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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`TEVA PHARMACEUTICALS USA, INC.,
`Petitioner,
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`v.
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`ASTRAZENECA
`Patent Owner.
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`Patent No. RE44,186
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`DECLARATION OF RAMAIAH MUTHYALA, PH.D.
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`TEVA - EXHIBIT 1028
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`TABLE F
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`TABLE OF CONTENTS
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`TE T
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`I.
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`QUALIFICATIONS ............................................................................................... 1
`QUALIFICATIONS ............................................................................................. .. 1
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`SCOPE OF WORK ............................................................................................... 2
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`SCOPE OF WORK ............................................................................................. ..2
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`II.
`III. OVERVIEW OF THE ’186 PATENT ....................................................................... 3
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`III.
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`OVERVIEW OF THE ’ 186 PATENT ..................................................................... ..3
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`IV.
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`IV. FILE HISTORY OF THE ’186 PATENT .................................................................... 6
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`FILE HISTORY OF THE ’186 PATENT .................................................................. .. 6
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`V.
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`LEGAL STANDARDS ....................................................................................... .. 10
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`LEGAL STANDARDS ......................................................................................... 10
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`VI.
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`VI. LEVEL OF ORDINARY SKILL AND RELEVANT TIME .......................................... 12
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`LEVEL OF ORDINARY SKILL AND RELEVANT TIME ........................................ .. 12
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`VII.
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`CLAIM CONSTRUCTION ................................................................................. ..17
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`VII. CLAIM CONSTRUCTION ................................................................................... 17
`VIII. THE STATE OF THE PRIOR ART ........................................................................ 17
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`VIII.
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`THE STATE OF THE PRIOR ART ...................................................................... .. 17
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`IX.
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`PRIOR ART REFERENCES DISCLOSE OR SUGGEST EACH OF THE CLAIMED
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`IX. PRIOR ART REFERENCES DISCLOSE OR SUGGEST EACH OF THE CLAIMED
`FEATURES OF THE ’186 PATENT ...................................................................... 26
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`FEATURES OF THE ’186 PATENT .................................................................... ..26
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`X. CONCLUDING STATEMENTS ............................................................................ 98
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`CONCLUDING STATEMENTS .......................................................................... ..98
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`XI.
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`XI. APPENDIX – LIST OF EXHIBITS ...................................................................... 100
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`APPENDIX — LIST OF EXHIBITS .................................................................... .. 100
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`-i-
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`I, Ramaiah Muthyala, declare and state as follows:
`I.
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`QUALIFICATIONS
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`I am over the age of eighteen (18) and otherwise competent to make
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`1.
`this declaration.
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`2. My name is Ramaiah Muthyala. I am currently Associate Professor in
`the Department of Experimental Clinical Pharmacology at the University of
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`Minnesota. I have been a member of the faculty of this university since 2006.
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`3.
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`I was formerly a research scientist at multiple pharmaceutical
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`companies during the years 1969-1999, including at Indian Drugs &
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`Pharmaceuticals Ltd., Schering Plough, Dow Chemical Company, and
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`3M/Imation Corporation. My industry experience focused on drug discovery and
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`development.
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`4.
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`I received a Ph.D. in natural products from Sagar University, India in
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`1970 and a Ph.D. in heterocyclic chemistry from the University of East Anglia,
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`UK in 1975. I also received an M.B.A. from St. Thomas University, MN, in
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`1999. I was a Postdoctoral Scholar at University of North Wales, UK, 1971-
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`1972 and at Wayne State University, MI, 1974-1976.
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`I have authored or co-authored numerous abstracts for presentation at
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`5.
`professional meetings, peer-reviewed journal articles, and am an inventor or co-
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`inventor on seven U.S. patents.
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`6. A summary of my education, experience, publications, awards and
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`-3-
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`honors, patents, publications, and presentations is provided in my CV, a copy of
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`which is submitted separately (Ex. 1029).
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`II.
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`SCOPE OF WORK
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`7.
`I have been retained as an expert witness on behalf of Teva
`Pharmaceuticals USA, Inc. (“Petitioner”) for the above captioned inter partes
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`review (“Teva IPR”). I am being compensated for my time in connection with this
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`IPR at my standard consulting rate, which is $450 per hour. My compensation is
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`not contingent on the conclusions I reach herein or on the specifics of my
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`testimony. I have no financial stake in the outcome of this proceeding.
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`8.
`I understand that a petition is being filed with the United States Patent
`and Trademark Office for Inter Partes Review of U.S. Reissued Patent No.
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`RE44,186 (hereinafter, “the ’186 patent,” Ex. 1001). I understand that the ’186
`patent is currently subject to a previous IPR, Mylan Pharmaceuticals Inc., v.
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`AstraZeneca AB, Case IPR2015-01340 (the “Mylan IPR”). I understand that
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`Petitioner Teva seeks to become a party to the Mylan IPR. I have reviewed the
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`materials submitted with the petition filed in the Mylan IPR, including the petition
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`itself (IPR2015-01340, Paper 3), the Declaration of Dr. David P. Rotella
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`(IPR2015-01340, Exhibit 1003), and the Board’s Decision Instituting Inter Partes
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`Review (IPR2015-01340, Paper 16). I have also reviewed and considered other
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`documents (such as the relevant prior art) in arriving at my opinions, and cite them
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`in this declaration. For convenience, documents cited in this declaration are listed
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`in the Appendix in Section XI.
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`9.
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`I note that I agree in all material respects with the analysis and
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`opinions set forth by the petitioner Mylan’s expert, Dr. Rotella, in the declaration
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`that was submitted in the Mylan IPR and share the same opinions below. Because
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`my independent analysis of the claims and prior art led to the same conclusions as
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`Dr. Rotella, coupled with the fact that the Petitioner Teva is seeking to become a
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`party to the Mylan IPR, I have incorporated Dr. Rotella’s opinions and
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`characterizations below as my own. I do not independently address claim
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`construction in this Declaration, because I understand that, in instituting IPR2015-
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`01340, the Board has credited the testimony of Dr. Rotella on the views of a
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`hypothetical person of ordinary skill in the art at the time of the invention, and has
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`already determined that the claim terms are to be given their ordinary and
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`customary meaning, as understood by one of ordinary skill in the art. IPR2015-
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`01340, Paper 16. Accordingly, for purposes of this Declaration only, I will adopt
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`the constructions set forth by Dr. Rotella in his Declaration.
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`10. I understand that in its Decision Instituting Inter Partes Review in
`connection with the Mylan IPR, the Board concluded that Petitioner Mylan
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`demonstrated a reasonable likelihood of prevailing on its assertion that claims 1, 2,
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`4, 6-22, 25-30, 32-37 and 39-42 of the ’186 patent are unpatentable. Specifically,
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`the Board instituted review on four grounds: (1) claims 1, 2, 4, 6-11, 25-28, 32-35,
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`39 and 40 are obvious over Ashworth, Villhauer, Raag and Hanessian; (2) claims
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`12-16, 29, 30, 36, 37, 41 and 42 are obvious over Ashworth, Villhauer, Raag,
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`Hanessian, Bachovchin and the GLUCOPHAGE Label; (3) claims 12, 17, 18 and
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`22 are obvious over Ashworth, Villhauer, Raag, Hanessian, Bachovchin and the
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`XENICAL Label; and (4) claims 12 and 19-21 are obvious over Ashworth,
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`-5-
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`Villhauer, Raag, Hanessian, Bachovchin and the MEVACOR Label (IPR2015-
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`01340, Paper 16). Therefore, because Petitioner Teva is seeking to join the
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`instituted review of the ’186 patent, the opinions expressed herein are limited to
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`the references discussed in the petition and supporting materials filed in that
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`proceeding.
`III. OVERVIEW OF THE ’186 PATENT
`11. The ’186 patent is entitled “Cyclopropyl-Fused Pyrrolidine-Based
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`Inhibitors of Dipeptidyl Peptidase IV and Method” and was issued on April 30,
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`2013. I have been advised that the ’186 patent issued from U.S. Application No.
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`13/308,658, which was filed on December 1, 2011, as a reissued application of U.S.
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`Application No. 09/788,173, which was filed on February 16, 2001 and issued as
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`U.S. Patent No. 6,395,767 on May 28, 2002. I have also been advised that U.S.
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`Application No. 09/788,173 claims priority to U.S. Provisional Application No.
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`60/188,555, which was filed on March 10, 2000.
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`12. The ’186 patent is generally directed to cyclopropyl-fused pyrrolidine-
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`based compounds with a variety of optional substituents, as well as pharmaceutical
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`combinations and methods for treating diabetes and additional diseases. According
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`to the ’186 patent, the “cyclopropyl-fused pyrrolidine-based compounds [of the
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`’186 patent are] inhibitors of dipeptidyl peptidase IV [(DP-IV)] . . . for treating
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`diabetes, especially Type II diabetes.” Ex. 1001 col. 1, ll. 19-21. The ’186 patent
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`describes the mechanism by which DP-IV inhibition treats type 2 diabetes as
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`follows: “[DP-IV] has been shown to be the primary degrading enzyme of GLP-
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`1(7-36) in vivo . . . [t]hus, inhibition of [DP-IV] in vivo should potentiate
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`endogenous levels of GLP-1(7-36) and . . . thus serve to ameliorate the diabetic
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`condition.” Id. at Col. 1, ll. 59-67.
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`Independent claim 1 discloses a genus of chemical compounds
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`13.
`comprising a cyclopropyl-fused pyrrolidine-based core with a variety of optional
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`substituents. Dependent claims 2-7 and independent claims 8 and 10 further limit
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`the substituent groups of the compound of claim 1. For example, independent
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`claim 8 recites the following:
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`A compound having the structure:
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`or a pharmaceutically acceptable salt thereof.
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`Dependent claim 9 is directed to the hydrochloride or trifluoroacetic acid salts of
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`the compounds of claim 8. Dependent claim 11 is directed to a pharmaceutical
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`composition comprising a compound within the scope of claim 1. Claims 12-21
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`recite pharmaceutical combinations comprising a compound within the scope of
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`claim 1 and an antidiabetic agent for treating diabetes and/or additional agents for
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`treating related diseases. Claim 22 recites pharmaceutical combinations comprising
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`a compound within the scope of claim 1 and an agent for treating obesity or other
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`related diseases. Claims 23 and 24 were canceled upon reissue.
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`14.
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`Independent claim 25 recites a single compound as follows:
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`or a pharmaceutically acceptable salt thereof.
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`The compound of claim 25 also falls within the scope of composition claims 1, 2,
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`4, 6, 7, 8 and 10. Dependent claim 26 recites the hydrochloride salt of the
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`compound of claim 25. Dependent claims 27 and 28 further recite pharmaceutical
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`compositions of the compound of claim 25. Dependent claims 29-31 recite a
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`combination of the compound of claim 25 and an antidiabetic agent other than a
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`DP-IV inhibitor. Claims 32-43 recite various methods of treatment using the
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`compound of claim 25, alone or in combination with an antidiabetic agent other
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`than a DP-IV inhibitor.
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`15. The compound of claim 25 is also known as (1S,3S,5S)-2-[(2S)-2-
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`amino-2-(3-hydroxy-1-adamantyl) acetyl]-2-azabicyclo[3.1.0]hexane-3-
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`carbonitrile. For convenience, this compound will be referred to as “saxagliptin” as
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`shown below:
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`-8-
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`Saxagliptin
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`16.
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`In my opinion, and as explained in detail below, the claims of the
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`’186 patent would have been obvious to individuals of ordinary skill in the field
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`prior to and at the time of the earliest possible priority filing date of the ’186 patent,
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`i.e., prior to March 10, 2000.
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`IV. FILE HISTORY OF THE ’186 PATENT
`I have been advised that the determination of the right to priority is
`17.
`controlled by the written description requirement of 35 U.S.C. § 112, and to satisfy
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`the written description requirement the disclosure of the prior application must
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`convey with reasonable clarity to those skilled in the art that, as of the filing date
`sought, the inventors were in possession of the invention. I have been further
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`advised that the prior application must indicate to a person skilled in the art that the
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`inventor was “in possession” of the invention as later claimed.
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`18.
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`I understand that U.S. Patent No. RE44,186, entitled “Cyclopropyl-
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`Fused Pyrrolidine-Based Inhibitors of Dipeptidyl Peptidase IV and Method” (“the
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`’186 patent”), issued April 30, 2013. I further understand that the ’186 patent
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`issued from U.S. Application Serial No. 13/308,658, filed December 1, 2011 as a
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`reissue application of U.S. Application Serial No. 09/788,173, filed February 16,
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`2001 and issued as U.S. Patent No. 6,395,767 on May 28, 2002. U.S. Application
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`-9-
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`Serial No. 09/788,173 (“the ’173 application”) and claims priority to U.S.
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`Provisional Application No. 60/188,555, filed on March 10, 2000 (“the ’555
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`application”).
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`19.
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`Several claim elements of the ’186 patent are not described in the
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`earliest-filed ’555 application, and instead appear for the first time in the later-filed
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`’173 application. For example, there is no description in the ’555 application of: (i)
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`the genus of compounds recited in claim 6; (ii) the specific compounds recited in
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`claim 8 or (iii) the specific compound of claim 25.
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`There is no disclosure in the earlier-filed ’555 application of the
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`20.
`specific genus of claim 6, in which claim 1 is further limited to:
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`R3 is H, R1 is H, alkyl, cycloalkyl, bicycloalkyl, tricycloalkyl,
`alkylcycloalkyl, hydroxyalkyl, hydroxyalkylcycloalkyl,
`hydroxycycloalkyl, hydroxybicycloalkyl, or hydroxytricycloalkyl,
`R2 is H or alkyl, n is 0,
`X is CN.
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`See, e.g., Ex. 1027, p. 0008, ll. 8-11; claim 6. Further, the ’555 application
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`exemplifies only short, straight and/or branched alkyl substituents at the 2-position
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`as shown below:
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`See, e.g., Ex. 1027, p. 0056; claim 13. Accordingly, one of ordinary skill in the art
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`would have understood that the inventors were not in possession of the genus
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`recited in claim 6 at the time of the ’555 application’s filing.
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`21.
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`Claim 8 of the ’186 patent recites a compound as defined in claim 1
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`having the structure:
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`or a pharmaceutically acceptable salt thereof.
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`The only specific compounds described in the ’555 application are directed to
`short, straight and/or branched alkyl substituents at the 2-position. See, e.g., Ex.
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`1027, p. 0056; claim 13. The compounds of claim 8 were first disclosed in the ’173
`application. See, e.g., Ex. 1005, p. 0010.
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`22.
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`Similarly, the compound of claim 25 is also not specifically disclosed
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`in the specification of the ’555 application. Independent claim 25 recites the
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`following:
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`or, a pharmaceutically acceptable salt thereof.
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`As discussed above, the only specific compounds described in the ’555 application
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`are directed to short, straight and/or branched alkyl substituents at the 2-position as
`depicted in the preceding paragraph. See, e.g., Ex. 1027, p. 0056; claim 13. The
`compound of claim 25 was first disclosed in the ’173 application. See, e.g., Ex.
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`1005, p. 0010. Accordingly, one of ordinary skill in the art could surmise that the
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`inventors were not in possession of the compounds of claims 8 or 25 at the time of
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`the ’555 application’s filing.
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`23. As discussed in detail above, several claim elements of the ’186 patent
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`are not described in the earliest-filed ’555 application, and instead appear for the
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`first time in the later-filed ’173 application. Accordingly, one of ordinary skill in
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`the art would have understood that the inventors were not in possession of the
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`claimed subject matter at the time of the ’555 application’s filing.
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`V. LEGAL STANDARDS
`I have been informed that a claimed invention is not patentable under
`24.
`35 U.S.C. § 103 (2012), for obviousness, if the differences between the invention
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`and the prior art are such that the subject matter as a whole would have been
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`obvious at the time the invention was made to a person having ordinary skill in the
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`field to which the subject matter pertains.
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`25.
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`I have been instructed that a determination of obviousness requires
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`inquiries into (i) the scope and content of the art when the invention was made; (ii)
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`the differences between the art and the claims at issue; (iii) the level of ordinary
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`skill in the pertinent art when the invention was made; and, to the extent they exist,
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`any secondary considerations.
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`26.
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`I understand that a claim can be found to have been obvious if all the
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`claimed elements were known in the prior art and one skilled in the field could
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`have combined the elements as claimed by known methods with no change in their
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`respective functions, and the combination would have yielded nothing more than
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`predictable and expected results to one of ordinary skill in the art.
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`I understand that improper hindsight must not be used when
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`27.
`comparing the prior art to the invention for obviousness. Thus, a conclusion of
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`obviousness must be firmly based on knowledge and skill of a person of ordinary
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`skill in the field at the time the invention was made without the use of post-filing
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`knowledge.
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`28.
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`I understand that in order for a claimed invention to be considered
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`obvious, there must be some supporting rationale for combining cited references as
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`proposed.
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`I have been informed that obviousness may be established by showing
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`29.
`that it would have been obvious to combine the teachings of more than one item of
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`prior art. In determining whether a piece of prior art could have been combined
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`with other prior art or with other information within the knowledge of one of
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`ordinary skill in the art, the following are examples of approaches and rationales
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`that may be considered: (i) combination of prior art elements according to known
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`methods to yield predictable results; (ii) simple substitution of one known element
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`for another to obtain predictable results; (iii) use of a known technique to improve
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`similar methods or products in the same way; (vi) application of a known technique
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`to a known method or product ready for improvement to yield predictable results;
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`(vii) application of a technique or approach that would have been “obvious to try”
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`(choosing from a finite number of identified, predictable solutions, with a
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`reasonable expectation of success); (viii) known work in one field of endeavor may
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`prompt variations of it for use in either the same field or a different one based on
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`design incentives or other market forces if the variations would have been
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`predictable to one of ordinary skill in the art; or (ix) some teaching, suggestion, or
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`motivation in the prior art that would have led one of ordinary skill to modify the
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`prior art reference or to combine prior art reference teachings to arrive at the
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`claimed invention.
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`30.
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`I also understand that evidence of “secondary considerations” may be
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`weighed against evidence of the scope and content of, and the level of skill in, the
`art to rebut a conclusion of obviousness where appropriate.
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`I understand that such secondary considerations when in evidence
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`31.
`may include: (i) commercial success of a product due to the merits of the claimed
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`invention; (ii) a long-felt, but unsatisfied need for the invention; (iii) failure of
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`others to find the solution provided by the claimed invention; (iv) deliberate
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`copying of the invention by others; (v) unexpected results achieved by the
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`invention; (vi) praise of the invention by others skilled in the art; (vii) lack of
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`independent simultaneous invention within a comparatively short space of time;
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`and (viii) teaching away from the invention in the prior art. Secondary
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`considerations are relevant where there is a connection, or relationship, between
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`the evidence and the claimed invention.
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`VI. LEVEL OF ORDINARY SKILL AND RELEVANT TIME
`I have been advised that the ’186 patent claims priority to U.S.
`32.
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`provisional application number 60/188,555 (“the ’555 application),” which was
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`filed on March 10, 2000. I further understand, however, that the ’186 patent may
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`not be entitled to that 2000 priority date. Each of the opinions expressed in this
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`declaration apply regardless of whether the priority date is March 10, 2000 (the
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`filing date of the ’555 application) or February 16, 2001 (the filing date of the ’173
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`application).
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`33. As discussed above, “a person of ordinary skill in the relevant field” is
`a hypothetical person who is presumed to have typical knowledge and experience
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`-12-
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`in the relevant field at the time of the invention. A person of ordinary skill in the
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`field is also a person of ordinary creativity. I have been asked to use the time prior
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`to March 10, 2000, as the relevant timeframe for assessing validity of the ’186
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`patent. When I refer to March 2000, I am referring specifically to prior to March
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`10, 2000.
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`34. By virtue of my education, experience, and training, I am familiar with
`the level of skill in the field of the ’186 patent on or about March 10, 2000.
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`35. One of ordinary skill in the field would likely have some combination
`of the following skills and experience: (i) designing target compounds towards
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`drug discovery; (ii) designing and preparing formulations of drugs that exhibit
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`inhibitory activity; (iii) understanding the biological aspects of drug development,
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`including the drug’s effect on the whole animal; and (iv) understanding work
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`presented or published by others in the field, including the patents and printed
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`publications discussed in this declaration.
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`36. Typically, a person of ordinary skill in the relevant field in March 2000
`could have an advanced degree (e.g., a Ph.D.) in pharmaceutics, pharmaceutical
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`chemistry, medicinal chemistry or a related field and at least 2-3 years of practical
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`experience in the design of drugs. Alternatively, a person of ordinary skill in the
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`relevant field could have less education but considerable professional experience.
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`37. My understanding of the level of ordinary skill in the art is
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`corroborated by the specification of the ’186 patent, which in many instances
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`provides general rather than specific guidance regarding how the invention would
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`be practiced. For example, the ’186 patent lacks specific guidance of the various
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`-13-
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`pharmaceutical combinations that it claims. There are no validated or tested
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`dosages for those combinations, nor any examples describing any actual
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`combinations produced by the inventors. Rather than providing specific guidance
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`regarding dosages for the claimed combinations, the ’186 patent invites those of
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`ordinary skill in the art to turn to the knowledge and resources readily available to
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`them when selecting and formulating appropriate combinations of known drugs.
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`For example, rather than providing specific guidance for the combination dosages,
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`the ’186 patent provides very broad dosage ranges (see, e.g., Ex. 1001, col. 4, ll.
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`48-53), which provide essentially no guidance for selecting actual dosages or
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`treatment regimens. The lack of specific guidance provided in the specification
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`reflects the high level of skill in the art.
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`38. WO Patent App. Pub. No. 98/19998 to Villhauer (pub’d May 14,1998)
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`(hereinafter “Villhauer,” Ex. 1008) similarly indicates a high level of skill in the art
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`by relying on that skill to select from the many options disclosed in the
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`specification or known to those in the art. See, e.g., id. at pp. 2-3 (disclosing large
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`and diverse R groups), id. at 3, ll. 20-27 (disclosing pharmaceutically acceptable
`salts and isomers), id. at 7, ll. 22 (teaching that “[t]he process of the invention may
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`be effected in conventional manner.”), id. at 8, ll. 1-10 (disclosing starting materials
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`known or prepared in known or conventional manner) and id. at 20 (disclosing
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`pharmaceutically acceptable carriers, adjuvants and modes of administration, and
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`conventional preparation of same). Villhauer thus reflects the conventional
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`approach in the art to prepare promising variants of lead compounds and compare
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`the results.
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`-14-
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`39. Claims 13-22 of the ’186 patent recite various combinations of DP-IV
`inhibitors and additional therapeutic agents (e.g., other antidiabetic agents, anti-
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`obesity agents, lipid-modulating agents, etc.). At multiple instances, the ’186
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`patent invites those of ordinary skill in the art to select additional agents or
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`mechanisms beyond those disclosed in the specification for use in combination
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`with the claimed DP-IV inhibitors, for example:
`
`The term “lipid-modulating” agent as employed herein refers to
`agents which lower LDL and/or raise HDL and/or lower triglycerides
`and/or lower total cholesterol and/or other known mechanisms for
`therapeutically treating lipid disorders.
`
`Ex. 1001, col. 4, ll. 43-47 (emphasis added).
`
`The other antidiabetic agent may also preferably be a sulfonyl urea . .
`., other known sulfonylureas or other antihyperglycemic agents
`which act on the ATP-dependent channel of the β-cells . . .
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`Id. at col. 15, ll. 5-11 (emphasis added).
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`The squalene synthetase inhibitors suitable for use herein include, but
`are not limited to, a-phosphono-sulfonates . . . as well as other
`known squalene synthetase inhibitors . . .
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`Id. at col. 17, ll. 47-52 (emphasis added).
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`Other hypolipidemic agents suitable for use herein include, but are not
`limited to, fibric acid derivatives . . . and other known serum
`cholesterol lowering agents.
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`Id. at col. 18, ll. 1-20 (emphasis added).
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`The beta 3 adrenergic agonist which may be optionally employed in
`combination with a compound of formula I may be AJ9677
`(Takeda/Dainippon), L750355 (Merck), or CP331648 (Pfizer) or
`other known beta 3 agonists . . .
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`Id. at col. 20, ll. 12-18 (emphasis added). The ’186 patent’s repeated reliance on
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`knowledge available outside the specification itself reflects the high level of skill
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`in the art.
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`40. Furthermore, the ’186 patent defers in several instances to resources
`readily available to those of ordinary skill in the art for determining dosages and
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`other treatment parameters for the claimed combinations, including 15 citations to
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`the Physician’s Desk Reference (PDR). See, e.g., Ex. 1001, col. 15, ll. 60-61; col.
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`16, ll. 4-5; col. 19, ll. 3 and 35; col. 20, ll. 43, 50, 57, and 67; col. 21, ll. 9, 15, 24,
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`41, 47, and 54. For example, the ’186 patent states that “[t]he amounts and dosages
`employed will be as indicated in the Physician’s Desk Reference . . .” id. at col. 19,
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`ll. 2-4. I agree that the PDR is a resource often used in the art for established
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`dosing and treatment regimens for FDA approved drugs.
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`41. The ’186 patent provides a reasonable expectation of success for
`practicing the claimed invention to the extent it is enabled by the specification. The
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`background section of the ’186 patent defines the mechanism by which DP-IV
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`inhibitors treat type 2 diabetes, for example, by providing that “[DP-IV] has been
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`shown to be the primary degrading enzyme of GLP-1(7-36) in vivo . . . [t]hus,
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`inhibition of [DP-IV] in vivo should potentiate endogenous levels of GLP-1(7-36)
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`and . . . thus serve to ameliorate the diabetic condition.” id. at col. 1, ll. 59-67.
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`Villhauer provides evidence for what was generally known in the art by teaching
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`that because “GLP-1 is a major stimulator of pancreatic insulin secretion and has
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`direct beneficial effects on glucose disposal, [DP-IV] inhibition . . . represent[s] an
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`attractive approach for treating non-insulin-dependent diabetes mellitus
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`(NIDDM).” Ex. 1008, p. 1. In addition, the ’186 patent teaches that the claimed
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`DP-IV inhibitors can be used “for treating diabetes, especially Type II diabetes.”
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`Ex. 1001, col. 3, l. 53 – col. 4, l. 1. Given the high level of skill in the art and the
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`advanced knowledge in the art regarding the activity of DP-IV inhibitors, one of
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`ordinary skill in the art would have had a reasonable expectation for treating
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`diabetes to the same extent the claims of the ’186 are enabled by the specification.
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`VII. CLAIM CONSTRUCTION
`I have been advised that, in the present proceeding, the ’186 patent
`42.
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`claims are to be given their broadest reasonable interpretation in view of the
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`specification. I also understand that, absent some reason to the contrary, claim
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`terms are typically given their ordinary and accustomed meaning as would have
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`been understood by one of ordinary skill in the art. I have followed these principles
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`in my analysis described throughout this declaration. The ’186 patent provides
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`definitions for certain claim terms. In my opinion, those definitions are
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`conventional.
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`VIII. THE STATE OF THE PRIOR ART
`43. Below I describe the details of what was generally known in the art as
`of March 2000, including: (i) the structure and activity of known DP-IV inhibitors;
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`(ii) principles for improving a compound’s drug-likeness and suitability as an
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`orally bioavailable drug and (iii) standard strategies for assessing and modulating
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`compound potency.
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`44. As set forth above, the Background section of the ’186 patent
`discloses that “inhibitors of dipeptidyl peptidase IV [(DP-IV) are known to] . . .
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`treat[ ] diabetes, especially Type II diabetes.” Ex. 1001 col. 1, ll. 19-21. The
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`Background of the ’186 patent also describes what was well known about the
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`mechanism by which DP-IV inhibitors treat type 2 diabetes: “[DP-IV] has been
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`shown to be the primary degrading enzyme of GLP-1(7-36) in vivo . . . [t]hus,
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`inhibition of [DP-IV] in vivo should potentiate endogenous levels of GLP-1(7-36)
`and . . . thus serve to ameliorate the diabetic condition.” Id. at col. 1, ll. 59-67.
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`45. Lin describes what was well known in the art in March 2000
`regarding the substrate structural elements required by DP-IV. Jian Lin et al.,
`Inhibition of dipeptidyl peptidase IV by fluoroolefin-containing N-peptidyl-O-
`hydroxylamine peptidomimetics, 95 PROC. NATL. ACAD. SCI. USA 14020 (1998) at
`14020 (hereinafter “Lin,” Ex. 1015). For example, Lin reports that “[DP-IV]
`substrates require the presence of a proline at the P1 position as well as a
`protonated free N terminus.” Id. The P1, etc. positions are depicted schematically
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`below:
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`-18-
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`46. Lin also describes what was generally known in the art in March 2000
`regarding DP-IV’s preferred substrate and inhibitor conformations. For example,
`Lin reports that “[DP-IV] possesses a high conformational specificity for a trans
`amide bond between the P1 and N-terminal P2 residues.” Ex. 1015 at 14020. Where
`the P1 residue is the C-terminal residue and the P2 residue is the N-terminal residue
`(see schematic above for P1 and P2 position designations). The trans and cis
`conformations of the Lin prolyl dipeptides are depicted below:
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`Id., p. 14022. Lin addresses the importance of the trans conformation
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`47.
`for compound stability and its effect on DP-IV inhibition as follows:
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`
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`Many of the problems associated with inefficient inactivation of [DP-
`IV] are a consequence of the importance of the trans conformation
`of the P1-P2 amide bond and the requirement for a protonated free N
`terminus. The cyclization reaction of the free N-terminal amino
`group with the reactive inhibitor . . . require[s] the molecule
`assume the cis conformation.
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`Id., at 14020-14021. Lin reports Ki values of 14,000 nM for a dipeptide in the cis
`conformation and 188 nM for a dipeptide of otherwise identical structure in the
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`trans conformation. Comparison of these Ki values for DP-IV inhibition reveals the
`significantly greater potency of, and preference for, inhibitors in the trans
`conformation. See, e.g., id. at 14023 and Table 2.
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`48. Lin also describes what was well known in the art in March 2000
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`regarding the effect of conformation on dipeptide stability. Specifically, Lin
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`describes “the cyclization reaction of the free N-terminal amino acid group with
`the reactive site of the inhibitor” for related dipeptide compounds (id. at 14020-
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`14021), which negatively impacts com