United States Patent And Trademark Office
`Patent Trial and Appeal Board
`
`Sandoz Inc.,
`Apotex Inc., Apotex Corp., Emcure Pharmaceuticals Ltd., Heritage Pharma Labs Inc.,
`Heritage Pharmaceuticals Inc., Glenmark Pharmaceuticals, Inc., USA, Glenmark
`Holdings SA, Glenmark Pharmaceuticals, Ltd., Mylan Laboratories Limited, Teva
`Pharmaceuticals USA, Inc., Fresenius KABI USA, LLC, and Wockhardt Bio AG
`
`Petitioners,
`
`v.
`
`Eli Lilly and Company
`
`Patent Owner
`
`IPR2016-003181
`U.S. Patent No. 7,772,209
`
`Petitioner Sandoz Inc.’s Oral Argument Demonstratives
`
`March 16, 2017
`
`1 Cases IPR2016-01429, IPR2016-01393, and IPR2016-01340 have been joined with the instant proceeding.
`
`
`Patent Trial and Appeal Board
`
`Sandoz Inc.,
`Apotex Inc., Apotex Corp., Emcure Pharmaceuticals Ltd., Heritage Pharma Labs Inc.,
`Heritage Pharmaceuticals Inc., Glenmark Pharmaceuticals, Inc., USA, Glenmark
`Holdings SA, Glenmark Pharmaceuticals, Ltd., Mylan Laboratories Limited, Teva
`Pharmaceuticals USA, Inc., Fresenius KABI USA, LLC, and Wockhardt Bio AG
`
`Petitioners,
`
`v.
`
`Eli Lilly and Company
`
`Patent Owner
`
`IPR2016-003181
`U.S. Patent No. 7,772,209
`
`Petitioner Sandoz Inc.’s Oral Argument Demonstratives
`
`March 16, 2017
`
`1 Cases IPR2016-01429, IPR2016-01393, and IPR2016-01340 have been joined with the instant proceeding.
`
`
`
`Background
`OVERVIEW OF GROUNDS
`
`Sandoz DX - 2
`
`
`
`U.S. Patent No. 7,772,209: Institution Grounds
`
`
`
`
`
`Insert Bullet Text
`Insert Bullet Text
`
`Paper No. 14, Institution, p.21
`
`Sandoz DX -
`
`3
`
`
`
`U.S. Patent No. 7,772,209: Institution Grounds
`
`Paper No. 14, Institution, p.21
`
`• EP005 not admitted at trial or cited by the district court in Lilly v.
`Teva et al. (S.D. Ind.), aff’d (Fed. Cir. 2017) (Ex. 1003).
`
`Sandoz DX -
`
`4
`
`
`
`U.S. Patent No. 7,772,209: Overview
`
`• 22 claims
`• 2 independent claims: 1
`and 12
`
`Sandoz DX - 5
`
`
`
`Background
`U.S. PATENT NO. 7,772,209
`
`Sandoz DX - 6
`
`
`
`U.S. Patent No. 7,772,209: Claims 1 and 12
`
`Sandoz DX - 7
`
`
`
`U.S. Patent No. 7,772,209: Claim 12 and its dependents
`
`Sandoz DX - 8
`
`
`
`Legal Framework
`PERSON OF ORDINARY SKILL
`IN THE ART
`
`Sandoz DX - 9
`
`
`
`Person of Ordinary Skill in the Art
`
`Ex. 1004, Schiff Decl. ¶13;
`Ex. 1075, Schiff Reply ¶¶7-9
`
`Sandoz DX - 10
`
`
`
`Person of Ordinary Skill in the Art: Lilly Definition
`
`Ex. 2120, Chabner Decl. ¶ 23.
`
`Sandoz DX - 11
`
`
`
`Person of Ordinary Skill in the Art: Lilly v. Teva Definition
`
`Ex.. 1003, Lilly v. Teva, No. 1:10-cv-1376 (S.D.
`Ind.), p. 9.
`
`Sandoz DX - 12
`
`
`
`Lilly v. Teva: Southern District of Indiana & Dr. Zeisel
`
`Ex. 1003, Lilly v. Teva (S.D. Ind.), pp. 18-19; see
`also id. at 11-12.
`
`Sandoz DX - 13
`
`
`
`Prior Art Disclosures
`PEMETREXED
`
`Sandoz DX - 14
`
`
`
`Prior Art: Pemetrexed
`
`• Pemetrexed disclosed in
`U.S. Pat. Nos. 5,217,974
`and 5,344,932
`• Lilly listed both patents
`in the Orange Book for
`pemetrexed/Alimta
`• Both the ’932 and ’974
`patents are now expired
`
`Exs. 1005, 1025, 1034
`
`Sandoz DX - 15
`
`
`
`Prior Art: ’974 Patent (Ex. 1005) GARFT or FBP Binders
`
`Pemetrexed disclosed in U.S. Pat.
`Nos. 5,217,974 and 5,344,932
`
`• Pemetrexed is both a GARFT inhibitor
`and FBP binder:
`Pemetrexed disclosed in U.S. Pat.
`Nos. 5,217,974 and 5,344,932
`
`Pemetrexed disclosed in U.S. Pat.
`Nos. 5,217,974 and 5,344,932
`
`Ex. 1005, ‘974 patent, 4:10-17; Ex. 1022, Westerhof, 463;
`Ex. 1074, Chabner Dep. 282:4-287:4
`
`Sandoz DX - 16
`
`
`
`Prior Art: ’932 Patent
`
`Pemetrexed:
`
`Ex. 1034, claims 1 & 2.
`Sandoz DX - 17
`
`
`
`Prior Art: Pemetrexed 2010 Orange Book Listing
`
`Ex. 1025, p. 4
`
`Sandoz DX - 18
`
`
`
`Prior Art: ’974 Patent
`
`Ex. 1005, col. 2, l. 66-col. 3, l. 19; Ex. 1004, Schiff
`¶¶ 34, 47; Ex. 1075, Schiff Reply, ¶ 61.
`
`Sandoz DX - 19
`
`
`
`Prior Art: ’974 Patent
`
`Ex. 1005, ‘974 patent, 1:47-58; Ex. 1074, Chabner Dep. 282:4-
`287:4; See also, Ex. 1075, Schiff Reply, ¶ 61.
`
`Sandoz DX - 20
`
`
`
`Prior Art: Shih (Ex. 1021)
`
`Ex. 1021, Shih, p. 1116; Ex. 1004, Schiff Decl. ¶33
`
`Sandoz DX - 21
`
`
`
`Prior Art Disclosures
`PEMETREXED + FOLIC ACID
`PRETREATMENT
`
`Sandoz DX - 22
`
`
`
`Prior Art: ’974 Patent
`
`Pemetrexed disclosed in U.S. Pat.
`Nos. 5,217,974 and 5,344,932
`
`Ex. 1005, col. 6, ll. 29-43; Ex. 1004, Schiff ¶¶ 112-
`14; Ex. 1075, Schiff Reply, ¶ 119-21.
`
`Sandoz DX - 23
`
`
`
`Prior Art: Hammond Abstracts (Ex. 1014, 1015)
`
`Ex. 1015, Hammond I (ESMO); Ex. 1004, Schiff
`¶¶54, 56; Ex. 1075, Schiff Reply, ¶36.
`
`Ex. 1014, Hammond II (ASCO); Ex. 1004, Schiff
`¶¶55-56; Ex. 1075, Schiff Reply, ¶36.
`
`Sandoz DX - 24
`
`
`
`Dr. Chabner’s Hammond v. Rinaldi Comparison
`
`Hammond Abstracts, Ex. 1014, 1015
`
`1. Cannot quantify efficacy in Phase 1
`2. Phase 1 trials lack randomized
`design or control groups
`3. A POSA would not consider
`Hammond to be a Phase 1B study
`
`Rinaldi Abstract, Ex. 2022
`
`Ex. 1075, Schiff Reply, ¶¶37-45.
`
`Sandoz DX - 25
`
`
`
`Flaw #1: Efficacy Cannot be Quantified in Phase I Trials
`
`Ex. 1095, Friedman, 3-4
`
`Ex. 1095, Friedman, 3-4; Ex. 2120, Chabner Decl, ¶ 72;
`see also, Ex. 1075, Schiff Reply, ¶¶ 37-45.
`
`Sandoz DX - 26
`
`
`
`Flaw #2: The Hammond and Rinaldi Phase I Trials Have
`Different Experimental Conditions
`
`Ex. 1015, Hammond I:
`
`Ex. 1014, Hammond II:
`
`Ex. 2022, Rinaldi I:
`
`.
`
`Sandoz DX - 27
`
`
`
`Flaw #3: A POSA would not consider Hammond to be a
`Phase 1B study
`
`Ex. 1098, Von Hoff, see also, Ex. 1075, Schiff Reply, ¶ 44.
`
`Sandoz DX - 28
`
`
`
`Flaw #3: A POSA would not consider Hammond to be a
`Phase 1B study
`
`Lilly Clinical Trial Website 2001:
`
`Lilly Clinical Trial Website 2006:
`
`Ex. 1082, 11, 15; Ex. 1075, Schiff Reply, ¶ 44.
`
`Sandoz DX - 29
`
`
`
`Dr. Chabner’s Alleged Concerns About Kidney Toxicity from
`Hammond Dose Escalation
`
`Ex. 1075, Schiff Reply, ¶51
`
`Sandoz Dx - 30
`
`
`
`Prior Art: Laohavinij (Ex. 2031)
`
`Ex. 2031, Laohavinij at 333-34; Ex. 1075, Schiff
`Reply ¶¶ 46-50
`
`Sandoz DX - 31
`
`
`
`Prior Art: Laohavinij (Ex. 2031)
`
`Ex. 2031, Laohavinij at 333; Ex. 1075, Schiff Reply ¶¶ 46-50
`
`Sandoz DX - 32
`
`
`
`Prior Art: Laohavinij (Ex. 2031)
`
`Ex. 2031, Laohavinij at 333; Ex. 1075,
`Schiff Reply ¶¶ 46-50
`
`Sandoz DX - 33
`
`
`
`Prior Art: Farber (Ex. 1009) and Folic Acid and Vitamin
`B12 Supplementation
`
`Ex. 1009, Farber at 788; Ex. 1075, Schiff Reply
`¶¶ 96-97; Ex. 2137 Stover Dep. 65-91
`
`Farber Case 1
`
`Sandoz DX - 34
`
`
`
`Prior Art: Farber (Ex. 1009) and Folic Acid and Vitamin
`B12 Supplementation
`
`Ex. 1009, Farber at 788; Schiff Reply ¶96
`
`Sandoz DX - 35
`
`
`
`Prior Art: Farber (Ex. 1009) and Vitamin B12
`Supplementation
`
`Farber Case 2
`
`Ex. 1009, Farber at 789; Ex. 1075, Schiff Reply ¶96; Stover Reply ¶17;
`Stover Dep. 65-91
`
`Sandoz DX - 36
`
`
`
`Prior Art: Farber (Ex. 1009) and Folic Acid and Vitamin
`B12 Supplementation
`
`Ex. 1009, Farber at 792; Ex. 1075, Schiff Reply
`¶96; Ex. 1091, Stover Reply ¶17; Ex. 2137,
`Stover Dep. 65-91
`
`Farber Case 5
`
`Sandoz DX - 37
`
`
`
`Prior Art: Farber (Ex. 1009) and Folic Acid and Vitamin B12
`Supplementation
`
`Ex. 2136, Schiff Dep. ¶45:10-46:25; Paper 70,
`4; Ex. 1075, Schiff reply ¶96
`
`Ex. 1091, Stover Reply ¶17
`
`Sandoz DX - 38
`
`
`
`Prior Art: Farber (Ex. 1009) and Folic Acid and Vitamin
`B12 Supplementation
`
`Ex. 2137, Stover Dep. 90:12-91:4
`
`Ex. 2137, Stover Dep. 82:5-12
`
`Sandoz DX - 39
`
`
`
`Prior Art: Worzalla (Ex. 1013)
`
`Ex. 1013, p. 3235; Ex. 1004, Schiff ¶¶ 57-62;
`Ex. 1075, Schiff Reply, ¶¶ 55-60.
`
`Sandoz DX - 40
`
`
`
`Prior Art: Worzalla (Ex. 1013)
`
`Ex. 1013, p. 3237; Ex. 1004, Schiff ¶¶ 58-59;
`Ex. 1075, Schiff Reply, ¶¶55-56.
`
`Ex. 1013, p. 3237-38; Ex. 1004, Schiff ¶¶ 58-59;
`Ex. 1075, Schiff Reply, ¶¶55-56.
`Sandoz DX - 41
`
`
`
`Prior Art: Worzalla (Ex. 1013)
`
`• Worzalla cited by others
`
`Ex. 1047, Calvert & Walling, at 39 (citing Ex. 1101,
`Worzalla at abstract); Ex. 1074, Chabner Dep.
`226:15-227:12
`
`Ex. 1052, Rusthoven, at 1195.
`
`Sandoz DX - 42
`
`
`
`Prior Art: Citations to Preclinical Worzalla Studies (Ex.
`1013 and Ex. 1101 )
`
`Ex. 1079, Paz Ares, 2059.
`
`Ex. _, p. _.
`
`Ex. 1078, Bunn, 20-21.
`
`Ex. 1075, Schiff Reply ¶55 (collection of references).
`
`Ex. 1103, Priest, 38.
`
`Sandoz DX - 43
`
`
`
`Prior Art: Worzalla (Ex. 1013)
`
`Ex. 1013, p. 3238; Ex. 1004, Schiff ¶¶ 57-62; Ex.
`1075, Schiff Reply, ¶¶55-56.
`
`Ex. 1013, p. 3238; Ex. 1004, Schiff ¶¶ 57-62; Ex.
`1075, Schiff Reply, ¶¶55-56.
`
`Sandoz DX - 44
`
`
`
`Prior Art: Worzalla (Ex. 1013)
`
`Ex. 1013, p. 3238; Ex. 1004, Schiff ¶¶ 57-62; Ex. 1075, Schiff Reply, ¶¶55-56.
`
`Sandoz DX - 45
`
`
`
`Prior Art: Worzalla (Ex. 1013)
`
`mice on low folate diet (LFD) with no folate supplementation
`
`mice on LFD with 15mg/kg/day folate supplementation
`
`standard diet mice
`
`vertical dashed lines = % lethality, dashed shapes indicate
`maximum % lethality
`
`Shading = range (if any) with 100% tumor inhibition, 0% lethality
`
`Ex. 1013, p. 3238; Ex. 1004, Schiff
`¶¶57-62; Ex. 1075, Schiff Reply
`¶¶57-58; Ex. 1074, Chabner Dep.
`121:5-23, 129:13-19 (citing Ex.
`1067, Demonstrative).
`
`Sandoz DX - 46
`
`
`
`Prior Art: Worzalla (Ex. 1013)
`
`Ex. 1013, p. 3235; Ex. 1004, Schiff ¶¶ 57-62;
`Ex. 1075, Schiff Reply, ¶ 56-58.
`
`Sandoz DX - 47
`
`
`
`Lilly’s Statements to FDA about Worzalla
`
`Ex. 1084, Feb. 16, 2000 Briefing Document at
`ELAP0013767; Paper 49, Sandoz Reply at 8-9.
`
`Sandoz DX - 48
`
`
`
`Lilly’s Statements to FDA about Hammond
`
`Ex. 1077, Dec. 3, 1999 Letter Lilly to FDA
`at ELAP00199798, -814; Paper 49,
`Sandoz Reply at 8-9.
`
`Sandoz DX - 49
`
`
`
`Lilly’s Statements to FDA about Worzalla
`
`Ex. 1084, Feb. 16, 2000 Briefing Document at
`ELAP0013768-69; Paper 49, Sandoz Reply at 8-9.
`
`Sandoz DX - 50
`
`
`
`Prior Art Disclosures
`
`FOLIC ACID + VITAMIN B12
`
`Sandoz DX - 51
`
`
`
`Prior Art: Calvert (Ex. 1007) and Pemetrexed Toxicity,
`Homocysteine, and Vitamins
`
`Ex. 1007, Calvert at 8-9; Ex. 1004, Schiff ¶¶71-73.
`Sandoz DX - 52
`
`
`
`Prior Art: Calvert (Ex. 1007) and Pemetrexed Toxicity,
`Homocysteine, and Vitamins
`
`Ex. 1007, Calvert at 8-9; Schiff ¶¶71-73.
`
`Sandoz DX - 53
`
`
`
`Prior Art: Calvert (Ex. 1007)
`
`Ex. 1007, Calvert at 7-8; Ex. 1004, Schiff ¶¶ 71-73; Ex. 1075, Schiff Reply, ¶¶75-76.
`
`Sandoz DX - 54
`
`
`
`Prior Art: Niyikiza Abstracts
`
`Niyikiza I (Ex. 1006)
`
`Niyikiza II (Ex. 1016)
`
`Ex. 1006, Niyikiza I (ESMO, Nov. 6-10, 1998); Ex. 1004,
`Schiff ¶¶67-68; Ex. 1075, Schiff Reply, ¶¶66-69.
`
`Ex. 1016, Niyikiza II (ASCO, May 16-19, 1998); Ex.
`1004, Schiff ¶69; Ex. 1075, Schiff Reply, ¶¶66-69.
`
`Sandoz DX - 55
`
`
`
`Prior Art: Niyikiza Abstracts - Lilly’s Claim that Niyikiza
`II (ASCO, Ex. 1016) Suggests A Lack Of B12 Deficiency
`
`Ex. 1016, Niyikiza II (ASCO, May 16-19, 1998); Ex.
`1004, Schiff ¶69; Ex. 1075, Schiff Reply, ¶¶66-69.
`
`Sandoz DX - 56
`
`
`
`Prior Art: Niyikiza Abstracts - Drs. Chabner’s and
`Zeisel’s Testimony
`
`Dr. Chabner
`
`Dr. Zeisel
`
`Ex. 1086, Zeisel Dep. Tr. 116:19-20; Paper 49, Sandoz
`Reply at 12.
`
`Ex. 1074, Chabner Dep. Tr. 152:23-153:13; Paper 49,
`Sandoz Reply at 12.
`
`Sandoz DX - 57
`
`
`
`Lilly’s Statements to FDA about the Niyikiza Abstracts
`
`Ex. 1088, June 4, 2001 Lilly Report, ELAP00019630; Paper
`49, Sandoz Reply at 13.
`
`Sandoz DX - 58
`
`
`
`Vitamin B12 and Methylmalonic Acid (MMA)
`
`Ex. 1086, Zeisel Dep. 95:11-12.; Ex. 1075, Schiff
`Reply ¶68; Ex. 1091, Stover Reply ¶42
`
`Ex. 1074, Chabner Dep. 206:12-21; Ex. 1075, Schiff
`Reply ¶68
`
`Ex. 1050, Allen at 97; Ex. 1075, Schiff Reply, ¶68.
`
`Sandoz DX - 59
`
`
`
`Niyikiza and Pretreatment Homocysteine Levels ≥ 10µM
`
`Ex. 1086, Zeisel Dep. 29:7-12; Ex. 1075, Schiff Reply ¶¶71-72.
`
`Ex. 1086, Zeisel Dep. 35:18-36:3; Ex. 1075, Schiff Reply ¶71.
`
`Sandoz DX - 60
`
`
`
`Homocysteine and Methylmalonic Acid (MMA)
`
`Ex. 1004, Schiff ¶80; Ex. 1075, Schiff Reply, ¶66; see
`also Ex. 2120, Chabner Decl. ¶122 . Sandoz DX - 61
`
`
`
`Prior Art: Brattström (Ex. 1020)
`
`Ex. 1020, Brattström at 1277S; Ex. 1004, Schiff Decl. ¶76.
`
`Sandoz DX - 62
`
`
`
`Prior Art: Brönstrup (Ex. 1040)
`
`Ex. 1040, Brönstrup at abstract, 1109; Ex. 1004, Schiff Decl. ¶78.
`
`Sandoz DX - 63
`
`
`
`Prior Art: Ubbink I (Ex. 1039)
`
`Ex. 1039, Ubbink I, 1931 ; Schiff Decl. ¶77.
`
`Sandoz DX - 64
`
`
`
`Prior Art: Ubbink II (Ex. 1041)
`
`Ex. 1041, Ubbink II, 321 ; Schiff Decl. ¶77.
`
`Sandoz DX - 65
`
`
`
`Prior Art: European Patent Application 0 595 005
`(EP005) (Ex. 1033)
`
`Ex. 1033 EP005, 3:7-9; Ex. 1004, Schiff ¶79; Ex. 1075, Schiff
`Reply, ¶¶78-82.
`
`Ex. 1033 EP005, 4:43-48; Ex. 1075, Schiff Reply, ¶¶78-82.
`
`. . .
`
`Ex. 1074, Chabner Dep. Tr. 185:24-185:7.; Ex. 1075, Schiff Reply, ¶78
`
`Sandoz DX - 66
`
`
`
`Prior Art: European Patent Application 0 595 005
`(EP005) (Ex. 1033)
`
`Ex. 1033 EP005, 4:43-48; Ex. 1075, Schiff Reply, ¶¶78-82.
`
`Ex. 1033, EP005, 9:51-57.
`
`Sandoz DX - 67
`
`
`
`Prior Art: European Patent Application 0 595 005
`(EP005) (Ex. 1033)
`
`Ex. 1033 EP005, 2:1-3, 4:24-42; Ex. 1004, Schiff Decl. ¶79; Ex. 1075, Schiff Reply, ¶¶78-82.
`
`Ex. 1033, EP005, 9:51-57.
`
`Sandoz DX - 68
`
`
`
`Prior Art: European Patent Application 0 595 005
`(EP005) (Ex. 1033)
`
`Ex. 1033 EP005, 11:20-25; Paper 49,Sandoz Reply, p. 14
`
`Ex. 1033 EP005, 18:25-26
`
`Sandoz DX - 69
`
`
`
`Prior Art: Folic Acid and Vitamin B12 With Antifolates
`Prior to June 1999
`
`Farber (1948)
`
`Ex. 1009, Farber at 792; Ex. 1075, Schiff Reply
`¶96; Ex. 1091, Stover Reply ¶17
`
`Tisman 1985
`
`Ex. 1028, Tisman; Ex. 1004, Schiff Decl. ¶89
`
`EP 005 (1994)
`
`Ex. 1033, EP005, 4:43-48; Ex. 1075, Schiff Reply, ¶¶78-82.
`
`Sandoz DX - 70
`
`
`
`Prior Art: Folic Acid and Vitamin B12 and Antifolates
`before June 1999
`
`Mendelsohn (1999)
`
`Ex. 1012, Mendelsohn at 270; Ex. 1004, Schiff Decl. ¶¶49; Ex. 1075, Schiff Reply ¶77
`
`Carrasco (1999)
`
`Ex. 1032, Carrasco, 768 ; Ex. 1075, Schiff Reply, ¶103; Paper 2, Pet. at 32.
`
`Sandoz DX - 71
`
`
`
`Prior Art: Tisman (1985)
`
`Ex. 1028, Tisman; Ex.
`1004, Schiff Decl. ¶89
`
`Ex. 1001, col. 1, ll. 43-51.
`
`Sandoz DX - 72
`
`
`
`Prior Art: Mendelsohn (1999)
`
`Ex. 1012, Mendelsohn at 270; Ex. 1004, Schiff Decl. ¶¶49; Ex. 1075,
`Schiff Reply ¶77
`
`Ex. 1012, Mendelsohn at 263; Ex. 1004, Schiff Decl. ¶¶49; Ex. 1075, Schiff Reply ¶77
`
`Sandoz DX - 73
`
`
`
`Prior Art: Carrasco (1999)
`
`Ex. 1032, Carrasco, 767-768 ; Ex. 1075, Schiff
`Reply, ¶103; Paper 2, Pet. at 32.
`
`Sandoz DX - 74
`
`
`
`Dr. Chabner’s Proposed Alternatives to Folic Acid +
`Vitamin B12
`
`1. Dose reductions
`2. Leucovorin Rescue
`3. Granulocyte Colony Stimulating Factor
`4. Betaine
`
`Ex. 1075, Schiff Reply, ¶¶22
`
`Sandoz DX - 75
`
`
`
`Dr. Chabner’s Alternative #1: Dose Reductions
`
`Ex. 1074, Chabner Dep. 234:11-17; Ex. 1075, Schiff Reply, ¶23; Ex. 1094, Erlichman, 230
`
`Sandoz DX - 76
`
`
`
`Dr. Chabner’s Alternative #2: Granulocyte Colony
`Stimulating Factor
`
`Ex. 1052, Rusthoven, 1195, 1196; Ex. 1075, Schiff Reply ¶¶ 28-31
`
`Ex. 1052, Rusthoven, 1195, 1196; Ex. 1075, Schiff Reply ¶¶ 28-31
`
`Ex. 1074, Chabner Dep. 234:24-236:7; 267:16-268:1; Ex. 1075, Schiff Reply ¶¶ 28-31
`
`Sandoz DX - 77
`
`
`
`Dr. Chabner’s Alternative #3: Leucovorin Rescue
`
`Ex. 2040, Smith & Amyx, 6119, 6120; Ex. 1075, Schiff Reply
`¶¶ 25-27
`
`Ex. 1074, Chabner Dep. 281:10-14; Ex. 1075, Schiff
`Reply, ¶¶ 25-27
`
`Sandoz DX - 78
`
`
`
`Dr. Chabner’s Alternative #4: Betaine
`
`Ex. 2033, Quinn
`
`Ex. 1074, Chabner Dep. 278:4-14; Ex. 1075, Schiff Reply, ¶ 33
`
`Ex. 1091 Stover Reply,¶¶ 32-34
`
`Ex. 1086, Zeisel Dep. 285:23-286:7; Ex. 1091, Stover Reply, ¶ 32
`
`Sandoz DX - 79
`
`
`
`Prior Art: Arsenyan (Ex. 1023)
`
`Ex. 1023, Arsenyan, 2; Ex. 1075, Schiff Reply, ¶ 90
`
`Sandoz DX - 80
`
`
`
`Prior Art: Sofyina (Ex. 1026)
`
`Ex. 1026, Sofyina, 7; Ex. 1075, Schiff Reply, ¶ 91
`
`Sandoz DX - 81
`
`
`
`Prior Art: McLean (Ex. 2058)
`
`Ex. 2058, McLean 4020, 4021; Ex. 1075, Schiff Reply ¶93
`
`Sandoz DX - 82
`
`
`
`Prior Art: ViDAL (Ex. 2032)
`
`ViDAL statement relied on by Lilly:
`
`Ex. 2032, Vidal, 24
`
`Ex. 1074, Chabner Dep., 106:5-107:4;
`Ex. 1075, Schiff Reply, ¶ 94
`
`Ex. 1086, Zeisel Dep., 42:4-25; Ex.
`1075, Schiff Reply, ¶ 94
`Sandoz DX - 83
`
`
`
`Prior Art: Non Prescription Physician’s Desk Reference
`(“PDR”) (Ex. 1106)
`
`Ex. 1106, Non-Prescription PDR, 403, 843; Ex.
`1075, Schiff Reply, ¶ 95
`
`Sandoz DX - 84
`
`
`
`Prior Art: PDR (Ex. 1092)
`
`Ex. 1092, PDR, 403, 843
`
`Ex. 1092, 1999 PDR, 2914-2915; Ex. 1075, Schiff Reply, ¶ 95
`
`Sandoz DX - 85
`
`
`
`Prior Art: PDR (Ex. 1092) (cont’d)
`
`Ex. 1092, 1999 PDR, 403, 843; Ex. 1075, Schiff Reply, ¶ 95
`
`Sandoz DX - 86
`
`
`
`Prior Art: PDR (Ex. 1092)
`
`Ex. 1092, 1999 PDR, 1666, 3170; Ex. 1075, Schiff Reply, ¶ 95
`
`Sandoz DX - 87
`
`
`
`Prior Art: Allen (Ex. 1018) and Masking: “[T]reatment with
`folate alone in such patients is extremely dangerous”
`
`Ex. 1018, ’126 Patent 7:51-59; Ex. 1004, Schiff Decl., ¶ 83
`
`Sandoz DX - 88
`
`
`
`Prior Art Disclosures
`STANDARD DOSES OF FOLIC
`ACID + VITAMIN B12
`
`Sandoz DX - 89
`
`
`
`'209 Patent: Narrowest Claimed Dosage Ranges
`
`• Dependent claims 15 and 18
`exemplary of narrowest
`dosages
`
`Claim 15: narrowest B12 dosage
`
`Claim 18: narrowest folic acid dosage
`
`Ex. 1001
`
`Sandoz DX - 90
`
`
`
`‘209 Patent
`
`Ex. 1001, ‘209 patent, col. 6, ll. 35-53; Ex. 1004, Schiff Decl. ¶¶ 19-20.
`
`Sandoz DX - 91
`
`
`
`Prior Art Disclosures
`STANDARD DOSES OF FOLIC
`ACID
`
`Sandoz DX - 92
`
`
`
`Folic Acid Dosage: ‘974 patent and dosages within 350-
`600 µg
`
`Ex. 1005, col. 6, ll. 38-39; Schiff ¶ 93; Ex. 1075,
`Schiff Reply, ¶ 111.
`
`Ex. 1005, col. 8, ll. 49-59; Schiff ¶ 93; Ex. 1075,
`Schiff Reply, ¶ 111.
`
`Sandoz DX - 93
`
`
`
`Folic Acid Dosage: European Patent Application 0 595
`005 (EP005) (Ex. 1033) and dosages within 350-600 µg
`
`Ex. 1033, EP 005 at 4-5, 9; Ex. 1004, Schiff Decl. ¶96
`
`Ex. 1004, Schiff Decl. ¶96
`
`Sandoz DX - 94
`
`
`
`Folic Acid Dosage: European Patent Application 0 595
`005 (EP005) (Ex. 1033) and dosages within 350-600 µg
`
`Ex. 1033 EP005 at 9; Paper 14, Institution at 15;
`Ex. 1004, Schiff Decl. ¶79; Ex. 1075, Schiff Reply,
`¶¶78-82.
`
`Ex. 1033, EP005, 9:51-57.
`
`Sandoz DX - 95
`
`
`
`Folic Acid Dosage: Morgan (Ex. 1010) and dosages
`within 350-600 µg
`
`Ex. 1010, Morgan at 838; Ex. 1004, Schiff Decl.,
`¶ 95; Ex. 1075, Schiff Reply, ¶ 109.
`
`Ex. 1013, Worzalla at 3239 n.10 (citing Ex. 2084,
`Morgan); Ex. 1075, Schiff Reply, ¶ 109.
`
`Sandoz DX - 96
`
`
`
`Folic Acid Dosage: Allen (Ex. 1018) and dosages within
`350-600 µg
`
`Ex. 1018, U.S. Pat. No. 5,563,126, col. 1, ll. 26-
`29; Ex. 1004, Schiff ¶ 94.
`
`Ex. 1018, U.S. Pat. No. 5,563,126, col. 7, ll.
`15-17; Ex. 1004, Schiff ¶ 94.
`
`Ex. 1018, U.S. Pat. No. 5,563,126, col. 6, ll. 3-7;
`Ex. 1004, Schiff ¶ 94.
`
`Sandoz DX - 97
`
`
`
`Folic Acid Dosage: testimony concerning dosages
`within 350-600 µg
`
`Ex. 1086, Zeisel Dep. 83:18-20; Ex. 1075, Schiff Reply ¶ 110.
`
`Ex. 2137, Stover Dep. 124:13-125:2; see also
`Paper 68, Sur-Reply at 13-14.
`
`Ex. 2136, Schiff Dep. Tr. 213:10-
`213:13.; Paper 70, p.5
`
`Sandoz DX - 98
`
`
`
`Folic Acid Dosage: Non Prescription Physician’s Desk
`Reference (“PDR”) (Ex. 1106) and dosages within 350-600 µg
`
`Ex. 1106, Non-Prescription PDR, 403, 843; Ex.
`1075, Schiff Reply, ¶ 95
`
`Sandoz Dx - 99
`
`
`
`Prior Art Disclosures
`STANDARD DOSES OF
`VITAMIN B12
`
`Sandoz DX -100
`
`
`
`Prior Art: Beutler (Ex. 1019)
`Vitamin B12 Dosage: 1000 µg Intramuscular Injection
`
`Beutler (hematologic
`disorders)
`
`Ex. 1019, Beutler at 302; Ex. 1004, Schiff Decl. ¶102; Ex. 1075,
`Schiff Reply, ¶112
`Sandoz DX -101
`
`
`
`Prior Art: Kinloch (Ex. 1029)
`Vitamin B12 Dosage: 1000 µg Intramuscular Injection
`
`Kinloch (anaemia)
`
`Ex. 1029, Kinloch at 99; Ex. 1004, Schiff Decl. ¶103; Ex. 1075,
`Schiff Reply, 112 ¶
`Sandoz DX -102
`
`
`
`Prior Art: Wray (Ex. 1030)
`Vitamin B12 Dosage: 1000 µg Intramuscular Injection
`
`Wray (apthae ulcers)
`
`Ex. 1030, Wray at 491; Ex. 1004, Schiff Decl. ¶104; Ex. 1075,
`Schiff Reply, ¶112
`Sandoz DX -103
`
`
`
`Prior Art: Tamura (Ex. 1031)
`Vitamin B12 Dosage: 1000 µg Intramuscular Injection
`
`Tamura (immunological,
`neurological, and
`oncological disorders)
`
`Ex. 1031, Tamura at 29; Ex. 1004, Schiff Decl. ¶105
`
`Sandoz DX -104
`
`
`
`Prior Art: Tamura (Ex. 1031)
`Vitamin B12 Dosage: 1000 µg Intramuscular Injection
`
`Tamura (immunological,
`neurological, and
`oncological disorders)
`
`Ex. 1031, Tamura at 31; Ex. 1004, Schiff Decl. ¶105; Ex. 1075,
`Schiff Reply ¶112
`Sandoz DX -105
`
`
`
`Prior Art: Clarke (Ex. 2070)
`Vitamin B12 Dosage: 1000 µg Intramuscular Injection
`
`Clarke
`
`Ex. 2070, Clarke at 897; Ex. 1075, Schiff
`Reply ¶115
`Sandoz DX -106
`
`
`
`Prior Art: EP005 (Ex. 1033)
`Vitamin B12 Dosage: 1000 µg Intramuscular Injection
`
`Ex. 1033, EP 005 at 4-5, 9; Ex. 1004, Schiff Decl. ¶107
`
`Ex. 1004, Schiff Decl. ¶107
`
`Sandoz DX -107
`
`
`
`Prior Art: EP005 (Ex. 1033)
`Vitamin B12 Dosage: 1000 µg Intramuscular Injection
`
`Ex. 1033, EP 005, 5:52-54; Ex. 1004, Schiff Decl. ¶107
`
`Ex. 2120, Chabner Decl. ¶¶214-15 (citing Ex. 1033, EP 005,
`7:48-51); Ex. 1004, Schiff Reply ¶116
`
`Sandoz DX -108
`
`
`
`Prior Art: EP005 (Ex. 1033)
`Vitamin B12 Dosage: 1000 µg Intramuscular Injection
`
`Ex. 1033, EP 005, 5:52-54; Ex. 1004, Schiff Decl. ¶107
`
`Ex. 1033, EP 005, 7:48-51; Ex. 1004, Schiff Reply ¶116
`
`Sandoz DX -109
`
`
`
`Prior Art: EP005 (Ex. 1033)
`Vitamin B12 Dosage: 1000 µg Intramuscular Injection
`
`• Dr. Ron Schiff, M.D., Ph.D.
`
`Ex. 1075, Schiff Reply ¶113
`
`• Dr. Patrick Stover, Ph.D.
`
`Ex. 2137, Stover Dep. Tr. 105:7-25; Ex. 1004, Schiff Decl.
`¶1004; see Paper 68, Sur-Reply at 13-14.
`
`Sandoz DX -110
`
`
`
`Dr. Zeisel’s Testimony
`Vitamin B12 Dosage: 1000 µg Intramuscular Injection
`
`Ex. 1086, Zeisel Dep. Tr. 89:14-91:14; see also Ex. 1075, Schiff Reply ¶116
`
`Sandoz DX -111
`
`
`
`Prior Art Disclosures
`DOSING SCHEDULES
`
`Sandoz DX -112
`
`
`
`'209 Patent: Dependent claims set out two pretreatment
`dosing schedules
`
`• 1-3 weeks: dependent claims
`6 & 19
`• 1-24 hours: dependent claims
`7 & 20
`
`Claim 19
`
`Claim 20
`
`Ex. 1001
`
`Sandoz DX -113
`
`
`
`Prior Art: ’974 Patent (Ex. 1005)
`
`Ex. 1005, col. 6, ll. 22-47; Ex. 1004, Schiff Decl.,
`¶¶112-14; Ex. 1075, Schiff Reply, ¶¶117-21.
`
`Sandoz DX -114
`
`
`
`Dosing Schedules
`
`Ex. 1075, Schiff Reply, ¶ 121.
`
`Ex. 1074, Chabner Dep. 296:23-297:20.; Ex .
`1075, Schiff Reply, ¶121
`
`Sandoz DX -115
`
`
`
`Prior Art Disclosures
`COMBINATION WITH
`CISPLATIN
`
`Sandoz DX -116
`
`
`
`'209 Patent: Dependent Claims 11, 13, and 22 Also
`Require Administration of Cisplatin
`
`Claim 22
`
`Ex. 1001
`
`Sandoz DX -117
`
`
`
`Prior Art: Thödtmann
`
`Ex. 1017, Thodtmann
`
`Ex. 1017, Thodtmann at 89.
`
`Sandoz DX -118
`
`
`
`Secondary Considerations
`PURPORTED SKEPTICISM
`
`Sandoz DX -119
`
`
`
`Dr. Chabner’s Purported Skepticism Based on Farber
`(1948) and “prior experiments” with “poor results”
`
`Ex. 2120, Chabner Decl. ¶2120.
`
`Sandoz DX -120
`
`
`
`Purported Skepticism: Lometrexol + Folic Acid
`
`Laohavinij (1996)
`
`Mendelsohn (1999)
`
`Ex. 1012, Mendelsohn at 277; Ex. 1075, Schiff
`Reply, ¶48.
`
`Ex. 2031, Laohavinij at 333-334.
`
`Tularik Clinical Trial (2002)
`
`Ex. 1099, clinicaltrials.gov; Ex. 1075, Schiff Reply, ¶49.
`
`Sandoz DX -121
`
`
`
`Purported Skeptism: FDA Statements
`
`Ex. 2100, Sept. 1998 FDA Minutes at 8044; Paper
`36, PO Resp. at 58.
`
`Sandoz DX -122
`
`
`
`Purported Skepticism: FDA Statements
`
`Ex. 2109, Mar. 20, 2000 FDA Minutes at 10; Paper 36, PO
`Resp. at 58; Ex. 2132, Ross Dep. 103:11-24.
`
`Sandoz DX -123
`
`
`
`Purported Skepticism: FDA Statements
`
`Ex. 1093, Ross Decl. ¶28.
`
`Sandoz DX -124
`
`
`
`Purported Skepticism: FDA Statements
`
`Ex. 1093, Ross Decl. ¶28.
`
`Sandoz DX -125
`
`
`
`Purported Skepticism: Wall Street Journal Article
`
`. . .
`
`Paper 49, Sandoz Reply 26-27; Ex. 1074, Chabner Dep. Tr. 182:15-183:14, 282:8-15, 300:7-20
`
`Sandoz DX -126
`
`
`
`Dr. Chabner’s Testimony
`
`Paper 49, Sandoz Reply 22-23; Ex. 1074, 146:6-15, 300:21-303:8
`
`Sandoz DX -127
`
`
`
`Dr. Chabner’s Testimony
`
`Paper 49, Sandoz Reply 22-23; Ex. 1074, 67:10-17, 309:20-310:20; see also id. at 62:5-64:1
`
`Sandoz DX -128
`
`
`
`Motion to Exclude: Dr. Niyikiza’s Hearsay Testimony
`
`• 9/30/16: PO Resp. filed
`
`• 10/10/16: Sandoz
`requests deposition of
`Dr. Niyikiza
`
`• 11/9/16: Sandoz files
`motion for deposition of
`Dr. Niyikiza (Paper 43),
`which was not ruled on
`
`• 2/14/17: Sandoz files
`motion to exclude
`(Papers 64, 77)
`
`Paper 36, PO Resp. at 57 (citing Ex. 2116,
`Niyikiza Trial Tr. (Lilly v. Teva))
`
`Sandoz DX -129
`
`
`
`Motion to Exclude: Dr. Niyikiza’s Hearsay Testimony
`
`• Exemplary hearsay statement
`
`• Exemplary district court reasoning for allowing such hearsay
`
`Ex. 2116, Niyikiza Trial Tr. (Lilly v. Teva) at 845
`cited by (Paper 36, PO Resp. at 59)
`
`Ex. 2116, Niyikiza Trial Tr. (Lilly v. Teva), 722:25-723:6.
`
`Sandoz DX -130
`
`
`
`Motion to Exclude: Dr. Zeisel’s Testimony
`
`• Agreed definition of POSA:
`
`Ex. 2120, Chabner Decl. ¶23; Paper 64 at 12
`
`• Dr. Zeisel’s background:
`
`Ex. 1086, Zeisel Dep. 118:15, 128:19; see also 61:6-7.
`
`• Dr. Zeisel’s opinions:
`
`Ex. 2118, Zeisel Decl. ¶¶46, 53
`
`Sandoz DX -131
`
`. . .
`
`. . .
`
`
`
`Prior Art Disclosures
`NUTRITION + ONCOLOGY
`
`Sandoz DX -132
`
`
`
`History: Nutrition + Antifolates
`
`Ex. 2137, Stover Dep. Tr. 11:17-12:6.
`
`Sandoz DX -133
`
`
`
`Nutrition + Antifolates: Lilly Statements
`
`Lilly’s 2000 Letter to FDA
`
`’209 Patent
`
`Ex. 1001, ‘209 Patent, col. 2, ll. 20-24; Paper 42,
`Sandoz Reply at 14-15.
`
`Ex. 1076, Feb. 2000 Letter Lilly to FDA at
`ELAP00013782.
`
`Sandoz DX -134
`
`
`
`Nutrition + Oncology: Dr. Stover’s Testimony
`
`Ex. 2137, Stover Dep. Tr. 26:9-22; .
`
`Ex. 2137, Stover Dep. Tr. 23:20-24:7.
`
`Ex. 2137, Stover Dep. Tr. 22:4-14.
`
`Ex. 2137, Stover Dep. 109:5-19; Paper 71, Resp. Observation at 3-5.
`
`Ex. 2137, Stover Dep. Tr. 25:21:26:2.
`
`Sandoz DX -135
`
`
`
`Dr. Schiff’s Testimony Regarding Overlap Between
`Nutrition and Oncology
`
`Ex. 2126, Schiff Dep. 43:12-44:22 .
`
`Sandoz DX -136
`
`
`
`Lilly’s Arguments
`
`METHYL TRAP + FOLIC ACID AS AN
`“ANTIDOTE” TO ANTIFOLATES
`
`Sandoz DX -137
`
`
`
`Methyl Trap: Results in decreased total tissue folate levels
`
`Ex. 1108, Shane at 122, 124; Ex. 1091, Stover Reply ¶¶29-30
`
`Ex. 1091, Stover Reply ¶¶29-30
`
`
`
`138Sandoz DX -
`
`
`
`Methyl Trap: Drs. Schiff and Stover’s Testimony
`
`Ex. 1075, Schiff Reply, ¶99
`
`Ex. 2137, Stover Dep. 215:4-217:20;
`Ex. 1091, Stover Reply ¶¶ 29-30; Ex. 1108,
`Shane, 122, 124; see also Paper 68, Patent
`Owner’s Sur-reply at 6-7
`
`Ex. 2126, Schiff Dep. 83:6-14; see also
`Paper 68, Sur-reply at 6-7
`
`
`
`139Sandoz DX -
`
`
`
`Lilly’s Antidote Argument: Dr. Stover’s Testimony Regarding
`Differences in Folate Catabolism
`
`Lilly’s Argument:
`
`Paper 68, Patent Owner’s Sur-reply at 7
`
`Ex. 2137, Stover Dep. 49:16-50:9 see also Ex. 1091, Stover
`Reply ¶ 22; Ex. 1112, Kelly, 305; Ex. 1113, Meenan, 1165, 1167
`
`Sandoz DX -140
`
`
`
`Lilly’s Antidote Argument: Dr. Stover’s Testimony Regarding
`Differences in Folate Catabolism
`
`Ex. 1091, Stover Reply ¶ 22
`
`Sandoz DX -141
`
`
`
`Lilly’s Antidote Argument: Dr. Stover’s Testimony Regarding
`Differences in Folate Catabolism
`
`Ex. 1113, Meenan, 1165, 1167; Ex. 1091, Stover Reply ¶ 22
`
`Sandoz DX -142
`
`
`
`Lilly’s Antidote Argument: Dr. Stover’s Testimony Regarding
`Binding Affinities
`
`Ex. 1091, Stover Reply ¶ 20
`
`Sandoz DX -143
`
`
`
`Claim Construction
`
`“PATIENT”
`
`Sandoz DX -144
`
`
`
`Claim Construction of “Patient”: Overview of Proposed
`Constructions
`
`Term
`
`Patient
`
`Sandoz’s Construction
`
`Lilly’s Construction
`
`“mammal,” i.e., all
`mammals, not limited to
`humans
`
`“human undergoing
`medical treatment”
`
`Paper 2, Petition 18-19.
`
`Sandoz DX -145
`
`
`
`Claim Construction of “Patient”: Claims
`
`Compare Ex. 1001, ‘209 patent, col. 6, ll. 35-49 with Ex. 1, claims 6-8; Ex. 1004, Schiff Decl. ¶¶19-22.
`
`Sandoz DX -146
`
`
`
`Claim Construction of “Patient”: Institution
`
`Paper 14, Institution Decision, 9, 17-18.
`
`Sandoz DX -147
`
`
`
`Claim Construction of “Patient”: Specification
`
`Ex. 1001, ‘209 patent, col. 4, ll. 9-16, col. 6, ll. 35-47 ; Ex. 1004, Schiff Decl. ¶¶19-20.
`
`Sandoz DX -148
`
`
`
`Claim Construction of “Patient”: Specification
`
`Ex. 1001, ‘209 patent, col. 3, ll. 1-37; Ex. 1004, Schiff Decl. ¶¶19-20.
`
`Sandoz DX -149
`
`
`
`Prior Litigation in the S.D. Ind.
`Eli Lilly & Co. v. Teva
`Parenteral Meds., Inc. (Fed. Cir.
`2017)
`
`Sandoz DX -150
`
`
`
`Lilly v. Teva (Fed. Cir.): Folate Combination
`
`Federal Circuit Analysis
`
`Slip op. at 26
`
`Sandoz DX -151
`
`
`
`Lilly v. Teva (Fed. Cir.): B12 Combination
`
`Federal Circuit Analysis
`
`Slip op. at 26-27
`
`Sandoz DX -152
`
`
`
`Lilly v. Teva (Fed. Cir.): B12 Combination (cont’d)
`
`Federal Circuit Analysis
`(Niyikiza abstracts)
`
`Slip op. at 26-27
`
`Sandoz DX -153
`
`
`
`Lilly v. Teva (Fed. Cir.): Dosages
`
`Federal Circuit Analysis
`
`Slip op. at 26-27
`
`Sandoz DX -154
`
`
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