`
`_______________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_______________________________
`
`SUN PHARMACEUTICAL INDUSTRIES LTD.,
`SUN PHARMA GLOBAL FZE and
`AMNEAL PHARMACEUTICALS LLC,
`Petitioners,
`
`v.
`
`ASTRAZENECA
`Patent Owner.
`
`___________________________
`
`Case No.: IPR2016-01104
`Patent No.: RE44,186
`
`___________________________
`
`DECLARATION OF DAVID P. ROTELLA, PH.D.
`
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:19)(cid:22)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:20)(cid:3)(cid:82)(cid:73)(cid:3)(cid:20)(cid:20)(cid:22)
`
`Ex. 1003
`
`
`
`Table of Contents
`
`Page
`
`QUALIFICATIONS .............................................................................. 1
`
`SCOPE OF WORK ............................................................................... 2
`
`OVERVIEW OF THE ’186 PATENT .................................................. 3
`
`FILE HISTORY OF THE ’186 PATENT ............................................ 7
`
`LEGAL STANDARDS ....................................................................... 11
`
`LEVEL OF ORDINARY SKILL AND RELEVANT TIME ............. 14
`
`CLAIM CONSTRUCTION ................................................................ 19
`
`THE STATE OF THE PRIOR ART ................................................... 20
`
`PRIOR ART REFERENCES DISCLOSE OR SUGGEST EACH OF
`THE CLAIMED FEATURES OF THE ’186 PATENT ..................... 28
`
`CONCLUDING STATEMENTS .....................................................109
`
`APPENDIX – LIST OF EXHIBITS .................................................110
`
`
`
`I.
`
`II.
`
`III.
`
`IV.
`
`V.
`
`VI.
`
`VII.
`
`VIII.
`
`IX.
`
`X.
`
`XI.
`
`
`
`i
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:19)(cid:22)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:21)(cid:3)(cid:82)(cid:73)(cid:3)(cid:20)(cid:20)(cid:22)
`
`
`
`
`
`I.(cid:3)
`
`I, David P. Rotella, declare as follows:
`
`QUALIFICATIONS
`
`1.
`
`My name is David P. Rotella. I am currently the Margaret and
`
`Herman Sokol Professor of Chemistry in the Department of Chemistry and
`
`Biochemistry and in the Sokol Institute of Pharmaceutical Life Sciences at
`
`Montclair State University. I have been a member of the faculty of this university
`
`since 2011.
`
`2.
`
`I am currently an adjunct professor in the Department of
`
`Pharmaceutical Sciences at the University of Pittsburgh, in the Center for Drug
`
`Discovery at Northeastern University, and in the Department of Medicinal
`
`Chemistry at the University of Mississippi. I have been a member of the faculty of
`
`these departments since 2010, 2010, and 2009, respectively.
`
`3.
`
`I was formerly a research scientist at multiple pharmaceutical
`
`companies during the years 1991-2010, including at Bristol-Myers Squibb PRI,
`
`Lexicon Pharmaceuticals, and Wyeth Research/Pfizer. My industry experience
`
`focused on drug discovery and development.
`
`4.
`
`I received my B.S. Pharm. from the University of Pittsburgh in 1981
`
`and Ph.D. in Medicinal Chemistry from The Ohio State University in 1985. I was a
`
`Postdoctoral Scholar in the Department of Chemistry at The Pennsylvania State
`
`University from 1985 to 1987.
`
`1
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:19)(cid:22)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:22)(cid:3)(cid:82)(cid:73)(cid:3)(cid:20)(cid:20)(cid:22)
`
`
`
`
`
`5.
`
`My current research focuses on protein kinase inhibitors for anti-
`
`infective and anti-inflammatory applications. Specifically, I work on the discovery
`
`of new agents useful for the potential treatment of parasitic and neurodegenerative
`
`diseases, including the synthesizing of new analogs of a lead structure as potential
`
`protein kinase inhibitors and investigation of structure-activity relationships in a
`
`product that has HSP90 inhibitor activity.
`
`6.
`
`I have authored or co-authored more than 20 abstracts for presentation
`
`at professional meetings, 40 peer-reviewed journal articles, and seven book
`
`chapters. I have also edited or co-edited five books in the field of Medicinal
`
`Chemistry. I have received numerous honors, fellowships and awards, and am an
`
`inventor or co-inventor on seven granted patents.
`
`7.
`
`A summary of my education, experience, publications, awards and
`
`honors, patents, publications, and presentations is provided in my CV, a copy of
`
`which is submitted separately (Ex. 1004).
`
`II.(cid:3)
`
`SCOPE OF WORK
`
`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.
`
`RE44,186 (hereinafter, “the ’186 patent,” Ex. 1001). I have been retained by Sun
`
`Pharma Global FZE, Sun Pharmaceutical Industries, Ltd., and Amneal
`
`Pharmaceuticals LLC as a technical expert to provide opinions regarding the ’186
`
`2
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:19)(cid:22)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:23)(cid:3)(cid:82)(cid:73)(cid:3)(cid:20)(cid:20)(cid:22)
`
`
`
`
`
`patent. I have reviewed the ’186 patent and relevant sections of its prosecution
`
`history in the US Patent and Trademark Office (Ex. 1006). I have also reviewed
`
`and considered other documents in arriving at my opinions, and cite them in this
`
`declaration. For convenience, documents cited in this declaration are listed in the
`
`Appendix in Section XI.
`
`9.
`
`I am compensated at the rate of $500/hour for my work. I have no
`
`financial interest in the outcome of this matter.
`
`III.(cid:3) OVERVIEW OF THE ’186 PATENT
`
`10.
`
`The ’186 patent is entitled “Cyclopropyl-Fused Pyrrolidine-Based
`
`Inhibitors of Dipeptidyl Peptidase IV and Method” and was issued on April 30,
`
`2013. I have been advised that the ’186 patent issued from U.S. Application No.
`
`13/308,658, which was filed on December 1, 2011, as a reissued application of
`
`U.S. Application No. 09/788,173, which was filed on February 16, 2001 and issued
`
`as U.S. Patent No. 6,395,767 on May 28, 2002. I have also been advised that U.S.
`
`Application No. 09/788,173 claims priority to U.S. Provisional Application No.
`
`60/188,555, which was filed on March 10, 2000.
`
`11.
`
`The ’186 patent is generally directed to cyclopropyl-fused pyrrolidine-
`
`based compounds with a variety of optional substituents, as well as pharmaceutical
`
`combinations and methods for treating diabetes and additional diseases. According
`
`to the ’186 patent, the “cyclopropyl-fused pyrrolidine-based compounds [of the
`
`3
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:19)(cid:22)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:24)(cid:3)(cid:82)(cid:73)(cid:3)(cid:20)(cid:20)(cid:22)
`
`
`
`
`
`’186 patent are] inhibitors of dipeptidyl peptidase IV [(DP-IV)] . . . for treating
`
`diabetes, especially Type II diabetes.” Ex. 1001 col. 1, ll. 19-21. The ’186 patent
`
`describes the mechanism by which DP-IV inhibition treats type 2 diabetes as
`
`follows: “[DP-IV] has been shown to be the primary degrading enzyme of
`
`GLP¬1(7-36) in vivo . . . [t]hus, 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.
`
`12.
`
`Independent claim 1 discloses a genus of chemical compounds
`
`comprising a cyclopropyl-fused pyrrolidine-based core with a variety of optional
`
`substituents. Dependent claims 2-7 and independent claims 8 and 10 further limit
`
`the substituent groups of the compound of claim 1. For example, independent
`
`claim 8 recites the following:
`
`A compound having the structure:
`
`4
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:19)(cid:22)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:25)(cid:3)(cid:82)(cid:73)(cid:3)(cid:20)(cid:20)(cid:22)
`
`
`
`
`
`
`
`or a pharmaceutically acceptable salt thereof.
`
`Dependent claim 9 is directed to the hydrochloride or trifluoroacetic acid salts of
`
`the compounds of claim 8. Dependent claim 11 is directed to a pharmaceutical
`
`composition comprising a compound within the scope of claim 1. Claims 12-21
`
`recite pharmaceutical combinations comprising a compound within the scope of
`
`claim 1 and an antidiabetic agent for treating diabetes and/or additional agents for
`
`treating related diseases. Claim 22 recites pharmaceutical combinations comprising
`
`a compound within the scope of claim 1 and an agent for treating obesity or other
`
`related diseases. Claims 23 and 24 were canceled upon reissue.
`
`13.
`
`Independent claim 25 recites a single compound as follows:
`
`5
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:19)(cid:22)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:26)(cid:3)(cid:82)(cid:73)(cid:3)(cid:20)(cid:20)(cid:22)
`
`
`
`
`
`or a pharmaceutically acceptable salt thereof.
`
`
`
`The compound of claim 25 also falls within the scope of composition claims 1, 2,
`
`4, 6, 7, 8 and 10. Dependent claim 26 recites the hydrochloride salt of the
`
`compound of claim 25. Dependent claims 27 and 28 further recite pharmaceutical
`
`compositions of the compound of claim 25. Dependent claims 29-31 recite a
`
`combination of the compound of claim 25 and an antidiabetic agent other than a
`
`DP-IV inhibitor. Claims 32-43 recite various methods of treatment using the
`
`compound of claim 25, alone or in combination with an antidiabetic agent other
`
`than a DP-IV inhibitor.
`
`14.
`
`The compound of claim 25 is also known as (1S,3S,5S)-2-[(2S)-2-
`
`amino-2-(3-hydroxy-1-adamantyl) acetyl]-2-azabicyclo[3.1.0]hexane-3-
`
`carbonitrile. For convenience, this compound will be referred to as “saxagliptin” as
`
`shown below:
`
`
`
`Saxagliptin
`
`6
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:19)(cid:22)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:27)(cid:3)(cid:82)(cid:73)(cid:3)(cid:20)(cid:20)(cid:22)
`
`
`
`
`
`15.
`
`In my opinion, and as explained in detail below, the claims of the ’186
`
`patent would have been obvious to individuals of ordinary skill in the field prior to
`
`and at the time of the earliest possible priority filing date of the ’186 patent, i.e.,
`
`prior to March 10, 2000.
`
`IV.(cid:3) FILE HISTORY OF THE ’186 PATENT
`
`16.
`
`I have been advised that the determination of the right to priority is
`
`controlled by the written description requirement of 35 U.S.C. § 112, and to satisfy
`
`the written description requirement the disclosure of the prior application must
`
`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
`
`advised that the prior application must indicate to a person skilled in the art that the
`
`inventor was “in possession” of the invention as later claimed.
`
`17.
`
`I understand that U.S. Patent No. RE44,186, entitled “Cyclopropyl-
`
`Fused Pyrrolidine-Based Inhibitors of Dipeptidyl Peptidase IV and Method” (“the
`
`’186 patent”), issued April 30, 2013. I further understand that the ’186 patent
`
`issued from U.S. Application Serial No. 13/308,658, filed December 1, 2011 as a
`
`reissue application of U.S. Application Serial No. 09/788,173, filed February 16,
`
`2001 and issued as U.S. Patent No. 6,395,767 on May 28, 2002. U.S. Application
`
`Serial No. 09/788,173 (“the ’173 application”) and claims priority to U.S.
`
`7
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:19)(cid:22)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:28)(cid:3)(cid:82)(cid:73)(cid:3)(cid:20)(cid:20)(cid:22)
`
`
`
`
`
`Provisional Application No. 60/188,555, filed on March 10, 2000 (“the ’555
`
`application”).
`
`18.
`
`Several claim elements of the ’186 patent are not described in the
`
`earliest-filed ’555 application, and instead appear for the first time in the later-filed
`
`’173 application. For example, there is no description in the ’555 application of: (i)
`
`the genus of compounds recited in claim 6; (ii) the specific compounds recited in
`
`claim 8 or (iii) the specific compound of claim 25.
`
`19.
`
`There is no disclosure in the earlier-filed ’555 application of the
`
`specific genus of claim 6, in which claim 1 is further limited to:
`
`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.
`
`
`See, e.g., Ex. 1027, p. 0008, ll. 8-11; claim 6. Further, the ’555 application
`
`exemplifies only short, straight and/or branched alkyl substituents at the 2-position
`
`as shown below:
`
`8
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:19)(cid:22)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:20)(cid:19)(cid:3)(cid:82)(cid:73)(cid:3)(cid:20)(cid:20)(cid:22)
`
`
`
`
`
`
`
`See, e.g., Ex. 1027, p. 0056; claim 13. Accordingly, one of ordinary skill in the art
`
`would have understood that the inventors were not in possession of the genus
`
`recited in claim 6 at the time of the ’555 application’s filing.
`
`20. Claim 8 of the ’186 patent recites a compound as defined in claim 1
`
`having the structure:
`
`or a pharmaceutically acceptable salt thereof.
`
`
`
`9
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:19)(cid:22)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:20)(cid:20)(cid:3)(cid:82)(cid:73)(cid:3)(cid:20)(cid:20)(cid:22)
`
`
`
`
`
`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.
`
`1027, p. 0056; claim 13. The compounds of claim 8 were first disclosed in the ’173
`
`application. See, e.g., Ex. 1005, p. 0010.
`
`21.
`
`Similarly, the compound of claim 25 is also not specifically disclosed
`
`in the specification of the ’555 application. Independent claim 25 recites the
`
`following:
`
`or, a pharmaceutically acceptable salt thereof.
`
`
`
`As discussed above, the only specific compounds described in the ’555 application
`
`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.
`
`1005, p. 0010. Accordingly, one of ordinary skill in the art could surmise that the
`
`inventors were not in possession of the compounds of claims 8 or 25 at the time of
`
`the ’555 application’s filing.
`
`22. As discussed in detail above, several claim elements of the ’186 patent
`
`are not described in the earliest-filed ’555 application, and instead appear for the
`
`10
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:19)(cid:22)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:20)(cid:21)(cid:3)(cid:82)(cid:73)(cid:3)(cid:20)(cid:20)(cid:22)
`
`
`
`
`
`first time in the later-filed ’173 application. Accordingly, one of ordinary skill in
`
`the art would have understood that the inventors were not in possession of the
`
`claimed subject matter at the time of the ’555 application’s filing.
`
`V.(cid:3) LEGAL STANDARDS
`
`23.
`
`I have been informed that a claimed invention is not patentable under
`
`35 U.S.C. § 103 (2012), for obviousness, if the differences between the invention
`
`and the prior art are such that the subject matter as a whole would have been
`
`obvious at the time the invention was made to a person having ordinary skill in the
`
`field to which the subject matter pertains.
`
`24.
`
`I have been instructed that a determination of obviousness requires
`
`inquiries into (i) the scope and content of the art when the invention was made; (ii)
`
`the differences between the art and the claims at issue; (iii) the level of ordinary
`
`skill in the pertinent art when the invention was made; and, to the extent they exist,
`
`any secondary considerations.
`
`25.
`
`I understand that a claim can be found to have been obvious if all the
`
`claimed elements were known in the prior art and one skilled in the field could
`
`have combined the elements as claimed by known methods with no change in their
`
`respective functions, and the combination would have yielded nothing more than
`
`predictable and expected results to one of ordinary skill in the art.
`
`11
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:19)(cid:22)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:20)(cid:22)(cid:3)(cid:82)(cid:73)(cid:3)(cid:20)(cid:20)(cid:22)
`
`
`
`
`
`26.
`
`I understand that improper hindsight must not be used when
`
`comparing the prior art to the invention for obviousness. Thus, a conclusion of
`
`obviousness must be firmly based on knowledge and skill of a person of ordinary
`
`skill in the field at the time the invention was made without the use of post-filing
`
`knowledge.
`
`27.
`
`I understand that in order for a claimed invention to be considered
`
`obvious, there must be some supporting rationale for combining cited references as
`
`proposed.
`
`28.
`
`I have been informed that obviousness may be established by showing
`
`that it would have been obvious to combine the teachings of more than one item of
`
`prior art. In determining whether a piece of prior art could have been combined
`
`with other prior art or with other information within the knowledge of one of
`
`ordinary skill in the art, the following are examples of approaches and rationales
`
`that may be considered: (i) combination of prior art elements according to known
`
`methods to yield predictable results; (ii) simple substitution of one known element
`
`for another to obtain predictable results; (iii) use of a known technique to improve
`
`similar methods or products in the same way; (vi) application of a known
`
`technique to a known method or product ready for improvement to yield
`
`predictable results; (vii) application of a technique or approach that would have
`
`been “obvious to try” (choosing from a finite number of identified, predictable
`
`12
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:19)(cid:22)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:20)(cid:23)(cid:3)(cid:82)(cid:73)(cid:3)(cid:20)(cid:20)(cid:22)
`
`
`
`
`
`solutions, with a reasonable expectation of success); (viii) known work in one field
`
`of endeavor may prompt variations of it for use in either the same field or a
`
`different one based on design incentives or other market forces if the variations
`
`would have been predictable to one of ordinary skill in the art; or (ix) some
`
`teaching, suggestion, or motivation in the prior art that would have led one of
`
`ordinary skill to modify the prior art reference or to combine prior art reference
`
`teachings to arrive at the claimed invention.
`
`29.
`
`I also understand that evidence of “secondary considerations” may be
`
`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.
`
`30.
`
`I understand that such secondary considerations when in evidence
`
`may include: (i) commercial success of a product due to the merits of the claimed
`
`invention; (ii) a long-felt, but unsatisfied need for the invention; (iii) failure of
`
`others to find the solution provided by the claimed invention; (iv) deliberate
`
`copying of the invention by others; (v) unexpected results achieved by the
`
`invention; (vi) praise of the invention by others skilled in the art; (vii) lack of
`
`independent simultaneous invention within a comparatively short space of time;
`
`and (viii) teaching away from the invention in the prior art. Secondary
`
`considerations are relevant where there is a connection, or relationship, between
`
`the evidence and the claimed invention.
`
`13
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:19)(cid:22)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:20)(cid:24)(cid:3)(cid:82)(cid:73)(cid:3)(cid:20)(cid:20)(cid:22)
`
`
`
`
`
`VI.(cid:3) LEVEL OF ORDINARY SKILL AND RELEVANT TIME
`
`31.
`
`I have been advised that the ’186 patent claims priority to U.S.
`
`provisional application number 60/188,555 (“the ’555 application”), which was
`
`filed on March 10, 2000. I further understand, however, that the ’186 patent may
`
`not be entitled to that 2000 priority date. Each of the opinions expressed in this
`
`declaration apply regardless of whether the priority date is March 10, 2000 (the
`
`filing date of the ’555 application) or February 16, 2001 (the filing date of the ’173
`
`application).
`
`32. 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
`
`in the relevant field at the time of the invention. A person of ordinary skill in the
`
`field is also a person of ordinary creativity. I have been asked to use the time prior
`
`to March 10, 2000, as the relevant timeframe for assessing validity of the ’186
`
`patent. When I refer to March 2000, I am referring specifically to prior to March
`
`10, 2000.
`
`33. 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.
`
`34. One of ordinary skill in the field would likely have some combination
`
`of the following skills and experience: (i) designing target compounds towards
`
`drug discovery; (ii) designing and preparing formulations of drugs that exhibit
`
`14
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:19)(cid:22)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:20)(cid:25)(cid:3)(cid:82)(cid:73)(cid:3)(cid:20)(cid:20)(cid:22)
`
`
`
`
`
`inhibitory activity; (iii) understanding the biological aspects of drug development,
`
`including the drug’s effect on the whole animal; and (iv) understanding work
`
`presented or published by others in the field, including the patents and printed
`
`publications discussed in this declaration.
`
`35.
`
`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 chemistry, medicinal chemistry or a related field and at least 2-3
`
`years of practical experience in the design of drugs. Alternatively, a person of
`
`ordinary skill in the relevant field could have less education but considerable
`
`professional experience.
`
`36. My understanding of the level of ordinary skill in the art is
`
`corroborated by the specification of the ’186 patent, which in many instances
`
`provides general rather than specific guidance regarding how the invention would
`
`be practiced. For example, the ’186 patent lacks specific guidance of the various
`
`pharmaceutical combinations that it claims. There are no validated or tested
`
`dosages for those combinations, nor any examples describing any actual
`
`combinations produced by the inventors. Rather than providing specific guidance
`
`regarding dosages for the claimed combinations, the ’186 patent invites those of
`
`ordinary skill in the art to turn to the knowledge and resources readily available to
`
`them when selecting and formulating appropriate combinations of known drugs.
`
`15
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:19)(cid:22)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:20)(cid:26)(cid:3)(cid:82)(cid:73)(cid:3)(cid:20)(cid:20)(cid:22)
`
`
`
`
`
`For example, rather than providing specific guidance for the combination dosages,
`
`the ’186 patent provides very broad dosage ranges (See, e.g., Ex. 1001, col. 4, ll.
`
`48-53), which provide essentially no guidance for selecting actual dosages or
`
`treatment regimens. The lack of specific guidance provided in the specification
`
`reflects the high level of skill in the art.
`
`37. WO Patent App. Pub. No. 98/19998 to Villhauer (pub’d May
`
`14,1998) (hereinafter “Villhauer,” Ex. 1008) similarly indicates a high level of
`
`skill in the art by relying on that skill to select from the many options disclosed in
`
`the specification or known to those in the art. See, e.g., id. at pp. 2-3 (disclosing
`
`large 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 be effected in conventional manner.”), id. at 8, ll. 1-10 (disclosing
`
`starting materials known or prepared in known or conventional manner) and id. at
`
`20 (disclosing pharmaceutically acceptable carriers, adjuvants and modes of
`
`administration, and conventional preparation of same). Villhauer thus reflects the
`
`conventional approach in the art to prepare promising variants of lead compounds
`
`and compare the results.
`
`38. Claims 13-22 of the ’186 patent recite various combinations of DP-IV
`
`inhibitors and additional therapeutic agents (e.g., other antidiabetic agents, anti-
`
`obesity agents, lipid-modulating agents, etc.). At multiple instances, the ’186
`
`16
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:19)(cid:22)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:20)(cid:27)(cid:3)(cid:82)(cid:73)(cid:3)(cid:20)(cid:20)(cid:22)
`
`
`
`
`
`patent invites those of ordinary skill in the art to select additional agents or
`
`mechanisms beyond those disclosed in the specification for use in combination
`
`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 (cid:533)-cells . . .
`
`
`Id. at col. 15, ll. 5-11 (emphasis added).
`
`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 . . .
`
`
`Id. at col. 17, ll. 47-52 (emphasis added).
`
`Other hypolipidemic agents suitable for use herein include, but are not
`
`limited to, fibric acid derivatives . . . and other known serum
`
`cholesterol lowering agents.
`
`
`Id. at col. 18, ll. 1-20 (emphasis added).
`
`The beta 3 adrenergic agonist which may be optionally employed in
`
`combination with a compound of formula I may be AJ9677
`
`17
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:19)(cid:22)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:20)(cid:28)(cid:3)(cid:82)(cid:73)(cid:3)(cid:20)(cid:20)(cid:22)
`
`
`
`
`
`(Takeda/Dainippon), L750355 (Merck), or CP331648 (Pfizer) or
`
`other known beta 3 agonists . . .
`
`
`Id. at col. 20, ll. 12-18 (emphasis added). The ’186 patent’s repeated reliance on
`
`knowledge available outside the specification itself reflects the high level of skill
`
`in the art.
`
`39.
`
`Furthermore, the ’186 patent defers in several instances to resources
`
`readily available to those of ordinary skill in the art for determining dosages and
`
`other treatment parameters for the claimed combinations, including 15 citations to
`
`the Physician’s Desk Reference (PDR). See, e.g., Ex. 1001, col. 15, ll. 60-61; col.
`
`16, ll. 4-5; col. 19, ll. 3 and 35; col. 20, ll. 43, 50, 57, and 67; col. 21, ll. 9, 15, 24,
`
`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,
`
`ll. 2-4. I agree that the PDR is a resource often used in the art for established
`
`dosing and treatment regimens for FDA approved drugs.
`
`40.
`
`The ’186 patent provides a reasonable expectation of success for
`
`practicing the claimed invention to the extent it is enabled by the specification. The
`
`background section of the ’186 patent defines the mechanism by which DP-IV
`
`inhibitors treat type 2 diabetes, for example, by providing that “[DP-IV] has been
`
`shown to be the primary degrading enzyme of GLP-1(7-36) in vivo . . . [t]hus,
`
`inhibition of [DP-IV] in vivo should potentiate endogenous levels of GLP-1(7-36)
`
`18
`(cid:54)(cid:88)(cid:81)(cid:16)(cid:36)(cid:80)(cid:81)(cid:72)(cid:68)(cid:79)(cid:16)(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:25)(cid:16)(cid:19)(cid:20)(cid:20)(cid:19)(cid:23)(cid:16)(cid:3)(cid:40)(cid:91)(cid:17)(cid:3)(cid:20)(cid:19)(cid:19)(cid:22)(cid:15)(cid:3)(cid:83)(cid:17)(cid:3)(cid:21)(cid:19)(cid:3)(cid:82)(cid:73)(cid:3)(cid:20)(cid:20)(cid:22)
`
`
`
`
`
`and . . . thus serve to ameliorate the diabetic condition.” id. at col. 1, ll. 59-67.
`
`Villhauer provides evidence for what was generally known in the art by teaching
`
`that because “GLP-1 is a major stimulator of pancreatic insulin secretion and has
`
`direct beneficial effects on glucose disposal, [DP-IV] inhibition . . . represent[s] an
`
`attractive approach for treating non-insulin-dependent diabetes mellitus
`
`(NIDDM).” Ex. 1008, p. 1. In addition, the ’186 patent teaches that the claimed
`
`DP-IV inhibitors can be used “for treating diabetes, especially Type II diabetes.”
`
`Ex. 1001, col. 3, l. 53 – col. 4, l. 1. Given the high level of skill in the art and the
`
`advanced knowledge in the art regarding the activity of DP-IV inhibitors, one of
`
`ordinary skill in the ar