S.A., INS.,
`
`Defendants.
`
`ASTRAZENECA AB,
`
`Plaintiff,
`
`v.
`
`C.A. No. 14-664-GMS (consolidated)
`
`C.A. No. 14-696-GMS
`
`MYLAN PHARMACEUTICALS INC.,
`
`Defendants.
`
`CONFIDENTIAL INFORMATION -
`SUBJECT TO PROTECTIVE ORDER
`
`REPLY EXPERT REPORT OF DAVID P. ROTELLA, PH.D.
`
`Page 1 of 404
`
`AstraZeneca Exhibit 2194
`Mylan v. AstraZeneca
`IPR2015-01340
`
`

`

`I!
`
`I.
`
`I
`
`.
`
`INTRODUCTION
`I, David P. Rotella, have been retained by counsel for Mylan Pharmaceuticals Inc.
`in connection with the above -captioned litigation matter to provide expert testimony concerning
`U.S. Patent No. RE 44,186 ( "the '186 patent ") by Robl et al., and entitled "Cyclopropyl -fused
`pyrrolidine -based inhibition of dipeptidyl peptidase IV and method." This report responds to
`various statements and issues raised in the March 4, 2016 report of Dr. Ann Weber concerning
`the invalidity of the '186 patent. This report sets forth further opinions as to which, if asked, I
`
`will testify at trial with respect to the '186 patent.
`I am the same David P. Rotella that previously submitted an expert report served
`
`2.
`
`on January 29, 2016 ( "Opening Report "). My Opening Report set forth my credentials,
`qualifications, publications, compensation, and prior testimony. That report also laid out the
`education and experience that a POSA would possess. That information all remains the same.
`In forming my opinions and preparing this report, I reviewed and considered the
`3.
`materials cited in this report and those materials listed in Exhibit A to this report. I have further
`relied on my knowledge, education, and training, as reflected in my qualifications and credentials
`
`set forth in my curriculum vitae, which is attached to my Opening Report.
`I reserve the right to provide further background regarding the relevant
`4.
`technology by way of tutorial at trial and any trial exhibits that would assist in communicating
`my opinions. I also reserve the right to supplement this report if I become aware of additional
`pertinent information. I may also testify or provide an opinion in rebuttal to testimony or
`
`opinions offered.
`
`For the reasons detailed below, it is my opinion that the supposed objective
`5.
`indicia of non -obviousness raised in Dr. Weber's report are not sufficient to support a finding
`
`Page 2 of 404
`
`

`

`that the claimed invention would not have been obvious. I have reveiwed Dr. Weber's report,
`
`and nothing contained therein alters my previously presented opinion that the asserted claims of
`
`the '186 patent would have been obvious in view of the prior art to a person of ordinary skill in
`
`the art at the time of the claimed invention. As an initial matter, Dr. Weber failed to establish a
`
`nexus between any of the supposed objective indicia of non -obviousness and anything novel in
`
`the purported invention.
`
`6.
`
`While I have confined this report to the topic of objective indicia of
`
`nonobviousness, I reserve the right to respond to other aspects of Dr. Weber's report.
`
`II.
`
`APPLICABLE LEGAL STANDARDS
`
`7.
`
`My understanding of the applicable legal standards, as explained by counsel, is set
`
`forth in my Opening Report.
`
`8.
`
`Additionally, I understand from counsel that the Court can consider what are
`
`known as objective indicia of non -obviousness presented by the patentee to rebut a showing of
`
`obviousness. I understand that the patentee has the burden of providing evidence of any alleged
`
`objective indicia, including evidence of a connection, or "nexus," between each alleged objective
`
`indicia and the invention of the asserted claims.
`
`9.
`
`I understand that unexpected results is one such objective indicia. I further
`
`understand when evaluating the objective indicia of unexpected results, the purported unexpected
`
`results should be evaluated based on what a POSA would or would not have expected at the time
`
`of the alleged invention. I further understand that that in order to allege unexpected results, the
`
`results of the claimed invention must be compared to the results of the closest prior art. I also
`
`understand that for an alleged unexpected result to be probative of non -obviousness, there must
`
`Page 3 of 404
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`

`

`be evidence showing show a difference in kind, not just in degree, as compared to the closest
`
`prior art.
`
`III.
`
`NONE OF THE OBJECTIVE INDICIA IDENTIFIED BY DR. WEBER PROVIDE
`EVIDENCE OF NON -OBVIOUSNESS
`
`A.
`
`Dr. Weber Provides No Evidence Of Unexpected Results That Is Probative
`Of Non -Obviousness
`
`10.
`
`As an initial matter, Dr. Weber overwhelmingly focuses her discussion of
`
`unexpected results on differences between saxagliptin and vildagliptin. Weber Report at ¶ ¶235-
`
`256. As discussed in my Opening Report (111107-113), it is my opinion that a POSA would have
`
`been motivated to select Ashworth compound 25 as a lead compound.
`
`It is my understanding
`
`from counsel that, in order to provide evidence of an unexpected result that is probative of non -
`
`obviousness, there must be a comparison between the claimed invention and the closest relevant
`
`prior art. Dr. Weber has not provided any evidence with respect to the differences between
`
`Ashworth compound 25 and saxagliptin in terms of unexpected results. Despite this lack of
`
`evidence, I will briefly address certain assertions made by Dr. Weber regarding unexpected
`
`results.
`
`11.
`
`As discussed in my Opening Report ( 1I39 -151), a POSA would have been
`
`motivated to improve upon the prior art Ashworth compound 25 by fusing a cyclopropane ring to
`
`the pyrrolidine ring, in part because there was a reasonable expectation that the resulting
`
`conformational restriction of the pyrrolidine ring would prevent intramolecular cyclization and
`
`thus increase stability. So motivated, the POSA would only have three choices as to the position
`
`for fusing the cyclopropyl ring, and two choices as to the spatial configuration of the cyclopropyl
`
`ring in each position. Opening Report at ¶145. Thus, the cis -4,5- configuration seen in
`
`saxagliptin is one of only six possible choices for cyclopropanation of the pyrrolidine ring. A
`
`Page 4 of 404
`
`

`

`POSA at the time of the invention would have had a reasonable expectation that at least one of
`
`these six possibilities would result in a configuration that would improve the stability of the
`
`molecule. Selecting the cis -4,5- orientation from such a small, discrete set of compounds would
`
`be a matter of routine optimization for a POSA. Thus, it is not unexpected that a POSA would
`
`be able to improve stability of the resulting compound by cyclopropanation of the pyrrolidine
`
`ring.
`
`12.
`
`Dr. Weber also alleges the "slow, tight binding kinetics" of saxagliptin constitutes
`
`an unexpected result. While Dr. Weber only compares the binding properties of saxagliptin to
`
`those of vildagliptin, DPP -4 inhibitors that demonstrated slow, tight binding were known in the
`
`prior art before the alleged invention of saxagliptin. For example, it was already known that
`
`"NVP- DPP728 inhibits DPP -IV by a slow- binding mechanism" (Hughes, et al. "NVP- DPP728
`
`(1- [[[2 -[(5- Cyanopyridin -2 -yl) amino] ethyl] amino] acetyl ] -2- cyano -(S)- pyrrolidine), a Slow -
`
`Binding Inhibitor of Dipeptidyl Peptidase IV," Biochem., 38:11597-11603, at 11598 (1999)),
`
`and that boroproline -based DPP4 inhibitors exhibited slow, tight binding inhibition of DPP -4.
`
`(Gutheil, W.G. & W.W. Bachovchin, "Separation of L- Pro -DL- boroPro into Its Component
`
`Diastereomers and Kinetic Analysis of Their Inhibition of Dipeptidyl Peptidase IV. A New
`
`Method for the Analysis of Slow, Tight- Binding Inhibition," Biochem., 32(34):8723 -8731 (Aug.
`
`31, 1993); Kelly, et al. "Immunosuppressive Boronic Acid Dipeptides: Correlation between
`
`Conformation and Activity," J. Am. Chem. Soc., 115:12637 -12638 (1993)) As such, at least the
`
`existence of compounds capable of slow, tight binding inhibition of DPP -4 is not unexpected.
`
`4
`
`Page 5 of 404
`
`

`

`B.
`
`13.
`
`The Purported Failure Of Others Does Not Indicate Non -Obviousness
`
`I disagree with Dr. Weber's assertion that the presence of "only four FDA -
`
`approved DPP -4 inhibitors on the market" indicates a failure of others that would support the
`
`non- obviousness of saxagliptin. Weber Report at 111257 -261.
`
`14.
`
`The fact that other DPP -4 inhibitor candidates did not ultimately receive FDA
`
`approval is not indicative of saxagliptin's non -obviousness, but simply a reflection of the risks
`
`inherent in the drug discovery process. Any person of ordinary skill in the field of drug
`
`discovery is well aware that most drug candidates ultimately fail to produce FDA -approved
`
`drugs, and that failure at the clinical trial stage is very common.
`
`15.
`
`Drug discovery, from lead compound identification to market entry, is a lengthy
`
`process which requires a substantial commitment of resources. It is not uncommon for drug
`
`discovery decisions to be driven as much by market and competitive concerns as by technical
`
`considerations rooted in chemistry and medicine. For example, a researcher might be instructed
`
`not to pursue a promising drug candidate because, even if the candidate were to lead to an
`
`approved product, that product would be a late entrant into a market where patients already have
`
`access to treatment options that act by the same mechanism. The existence of four different
`
`FDA -approved DPP -4 inhibitor products merely indicates that four different companies were
`
`willing to enter that particular sub -section of the diabetes treatment market; it is not indicative of
`
`any particular scientific difficulty in the underlying drug development process. Thus the
`
`existence of "only four" DPP -4 inhibitors on the market cannot reasonably be taken as evidence
`
`that saxagliptin was non -obvious.
`
`5
`
`Page 6 of 404
`
`

`

`C.
`
`16.
`
`Saxagliptin Did Not Meet Any Long -Felt Unmet Need
`
`1 disagree with Dr. Weber's assertion that saxagliptin met a long -felt need for
`
`alternative therapies for type -2 diabetes. Weber Report at ¶ ¶262 -264. As discussed above,
`
`saxagliptin was one of several DPP -4 inhibitor drugs developed to treat type -2 diabetes. But, as
`
`Dr. Weber herself admits, saxagliptin was not the first DPP -4 inhibitor approved by the FDA to
`
`treat type -2 diabetes. Id. at ¶264. The first DPP-4 inhibitor therapy for treat type -2 diabetes was
`
`sitagliptin, which received FDA -approval three years before saxagliptin was approved by the
`
`FDA. (See JANUVIA® Prescribing Information (Aug. 2015), at 1; ONGLYZA® Prescribing
`
`Information (Apr. 2016), at 1)
`
`17.
`
`Nothing in Dr. Weber's report suggests that saxagliptin met any need for a DPP-4
`
`therapy that was left unmet by sitagliptin. Indeed, I am unaware of any evidence that or
`
`indication in saxagliptin's FDA -approved drug information label suggesting any material
`
`benefits compared to sitagliptin. (Id.) I am thus unaware of any unmet need which was met by
`
`saxagliptin.
`
`IV.
`
`CONCLUSION
`
`18.
`
`For the foregoing reasons it is my opinion that Dr. Weber has not identified any
`
`evidence of objective indicia that would support the non -obviousness of the asserted claims. I
`
`maintain my opinion, as laid out in my Opening Report, that claims 8, 9, 25, and 26 of the '186
`
`patent are obvious.
`
`Executed on this jWday of April, 2016.
`
`David P. Rotella, Ph.D.
`
`Page 7 of 404
`
`

`

`EXHIBIT A
`EXHIBIT A
`
`
`
`Page 8 of 404
`
`Page 8 of 404
`
`

`

`EXHIBIT A
`
`Materials Considered by David P. Rotella, Ph.D.
`
`Di artliWlaini
`Hughes, et al., "NVP- DPP728 (1- [[[2- [(5- Cyanopyrídin -2-
`yl)amino]ethyl] amino] acetyl ] -2- cyano -(S)- pyrrolidine), a
`Slow -Binding Inhibitor of Dipeptidyl Peptidase IV,"
`Biochem., 38:11597-11603 (1999)
`Gutheil, W.G. & W.W. Bachovchin, "Separation of L- Pro -n-
`boroPro into Its Component Diastereomers and Kinetic
`Analysis of Their Inhibition of Dipeptidyl Peptidase IV. A
`New Method for the Analysis of Slow, Tight- Binding
`Inhibition," Biochem., 32(34):8723 -8731 (Aug. 31, 1993)
`Kelly, et al., "Immunosuppressive Boronic Acid Dipeptides:
`Correlation between Conformation and Activity," J. Am.
`Chem. Soc., 115:12637 -12638 (1993)
`JANUVIA® Prescribing Information (Aug. 2015)
`
`ONGLYZA® Prescribing Information (Apr. 2016)
`
`MYL_SAX0298717-
`MYLSAX0298725
`
`MYLSAX0298726 -
`MYL_SAX0298732
`
`MYL_SAX0298733 -
`MYL_SAX0298734
`MYLSAX0298735 -
`_
`SAX0298757
`MYL
`MYL_SAX0298758 -
`MYL SAX0298790
`
`Page 9 of 404
`
`

`

`DAVID P. ROTELLA, Ph.D.
`Margaret & Herman Sokol Professor of Medicinal Chemistry
`Department of Chemistry & Biochemistry
`Montclair State University
`1 Normal Avenue
`Montclair NJ 07043
`Voice: 973 -655 -7204
`Fax: 973 -655 -7772
`Email: rotellad @mail.montclair.edu
`
`Summary of Accomplishments:
`
`Montclair State University- Obtained $2.5MM, 5 year drug discovery research grant from
`Defense Threat Reduction Agency and an additional $300K in pharmaceutical industry research
`funding in three years.
`Wyeth Research -led chemistry teams in CNS drug discovery projects and key leader for
`collaboration with Solvay Pharmaceuticals. Delivered a clinical candidate, managed chemists in
`group that delivered another.
`Lexicon Pharmaceuticals - Beginning from a screening hit, in less than one year, led project
`team that identified potent, selective, orally bioavailable inhibitors of PDE7A.
`Bristol -Myers Squibb -First to publish the discovery of novel phosphodiesterase type 5 inhibitors
`with better in vitro potency and selectivity compared to sildenafil. Contributed to discovery of 2
`clinical candidates (PDE5 inhibitor, DPP4 inhibitor).
`Cephalon- Responsible for initial conception and development of several programs. Key leader in
`collaborations with Kyowa Hakko and Schering Plough. Discovered CEP 1347, which advanced
`to phase III trials for Parkinson's Disease.
`
`Experience:
`
`Montclair State University July 2011 -present
`Margaret and Herman Sokol Professor of Chemistry, Department of Chemistry and Biochemistry;
`joint appointment in Sokol Institute of Pharmaceutical Life Sciences
`Independent Consultant, February 2010 -present
`Established consulting agreements with pharmaceutical companies and law firms to advance drug
`discovery programs and provide expert information on selected topics in drug development
`Wyeth Research /Pfizer, 2005 -February 2010
`Principal Research Scientist III, chemistry team leader. Directed up to 20 chemists. Member of
`Princeton Chemical Science leadership team.
`Lexicon Pharmaceuticals, 2003 -2005
`Senior Group Leader, responsible for multiple drug discovery programs. Directed up to 18 FTEs
`with 4 direct reports. Member of department leadership team.
`Bristol -Myers Squibb PRI, 1997 -2003
`Principal Scientist, cardiovascular and metabolic disease drug discovery
`Cephalon, Incorporated, 1991 -1997
`Group Leader, CNS and cancer drug discovery.
`School of Pharmacy, University of Mississippi
`
`EXHIBIT
`
`WIT:
`
`DATE:
`TOM FRASIK, C R 6961
`
`Page 10 of 404
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`

`

`Assistant Professor, Department of Pharmacognosy 1987 -1991
`Adjunct Professor, Department of Medicinal Chemistry, 2009 -present
`School of Pharmacy, University of Pittsburgh, 2010 -present
`Adjunct Professor, Department of Pharmaceutical Sciences
`Center for Drug Discovery, Northeastern University, 2010 -present
`Adjunct Professor
`Registered pharmacist, Pennsylvania, 1981 -1991, 2010 -present
`
`Education:
`
`Postdoctoral Scholar, Department of Chemistry, The Pennsylvania State University,
`1985 -1987, under the direction of Prof. K. S. Feldman.
`Ph.D. Medicinal Chemistry, The Ohio State University, 1985, under the direction of Prof.
`D. T. Witiak.
`B.S. Pharm., Magna cum laude, School of Pharmacy, University of Pittsburgh, April
`1981.
`
`Professional Service:
`
`American Chemical Society, Organic and Medicinal Chemistry Divisions
`Fellow, Royal Society of Chemistry
`
`Division of Medicinal Chemistry, American Chemical Society:
`Five year term as Vice Chair /Long Range Planning Committee chair, Program Chair,
`Chair and past Chair (2004- 2008). These roles required leadership and collaborative
`interactions nationally and internationally.
`Three year term as academic councilor (2012 -2014)
`Treasurer, 2015 -2017
`
`Gordon Research Conference on Medicinal Chemistry
`2012 vice chair elect
`2013 vice chair
`2014 chair
`
`Co- editor, 3`d edition, Comprehensive Medicinal Chemistry 2014 -present
`
`Co- editor, 7th edition, Burger's Medicinal Chemistry 2007 -present
`
`Senior Editor, Royal Society of Chemistry series on Drug Discovery, 2008 -present
`
`Co- editor, "Successful Drug Discovery ", (2014), Wiley VCH
`
`Co- editor, "Analogue -Based Drug Discovery ", volume 3, (2012), Wiley VCH
`
`Program co- chair, National Medicinal Chemistry Symposium (2010)
`
`Page 11 of 404
`
`

`

`Scientific Advisory Board National Medicinal Chemistry Symposium (2014)
`
`Scientific Advisory Board Frontiers in Medicinal Chemistry 2014 -2015
`
`Organizer and conference co -chair for "Frontiers in CNS and Oncology Medicinal Chemistry ",
`Siena, Italy, October 7 -9, 2007, jointly organized with European Federation for Medicinal
`Chemistry.
`
`Current Research Funding:
`
`Discovery of Novel Botulinum Toxin Protease A Inhibitors, 9/29/14- 9/28/19, $2.5MM,
`Defense Threat Reduction Agency
`for Parasitic Diseases, 3/1/14- 2/28/15, $90,000, Celgene
`Inhibitors
`Protein Kinase
`Corporation
`Research Support, 9/1/11 -8/31/16, $50,000 annually, Margaret and Herman Sokol
`Endowment
`
`Past Research Funding:
`
`Inhibitors
`
`for Parasitic Diseases, 3/1/12- 2/28/13, $90,000, Celgene
`
`Protein Kinase Inhibitors for Parasitic Diseases, 3/1/13- 2/28/14, $115,000, Celgene
`Corporation
`Protein Kinase
`Corporation
`Purchase of LCMS, 10/1/13, $70,000, Shimadzu Corporation
`Lactam Inhibitors of Phospholipase A2, 7/1/88- 6/30/90, direct costs $25,000, Mississippi
`Affiliate, American Heart Association
`Novel Calmodulin Inhibitors, 7/1/89- 6/30/91, direct costs $35,000, Elsa U Pardee Foundation
`Phospholipase A2 Inhibitors as Novel Anti -inflammatory Agents, 7/1/89- 6/30/91, direct costs
`$200,000, American Lung Association
`
`Publications:
`
`1. "Stereocontrolled Syntheses for the Six Diasteromeric 1,2- Dihydroxy -4,5-
`Diaminocyclohexanes: Pt(II) Complexes and P388 Antitumor Properties ", Donald T. Witiak,
`David P. Rotella, Joyce A. Filppi, and Judith Galucci, J. Med. Chem. 30, 1327 (1987).
`
`"Synthesis and P -388 Antitumor Properties of the Four Diastereomeric Dichloro I- Hydroxy -3,4
`2.
`diaminocyclohexane Pt(II) Complexes" , Donald T. Witiak, David P. Rotella, Yong Wei, Joyce A. Filppi
`and Judith C. Gallucci J. Med. Chem. 32, 214 (1989).
`
`3. "Mechanistic and Preparative Studies of the Intramolecular Photocyclization of Methylated 2 -(4-
`Pentenyl)tropones", Ken S. Feldman, Jon H. Come, Benedict J. Kosmider, Pamela M. Smith, David P.
`Rotella and Ming -Jung Wu, J. Org. Chem. 54, 592 (1989).
`
`"Homoallylically Controlled Epoxidation of A4- cis -1,2- Disubstituted Cyclohexenes ", David P.
`4.
`Rotella, Tetrahedron Letters, 1913 (1989).
`
`Page 12 of 404
`
`

`

`"Application of an Intramolecular Tropone -Alkene Photocyclization to the Total Synthesis of (±)
`5.
`Dactylol ", Ken S. Feldman, Ming -Jung Wu and David P. Rotella, J. Am. Chem. Soc. 111, 6457 (1989).
`
`6. "Chloroperoxidase Mediated Halogenation of Phenols ", Cheryl F. Wannstedt, David P. Rotella and
`Jerome F. Siuda, Bull. Contamin. Environ. Toxicol. 44, 282 (1990).
`
`"Stereocontrolled lodolactonization of Erythro and Threo Tertiary Amides ", David P. Rotella and
`7.
`Xun Li, Heterocycles 31, 1205 (1990).
`
`"The Total Synthesis of (±) Dactylol and Related Studies ", Ken S. Feldman, Ming -Jung Wu and
`8.
`David P. Rotella, J. Am. Chem. Soc. 112, 8490 (1990).
`
`"Synthesis and Structural Analysis of Stereospecific 3,4,5 -Trisubstituted y- Butyrolactone
`9.
`Phospholipids ", Xun Li and David P. Rotella, Lipids 29, 211 -224 (1994).
`
`"The Effect of Pyrrolo[3,4- c]Carbazole Derivatives on Spinal Cord ChAT Activity" David P.
`10.
`Rotella, Marcie A. Glicksman, J. Eric Prantner, Nicola Neff and Robert L Hudkins, Bioorganic and
`Medicinal Chemistry Letters. 5,1167-1170 (1995).
`
`11. "Microbial Metabolites of Ophiobolin A and Antimicrobial Evaluation of Ophiobolins ",
`Li, Alice M. Clark, David P. Rotella and Charles D. Hufford, J. Nat. Products 58, 74 -81, (1995).
`
`Erguang
`
`12. "Stereoselective Synthesis of Erythro a -Amino Epoxides" David P. Rotella, Tetrahedron Letters
`35, 5453 -5456 (1995).
`
`13. "Genesis and Degradation of Af3 Protein by Cultured Human Neuroblastoma Cells ", Robert Siman,
`John T. Durkin, E. Jean Husten, Mary J. Savage, Seetha Murthy, Suzanne Mistretta, David P. Rotella,
`Sankar Chatterjee, Bruce Dembofsky, Roger Poorman and Barry D. Greenberg, Recent Advances in
`Alzheimer's Disease and Related Disorders, John Wiley and Sons (1995).
`
`14. "Facile Lewis Acid- Mediated Ring Opening of 4- Hydroxypyrrolidin -2 -ones by Amino Acid Esters ",
`David P. Rotella, Synlett, 479 -480 (1996).
`
`15. "Solid Phase Synthesis of Olefin and Hydroxyethylene Peptidomimetics ", David P. Rotella, J Am.
`Chem. Soc. 118, 12246 -12247 (1996).
`
`"Neurotrophic 3,9- Bis[(alkylthio)methyl]- and -Bis(alkoxymethyl)- K -252a Derivatives ", Masami
`16.
`Kaneko, Yutaka Saito, Hiromitsu Saito, Tadashi Matsumoto, Yuzuru Matsuda, Jeffry L. Vaught, Craig
`A. Dionne, Thelma S. Angeles, Marcie A. Glicksman, Nicola T. Neff, David P. Rotella, James C. Kauer,
`John P. Mallamo, Robert L. Hudkins, Chikara Murakata, J. Med. Chem. 40, 1863 -1869 (1997).
`
`"An Update on COX -2 and Farnesyltransferase Inhibitor Development ", David P. Rotella, Curr.
`17.
`Opin. Drug Discovery and Development, 1, 165 -174 (1998).
`
`Page 13 of 404
`
`

`

`18. "Rank -Order of Potencies for Inhibition of the Secretion of Aß40 and Aß42 Suggests that Both are
`Generated by a Single y- Secretase ", John T. Durkin, Seetha Murthy, E. Jean Husten, Stephen P. Trusko,
`Mary J. Savage, David P. Rotella, Barry D. Greenberg and Robert Sirvan, J. Biol. Chem. 274, 20499-
`20504 (1999).
`19. "N -3 Substituted Imidazaquinazolinones: Potent and Selective PDE5 Inhibitors as Potential Agents
`for Treatment of Erectile Dysfunction" David P. Rotella, Yeheng Zhu, Zhong Sun, John Krupinski,
`Ronald Pongrac, Laurie Seliger, Diane Normandin, John E. Macor, J. Med. Chem. 43, 1257 -1263
`(2000).
`20. "Optimization of Substituted N- 3- Benzyl Imidazoquinazolinone Sulfonamides as Potent and
`Selective PDE5 Inhibitors" David P. Rotella, Yeheng Zhu, Zhong Sun, John Krupinski, Ronald Pongrac,
`Laurie Seliger, Diane Normandin, John E. Macor, J. Med. Chem. 43, 5037 -5043 (2000).
`21. "Phosphodiesterase 5 Inhibitors: Discovery and Therapeutic Utility ", David P. Rotella, Drugs of the
`Future 26, 153 -162 (2001).
`"Osteoporosis: Challenges and New Opportunities for Therapy ", Curr. Opin. In Drug Discovery
`22.
`and Development 5, 477 -486 (2002).
`"Phosphodiesterase Type 5 Inhibitors: Current Status and Potential Applications ", Nature Reviews
`23.
`Drug Discovery 1, 674 -683 (2002).
`
`24.
`
`"Tadalafil (Lilly /ICOS) ", Curr. Opin. Invest. Drugs 4, 60 -65 (2003).
`
`25.
`
`"SB- 480848. GlaxoSmithKline ", Curr. Opin. Invest. Drugs 5, 348 -351 (2004).
`"Novel Second Generation Approaches for the Control of Type 2 Diabetes ", J. Med. Chem. 47,
`26.
`4111 -4112 (2004).
`
`2- Benzylpyrrolidine -Substituted
`of
`Structure Activity Relationships
`and
`"Discovery
`27
`Aryloxypropanols as Calcium -Sensing Receptor Antagonists ", Wu Yang, Yufeng Wang, Jacques
`Roberge, Zhengping Pa, Yalei Yu, David P. Rotella, Ramakrishna Seethala, R. Michael Lawrence, Jean
`H. M. Feyen, John K. Dickson, Bioorg. Med. Chem. Lett. 15,1225 -1228 (2005).
`28. "Phosphodiesterase Inhibitors: Potential CNS Applications ", Nicholas J. Brandon, David P. Rotella,
`Annual Reports in Medicinal Chemistry, 42, 3 -12 (2007)
`"Potent Non -nitrile Dipeptidic Dipeptidyl Peptidase IV Inhibitors ", Ligaya M. Simpkins, Scott
`29.
`Bolton, Zulan Pi, James C. Sutton, Chet Kwon, Guohua Zhao, David R. Magnin, David J. Augeri, Timur
`Gungor, David P. Rotella, Zhong Sun, Yajun Liu, William S. Slusarchyk, Jovita Marcinkeviciene, James
`G. Robertson, Aiying Wang, Jeffrey A. Robl, Karnail S. Atwal, Robert Zahler, Rex A. Parker, Mark S.
`Kirby, Lawrence G. Hamann, Bioorg. Med. Chem. Lett. 17, 6476 -6480 (2007).
`"Alzheimer's Disease: A Light at the End of the Tunnel ? ", Albert J. Robichaud, David P. Rotella,
`30.
`Drug. Development Res. 2009, 70, 57 -59.
`
`Page 14 of 404
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`

`

`31.
`"Tetrahydrocarbazole -based Serotonin Reuptake Inhibitors /Dopamine D2 Partial Agonists for the
`Potential Treatment of Schizophrenia ", David P. Rotella, Geraldine R. McFarlane, Alexander Greenfield,
`Cristina Grosanu, Albert J. Robichaud, Rajiah Aldrin Denny, Rolf W. Feenstra, Sara Núñez- García, Jan -
`Hendrik Reinders, Martina van der Neut, Andrew McCreary, Chris G. Kruse, Kelly Sullivan, Farhana
`Pruthi, Margaret Lai, Jean Zhang, Dianne M. Kowal, Tikva Carrick, Steven M. Grauer, Rachel L.
`Navarra, Radka Graf, Julie Brennan, Karen L. Marquis, Mark H. Pausch, Bioorg. Med. Chem. Leu. 2009,
`19, 5552 -5555.
`
`"WS -50030 [7- {4- [3 -(IH- inden- 3- yl)propyl] piperazin- I- yl } -1.3- benzoxazol -2(3H) -one }: A Novel
`32.
`Dopamine Receptor Partial Agonist /Serotonin Reuptake Inhibitor with Preclinical Antipsychotic -Like
`and Antidepressant -Like Activity ", Julie A. Brennan, Karen L. Marquis, Mark H. Pausch, Chad E. Beyer,
`Zoe Hughes, Radka Graf, Steven Grauer, Qian Lin, Sharon Rosenzweig- Lipson, Farhana Pruthi,
`Claudine Pulicicchio, David P. Rotella, Albert J. Robichaud, Deborah L. Smith, Rolf Feenstra, Chris G.
`Kruse, Andrew McCreary, Pierre Broqua, Wouter Grotier, Martina van der Neut, J. Pharmacol. Exp.
`Ther. 2010, 332, 190 -201.
`
`"Potent Dihydroisoquinolone -Based Dopamine D2 Partial Agonist /Serotonin Reuptake Inhibitors
`33.
`for Treatment of Schizophrenia ", Yinfa Yan, Ping Zhou, David P. Rotella, Rolf Feenstra, Chris G. Kruse,
`Martina van der Neut, Jan -Hendrik Reinders, Farhana Pruthi, Dianne Kowal, Tikva Carrick, Margaret
`Lai, Karen L. Marquis, Mark H. Pausch, Albert J. Robichaud, Bioorg. Med. Chem. Lett. 2010, 20, 2983-
`2986.
`
`34.
`
`"Drug Discovery 2012 and Beyond ", David P. Rotella, ACS Med. Chem. Leu. 2012, 3, 172 -174.
`35.
`"Recent Results on Protein Kinase Inhibition for Tropical Diseases ", David P. Rotella, Bioorg.
`Med. Chem. Lett. 2012, 22, 6788 -6793.
`
`"Discovery and Development of Boceprevir ", David P. Rotella, Expert Opin. Drug Discovery
`36.
`2013, 8, 1 -9.
`
`"The Spectral Properties of ( -)- Epigallocatechin -3 -O- Gallate (EGCG) Fluorescence in Different
`37.
`Solvents: Dependence on Solvent Polarity ", Vladislav Snitsarev, Michael N. Young, Ross M. S. Miller,
`David P. Rotella, PLoS One, 2013, 8(11) e79834.
`
`"Toward the Discovery of Drug Like Epigallocatechin Gallate Analogs as Hsp90 Inhibitors ", Rohit
`38.
`Bhat, Amna Adam, Jungeun Jasmine Lee, Ellen C. Henry, Thomas A. Gasiewicz, David P. Rotella,
`Bioorg. Med. Chem. Lett. 2014, 24, 2263 -2266.
`
`"Structure- activity Studies of (- )- Epigallocatechin Gallate Derivatives as HCV Entry
`39.
`Inhibitors" Rohit Bhat, Amna Adam, Jungeun Jasmine Lee, Gaspard Deloison, Yves Rouillé,
`Karin Séron, David P. Rotella, Bioorg. Med. Chem. Lett. 2014, 24, 4162 -4165.
`
`40.
`"Progress in the Discovery and Development of Hsp90 Inhibitors ", Rohit Bhat, Sreedhar
`Reddy Tummalapalli, David P. Rotella, invited perspective J. Med. Chem. 2014, 57, 8718 -8728.
`
`Page 15 of 404
`
`

`

`Patents:
`
`1. "Diastereomeric Mono- and Di- Substituted Diaminocyclohexane Compounds and Methods of
`Preparation Thereof' Donald T. Witiak and David P. Rotella, US 5,206,400.
`
`2. "K252a Functional Derivatives Potentiate Neurotrophin -3 Activity for the Treatment of Neurological
`Disorders" Marcie A. Glicksman, Robert L. Hudkins, David P. Rotella, Nicola Neff and Chikara
`Murakata, US 5,468,872.
`
`3. "K252 Derivatives Which Enhance Neurotrophin- Induced Activity" Marcie A. Glicksman, Robert L.
`Hudkins, David P. Rotella, Nicola Neff and Chikara Murakata, US 5,516,772.
`
`4. "Quinazolinone Inhibitors of cGMP Phosphodiesterase ", David P. Rotella, John E. Macor, David
`Cushman, Joseph Yevich, US 6,087,368
`
`5. "Quinoline Inhibitors of cGMP Phosphodiesterase ", Yingzhi Bi, David P. Rotella, Guixue Yu, John
`E. Macor, US 7,378,430 .
`
`6. "2- Substituted cyclic amines as calcium sensing receptor modulators ", Ashvinikumar Gavai, Roy J.
`Vaz, John K. Dickson, Jacques Y. Roberge, Wu Wang, Timur Gungor, James R. Corte, David P.
`Rotella, Yufeng Wang, Wu Yang, US 7,105,537.
`
`7. "Preparation of substituted piperidines and pyrrolidines as calcium sensing receptor modulators ",
`John K. Dickson, Michael R. Lawrence, Jacques Y. Roberge, David P. Rotella, Wu Yang, US
`7,265,145.
`
`Book Chapters:
`
`"Recent Results in Phosphodiesterase Inhibitor Development and CNS Applications","Cyclic-
`Nucleotide Phosphodiesterases
`the Central Nervous System: From Biology
`to Drug
`in
`Discovery ", John Wiley and Sons, 2014 115 -144, Anthony West, Nicholas J. Brandon, editors.
`
`"Monoaminergic Targets for Treatment of Schizophrenia ", "New Approaches to Psychiatric Drug
`Discovery ", Royal Society of Chemistry Press, 2012, 33 -47, Zoran Rankovic, editor.
`
`"Pioneer and Analogue Drugs ", "Analogue -based Drug Discovery ", volume 3, Wiley VCH, 2012,
`3 -18, edited by Janos Fischer, C. Robin Ganellin, David P. Rotella
`
`"SSRIs" David P. Rotella and Wayne E. Childers, "Analogue -Based Drug Discovery, volume 2,
`Wiley -VCH, 2010, 269 -296, Janos Fischer and Robin Ganellin, editors.
`
`"Medicinal Chemistry Challenges in the Discovery of Novel Antidepressants ", "Next Generation
`Antidepressants ", 2010, 102 -118, Cambridge University Press, Chad E. Beyer, Stephen M. Stahl,
`editors.
`
`Page 16 of 404
`
`

`

`"Drug Discovery for Non -Life Threatening Disorders ", "Burger's Medicinal Chemistry ", volume
`5, 711i edition, John Wiley and Sons, 2010, 711 -728, Donald J. Abraham and David P. Rotella, co-
`editors.
`
`Inhibitors and Therapeutic Applications" "Comprehensive
`"Phosphodiesterase Enzymes,
`Medicinal Chemistry I1" Elsevier Science, 2006, 919 -957, Walter 1 -l. Moos editor.
`
`Abstracts and Presentations:
`
`"A Natural Product Template
`Kenilworth NJ, March 2014.
`
`for Medicinal Chemistry" Merck Research Laboratories,
`
`"Progress Toward the Identification of Drug -Like Hsp90 Inhibitors based on (- )- Epigallocatechin
`Gal late ", Department of Medicinal Chemistry, University of Illinois at Chicago, October 2013.
`
`"Design, Synthesis and Use of Novel Diamine Templates in Medicinal Chemistry" Eli Lilly
`Research Laboratories, May 2013.
`
`"Structure- activity Relationships of Novel Inhibitors of the Brugia malayi Stress -activated
`Protein Kinase, Bm -MPKI" David P. Rotella, Sreedhar R. Tummalapalli, Agnieska Chojnowski,
`Tamara W. Kreiss, Deborah S. Mortensen, Veronique Plantevin, Stacie Canan, Vikram Khetani,
`Jerome B. Zeldis, Ronald Goldberg, John Siekierka, poster presentation American Society of
`Tropical Medicine and Health national meeting, Washington DC November 5, 2013.
`
`"Novel inhibitors of the Brugia malayi stress -activated protein kinase, Bm- MPKI ", Mortensen
`DS, Khetani V, Satoh Y, Cathers B, Canan S, Zeldis J, Chojnowski AN, Patel A, Goldberg R,
`Rotella D, Siekierka J. poster presentation American Society of Tropical Medicine and Hygiene
`national meeting, Atlanta, GA, November I 1 -15, 2012.
`
`"Antipsychotic -like profile of WS- 50030, a combined partial D2 receptor agonist and selective
`serotonin reuptake inhibitor ", Julie Brennan, Karen Marquis, Claudine Pulichiccio, Mark Pausch,
`Steven Grauer, David P. Rotella, Rolf Feenstra, Andrew McCreary, poster presentation, Society
`for Neuroscience meeting 2008, Washington DC, November 2008.
`
`"PDE5 Inhibitors: Comparison of Current Agents and Future Prospects ", David P. Rotella, 2 "d
`Annual Phosphodiesterases in Drug Discovery and Development, November 8 -9, 2004.
`
`"Phosphodiesterase Type 5 Inhibitors:
`Is There Room for More ?" David P. Rotella, American
`Society of Andrology 29th National Meeting, April 18, 2004.
`
`"Effects of the M3 antagonist, darafenicin, on food intake and body weight in two models
`of obesity." M.J. Cullen, M.A. Pelleymounter, D. Rotella, K Carlson and K. Behnia,
`into Pathogenesis and Treatment,
`Keystone Symposium: Obesity: New Insights
`Keystone, CO, January 21 -26, 2003.
`
`Page 17 of 404
`
`

`

`"Discovery and Optimization of PDE5 Inhibitors" David P. Rotella, Zhong Sun, Yeheng Zhu,
`Laurie Seliger, Ronald Pongrac, Diane Normandin, John Krup