UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`MYLAN PHARMACEUTICALS INC.,
`
`Petitioner,
`
`V.
`
`ASTRAZENECA
`
`Patent Owner.
`
`Patent No. RE44,186
`
`DECLARATION OF DAVID P. ROTELLA, PH.D.
`
`AURO — EXHIBIT 1003
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`

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`
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`
`
`I.
`
`II.
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`TABLE OF CONTENTS
`TABLE OF CONTENTS
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`QUALIFICATIONS............................................................................................... 1
`QUALIFICATIONS ............................................................................................. .. 1
`
`SCOPE OF WORK ............................................................................................... 2
`SCOPE OF WORK ............................................................................................. ..2
`
`III. OVERVIEW OF THE ’186 PATENT ....................................................................... 3
`III.
`OVERVIEW OF THE ’ 186 PATENT ..................................................................... ..3
`
`IV. FILE HISTORY OF THE ’186 PATENT .................................................................. 6
`IV.
`FILE HISTORY OF THE ’ 186 PATENT ................................................................ ..6
`
`V.
`
`LEGAL STANDARDS ........................................................................................ 10
`LEGAL STANDARDS ...................................................................................... .. 10
`
`VI. LEVEL OF ORDINARY SKILL AND RELEVANT TIME ......................................... 12
`VI.
`LEVEL OF ORDINARY SKILL AND RELEVANT TIME ....................................... .. 12
`
`VII. CLAIM CONSTRUCTION ................................................................................... 17
`VII.
`CLAIM CONSTRUCTION ................................................................................. .. 17
`
`VIII. THE STATE OF THE PRIOR ART ........................................................................ 17
`VIII.
`THE STATE OF THE PRIOR ART ...................................................................... .. 17
`
`IX. PRIOR ART REFERENCES DISCLOSE OR SUGGEST EACH OF THE CLAIMED
`PRIOR ART REFERENCES DISCLOSE OR SUGGEST EACH OF THE CLAIMED
`FEATURES OF THE ’186 PATENT ...................................................................... 26
`FEATURES OF THE ’ 186 PATENT .................................................................... ..26
`
`X.
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`CONCLUDING STATEMENTS ............................................................................ 98
`CONCLUDING STATEMENTS .......................................................................... ..98
`
`XI. APPENDIX – LIST OF EXHIBITS ..................................................................... 100
`XI.
`APPENDIX — LIST OF EXHIBITS ................................................................... .. 100
`
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`-i-
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`
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`I, David P. Rotella, declare as follows:
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`I.
`
`QUALIFICATIONS
`
`1. My name is David P. Rotella. I am currently the Margaret and
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`Herman Sokol Professor of Chemistry in the Department of Chemistry and
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`Biochemistry and in the Sokol Institute of Pharmaceutical Life Sciences at
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`Montclair State University. I have been a member of the faculty of this university
`
`since 2011.
`
`2.
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`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
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`Chemistry at the University of Mississippi. I have been a member of the faculty of
`
`these departments since 2010, 2010, and 2009, respectively.
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`3.
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`I am currently a registered pharmacist in the Commonwealth of
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`Pennsylvania.
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`4.
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`I was formerly a research scientist at multiple pharmaceutical
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`companies during the years 1991-2010, including at Bristol-Myers Squibb PRI,
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`Lexicon Pharmaceuticals, and Wyeth Research/Pfizer. My industry experience
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`focused on drug discovery and development.
`
`5.
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`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
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`Postdoctoral Scholar in the Department of Chemistry at The Pennsylvania State
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`University from 1985 to 1987.
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`-1-
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`6. My current research focuses on protein kinase inhibitors for anti-
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`infective and anti-inflammatory applications. Specifically, I work on the discovery
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`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
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`protein kinase inhibitors and investigation of structure-activity relationships in a
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`product that has HSP90 inhibitor activity.
`
`7.
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`I have authored or co-authored more than 20 abstracts for presentation
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`at professional meetings, 40 peer-reviewed journal articles, and seven book
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`chapters. I have also edited or co-edited five books in the field of Medicinal
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`Chemistry. I have received numerous honors, fellowships and awards, and am an
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`inventor or co-inventor on seven granted patents.
`
`8.
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`A summary of my education, experience, publications, awards and
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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. 1004).
`
`II.
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`SCOPE OF WORK
`
`9.
`
`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
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`Mylan Pharmaceuticals Inc. as a technical expert to provide opinions regarding the
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`’186 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
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`in this declaration. For convenience, documents cited in this declaration are listed
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`-2-
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`

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`
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`in the Appendix in Section XI.
`
`10.
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`I am compensated at the rate of $500/hour for my work. I have no
`
`financial interest in the outcome of this matter.
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`III. OVERVIEW OF THE ’186 PATENT
`
`11. 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.
`
`12. 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
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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
`
`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.
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`-3-
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`

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`13.
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`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
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`the substituent groups of the compound of claim 1. For example, independent
`
`claim 8 recites the following:
`
` A
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` compound having the structure:
`
`
`
`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
`
`-4-
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`

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`
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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
`
`related diseases. Claims 23 and 24 were canceled upon reissue.
`
`14.
`
`Independent claim 25 recites a single compound as follows:
`
`
`
`or a pharmaceutically acceptable salt thereof.
`
`
`
`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
`
`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
`
`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
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`than a DP-IV inhibitor.
`
`15. 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:
`
`-5-
`
`

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`
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`
`
`Saxagliptin
`
`16.
`
`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. FILE HISTORY OF THE ’186 PATENT
`
`17.
`
`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.
`
`18.
`
`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
`
`-6-
`
`

`
`
`
`Serial No. 09/788,173 (“the ’173 application”) and claims priority to U.S.
`
`Provisional Application No. 60/188,555, filed on March 10, 2000 (“the ’555
`
`application”).
`
`19. 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.
`
`20. There is no disclosure in the earlier-filed ’555 application of the
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`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:
`
`-7-
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`

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`
`
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`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.
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`21. Claim 8 of the ’186 patent recites a compound as defined in claim 1
`
`having the structure:
`
`
`
`or a pharmaceutically acceptable salt thereof.
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`
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`-8-
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`

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`
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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.
`
`1027, p. 0056; claim 13. The compounds of claim 8 were first disclosed in the ’173
`
`application. See, e.g., Ex. 1005, p. 0010.
`
`22. 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
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`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.
`
`23. 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
`
`first time in the later-filed ’173 application. Accordingly, one of ordinary skill in
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`-9-
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`

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`
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`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. LEGAL STANDARDS
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`24.
`
`I have been informed that a claimed invention is not patentable under
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`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.
`
`25.
`
`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
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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.
`
`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.
`
`27.
`
`I understand that improper hindsight must not be used when
`
`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
`
`skill in the field at the time the invention was made without the use of post-filing
`
`knowledge.
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`-10-
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`28.
`
`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.
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`29.
`
`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
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`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
`
`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.
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`-11-
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`30.
`
`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.
`
`31.
`
`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
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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
`
`the evidence and the claimed invention.
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`VI. LEVEL OF ORDINARY SKILL AND RELEVANT TIME
`
`32.
`
`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
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`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).
`
`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
`
`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.
`
`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.
`
`35. 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
`
`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.
`
`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
`
`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.
`
`37.
`
` 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
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`-13-
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`
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`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.
`
`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.
`
`38. 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.
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`-14-
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`
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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-
`
`obesity agents, lipid-modulating agents, etc.). At multiple instances, the ’186
`
`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 b -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.
`
`-15-
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`

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`
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`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
`(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.
`
`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
`
`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.
`
`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
`
`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)
`
`-16-
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`

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`
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`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
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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
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`42.
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`I have been advised that, in the present proceeding, the ’186 patent
`
`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
`
`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
`
`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
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`43. Below I describe the details of what was generally known in the art as
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`of March 2000, including: (i) the structure and activity of known DP-IV inhibitors;
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`

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`
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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.
`
`44. As set forth above, the Background section of the ’186 patent
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`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)
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`and . . . thus serve to ameliorate the diabetic condition.” Id. at col. 1, ll. 59-67.
`
`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.,
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`Inhibition of dipeptidyl peptidase IV by fluoroolefin-containing N-peptidyl-O-
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`hydroxylamine peptidomimetics, 95 PROC. NATL. ACAD. SCI. USA 14020 (1998) at
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`14020 (hereinafter “Lin,” Ex. 1015). For example, Lin reports that “[DP-IV]
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`substrates require the presence of a proline at the P1 position as well as a
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`protonated free N terminus.” Id. The P1, etc. positions are depicted schematically
`
`below:
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`
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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
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`amide bond between the P1 and N-terminal P2 residues.” Ex. 1015 at 14020. Where
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`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
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`conformations of the Lin prolyl dipeptides are depicted below:
`
`
`
`
`47.
`
`Id., p. 14022. Lin addresses the importance of the trans conformation
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`for compound stability and its effect on DP-IV inhibition as follows:
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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.
`
`Id., at 14020-14021. Lin reports Ki values of 14,000 nM for a dipeptide in the cis
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`conformation and 188 nM for a dipeptide of otherwise identical structure in the
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`-19-
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`

`
`
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`trans conformation. Comparison of these Ki values for DP-IV inhibition reveals the
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`significantly greater potency of, and preference for, inhibitors in the trans
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`conformation. See, e.g., id. at 14023 and Table 2.
`
`48. Lin also describes what was well known in the art in March 2000
`
`regarding the effect of conformation on dipeptide stability. Specifically, Lin
`
`describes “the cyclization reaction of the free N-terminal amino acid group with
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`the reactive site of the inhibitor” for related dipeptide compounds (id. at 14020-
`
`14021), which negatively impacts compound stability. Lin also observed that
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`intramolecular cyclization was minimized by selecting the trans instead of cis
`
`conformation. Id. Thus from these teachings, a person of ordinary skill in the art
`
`would have understood that intramolecular cyclization could be reduced by both
`
`selecting against a conformation that favors intramolecular cyclization (i.e., the cis
`
`conformation) and through the addition of a large, steric group to the compound,
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`which would also limit the interaction between the free N-terminal amine and the
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`reactive inhibitor.
`
`49. Howared E. Hoffman et al., Pharmacokinetics and Metabolism of
`
`Rimantadine Hydrochloride in Mice and Dogs, 32(11) ANTIMICROBIAL AGENTS
`
`AND CHEMOTHERAPY 1699 (1988) (hereinafter “Hoffman,” Ex. 1016), describes
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`the use of a large, steric adamantyl group in the antiviral drug, rimantadine. As
`
`described by Hoffman, the adamantyl moiety was known to be metabolized to a
`
`hydroxylated derivative at the 3-position as shown below:
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`-20-
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`

`
`
`
`
`3-hydroxy rimantidine
`
`Hoffman thus serves as further basis that adamantane was generally known in the
`
`art to undergo metabolism to yield a 3-hydroxylated adamantyl group.
`
`50. Lipinski ( Ex. 1017), Hansch (Ex. 1018), Cates (Ex. 1019) and other
`
`references available to one of ordinary skill in the art describe well-known
`
`guidelines and strategies for enhancing the drug-like properties of a compound,
`
`such as by reducing a compound’s partition coefficient, and thus potentially
`
`increasing its solubility in aqueous solution. The partition coefficient (P) is a ratio
`
`of concentrations of un-ionized compound between two liquid phases, and Log P is
`
`a measure of a compound’s lipophilicity. For example, addition of a hydroxyl
`
`group at the 3-position of an adamantyl moiety would improve the Lipinski
`
`parameters, such as reducing Log P and improving permeability as discussed
`
`below.
`
`51. According to Christopher A. Lipinski et al., Experimental and
`
`computational approaches to estimate solubility and pe