Filed on behalf of Petitioner COALITION FOR AFFORDABLE DRUGS II
`LLC
`
`By:
`
`
`Jeffrey D. Blake, Esq.
`MERCHANT & GOULD P.C.
`191 Peachtree Street N.E., Suite 4300
`Atlanta, GA 30303
`jblake@merchantgould.com
`Main Telephone: (404) 954-5100
`Main Facsimile: (404) 954-5099
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`__________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________________
`
`COALITION FOR AFFORDABLE DRUGS II LLC
`Petitioner
`
`v.
`
`NPS PHARMACEUTICALS, INC.
`Patent Owner
`__________________
`
`Case No. To be assigned
`Patent 7,056,886
`__________________
`
`DECLARATION OF ANTHONY PALMIERI III, Ph.D., R.Ph.
`FOR INTER PARTES REVIEW OF U.S. PATENT NO. 7,056,886
`(CLAIMS 46-52 and 61-75) UNDER 35 U.S.C. §§ 311-319
`AND 37 C.F.R. § 42.100 et seq.
`
`CFAD Exhibit 1001
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`

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`Declaration of Anthony Palmieri III, Ph.D.
`Inter Partes Review of U.S. Patent No. 7,056,886
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`TABLE OF CONTENTS
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`INTRODUCTION .......................................................................................... 1
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`LEGAL STANDARDS ................................................................................... 7
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`A.
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`Claim Construction ............................................................................... 8
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`B. Obviousness .......................................................................................... 8
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`C. A Person of Ordinary Skill in the Art ................................................... 8
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`I.
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`II. QUALIFICATIONS ........................................................................................ 3
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`III. COMPENSATION, PRIOR TESTIMONY, AND RELATIONSHIP
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`TO THE PARTIES .......................................................................................... 5
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`IV. SUMMARY OF OPINION ............................................................................. 5
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`V.
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`VI. CONCURRENT LITIGATION ...................................................................... 9
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`VII. DETAILED OPINION .................................................................................... 9
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`A.
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`Person of Ordinary Skill in the Art ....................................................... 9
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`B. How the Challenged Claims Are to Be Construed ............................. 10
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`C.
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`Relevant Time Frame for Analysis of the '886 Patent ........................ 12
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`D. Overview of the State of the Art Prior to December 29, 2000
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`and the Cited Prior Art ........................................................................ 13
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`E.
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`F.
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`Cited Art Applied is Prior Art to the '886 Patent ................................ 15
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`Claims 46-52 and 69-75 Are Unpatentable Because They
`Would Have Been Obvious Over Drucker '379 in view of
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`i
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`Declaration of Anthony Palmieri III, Ph.D.
`Inter Partes Review of U.S. Patent No. 7,056,886
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`Kornfelt, Osterberg, and Munroe ........................................................ 16
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`1.
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`Each of the Limitations of Claims 46-52 and 69-75
`Are Found in Drucker '379, Kornfelt, Osterberg, and
`Munroe ...................................................................................... 16
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`a.
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`Independent Claim 46 ..................................................... 29
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`i.
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`ii.
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`A GLP-2 Formulation was Known ...................... 30
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`About 0.1 to About 50 mg/ml of A GLP-2
`Peptide Or An Analog Thereof was
`Known .................................................................. 30
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`iii. A Phosphate Buffer In An Amount Sufficient
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`to Adjust the pH Of The Formulation To
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`A Pharmaceutically Tolerable Level
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`was Known ........................................................... 32
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`iv. About 0.5 to About 1% L-histidine and
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`About 2% to About 5% Mannitol Would Be
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`Obvious to Use ..................................................... 34
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`b.
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`Independent Claim 52 ..................................................... 41
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`A GLP-2 Formulation was Known ...................... 42
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`A Medically Useful Amount of a Naturally
`Occurring GLP-2 Peptide or an Analog
`Thereof was Known ............................................. 42
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`iii. A Phosphate Buffer in an Amount Sufficient
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`to Adjust the pH of the Formulation to a
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`Physiologically Tolerable Level was
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`Known .................................................................. 44
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`iv.
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`L-Histidine in an Amount Sufficient to
`Stabilize the Formulation Would be Obvious
`to Use .................................................................... 46
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`Declaration of Anthony Palmieri III, Ph.D.
`Inter Partes Review of U.S. Patent No. 7,056,886
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`v.
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`Using a Bulking Agent Selected from the
`Group Consisting of Mannitol and Sucrose
`is Obvious ............................................................. 48
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`c.
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`Independent Claim 69 ..................................................... 53
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`d.
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`e.
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`f.
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`g.
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`i.
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`ii.
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`A Method for Treating a Human or Animal
`having a Gastrointestinal Disorder, Disease
`or Condition for Which Treatment with
`GLP-2 is Indicated Including Administering
`a Therapeutically Effective Amount of a
`GLP-2 Formulation was Known .......................... 54
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`A GLP-2 Peptide or an Analog Thereof was
`Known .................................................................. 57
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`iii. A Phosphate Buffer in an Amount Sufficient
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`to Adjust the pH of the Formulation to a
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`Pharmaceutically Tolerable Level was
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`Known .................................................................. 57
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`iv.
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`L-histidine Would be Obvious to Use .................. 59
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`v.
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`vi.
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`A Bulking Agent Selected from the Group
`Consisting of Mannitol and Sucrose
`Would be Obvious to Use .................................... 60
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`Enhancing, Maintaining, or Promoting the
`Growth or Functioning of the
`Gastrointestinal Tract Was Known ...................... 62
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`Claims 47-72 ................................................................... 67
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`Claim 48 .......................................................................... 67
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`Claims 49 and 70 ............................................................ 68
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`Claims 50 and 71 ............................................................ 69
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`iii
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`Declaration of Anthony Palmieri III, Ph.D.
`Inter Partes Review of U.S. Patent No. 7,056,886
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`
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`G.
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`h.
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`i.
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`Claims 51 and 75 ............................................................ 69
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`Claims 73 and 74 ............................................................ 70
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`Claims 61-68 Are Unpatentable Because They Would Have
`Been Obvious Over Drucker '600 in view of Kornfelt, Holthuis,
`Osterberg, and Munroe ........................................................................ 71
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`1.
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`Each of the Limitations of Claims 61-68 Are Found in
`Drucker '600, Kornfelt, Osterberg, and Munroe ....................... 72
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`a.
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`Independent Claim 61 ..................................................... 81
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`i.
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`ii.
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`A Kit Including a Lyophilized GLP-2
`Formulation was Known ...................................... 82
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`A GLP-2 Peptide or an Analog Thereof was
`Known .................................................................. 83
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`iii. A Phosphate Buffer in an Amount Sufficient
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`to Adjust the pH of the Formulation to a
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`Pharmaceutically Acceptable Level
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`was Known ........................................................... 83
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`iv.
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`L-histidine Would be Obvious to Use .................. 85
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`v.
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`A Bulking Agent Selected from the Group
`Consisting of Mannitol and Sucrose
`Would be Obvious to Use .................................... 87
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`vi. A Vial of Sterile Water for Reconstitution
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`Would be Obvious to Use .................................... 88
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`vii.
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`Instructions Directing Reconstitution were
`Known, or Alternatively, Obvious to Use ............ 89
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`b.
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`Claims 62 and 63 ............................................................ 95
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`c.
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`d.
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`e.
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`f.
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`Claims 66 and 67 ............................................................ 97
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`Claim 68 .......................................................................... 98
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`Declaration of Anthony Palmieri III, Ph.D.
`Inter Partes Review of U.S. Patent No. 7,056,886
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`Claim 64 .......................................................................... 96
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`Claim 65 .......................................................................... 96
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`VIII. CONCLUSION ............................................................................................ 100
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`v
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`

`

`
`I, Dr. Anthony Palmieri III, hereby state the following:
`
`Declaration of Anthony Palmieri III, Ph.D.
`Inter Partes Review of U.S. Patent No. 7,056,886
`
`I.
`
`1.
`
`INTRODUCTION
`
`I have been retained to provide technical assistance related to the
`
`filing of a Petition for Inter Partes Review of U.S. Patent No. 7,056,886 (“the ‘886
`
`Patent”) (Ex. 1003). I am working as a private consultant on this matter and the
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`opinions presented here are my own.
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`2.
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`I have been asked to prepare a written report including comments
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`related to the Petition regarding whether certain claims of the ‘886 Patent are
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`unpatentable because they would have been obvious in view of the documents
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`cited herein. This Declaration sets forth the bases and reasons for my opinions,
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`including the additional materials and information relied upon in forming those
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`opinions and conclusions. I have reviewed Exhibits 1003-1030 set forth in the table
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`below.
`
`EXHIBIT
`
`1001
`
`1002
`
`1003
`
`1004
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`1005
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`1006
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`DESCRIPTION
`
`Declaration of Dr. Anthony Palmieri III, Ph.D., R.Ph.
`
`CV of Dr. Palmieri
`
`U.S. Patent No. 7,056,886 to Isaacs
`
`U.S. Patent Application Ser. No. 09/750,022
`
`U.S. Patent No.5,496,801 to Holthuis et al.
`
`U.S. Patent No.6,120,761 to Yamazaki et al.
`
`
`
`1
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`

`

`Declaration of Anthony Palmieri III, Ph.D.
`Inter Partes Review of U.S. Patent No. 7,056,886
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`March 8, 2002 Non Final Office Action
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`June 10, 2002 Amendment and Reply
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`February 5, 2003 Non Final Office Action
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`July 9, 2003 Amendment and Reply
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`September 16, 2003 Non Final Office Action
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`March 16, 2004 Amendment and Reply
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`June 8, 2004 Final Office Action
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`September 7, 2004 Amendment and Reply
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`October 4, 2004 Non Final Office Action
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`January 4, 2005 Amendment and Reply
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`April 4, 2005 Notice of Allowance and Fee(s) Due
`
`Kieffer & Habener, The Glucagon-Like Peptides, Endocrine
`Reviews 20(6): 876-913 (1999)
`
`Lomize et al., Thermodynamic Model of Secondary Structure
`for α-Helical Peptides and Proteins, Bioploymers 42:239 (1997)
`
`Dacambra et al., Structural Determinants for Activity of
`Glucagon-like Peptide-2. Biochemistry 39:8888-8894 (July
`2000)
`
`Drucker et al., Regulation of the biological activity of glucagon-
`like peptide 2 in vivo by dipeptidyl peptidase IV, Nat.
`Biotechnol. 15(7):673-7. (July 1997)
`
`Munroe et al.,Prototypic G-protein coupled receptor for the
`intestinotrophic factor glucagon –like peptide 2, Proc. Nat’l
`Acad. Sci. 96:1569 (1999)
`
`Drucker et al., Human [Gly2]GLP-2 reduces the severity of
`colonic injury in a murine model of experimental colitis, Am J.
`
`2
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`1007
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`1008
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`1009
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`1010
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`1011
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`1012
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`1013
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`1014
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`1015
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`1016
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`1017
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`1018
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`1019
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`1020
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`1021
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`1022
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`1023
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`

`

`Declaration of Anthony Palmieri III, Ph.D.
`Inter Partes Review of U.S. Patent No. 7,056,886
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`Physiology 276:G79 (1999)
`
`Cleland et al., Formulation and Delivery of Proteins and
`Peptides, American Chemical Society,Washington D.C.,
`Chapter 1 (1994)
`
`WO 99/043361 to Knudsen
`
`U.S. Patent No. 4,985,244 to Makino
`
`U.S. Patent No. 5,652,216 to Kornfelt et al.
`
`PCT Publication WO98/52600
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`U.S. Patent No. 5,789,379 to Drucker et al.
`
`Osterberg et al., Physical state of L-histidine after freeze-drying
`and long-term storage, EP. J. of Pharm. Sci. 1999 Aug., 8:301-
`308.
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`1024
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`1025
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`1026
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`1027
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`1028
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`1029
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`1030
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`This report is based on information currently available to me. I reserve the
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`3.
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`right to continue my investigation and analysis, which may include a review of
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`documents and information not yet produced. I further reserve the right to expand
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`or otherwise modify my opinions and conclusions as my investigation and study
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`continues, and to supplement my opinions and conclusions in response to any
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`additional information that becomes available to me.
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`II. QUALIFICATIONS
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`4.
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`I received my Ph.D. in Pharmaceutics from the University of Georgia and
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`my M.S. and B.S. in Pharmacy from the University of Rhode Island. My research
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`3
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`interests include dose form design, dissolution, pharmaceutical patents and drug
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`Declaration of Anthony Palmieri III, Ph.D.
`Inter Partes Review of U.S. Patent No. 7,056,886
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`release, among other topics, and I am the author of over 80 publications and
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`presentations on pharmaceutics, intellectual property, dosage forms, dissolutions,
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`pharmacy education, and the history of pharmacy.
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`5.
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`I am currently on the faculty of the College of Pharmacy at the University of
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`Florida in the Department of Pharmaceutics, and I have taught and/or worked in
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`the field of pharmacy for over 35 years. In my present position, I instruct graduate
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`and undergraduate students in topics such as dissolution, dose form design, and
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`sustained release, stability of formulations, physical pharmacy, clinical
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`biochemistry, biopharmaceutics, and pharmacokinetics.
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`6.
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`I am on the Editorial Advisory Board of the Journal of Chemical and
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`Pharmaceutical Sciences and the Research Journal of Pharmaceutical Biological
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`and Chemical Sciences. I was on the Steering Committee for the second through
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`fifth editions of the American Pharmacists Association’s Handbook of
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`Pharmaceutical Excipients, and I was Steering Committee chairman for the second
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`edition. I have reviewed and written monographs for all editions. I am a Fellow of
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`the Academy of Pharmaceutical Research and Sciences and the past president of
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`that organization.
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`7. My CV, which lists in detail my relevant professional experience, is attached
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`as Exhibit 1002.
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`
`4
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`

`

`Declaration of Anthony Palmieri III, Ph.D.
`Inter Partes Review of U.S. Patent No. 7,056,886
`
`
`III. COMPENSATION, PRIOR TESTIMONY, AND RELATIONSHIP TO
`THE PARTIES
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`8.
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`I am being compensated at an hourly rate of $500 per hour for the time I
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`spend studying materials and issues associated with this matter and for the time I
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`spend providing testimony. This rate is my standard consulting rate. My
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`compensation is not contingent upon the outcome of this matter. I expect to be
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`reimbursed for reasonable expenses associated with travel, including lodging,
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`ground transportation, and other expenses incurred in connection with this matter.
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`9.
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`It is my understanding that NPS Pharmaceuticals, Inc. is the assignee of the
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`‘886 Patent. Prior to this matter, I have not worked for NPS Pharmaceuticals, Inc.
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`or have any vested interest in any entity falling under the umbrella of the
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`“Coalition For Affordable Drugs II LLC.” I own no stock in NPS
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`Pharmaceuticals, Inc. or any entity falling within the “Coalition For Affordable
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`Drugs II LLC” and am aware of no other financial interest I have with those
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`companies.
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`IV. SUMMARY OF OPINION
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`10.
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`It is my understanding that the Coalition for Affordable Drugs II LLC (or
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`“Petitioner”) requests Inter Partes review for claims 46-52 and 61-75 of the ‘886
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`Patent, which issued on June 6, 2006, to Isaacs (Ex. 1003).
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`
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`5
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`Declaration of Anthony Palmieri III, Ph.D.
`Inter Partes Review of U.S. Patent No. 7,056,886
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`I have been asked whether it is my opinion that Claims 46-52 and 61-75 are
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`11.
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`unpatentable because they would have been obvious to a person of ordinary skill in
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`the art. It is my opinion that Claims 46-52 and 61-75 are unpatentable because they
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`would have been obvious to a person of ordinary skill in the art.
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`12. Claims 46-52 and 61-75 of the ‘886 Patent are directed to formulations
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`containing “glucagon-like peptide-2” (GLP-2); a kit containing a GLP-2
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`formulation; and a method of treatment using a GLP-2 formulation. In particular,
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`independent claims 46 and 52 are directed to formulations containing GLP-2 or
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`analog thereof. Independent claim 61 is directed to a kit containing a GLP-2
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`formulation along with a vial of sterile water for reconstitution and instructions
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`directing reconstitution. Independent claim 69 is directed to a method of treatment
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`comprising administering a GLP-2 formulation to effect the growth or functioning
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`of the gastrointestinal tract.
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`13.
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`It is my opinion that a person of ordinary skill in the art would have arrived
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`at each and every limitation of each of Claims 46-52 and 61-75 in view of the
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`disclosures of the prior art references and also in view of the knowledge and skill
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`of a person of ordinary skill in the art prior to December 29, 2000, as I discuss
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`below.
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`14.
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`It is also my opinion that a person of ordinary skill in the art would combine
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`the prior art references I identify below in view of the knowledge and skill of a
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`6
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`person of ordinary skill in the art prior to December 29, 2000 to arrive at the claims
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`Declaration of Anthony Palmieri III, Ph.D.
`Inter Partes Review of U.S. Patent No. 7,056,886
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`at issue. This includes the knowledge of GLP-2’s structural relationship to
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`glucagon, and GLP-2’s therapeutic use, which was well established before the date
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`on which the ‘886 Patent was filed at the U.S. Patent and Trademark Office. This
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`also includes the necessity of formulating a stable GLP-2 formulation.
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`15. As a result, it is my opinion that a person of ordinary skill in the art would
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`reasonably expect the combination of the prior art references I discuss below to
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`result in a stable GLP-2 formulation in view of the knowledge and skill of a person
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`of ordinary skill in the art prior to December 29, 2000.
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`16. Furthermore, it is my opinion that claims 46-52 and 61-75 of the ‘886 Patent
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`are not directed to anything inventive and merely demonstrate an attempt to
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`capture that which was already in the prior art before December 29, 2000. Claims
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`46-52 and 61-75 of the ‘886 Patent, therefore, are unpatentable because they would
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`have been obvious to a person of ordinary skill in the art.
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`V. LEGAL STANDARDS
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`17.
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`I am not an attorney and do not proffer myself to be one. I do not expect to
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`offer any opinions regarding the law. However, I have been informed of certain
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`legal principles relating to standards of patentability that I relied on in forming the
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`opinions set forth in this report.
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`7
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`Declaration of Anthony Palmieri III, Ph.D.
`Inter Partes Review of U.S. Patent No. 7,056,886
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`A. Claim Construction
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`18.
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`I understand that for purposes of this matter, the terms used to form the
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`claims in the ‘886 Patent are to be given their broadest reasonable interpretation,
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`taking into account the specification and the prosecution history of the ‘886 Patent,
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`as understood by a person of ordinary skill in the art as of the earliest possible
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`priority date of the ‘866 Patent.
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`B. Obviousness
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`19.
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`I understand that if an invention would have been obvious to a person of
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`ordinary skill at the time of the invention, it is not patentable. I understand that
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`obviousness is determined by considering several factors, including: the state of
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`the art at the time the invention was made; the level of ordinary skill in the art;
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`differences between what is described in the art and the claims at issue; and
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`objective evidence of nonobviousness. Objective evidence relevant to the issue of
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`obviousness includes evidence of commercial success, long-felt but unsolved
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`needs, failure of others, and unexpected results. I understand that claims are
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`unpatentable if they would have been obvious in view of the prior art.
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`C. A Person of Ordinary Skill in the Art
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`20.
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`I have been informed that a legal definition of a person of ordinary skill in
`
`the art is that this person is a hypothetical person who is presumed to have known
`
`all of the relevant art at the time of the invention. Factors that may be considered in
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`determining the level of ordinary skill in the art may include: (1) type of problems
`
`Declaration of Anthony Palmieri III, Ph.D.
`Inter Partes Review of U.S. Patent No. 7,056,886
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`encountered in the art; (2) prior art solutions to those problems; (3) rapidity with
`
`which innovations are made; (4) sophistication of the technology; and (5)
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`educational level of active workers in the field.
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`
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`VI. CONCURRENT LITIGATION
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`21.
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`I have been informed the ‘886 Patent is not subject to any pending litigation.
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`Thus, it is my understanding there is no concurrent litigation.
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`VII. DETAILED OPINION
`
`A.
`
`Person of Ordinary Skill in the Art
`
`22. Based on the disclosures of the ‘886 Patent, in my opinion, a person of
`
`ordinary skill in the art relevant to the patent-at-issue is a person who, at the time
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`of the invention, would be a pharmaceutical scientist having an advanced degree (a
`
`Master’s or a Ph.D.) or equivalent experience in pharmaceutics, pharmaceutical
`
`formulations or the pharmaceutical arts with knowledge of formulating peptide
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`formulations and of the clinical application of therapeutics in treating
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`gastrointestinal disorders.
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`23. Each of the opinions I provide in my analyses below are from the
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`perspective of this hypothetical person of ordinary skill in the art.
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`Declaration of Anthony Palmieri III, Ph.D.
`Inter Partes Review of U.S. Patent No. 7,056,886
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`B. How the Challenged Claims Are to Be Construed
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`
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`24.
`
`I understand that the terms of the claims of the ‘886 Patent are to be given
`
`their broadest reasonable interpretation in light of the specification, as understood
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`by a person of ordinary skill in the art.
`
`25. There are certain terms that I believe should be construed and I provide these
`
`constructions below.
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`26. An “analog” of GLP-2 is construed to mean a peptide that incorporates one
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`or more amino acid substitutions, deletions, additions, or modifications into a
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`natural GLP-2 peptide and retains biological activity (Ex. 1003 at 4:33-36 and
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`1:30-37). It is my understanding that during prosecution, the Applicant overcame
`
`an indefiniteness rejection by confirming that term “analog” conformed to this
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`definition (Ex. 1008 at 3). It is also my understanding that Applicant stated that
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`“biological activity” means that “GLP-2 and analogs thereof act as trophic agents
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`to enhance and maintain the functioning of the gastrointestinal tract and to promote
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`the growth of intestinal tissue” to overcome a similar indefiniteness rejection (Ex.
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`1008 at 4).
`
`27.
`
`“Medically useful amount” is defined in the specification to mean an amount
`
`of GLP-2 or analog thereof that ranges from a few micrograms to milligrams. This
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`amount includes the ranges specified in the specification of about 0.1 to about 50
`
`mg/ml of GLP-2, preferably about 5 to about 40 mg/ml, more preferably about 7 to
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`10
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`about 30 mg/ml, even more preferably about 10 to about 20 mg/ml, and most
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`Declaration of Anthony Palmieri III, Ph.D.
`Inter Partes Review of U.S. Patent No. 7,056,886
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`preferably about 20 mg/ml (Ex. 1003 at 2:14-19,5:59-61, and 6:12-19). It is my
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`understanding that “medically useful amount” or “medically effective amount”
`
`includes an amount which is useful either therapeutically or diagnostically (Ex.
`
`1003 at 5:59-61).
`
`28.
`
`“Therapeutically effective amount” is defined in the specification to mean an
`
`amount of GLP-2 or analog thereof including unit dosage amounts useful to treat a
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`subject including multidose amounts (Ex. 1003 at 5:64-67, 6:5-7).
`
`29.
`
`“An amount sufficient to adjust the pH of the formulation to a physiological
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`tolerable level” is defined in the ‘886 specification to mean an amount that buffers
`
`the formulation to a pH that elicits reactions, in a recipient, that are not so extreme
`
`to preclude further administration of the formulation (Ex. 1003 at 5:48-52). After
`
`reviewing the specification, I see that it states that this includes a pH of greater
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`than about 5.5, more preferably greater than about 6, even more preferably of
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`about 6.9 to about 7.9, and most preferably about 7.3 to about 7.4 (Ex. 1003 at
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`5:52-56).
`
`30.
`
`“An amount sufficient to adjust the pH of the formulation to a
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`pharmaceutically tolerable level” is also discussed in the specification and refers to
`
`an exemplary pH of “above about 6.0” (Ex. 1003 at 2:8-11).
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`Declaration of Anthony Palmieri III, Ph.D.
`Inter Partes Review of U.S. Patent No. 7,056,886
`
`“An amount sufficient to stabilize the formulation” is defined in the
`
`
`31.
`
`specification, as an amount of histidine that increases “the length of time that the
`
`GLP-2 peptide remains intact prior to degradation” (Ex. 1003 at 5:30-32). This
`
`amount includes 0.5 to 1% histidine (Ex. 1003 at 6:25-26). The specification
`
`specifies that the formulation when reconstituted from a lyophilized form is stable
`
`at least about 12 hours and preferably up to 24 hours at 4°C (Ex. 1003 at 7:1-3).
`
`The stability of GLP-2 or analogs thereof is measured by determining the purity
`
`and quantity of the peak of GLP-2 using reverse phase high pressure liquid
`
`chromatography (Ex. 1003 at 9:65-10:8).
`
`C. Relevant Time Frame for Analysis of the ‘886 Patent
`
`32.
`
`I have been informed that any analysis that I perform, must be done from the
`
`perspective of a person of ordinary skill in the art at the time an invention is made
`
`or filed at the United States Patent and Trademark Office. This includes any
`
`analysis that I make with regard to the obviousness of the claims at issue.
`
`33. The ‘886 Patent issued on June 6, 2006 from U.S. Patent
`
`Application Serial No. 09/750,022, filed on December 29, 2000 (“the ‘022
`
`Application”) (Ex. 1004). I know this because the information is printed on the
`
`cover page of the ‘886 Patent. I have been informed that the ‘022 Application
`
`claims priority to Application No. 9930882 filed December 30, 1999 in Great
`
`Britain.
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`34. For purposes of the analysis below, I considered the relevant time frame to
`
`Declaration of Anthony Palmieri III, Ph.D.
`Inter Partes Review of U.S. Patent No. 7,056,886
`
`be prior to December 29, 2000.
`
`D. Overview of the State of the Art Prior to December 29, 2000 and
`the Cited Prior Art
`35. Formulations of GLP-2, methods of using formulations of GLP-2, and kits
`
`containing GLP-2 formulations were known prior to the effective filing date of the
`
`’886 patent (Ex. 1028 at p.19:15-36). Drucker ‘600 describes formulations of GLP-
`
`2 and analogs for use in promoting the proliferation of intestinal tissue (Ex. 1028 at
`
`2:25-32). Biologically active analogs of GLP-2 with amino acid substitutions were
`
`also known as described extensively in Drucker ‘379 (Ex.1029 at 4:6-7:20, at 15:1-
`
`35). Drucker ‘379 teaches that GLP-2 was known to be susceptible to DPP-IV
`
`cleavage (Ex.1029 at 6:36-45; Ex. 1021 at 675). This led to the development of
`
`analogs with replacement of an amino acid at position 2; the DPP-IV cleavage site
`
`(Ex.1029 at 6:36-45). One such analog of human GLP-2, h[Gly2]GLP-2, was
`
`shown to be effective in an animal model of colitis (Ex. 1023 at G79). Munroe
`
`shows that GLP-2 analogs that stimulate intestinal cell proliferation, such as
`
`[Gly2]GLP-2, were also known to bind to GLP-2 receptors (Ex.1022 at 1573,Table
`
`2).
`
`36.
`
`It was known that GLP-2 and glucagon are structurally related. GLP-2 is a
`
`well-known peptide hormone member of the glucagon superfamily of peptide
`
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`hormones and has been described in the prior art since the 1980s (Ex. 1018 at 876,
`
`Declaration of Anthony Palmieri III, Ph.D.
`Inter Partes Review of U.S. Patent No. 7,056,886
`
`879). GLP-2 and glucagon are generated from a single precursor, proglucagon,
`
`produced in intestinal enteroendocrine cells (Id. at 885, Figure 8b). GLP-2 shares
`
`50% amino acid sequence similarity to glucagon and has a similar molecular
`
`weight (Ex. 1018 at 879, Fig.3). Despite some differences in amino acid sequence,
`
`glucagon (Ex.1019 at 254, Table V) and GLP-2 (Ex. 1025 at 3:1-10) share a
`
`secondary structural feature of an alpha helix region. Analogs of GLP-2 retain the
`
`alpha helix motif and as well as binding capacity to the GLP-2 receptor (Ex.1022
`
`at 1573, Table 2; Ex. 1020 at 8888, Abstract).
`
`37.
`
`It was known that pharmaceutical formulations of peptides for therapeutic
`
`use need to be storage stable (Ex.1024 at 8). At the time of filing of the ‘886
`
`patent, it was standard in the art to prepare a lyophilized formulation to improve
`
`storage stability of pharmaceutical compositions containing a peptide (Ex.1030 at
`
`301). L-Histidine was well known as a buffer and a stabilizing amino acid in
`
`lyophilized pharmaceutical formulations of peptides such as glucagon (Ex.1030 at
`
`301; Ex.1027 at 2:28-38).
`
`38. The addition of a bulking agent or excipient was known to be necessary
`
`to provide a functional formulation for lyophilization of pharmaceutical
`
`compositions. Sucrose and mannitol were both well known as conventional
`
`bulking agents or excipients in the art of pharmaceutical formulations prior to
`
`
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`14
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`
`the effective filing date of the ‘886 patent (Ex. 1030 at 301; Ex. 1027 at 2:43-
`
`Declaration of Anthony Palmieri III, Ph.D.
`Inter Partes Review of U.S. Patent No. 7,056,886
`
`57).
`
`39.
`
`E. Cited Art Applied is Prior Art to the ‘886 Patent
`I have been informed by counsel for Petitioner that Drucker ‘379 (Ex. 1029)
`
`is prior art to the ‘886 Patent under 35 U.S.C. § 102(b) because it published and
`
`issued on August 4, 1998, which is more than one year prior to December 29,
`
`2000, the filing date of the ‘022 Application.
`
`40.
`
`I have been informed by counsel for Petitioner that Drucker ‘600 (Ex. 1028)
`
`is prior art to the ‘886 Patent under 35 U.S.C. § 102(b) because it published on
`
`November 26, 1998, which is more than one year prior to December 29, 2000, the
`
`filing date of the ‘022 Application.
`
`41.
`
`I have been informed by counsel for Petitioner that Kornfelt (Ex. 1027) is
`
`prior art to the ‘886 Patent under 35 U.S.C. § 102(b) because it published and
`
`issued on July 29, 1997, which is more than one year prior to December 29, 2000,
`
`the filing date of the ‘022 Application.
`
`42.
`
`I have been informed by counsel for Petitioner that Osterberg (Ex. 1030) is
`
`prior art to the ‘886 Patent under 35 U.S.C. § 102(b) because it published in
`
`August 1999, which is more than one year prior to December 29, 2000, the filing
`
`date of the ‘022 Application.
`
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`

`Declaration of Anthony Palmieri III, Ph.D.
`Inter Partes Review of U.S. Patent No. 7,056,886
`
`I have been informed by counsel for Petitioner that Munroe is prior art to the
`
`
`43.
`
`‘886 Patent under 35 U.S.C. § 102(b) because it published in 1999, which is more
`
`than one year prior to December 29, 2000, the filing date of the ‘022 Application.
`
`44.
`
`I have been informed by counsel for Petitioner that Holthuis (Ex. 1005) is
`
`prior art to the ‘886 Patent under 35 U.S.C. § 102(b) because it published and
`
`issued on Mar. 5, 1996, which is more than one year prior to December 29, 2000,
`
`the filing date of the ‘022 Application.
`
`F. Claims 46-52 and 69-75 Are Unpatentable Because They Would
`Have Been Obvious Over Drucker ‘379 in view of Kornfelt,
`Osterberg, and Munroe
`
`45.
`
`I explain below, in detail, why Claims 46-50, 52, and 69-74 are obvious over
`
`Drucker ‘379 (Ex. 1029) in view of Kornfelt (Ex. 1027), and Osterberg (Ex. 1030)
`
`as described in Ground 1. I also explain, in detail, why claims 51 and 75 are
`
`obvious over Drucker ‘379 (Ex. 1029) in view of Kornfelt (Ex. 1027),