Mylan Pharmaceuticals Inc.,
`v.
`AstraZeneca AB
`Case IPR2015-01340
`Patent RE44,186
`
`AstraZeneca Demonstrative Exhibit 1
`
`
`v.
`AstraZeneca AB
`Case IPR2015-01340
`Patent RE44,186
`
`AstraZeneca Demonstrative Exhibit 1
`
`
`
`Holst and Deacon (1998)
`
`Ex. 2005 at 7
`
`Ex. 2056 ¶ 86; see also Paper 7 at 9; see Paper 28 at 6 (citing Ex. 2057 ¶¶ 37-39)
`
`AstraZeneca Demonstrative Exhibit 2
`
`
`
`Prior Art DPP-4 Inhibitors: None FDA-Approved
`
`Ex. 2075
`
`Ex. 2008
`
`Ex. 2078
`
`Ex. 2078
`
`Ex. 2083
`
`Ex. 2095
`
`Ex. 2095
`
`Ex. 2149
`
`Ex. 2042
`
`PT-100 (Talabostat)
`Ex. 2150
`
`Ex. 2153
`
`Ex. 1007
`
`Ex. 2151
`
`Ex. 2151
`
`Ex. 2151
`
`Ex. 2151
`
`Ex. 2151
`
`Ex. 2151
`
`Ex. 2158
`
`Ex. 2007
`
`Ex. 1015
`
`Ex. 2152
`
`Ex. 2152
`
`Ex. 2017
`
`Ex. 1008
`
`Ex. 2157
`
`Ex. 1007
`
`Ex. 2001
`
`Ex. 2154
`
`X is CH2, S, O, or
`C(CH3)2
`Ex. 2156
`Paper 62 at Observation 28; Ex. 2246
`
`Ex. 2155
`
`Ashworth I
`Ex. 1007
`
`P32/98
`Ex. 2009
`
`NVP-DPP728
`Ex. 2016
`
`Vildagliptin
`Ex. 2013
`AstraZeneca Demonstrative Exhibit 3
`
`
`
`Saxagliptin
`
`
`
`“P2” Group“P2” Group
`
`
`
`“P1” Group“P1” Group
`
`Adamantyl
`
`3-Hydroxy
`
`Quaternary carbon
`
`C-linked
`
`C
`
`Primary amine
`
`cis-4,5-cyclopropyl
`
`5
`
`4
`
`2
`
`3
`
`Pyrrolidine
`
`Cyano (or “nitrile”)
`
`Paper 28 at 4
`AstraZeneca Demonstrative Exhibit 4
`
`
`
`Claim 25
`
`Ex. 1001; Paper 28 at 19
`AstraZeneca Demonstrative Exhibit 5
`
`
`
`The Experts
`
`AstraZeneca Demonstrative Exhibit 6
`
`
`
`Dr. Weber
`
`• Co-lead of program core team
`that identified JANUVIA®
`(sitagliptin)
`• Authored/co-authored thirty-eight
`publications relating to DPP-4
`inhibitors
`• Co-inventor of thirty-three patents
`relating to DPP-4 inhibitors
`• Presented forty-eight times on
`DPP-4 inhibitors
`• Chaired two symposiums relating
`to DPP-4 inhibitors
`• Vice President of Lead
`Optimization Chemistry at Merck
`
`Ex. 2210
`
`AstraZeneca Demonstrative Exhibit 7
`
`
`
`Dr. Weber
`
`Ex. 1073 (Weber Redirect) at 111:11-19
`AstraZeneca Demonstrative Exhibit 8
`
`
`
`Dr. Rotella
`
`Paper 62 at Observation 31; Ex. 2221 at 109:4-8, 116:22-25
`AstraZeneca Demonstrative Exhibit 9
`
`
`
`Dr. Rotella
`
`Paper 62 at Observation 31; Ex. 2174 at 125:10-25; Ex. 2221 at 109:14-113:6
`AstraZeneca Demonstrative Exhibit 10
`
`
`
`Lead Compound Selection
`
`AstraZeneca Demonstrative Exhibit 11
`
`
`
`The Principal Prior Art
`
`Clinical Trial Compounds
`
`NVP-DPP728
`
`Ex. 2016
`
`Other Compounds
`
`P32/98
`
`Ex. 2078
`
`Villhauer-063
`Ex. 1
`
`Ex. 2013
`
`Ashworth I
`Compound 25
`
`Ex. 1007
`
`Ashworth II
`Compound 3
`
`Ex. 2001
`AstraZeneca Demonstrative Exhibit 12
`
`
`
`Dr. Weber
`
`Ex. 1073 (Weber Redirect) at 114:5-14
`AstraZeneca Demonstrative Exhibit 13
`
`
`
`Weber (2007): Discovery of Januvia™
`
`Ex. 2161 at 2; Ex. 2056 ¶¶ 115, 118; Paper 28 at 16
`AstraZeneca Demonstrative Exhibit 14
`
`
`
`Weber (2007): Discovery of Januvia™
`
`Ex. 2161 at 2; Ex. 2056 ¶ 118
`AstraZeneca Demonstrative Exhibit 15
`
`
`
`Dr. Rotella
`
`Paper 28 at 24; Ex. 2174 at 63:18-64:5, 65:18-23
`AstraZeneca Demonstrative Exhibit 16
`
`
`
`Mylan Demonstrative Exhibit
`
`AstraZeneca Demonstrative Exhibit 17
`
`
`
`Rothenberg (2000): Ex. 2012
`
`Paper 28 at 14; Ex. 2012 at 2
`AstraZeneca Demonstrative Exhibit 18
`
`
`
`Demuth 2000: Ex. 2010
`
`Paper 28 at 14; Ex. 2010
`AstraZeneca Demonstrative Exhibit 19
`
`
`
`Dr. Weber
`
`Paper 28 at 11, 24; Ex. 2056 ¶ 171
`AstraZeneca Demonstrative Exhibit 20
`
`
`
`Intramolecular Cyclization
`
`Cyano
`“Electrophile”
`
`CN
`
`NH2
`Amine
`“Nucleophile”
`
`Active
`
`Inactive
`
`Paper 28 at 8; Ex. 2056 ¶ 116
`AstraZeneca Demonstrative Exhibit 21
`
`
`
`DPP-4 Inhibitors in the Clinic (2000)
`
`Dr. Weber’s Lead Compounds
`
`NVP-DPP728
`
`P32/98
`
`Paper 28 at 14-16, 23-26; Ex. 2010; Ex. 2012; Ex. 2226
`AstraZeneca Demonstrative Exhibit 22
`
`
`
`Villhauer’s DPP-4 Inhibitor Compounds
`
`Exhibit #
`
`Reference
`
`Structure
`
`Ex. 1008
`
`WO
`98/19998
`
`Ex. 2157
`
`6,107,317
`
`Ex. 2158
`
`6,110,949
`
`Paper 28 at 12; Ex. 2056 ¶ 113
`AstraZeneca Demonstrative Exhibit 23
`
`
`
`Hughes (1999): Ex. 2016
`
`Ex. 2016 at 3; Ex. 2056 ¶¶ 144, 190; Paper 28 at 12
`AstraZeneca Demonstrative Exhibit 24
`
`
`
`Dr. Weber
`
`Paper 28 at 11-12; Ex. 2056 ¶ 125
`AstraZeneca Demonstrative Exhibit 25
`
`
`
`Peters and Mattei (2010): Ex. 2262
`
`Paper 62 at Observation 9; Ex. 2262 at 9; Ex. 2174 at 77:5-80:14
`AstraZeneca Demonstrative Exhibit 26
`
`
`
`Ashworth I (1996): Ex. 1007
`
`Paper 28 at 9, 26; Ex. 1007 at 1165
`AstraZeneca Demonstrative Exhibit 27
`
`
`
`Ashworth II (1996): Ex. 2001
`
`Paper 28 at 9-10, 27; Ex. 2001 at 2
`AstraZeneca Demonstrative Exhibit 28
`
`
`
`Ashworth II (1996): Ex. 2001
`
`Compound 5
`Ki = 2.2 nM ± 0.50
`
`Compound 3
`Ki = 0.41 nM ± 0.15
`
`Paper 28 at 9, 27; Ex. 2056 ¶¶ 107-108; Ex. 2001 at 3, Table I; Ex. 2231
`AstraZeneca Demonstrative Exhibit 29
`
`
`
`Ashworth II (1996): Ex. 2001
`
`Ex. 2001 at 2
`AstraZeneca Demonstrative Exhibit 30
`
`
`
`Villhauer-949: Ex. 2158
`
`Paper 62 at Observation 13; Ex. 2158; Ex. 2056 ¶ 113
`AstraZeneca Demonstrative Exhibit 31
`
`
`
`Cyclopropanation
`
`AstraZeneca Demonstrative Exhibit 32
`
`
`
`Prior Art DPP-4 Inhibitors: None FDA-Approved
`
`Ex. 2075
`
`Ex. 2008
`
`Ex. 2078
`
`Ex. 2078
`
`Ex. 2083
`
`Ex. 2095
`
`Ex. 2095
`
`Ex. 2149
`
`Ex. 2042
`
`PT-100 (Talabostat)
`Ex. 2150
`
`Ex. 2153
`
`Ex. 1007
`
`Ex. 2151
`
`Ex. 2151
`
`Ex. 2151
`
`Ex. 2151
`
`Ex. 2151
`
`Ex. 2151
`
`Ex. 2158
`
`Ex. 2007
`
`Ex. 1015
`
`Ex. 2152
`
`Ex. 2152
`
`Ex. 2017
`
`Ex. 1008
`
`Ex. 2157
`
`Ex. 1007
`
`Ex. 2001
`
`Ex. 2154
`
`X is CH2, S, O, or
`C(CH3)2
`Ex. 2156
`Paper 62 at Observation 28; Ex. 2246
`
`Ex. 2155
`
`Ashworth I
`Ex. 1007
`
`P32/98
`Ex. 2009
`
`NVP-DPP728
`Ex. 2016
`
`Vildagliptin
`Ex. 2013
`AstraZeneca Demonstrative Exhibit 33
`
`
`
`Dr. Weber
`
`Ex. 1073 (Weber Redirect) at 117:4-11; Ex. 2056 ¶ 187; Paper 28 at 37
`AstraZeneca Demonstrative Exhibit 34
`
`
`
`Dr. Weber
`
`Ex. 1073 (Weber Redirect) 117:12-20; Ex. 2056 ¶ 187; see Paper 28 at 37
`AstraZeneca Demonstrative Exhibit 35
`
`
`
`Ashworth II (1996): Ex. 2001
`
`Compound 5
`Ki = 2.2 nM
`5-membered ring
`
`Compound 8
`Ki = 260 nM
`6-membered ring
`
`Compound 11
`Ki = 4200 nM
`2-methyl
`
`Paper 28 at 10; Ex. 2056 ¶¶ 107-108, 173-174; Ex. 2001 at 3, Table I; Ex. 2230
`AstraZeneca Demonstrative Exhibit 36
`
`
`
`Augustyns (1997): Ex. 2151
`
`Compound 8b
`IC50 = 270 µM
`4-membered ring
`
`Compound 3
`IC50 = 21 µM
`5-membered ring
`
`Compound 6b
`IC50 = 510 µM
`6-membered ring
`
`Compound 7b
`IC50 = 2700 µM
`7-membered ring
`
`Paper 28 at 10; Ex. 2151 at 2, 4; Ex. 2228
`AstraZeneca Demonstrative Exhibit 37
`
`
`
`Augustyns (1997): Ex. 2151
`
`Paper 28 at 10; Ex. 2151 at 3
`AstraZeneca Demonstrative Exhibit 38
`
`
`
`Standard IUPAC Name
`
`Ex. 2221 at 30:14-31:20; Ex. 2258; Paper 62 at Observation 10
`AstraZeneca Demonstrative Exhibit 39
`
`
`
`Augustyns (1997): Ex. 2151
`
`Compound 3
`IC50 = 21 µM
`
`Compound 17b
`IC50 = 27 µM
`
`Compound 16b
`IC50 = 740 µM
`
`Compound 19b
`IC50 = 610 µM
`
`Compound 20b
`IC50 = 1070 µM
`
`Compound 21b
`IC50 = 6200 µM
`
`Compound 22b
`IC50 = >10,000 µM
`
`Compound 23b
`IC50 = 320 µM
`
`Paper 28 at 10; Ex. 2151 at 2, 4; Ex. 2229
`AstraZeneca Demonstrative Exhibit 40
`
`
`
`Augustyns (1997): Ex. 2151
`
`Ex. 2151 at 3
`
`AstraZeneca Demonstrative Exhibit 41
`
`
`
`Augustyns (1999): Ex. 2007
`
`Paper 28 at 35; Ex. 2007 at 4
`
`AstraZeneca Demonstrative Exhibit 42
`
`
`
`Dr. Rotella
`
`* * *
`
`Paper 62 at Observation 14; Ex. 2221 at 52:10-18, 53:3-11; Ex. 2257
`AstraZeneca Demonstrative Exhibit 43
`
`
`
`Mylan Demonstrative Exhibit
`
`AstraZeneca Demonstrative Exhibit 44
`
`
`
`Chiou: Ex. 1021
`
`Acyclic, Single Bond
`
`Acetylcholine
`
`Cyclopropyl-fused acetylcholine
`
`Paper 28 at 31; Ex. 1021 at 243; Ex. 2056 ¶¶ 177-178
`AstraZeneca Demonstrative Exhibit 45
`
`
`
`Ashworth II (1996): Ex. 2001
`
`Compound 3
`Ki = 0.41 nM ± 0.15
`
`Compound 4
`Ki = 1.70 nM ± 0.50
`
`Compound 5
`Ki = 2.2 nM ± 0.50
`
`Ex. 2001 at 3, Table I; Ex. 2232
`AstraZeneca Demonstrative Exhibit 46
`
`
`
`Rotella: Ex. 2254
`
`Paper 62 at Observation 11; Ex. 2221 at 36:1-38:3; Ex. 2254 at 2
`AstraZeneca Demonstrative Exhibit 47
`
`
`
`Dr. Rotella
`
`Paper 62 at Observation 12; Ex. 2221 at 38:6-12, 38:16-18
`AstraZeneca Demonstrative Exhibit 48
`
`
`
`Dr. Weber
`
`Ex. 1073 (Weber Redirect) at 104:3-13, 121:14-122:1 (correcting Augustyns 2 to Ashworth II)
`AstraZeneca Demonstrative Exhibit 49
`
`
`
`Villhauer-949: Ex. 2158
`
`Paper 62 at Observation 13; Ex. 2158; Ex. 2056 ¶ 113
`AstraZeneca Demonstrative Exhibit 50
`
`
`
`Teachings of Hanessian
`
`AstraZeneca Demonstrative Exhibit 51
`
`
`
`Mylan Demonstrative Exhibit
`
`AstraZeneca Demonstrative Exhibit 52
`
`
`
`Dr. Rotella
`
`Paper 62 at Observation 15; Ex. 2221 at 58:21-24; Ex. 2151; Ex. 2233
`AstraZeneca Demonstrative Exhibit 53
`
`
`
`Augustyns (1997): Ex. 2151
`
`Ex. 2151 at 3
`AstraZeneca Demonstrative Exhibit 54
`
`
`
`Hanessian (1996): Ex. 2043
`
`Ex. 2043 at 3; Paper 62 at Observation 16; Ex. 2221, 62:1-63:3
`AstraZeneca Demonstrative Exhibit 55
`
`
`
`Hanessian (1998): Ex. 2028
`
`Paper 62 at Observation 16; Ex. 2028
`AstraZeneca Demonstrative Exhibit 56
`
`
`
`Dr. Rotella
`
`Paper 62 at Observation 16; Ex. 2221 at 65:19-23
`AstraZeneca Demonstrative Exhibit 57
`
`
`
`Dr. Weber
`
`Ex. 1073 (Weber Redirect) at 118:11-119:5; see Ex. 2056 ¶ 187; see also Paper 28 at 37
`AstraZeneca Demonstrative Exhibit 58
`
`
`
`Mylan’s Position on Stability
`
`Motivation to modify:
`
`Paper 28 at 28-29; Paper 11 at 4, 5
`AstraZeneca Demonstrative Exhibit 59
`
`
`
`Dr. Rotella
`
`Ashworth I
`Compound 25
`
`Paper 28 at 25; Ex. 2174 at 115:21-116:13
`
`AstraZeneca Demonstrative Exhibit 60
`
`
`
`Dr. Rotella
`
`Paper 28 at 33; Ex. 2174 at 127:1-4
`AstraZeneca Demonstrative Exhibit 61
`
`
`
`Dr. Rotella
`
`Paper 28 at 32; Ex. 2174 at 142:3-9
`AstraZeneca Demonstrative Exhibit 62
`
`
`
`Dr. Rotella
`
`Paper 28 at 32-33; Ex. 2174 at 119:10-13, 119:22-120:5
`AstraZeneca Demonstrative Exhibit 63
`
`
`
`KSR Int'l Co. v. Teleflex Inc.
`
`127 S. Ct. 1727, 1742 (2007)
`
`AstraZeneca Demonstrative Exhibit 64
`
`
`
`Effects of Cyclopropanation in DPP-4
`Inhibitors
`
`AstraZeneca Demonstrative Exhibit 65
`
`
`
`Hanessian (1998): Ex. 2028
`
`Paper 62 at Observation 16; Ex. 2028 at 4-5, Table 1
`AstraZeneca Demonstrative Exhibit 66
`
`
`
`Effects of Cyclopropanation: Magnin (2004)
`
`Effect of ORIENTATION
`
`Compound 24 (cis-4,5)
`Ki = 25 nM
`
`Compound 22 (trans-4,5)
`Ki = 1620 nM
`
`Paper 62 at Observation 17; Ex. 2002 at 3; Ex. 2234
`AstraZeneca Demonstrative Exhibit 67
`
`
`
`Knoll Pharm. Co. v. Teva Pharm. USA, Inc.
`
`367 F.3d 1381, 1385 (Fed. Cir. 2004)
`
`AstraZeneca Demonstrative Exhibit 68
`
`
`
`Effects of Cyclopropanation: Magnin (2004)
`Effect of LOCATION on Stability
`
`Compound 21
`t½ = 5 h
`
`Compound 25 (cis-3,4)
`t½ = 4 h
`
`Compound 24 (cis-4,5)
`t½ = 22 h
`
`Compound 28
`t½ = 27 h
`
`Compound 30 (cis-3,4)
`t½ = 4 h
`
`Compound 29 (cis-4,5)
`t½ = 42 h
`
`Paper 62 at Observation 17; Ex. 2002 at 3; Ex. 2235
`
`AstraZeneca Demonstrative Exhibit 69
`
`
`
`Effects of Cyclopropanation: Magnin (2004)
`Effect of LOCATION on Potency
`
`Compound 21
`Ki = 2 nM
`
`Compound 25 (cis-3,4)
`Ki = 15 nM
`
`Compound 24 (cis-4,5)
`Ki = 25 nM
`
`Compound 28
`Ki = 8 nM
`
`Compound 30 (cis-3,4)
`Ki = 14 nM
`
`Compound 29 (cis-4,5)
`Ki = 7 nM
`
`Paper 62 at Observation 17; Ex. 2002 at 3; Ex. 2236
`
`AstraZeneca Demonstrative Exhibit 70
`
`
`
`Effects of Cyclopropanation: Magnin (2004)
`Effect of the P2 GROUP
`
`Compound 21
`Ki = 2 nM
`
`Compound 24 (cis-4,5)
`Ki = 25 nM
`
`Compound 28
`Ki = 8 nM
`
`Compound 29 (cis-4,5)
`Ki = 7 nM
`
`Paper 62 at Observation 18; Ex. 2002 at 3; Ex. 2237
`
`AstraZeneca Demonstrative Exhibit 71
`
`
`
`Effects of Cyclopropanation: Magnin (2004)
`
`Effect on Stability and Potency From Cis-4,5-Cyclopropyl +
`Quaternary Carbon
`
`Compound 29 (cis-4,5)
`Ki = 7 nM
`t½ = 42 h
`
`Paper 62 at Observation 19; Ex. 2002 at 3; Ex. 2238
`
`AstraZeneca Demonstrative Exhibit 72
`
`
`
`December 16, 1999: Ex. 2187
`
`Ex. 2187; Ex. 2173 ¶ 11
`AstraZeneca Demonstrative Exhibit 73
`
`
`
`Cis-4,5-Cyclopropyl + Quaternary Carbon
`
`Saxagliptin
`
`Paper 62 at Observation 20; Ex. 2239
`
`AstraZeneca Demonstrative Exhibit 74
`
`
`
`Ashworth II (1996): Ex. 2001
`
`Ex. 2001 at 2, 4, Table II
`AstraZeneca Demonstrative Exhibit 75
`
`
`
`Selection of an “Adamantyl” P2 Group
`
`AstraZeneca Demonstrative Exhibit 76
`
`
`
`Declaration of Dr. Rotella
`
`Ex. 1074 ¶ 19
`AstraZeneca Demonstrative Exhibit 77
`
`
`
`Ashworth I (1996): Ex. 1007
`
`Ex. 1007 at 1165
`AstraZeneca Demonstrative Exhibit 78
`
`
`
`Ashworth I’s largest P2 group is less stable
`
`O
`
`O
`
`NH
`
`N
`
`H2N
`
`CN
`
`O
`Compound 25
`t½ > 48 h
`
`N
`
`H2N
`
`O
`Compound 28
`t½ = 24 h
`
`CN
`
`Paper 62 at Observation 3; Paper 28 at 46; Ex. 2261; Ex. 1007 at 4, Table II
`AstraZeneca Demonstrative Exhibit 79
`
`
`
`Mylan Demonstrative Exhibit
`
`AstraZeneca Demonstrative Exhibit 80
`
`
`
`Mentlein (1993): Ex. 2096
`
`HN
`
`N
`
`H2N
`
`N
`
`O
`
`CN
`
`Histidine
`
`Tyrosine
`
`Ex. 2096, 2 (Figure 1); Ex. 2056, ¶¶ 57, 90
`AstraZeneca Demonstrative Exhibit 81
`
`
`
`Ashworth I’s largest P2 group is less stable
`
`O
`
`O
`
`NH
`
`N
`
`H2N
`
`CN
`
`O
`Compound 25
`t½ > 48 h
`
`N
`
`H2N
`
`O
`Compound 28
`t½ = 24 h
`
`CN
`
`Paper 62 at Observation 3; Paper 28 at 46; Ex. 2261; Ex. 1007 at 4, Table II
`AstraZeneca Demonstrative Exhibit 82
`
`
`
`Villhauer-1998’s large alkyl groups
`
`12 Carbons
`Ex. 57
`
`10 Carbons
`Ex. 25
`
`10 Carbons
`Ex. 33
`
`10 Carbons
`Ex. 44
`
`8 Carbons
`Ex. 58
`
`8 Carbons
`Ex. 27
`
`8 Carbons
`Ex. 48
`Paper 28 at 45; Ex. 2056 ¶ 203; Ex. 1008 at 11-16
`
`7 Carbons
`Ex. 24
`
`7 Carbons
`Ex. 29
`AstraZeneca Demonstrative Exhibit 83
`
`
`
`Villhauer-1998: Ex. 1008
`
`Ex. 1008 at 23
`AstraZeneca Demonstrative Exhibit 84
`
`
`
`Villhauer-1998: Ex. 1008
`
`Example
`
`Structure
`
`Increase of
`Insulin
`Response at
`10 µmol/kg
`
`Human
`Plasma DPP-
`4 IC50 (nM)
`
`Rat Plasma
`DPP-4 IC50
`(nM)
`
`Caco-2
`DPP-4 (nM)
`
`NVP-DPP728
`
`Ex. 1
`
`Ex. 3
`
`Ex. 5
`
`Ex. 8
`
`Ex. 12
`
`61%
`
`66%
`
`108%
`
`144%
`
`59%
`
`27
`
`7
`
`37
`
`12
`
`95
`
`22
`
`6
`
`18
`
`11
`
`38
`
`36
`
`22
`
`26
`
`8
`
`279
`
`Ex. 1008 at 19, 21; Ex. 2056 ¶¶ 201-202
`AstraZeneca Demonstrative Exhibit 85
`
`
`
`Daiichi Sankyo Co. v. Matrix Labs., Ltd.
`
`619 F.3d 1346, 1354 (Fed. Cir. 2010)
`
`AstraZeneca Demonstrative Exhibit 86
`
`
`
`C-linked v. N-linked
`
`C-linked
`
`N-linked
`
`Paper 62 at Observation 7; Ex. 2056 ¶ 200; Ex. 2259
`AstraZeneca Demonstrative Exhibit 87
`
`
`
`Dr. Weber Declaration
`
`Paper 28 at 42-43; Ex. 2056 ¶ 197
`AstraZeneca Demonstrative Exhibit 88
`
`
`
`Dr. Weber
`
`Paper 28 at 11-12; Ex. 2056 ¶ 125
`AstraZeneca Demonstrative Exhibit 89
`
`
`
`Peters and Mattei (2010): Ex. 2262
`
`Paper 62 at Observation 9; Ex. 2262 at 9; Ex. 2174 at 77:5-80:14
`AstraZeneca Demonstrative Exhibit 90
`
`
`
`Hydroxylating an Adamantyl P2 Group
`
`AstraZeneca Demonstrative Exhibit 91
`
`
`
`Substrate Differences & Potential Oxidation Sites
`
`Paper 28 at 52; Ex. 2056 ¶ 212; Ex. 2174 at 164:19-165:3
`AstraZeneca Demonstrative Exhibit 92
`
`
`
`Dr. Rotella
`
`Paper 28 at 52; Ex. 2174 at 164:19-24, 165:4-9
`AstraZeneca Demonstrative Exhibit 93
`
`
`
`Hoffman (Ex. 1016)
`
`Amantadine
`
`Ex. 1016 at 1703; Ex. 2056 ¶ 215; Ex. 2174 at 168:8-21; Paper 28 at 53
`AstraZeneca Demonstrative Exhibit 94
`
`
`
`Mylan Demonstrative Exhibit
`
`AstraZeneca Demonstrative Exhibit 95
`
`
`
`Torrent Pharm. Ltd. v. Merck Frosst Canada & Co.
`
`IPR2014-00559, Paper 8 at 9 (PTAB Oct. 1, 2014)
`AstraZeneca Demonstrative Exhibit 96
`
`
`
`Mylan Demonstrative Exhibit
`
`AstraZeneca Demonstrative Exhibit 97
`
`
`
`Unexpected Results
`
`AstraZeneca Demonstrative Exhibit 98
`
`
`
`Vildagliptin and Saxagliptin
`
`Vildagliptin
`
`Saxagliptin
`
`Villhauer ’063 Patent – Ex. 1
`Ex. 2013
`
`Paper 28 at 15; Paper 62 at Observation 22; Ex. 2176 at 3, 4; Ex. 2241; Ex. 2056 at ¶ 234
`AstraZeneca Demonstrative Exhibit 99
`
`
`
`Su (2012): Ex. 2045
`
`Metabolism of Saxagliptin
`
`Paper 28 at 62-63; Ex. 2056 ¶¶ 236-240; Ex. 2045 at 2
`AstraZeneca Demonstrative Exhibit 100
`
`
`
`He (2009): Ex. 2046
`Metabolism of Vildagliptin
`
`M20.7
`
`M15.3
`
`M21.6
`
`Vildagliptin
`
`M20.2
`
`M20.9
`
`Paper 28 at 62-63; Paper 62 at Observation 23; Ex. 2046 at 8; Ex. 2244; Ex. 2056 ¶ 241
`
`AstraZeneca Demonstrative Exhibit 101
`
`
`
`Novartis’ Galvus (Vildagliptin) European Label:
`Ex. 2080
`
`Paper 28 at 62-63; Ex. 2056 ¶ 241; Ex. 2080 at 15
`AstraZeneca Demonstrative Exhibit 102
`
`
`
`Knoll Pharm. Co. v. Teva Pharm. USA, Inc.
`
`367 F.3d 1381, 1385 (Fed. Cir. 2004)
`
`AstraZeneca Demonstrative Exhibit 103
`
`
`
`C-linked v. N-linked
`
`C-linked
`
`N-linked
`
`C-linked
`
`N-linked
`Paper 62 at Observation 21; cf. Ex. 2056 ¶ 200; Ex. 2259A
`AstraZeneca Demonstrative Exhibit 104
`
`
`
`Dr. Rotella
`
`Paper 62 at Observation 21; Ex. 2221 at 83:8-84:2; Ex. 2259A
`AstraZeneca Demonstrative Exhibit 105
`
`
`
`Nabeno (2013): Ex. 2176
`Binding Interactions of Vildagliptin and Saxagliptin
`
`Vildagliptin
`
`Saxagliptin
`
`Paper 28 at 63-64; Paper 62 at Observation 22; Ex. 2176 at 3, 4; Ex. 2241; Ex. 2056 ¶ 244
`AstraZeneca Demonstrative Exhibit 106
`
`
`
`Wang (2012): Ex. 2018
`
`Enzyme Binding of Saxagliptin and Vildagliptin
`
`Paper 28 at 61; Ex. 2018 at 4; Ex. 2056 ¶¶ 235-236
`AstraZeneca Demonstrative Exhibit 107
`
`
`
`Wang (2012): Ex. 2018
`
`Potency of Saxagliptin and Vildagliptin
`
`Paper 28 at 61; Ex. 2018 at 3; Ex. 2056 ¶ 235
`AstraZeneca Demonstrative Exhibit 108
`
`
`
`Su (2012): Ex. 2045
`
`Pharmacokinetics of Saxagliptin
`
`Paper 62 at Observation 24; Ex. 2045 at 6; Ex. 2243; Ex. 2056 ¶¶ 239-240
`
`AstraZeneca Demonstrative Exhibit 109
`
`
`
`Fura (2009): Ex. 2073
`
`Paper 28 at 63; Ex. 2073 at 7; Ex. 2221 at 95:7-19; Ex. 2056 ¶ 238
`AstraZeneca Demonstrative Exhibit 110
`
`
`
`Saxagliptin Label: Ex. 2047
`
`Paper 7 at 53-54; Ex. 2047 at 1; Ex. 2056 ¶ 248; Paper 28 at 64 (citing Ex. 2057 ¶¶ 78-85)
`AstraZeneca Demonstrative Exhibit 111
`
`
`
`Galvus Label: Ex. 2050
`
`Ex. 2050 at 3; Paper 28, 15, 59, 65 ; Ex. 2057 ¶ 68
`AstraZeneca Demonstrative Exhibit 112
`
`
`
`Novartis’ Galvus (Vildagliptin) European Press
`Release (2007): Ex. 2081
`
`Paper 28 at 15, 59, 65; Ex. 2081 at 1; Ex. 2056 ¶ 248
`
`AstraZeneca Demonstrative Exhibit 113
`
`
`
`Long-Felt Need and Failures of Others
`
`AstraZeneca Demonstrative Exhibit 114
`
`
`
`Oral Treatments From the Late 1990s
`
`Class
`
`Sulfonylureas/Meglitinides
`
`Compounds
`Tolbutamide
`Chlorpropamide
`Tolazamide
`Acetohexamide
`Glyburide
`Glipizide
`Glimepiride
`Repaglinide
`Nateglinide
`
`Biguanides
`
`Metformin
`
`TZDs
`
`Alpha-Glucosidase Inhibitors
`
`Rosiglitazone
`Pioglitazone
`
`Acarbose
`Miglitol
`
`Side Effects
`
`Hypoglycemia
`Weight gain
`
`Lactic acidosis
`Gastrointestinal distress
`
`Edema
`Weight gain
`Fractures
`Hepatic toxicity
`
`Gastrointestinal distress
`Hepatic toxicity
`
`Paper 28 at 5; Ex. 2057 ¶ 34, Table 2; Ex. 2063 at 8-9, 17; Ex. 2067 at 2-7
`
`AstraZeneca Demonstrative Exhibit 115
`
`
`
`Prior Art DPP-4 Inhibitors: None FDA-Approved
`
`Ex. 2075
`
`Ex. 2008
`
`Ex. 2078
`
`Ex. 2078
`
`Ex. 2083
`
`Ex. 2095
`
`Ex. 2095
`
`Ex. 2149
`
`Ex. 2042
`
`PT-100 (Talabostat)
`Ex. 2150
`
`Ex. 2153
`
`Ex. 1007
`
`Ex. 2151
`
`Ex. 2151
`
`Ex. 2151
`
`Ex. 2151
`
`Ex. 2151
`
`Ex. 2151
`
`Ex. 2158
`
`Ex. 2007
`
`Ex. 1015
`
`Ex. 2152
`
`Ex. 2152
`
`Ex. 2017
`
`Ex. 1008
`
`Ex. 2157
`
`Ex. 1007
`
`Ex. 2001
`
`Ex. 2154
`
`X is CH2, S, O, or
`C(CH3)2
`Ex. 2156
`Paper 62 at Observation 28; Ex. 2246
`
`Ex. 2155
`
`Ashworth I
`Ex. 1007
`
`P32/98
`Ex. 2009
`
`NVP-DPP728
`Ex. 2016
`
`Vildagliptin
`Ex. 2013
`AstraZeneca Demonstrative Exhibit 116
`
`
`
`Clinical Failures of Others
`
`DPP-4 Inhibitor
`
`LAF-237
`(vildagliptin)
`GW823093C
`(denagliptin)
`PHX 1149
`(dutogliptin)
`PT-630
`AMG-222
`NVP-DPP728
`
`PSN-9301
`
`P32/98
`R-1438
`TA-6666
`
`TS-021
`
`Point Therapeutics, Inc.
`Amgen Inc.
`Novartis AG
`Probiodrug AG, Prosidion Ltd., and OSI
`Pharmaceuticals, Inc.
`Probiodrug AG
`F. Hoffmann-La Roche Ltd.
`Mitsubishi Tanabe Pharma Corp.
`Taisho Pharmaceutical Co., Ltd. and Eli Lilly
`and Co.
`Sanofi-Aventis U.S. LLC
`SSR-162339
`Takeda Pharmaceutical Co. Ltd.
`SYR-619
`See Paper 28 at 59; Ex. 2057 ¶ 66, Table 4; Ex. 2086
`
`Developer
`
`Novartis AG
`
`GlaxoSmithKline PLC
`
`Phenomix Corp. and Forrest Laboratories, Inc.
`
`Clinical
`Phase
`3
`
`FDA Status
`
`Discontinued
`
`Discontinued
`
`Discontinued
`
`Discontinued
`Discontinued
`Discontinued
`
`Discontinued
`
`Discontinued
`Discontinued
`Discontinued
`
`Discontinued
`
`Discontinued
`Discontinued
`AstraZeneca Demonstrative Exhibit 117
`
`3
`
`3
`
`3
`2
`2
`
`2
`
`2
`2
`2
`
`2
`
`1
`1
`
`
`
`In re Cyclobenzaprine Hydrochloride Extended-Release
`Capsule Patent Litig.
`
`The Federal Circuit has implicitly accepted
`that failure to obtain FDA approval is
`relevant evidence of failure of others. Knoll
`Pharm. Co. v. Teva Pharm. USA, Inc., 367
`F.3d 1381, 1385 (Fed.Cir.2004). In Pfizer
`Inc. v. Teva Pharmaceuticals USA, Inc., 460
`F.Supp.2d 659, 662 (D.N.J.2006), the court
`went one step further, and expressly stated
`that “[n]ot getting to market with FDA
`approval is an appropriate benchmark for
`failure [of others].”
`
`No. CIV. 09-MD-2118-SLR,
`2010 WL 3766530, at *1 (D. Del. Sept. 21, 2010)
`
`AstraZeneca Demonstrative Exhibit 118
`
`
`
`Post Invention Compounds Not FDA Approved
`
`DDP-4 Inhibitor
`
`Developer
`
`Structure
`
`FDA Status
`
`GW823093C
`(denagliptin)
`
`PHX1149T
`(dutogliptin)
`
`GlaxoSmithKline PLC
`
`Phenomix Corp. and Forrest
`Laboratories, Inc.
`
`PT-630
`
`Point Therapeutics, Inc.
`
`AMG-222
`
`PSN-9301
`
`R-1438
`
`TA-6666
`
`TS-021
`
`Amgen Inc.
`
`Probiodrug AG, Prosidion Ltd., and OSI
`Pharmaceuticals, Inc.
`
`F. Hoffmann-La Roche Ltd.
`
`Mitsubishi Tanabe Pharma Corp.
`
`Taisho Pharmaceutical Co., Ltd. and Eli
`Lilly and Co.
`
`Discontinued
`
`Discontinued
`
`Discontinued
`
`Discontinued
`
`Discontinued
`
`Discontinued
`
`Discontinued
`
`Discontinued
`
`Paper 62 at Observation 30; Ex. 2056 ¶¶ 253-54; Ex. 2247
`AstraZeneca Demonstrative Exhibit 119
`
`
`
`In re Cyclobenzaprine Hydrochloride Extended-Release
`Capsule Patent Litig.
`
`Because science necessarily builds upon past
`discoveries, failure of others after a patent's
`issue date may be more persuasive than
`failures that occur before. See generally
`Kristen C. Buteau, Denuterated Drugs:
`Unexpectedly Nonobvious, 10 J. High Tech.
`L. 22 (2009).
`
`No. CIV. 09-MD-2118-SLR,
`2010 WL 3766530, at *2 (D. Del. Sept. 21, 2010)
`
`AstraZeneca Demonstrative Exhibit 120
`
`
`
`FDA Approved DPP-4 inhibitors (2016)
`
`Saxagliptin
`First Invented
`
`Sitagliptin
`
`Alogliptin
`
`Linagliptin
`Paper 62 at Observation 29; Ex. 2047; Ex. 2049; Ex. 2079; Ex. 2077; Ex. 2245
`AstraZeneca Demonstrative Exhibit 121
`
`
`
`Procter & Gamble Co. v. Teva Pharm. USA, Inc.
`
`566 F.3d 989, 998 (Fed. Cir. 2009)
`
`AstraZeneca Demonstrative Exhibit 122
`
`
`
`Commercial Success
`
`AstraZeneca Demonstrative Exhibit 123
`
`
`
`U.S. Total Dispensed Prescriptions for
`Onglyza Family Products
`Q3 2009 through Q3 2015
`
`Total Onglyza Family
`
`Onglyza® Total
`
`
`
`12.8 Million12.8 Million
`
`
`
`Total Onglyza FamilyTotal Onglyza Family
`
`800,000
`
`700,000
`
`600,000
`
`500,000
`
`400,000
`
`300,000
`
`200,000
`
`100,000
`
`0
`
`Total Dispensed Prescriptions (No.)
`
`Paper 28 at 66; Ex. 2059A ¶ 33, Table 2(a), Fig. 1; Ex. 2117
`AstraZeneca Demonstrative Exhibit 124
`
`
`
`U.S. Sales of Onglyza Family
`Products in Dollars
`Q3 2009 through Q3 2015
`
`Total Onglyza Family
`
`Onglyza®
`
`$250,000,000
`
`$200,000,000
`
`$150,000,000
`
`$100,000,000
`
`$50,000,000
`
`$0
`
`
`
`$3.5 Billion$3.5 Billion
`
`
`
`Total Onglyza FamilyTotal Onglyza Family
`
`Paper 28 at 66; Ex. 2059A ¶ 34, Table 3, Fig. 2; Ex. 2118
`AstraZeneca Demonstrative Exhibit 125
`
`
`
`U.S. Net Revenues from Sales
`of Onglyza Family Products
`Q3 2009 through Q3 2015
`
`Total Onglyza Family
`
`$700,000,000
`
`$600,000,000
`
`$500,000,000
`
`$400,000,000
`
`$300,000,000
`
`$200,000,000
`
`$100,000,000
`
`
`
`$2.5 Billion$2.5 Billion
`
`
`
`Total Onglyza FamilyTotal Onglyza Family
`
`$0
`2009
`
`2010
`
`2011
`
`2012
`
`2013
`
`2014
`
`2015
`
`Ex. 2059A ¶ 35, Table 4, Fig. 3; Exs. 2004, 2111-2115, 2108
`AstraZeneca Demonstrative Exhibit 126
`
`
`
`First-Mover Advantage
`
`Ex. 2141 at 2
`
`Paper 28 at 67; Ex. 2059A ¶¶ 42-43
`AstraZeneca Demonstrative Exhibit 127
`
`
`
`Dr. McDuff
`
`Ex. 2220 at 134:8-16
`
`Ex. 2220 at 136:14-137:7
`
`Paper 61 at Observation 15
`AstraZeneca Demonstrative Exhibit 128
`
`
`
`Back Up
`
`AstraZeneca Demonstrative Exhibit 129
`
`
`
`Dr. Rotella
`
`Paper 62 at Observation 8; Ex. 2221 at 24:7-16
`AstraZeneca Demonstrative Exhibit 130
`
`
`
`Dr. Rotella
`
`Paper 62 at Observation 13; Ex. 2221 at 43:12-21
`AstraZeneca Demonstrative Exhibit 131
`
`
`
`Dr. Rotella
`
`Paper 62 at Observation 14; Ex. 2221 at 53:12-54:3; Ex. 2257
`AstraZeneca Demonstrative Exhibit 132
`
`
`
`Dr. Weber
`
`Ex. 1073 (Weber Cross-Examination) 85:2-86:4; Ex. 2056 ¶¶ 112, 174-176; Paper 28 at 10, 35-36
`AstraZeneca Demonstrative Exhibit 133
`
`
`
`Dr. Rotella
`
`Paper 62 at Observation 11; Ex. 2221 at 35:15-19
`AstraZeneca Demonstrative Exhibit 134
`
`
`
`Augustyns (1997): Ex. 2151
`
`Effect of ring “flattening” with a double bond
`
`Compound 3
`IC50 = 21 µM
`Saturated
`
`Compound 9b
`IC50 = 100 µM
`Unsaturated
`
`Paper 28 at 10; Ex. 2151 at 2, 4; Ex. 2233
`AstraZeneca Demonstrative Exhibit 135
`
`
`
`Villhauer-1998: Ex. 1008
`
`Ex. 1008 at 2, 5
`
`Ex. 2221 at 21:7-14; Paper 62 at Observation 6
`AstraZeneca Demonstrative Exhibit 136
`
`
`
`Dr. Rotella
`
`Ex. 2221 at 22:23-23:8; Paper 62 at Observation 7
`AstraZeneca Demonstrative Exhibit 137
`
`
`
`Dr. Weber Declaration
`
`Paper 28 at 52; Ex. 2056 ¶ 213
`AstraZeneca Demonstrative Exhibit 138
`
`
`
`Dr. Rotella
`
`Paper 62 at Observations 23, 24; Ex. 2221 at 89:17-21, 90:7-11
`AstraZeneca Demonstrative Exhibit 139
`
`
`
`Dr. Rotella
`
`Paper 62 at Observation 23; Ex. 2221 at 88:19-89:4
`AstraZeneca Demonstrative Exhibit 140
`
`
`
`Dr. Rotella
`
`Paper 62 at Observation 24; Ex. 2221 at 91:1-11
`AstraZeneca Demonstrative Exhibit 141
`
`
`
`Dr. Rotella
`
`Paper 62 at Observation 22; Ex. 2221 at 84:21-23, 86:4-21
`AstraZeneca Demonstrative Exhibit 142
`
`
`
`Dr. Rotella
`
`Paper 62 at Observation 25; Ex. 2221 at 92:18-21, 93:20-23
`AstraZeneca Demonstrative Exhibit 143
`
`
`
`Dr. Rotella
`
`Paper 62 at Observation 24; Ex. 2221 at 91:12-22
`AstraZeneca Demonstrative Exhibit 144
`
`
`
`Dr. Rotella
`
`Paper 62 at Observation 26; Ex. 2221 at 94:25-95:3, 95:23-96:1
`AstraZeneca Demonstrative Exhibit 145
`
`
`
`Dr. Tanenberg
`
`Paper 63 at Observation 8; Ex. 2222 at 40:23-41:12
`
`AstraZeneca Demonstrative Exhibit 146
`
`
`
`Dr. Tanenberg
`
`Paper 63 at Observation 4; Ex. 2222 at 35:22-24
`AstraZeneca Demonstrative Exhibit 147
`
`
`
`Dr. Tanenberg
`
`Paper 63 at Observation 1; Ex. 2222 at 23:3-8
`AstraZeneca Demonstrative Exhibit 148
`
`
`
`October 30, 2000: Ex. 2189
`
`Paper 28 at 4; Ex. 2173 ¶ 13; Ex. 2189 at 5
`AstraZeneca Demonstrative Exhibit 149
`
`
`
`Augustyns (1997): Ex. 2151
`
`Ex. 2151 at 2
`AstraZeneca Demonstrative Exhibit 150
`
`
`
`DPP-4 versus ACE
`
`Cleavage site
`
`GLP-1
`
`Ex. 2056 ¶¶ 82, 181
`AstraZeneca Demonstrative Exhibit 151
`
`
`
`Challenged Claims
`
`Claim(s)
`
`1
`
`2
`
`4
`
`6
`7
`
`8, 9
`
`10
`
`11
`
`12-22
`
`25-28, 32-35,
`39, 40
`
`29-30, 36-37,
`41-42
`
`1
`
`1
`
`1
`
`1
`1
`
`1
`
`1
`
`1
`
`Ground Scope of Claim(s)
`cyclopropyl-fused pyrrolidine
`and cyanopyrrolidine compounds
`4,5-cyclopropyl pyrrolidine
`and cyanopyrrolidine compounds
`cis-4,5-cyclopropyl
`cyanopyrrolidine compounds
`“C-linked” compounds of claim 1
`“up” cyclopropyl compounds of claim 1
`subgenera comprising eight cis-4,5-cyclopropyl
`cyanopyrrolidine compounds, each containing a
`quaternary β-carbon in the P2 group
`cis-3,4 and cis-4,5-cyclopropyl cyanopyrrolidine
`compounds, each with a C-linked alkyl at P2
`pharmaceutical compositions comprising a
`compound of claim 1 and a carrier
`pharmaceutical combinations comprising a
`compound of claim 1 and another agent
`
`2-4
`
`1
`
`2
`
`saxagliptin
`
`pharmaceutical combinations comprising
`saxagliptin and another agent or methods of
`treating with such combinations
`
`Paper 28 at 19-21; Ex. 2056 ¶¶ 19-38
`AstraZeneca Demonstrative Exhibit 152
`
`
`
`CERTIFICATE OF SERVICE
`
`In addition to the service via email on January 23, 2017 per the Order of
`
`
`
`Paper No. 69, the undersigned certifies that a copy of the foregoing PATENT
`
`OWNER’S DEMONSTRATIVES was served electronically via e-mail on
`
`January 24, 2017, pursuant to 37 C.F.R. 42.70(b), in its entirety to the following:
`
`Counsel for Petitioner Mylan Pharmaceuticals Inc.:
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`Steven W. Parmelee
`sparmelee@wsgr.com
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`Richard Torczon
`rtorczon@wsgr.com
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`Jad A. Mills
`jmills@wsgr.com
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`Douglas H. Carsten
`dcarsten@wsgr.com
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`Counsel for Petitioner Wockhardt BIO AG.:
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`Counsel for Petitioner Teva Pharmaceuticals U.S.A., Inc..:
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`Patrick Gallagher
`PCGallagher@duanemorris.com
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`Gary Speier
`gspeier@carlsoncaspers.com
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`Iain McIntyre
`imcintyre@carlsoncaspers.com
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`Counsel for Petitioner Aurobindo Pharma U.S.A., Inc..:
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`Sailesh K. Patel
`SPatel@schiffhardin.com
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`George Yu
`GYu@schiffhardin.com
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`Counsel for Petitioners Sun/Amneal:
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`Samuel Park
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`SPark@winston.com
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`Dated: January 24, 2017
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`Andrew Sommer
`ASommer@winston.com
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`By: /Lauren K. Young/
`Lauren K. Young
`Litigation Legal Assistant
`FINNEGAN, HENDERSON, FARABOW,
`GARRETT & DUNNER, L.L.P.
`
`
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