IPR2020-00324
`Patent 8,114,833 B2
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`______________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`______________
`
`MYLAN INSTITUTIONAL LLC and PFIZER INC.,
`Petitioners,
`
`v.
`
`NOVO NORDISK A/S,
`Patent Owner.
`______________
`
`Case IPR2020-003241
`Patent 8,114,833
`______________
`
`PATENT OWNER’S DEMONSTRATIVE EXHIBITS
`
`1 IPR2020-01252 has been joined with this proceeding.
`
`

`

`IPR2020-00324*
`Mylan Institutional LLC v. Novo Nordisk A/S
`
`*IPR2020-01252 has been joined with this proceeding
`
`PATENT OWNER’S PRESENTATION
`MARCH 26, 2021
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`1
`
`

`

`The ’833 Patent
`
`“[T]he peptide to be included in the formulation of the
`invention is a GLP-1 agonist”
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Ex1001 at 1; col. 4, ll. 25-26; Paper 25 at 5, 9
`
`2
`
`

`

`GLP-1 Was Known to Be Difficult to Formulate
`
`“GLP-1…is a
`very difficult
`molecule to
`handle in
`solution.”
`
`“While much attention has been
`focused on the pharmacological
`properties of acylated GLP-1
`compounds, hitherto little is known
`about their physico-chemical and
`solution structural properties.”
`
`Ex1004 at 3, ll. 7-9
`
`Ex2011 at 1
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Ex2022 at ¶52; Paper 25 at 5
`
`3
`
`

`

`Initial Formulations Focused on Stability – Flink Reference
`
`“We have discovered that certain modified
`GLP-1 or analogues thereof when
`formulated in aqueous solution together
`with a buffer, are physically stable at high
`concentrations of the modified GLP-1 or
`analogues thereof, when kept in the pH
`range from about 7 to about 10.”
`“In another aspect of the invention the
`formulation has a pH from 7.5 to 10.”
`Ex1004 at 4, ll. 17-20; 5, l. 12
`
`“The chemical stability of
`modified GLP-1 can be
`significantly improved by
`the use of certain amino
`acids (charged-basic) and
`imidazole as stabilizers.”
`Ex1004 at 45, ll. 3-4
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Ex2022 at ¶¶112-113; Paper 25 at 2
`
`4
`
`

`

`The Problem Solved by the ’833 Patent
`
`Deposits and Clogging
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Ex1001, col.1, ll.30-49; Ex2022 at ¶88; Paper 25 at 1, 9-10
`
`5
`
`

`

`Propylene Glycol Was Known to Cause Hemolysis
`
`Remington’s 1990 (Ex1013)
`“The usual practice is to add either sodium chloride or
`dextrose to adjust hypotonic parenteral solutions to
`isotonicity. Certain solutes, including …propylene glycol,
`cause hemolysis even when they are present in a
`concentration that is isoosmotic and such solutions obviously
`are not isotonic.”
`
`Ex1013 at 311
`
`Hammarlund (Ex2033)
`Reproduction of Table 1 Insert
`Substance
`Iso-osmotic
`Hemolysis,
`Concentration, %
`%
`
`Approx.
`pH
`
`Propylene
`Glycol
`Quinine and
`urea HCl N.F.
`Racephedrine
`HCl N.F.
`
`2.00
`
`4.50
`
`3.07
`
`100
`
`64
`
`94
`
`5.5
`
`2.9
`
`5.7
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Ex2033 at 3-4
`
`Ex2022 at ¶¶71-72; Paper 25 at 8-9
`
`6
`
`

`

`Propylene Glycol Was Known to Cause Hemolysis
`
`Akers (Ex1067)
`
`“a commonly used parenteral cosolvent,
`propylene glycol…was found to produce a large
`hemolytic response”
`
`Ex2036 at 1
`
`Fu (Ex2036)
`
`“solutions most prone to elicit a hemolytic
`response were those containing propylene glycol”
`
`Ex1067 at 3
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Ex2022 at ¶¶68, 72; Paper 25 at 8-9
`
`7
`
`

`

`Propylene Glycol Was Known to Cause Hemolysis and Pain on
`Injection
`
`Doenicke (Ex2016)
`
`Ex2016 at 3
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Ex2022 at ¶69; Paper 25 at 8-9
`
`8
`
`

`

`Propylene Glycol Was Unexpectedly the Best Candidate
`
`Isotonicity Agent
`
`Drop Test
`
`Clogging
`Test
`
`Simulated
`Filling Test
`
`Reducing
`Saccharide
`
`Physical Stability
`Test
`
`Chemical
`Stability Test
`
`Antimicrobial
`Preservative Test
`
`X
`X
`X
`
`Propylene Glycol
`Mannitol
`Arginine
`Myo-inositol
`Maltose
`Lactose
`Dimethylsulfon
`Glycine
`Sucrose
`Sorbitol
`Glucose
`Glycerol
`Xylitol
`PEG 400
`
`X
`X
`X
`X
`X
`X
`X
`X
`X
`X
`X
`X
`X
`
`X
`X
`X
`
`X
`X
`X
`X
`X
`
`X
`
`X
`X
`
`X
`X
`
`X = negative finding
`
`Ex2022 at ¶¶104-105; Paper 25 at 10-13, 45-48
`
`X
`
`X
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`9
`
`

`

`The Claims of the ’833 Patent
`
`Group 1
`(claims 1-15)
`
`Formulations containing propylene glycol,
`disodium phosphate dihydrate
`
`Group 2
`(claims 16-22)
`
`Methods of preparing formulations
`
`Group 3
`(claims 23-31)
`
`Methods of reducing deposits and clogging
`by replacing the previously-used isotonicity
`agent with propylene glycol
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Ex2022 at ¶86; Paper 25 at 13
`
`10
`
`

`

`Claim Construction
`
`• The preambles of claim
`23, 26, and 29 recite
`methods for reducing
`deposits or clogging
`• These preambles should
`be construed as express
`limitations
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Ex2022 at ¶¶108-110; Paper 25 at 13-15
`
`11
`
`

`

`Claim Construction
`
`• Preamble is limiting when it:
`• Describes the “essence of the invention”
`• Maintains claim differentiation (without it,
`the claims become identical)
`• Provides antecedent basis for subsequent
`limitations
`• All three of these factors are present here
`
`Ex2022 at ¶¶108-110; Paper 25 at 13-15
`
`The District Court presiding over the
`pending litigation between the
`parties has construed the preambles
`of claims 23, 26, and 29 to be
`express limitations.
`
`Paper 25 at 13; Ex2082
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`12
`
`

`

`Petitioners’ Ground 1: Anticipation By Flink
`
`A reference does not anticipate unless it “discloses within the four
`corners of the document not only all of the limitations claimed but also
`all of the limitations arranged or combined in the same way as
`recited in the claim.”
`
`• Net MoneyIN, Inc. v. VeriSign, Inc., 545 F.3d 1359, 1371 (Fed. Cir. 2008)
`
`A reference that does not expressly disclose the complete invention as
`claimed can anticipate only under narrow circumstances: if a skilled
`artisan, “reading the reference, would ‘at once envisage,’” or
`“immediately envisage,” the claimed subject matter.
`
`• Kennametal, Inc. v. Ingersoll Cutting Tool Co., 780 F.3d 1376, 1381-82, (Fed. Cir. 2015); Wm. Wrigley Jr.
`Co. v. Cadbury Adams USA, LLC, 683 F.3d 1356, 1361 (Fed. Cir. 2012)
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Paper 25 at 16-18
`
`13
`
`

`

`Petitioners’ Ground 1: Anticipation By Flink
`
`To anticipate, a reference must clearly, unequivocally disclose
`the claimed invention without any need for picking, choosing,
`and combining various disclosures that are not directly related
`to each other by the teachings of the cited reference.
`
`• Akzo v. ITC, 808 F.2d 1471, 1480 (Fed. Cir. 1986); In re Arkley, 455 F.3d 586, 587 (CCPA 1972)
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Paper 25 at 25-26
`
`14
`
`

`

`Flink Does Not Anticipate Claims 1-15 of the ’833 Patent
`
`Flink
`
` Propylene glycol is mentioned once, as an example of one
`of six possible genuses of chemicals (polyhydric alcohol)
` The members of the six genuses present a skilled artisan
`with a broad choice of chemicals
` Propylene glycol is not mentioned in any exemplary
`formulation or in any claims
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`15
`
`Ex1004 at 19, l. 33-20, l. 9; Ex 2022 at ¶¶133-142; Paper 25 at 16, 19-21
`
`

`

`The Formulations in Flink Used Only Mannitol or Glycerol
`
`Flink’s Examples
`• Mannitol: 20 formulations
`• Glycerol: 10 formulations
`• Other Agents: 0 formulations
`Flink’s “Typical” Formulations
`• Mannitol: 55 formulations
`• Glycerol: 23 formulations
`• Other Agents: 0 formulations
`
`• Every formulation in Flink that
`contains an isotonic agent
`uses mannitol or glycerol
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Ex1004 at 27, l. 28-35, l. 29; 38-46; Ex2022 at ¶141; Paper 25 at 16
`
`16
`
`

`

`Flink’s Genus Disclosures of Chemicals – Isotonicity Agents
`
`In a further embodiment of the invention the isotonic agent is selected from the
`group consisting of a salt (e.g. sodium chloride), a polyhydric alcohol (e.g.
`propyleneglycol, xylitol, mannitol, sorbitol or glycerol), a monosaccharide (e.g.
`glucose or maltose), a disaccharide (e.g. sucrose), an amino acid (e.g. L-
`glycine, L-histidine, arginine, lysine, isoleucine, aspartic acid, tryptophan,
`threonine), polyethyleneglycol (PEG400), or mixtures thereof.
`
`6 broad genuses
`of chemicals with
`18 examples +
`mixtures
`
`In a further embodiment of the invention the isotonic agent is selected from the
`group consisting of sodium chloride, glycerol, mannitol, glucose, sucrose,
`L-glycine, L-histidine, arginine, lysine or mixtures thereof. Each one of these
`specific isotonic agents constitutes an alternative embodiment of the invention.
`
`9 specific
`compounds +
`mixtures
`
`In a preferred embodiments of the invention the isotonic agent is mannitol or
`glycerol.
`
`Preferred
`isotonicity agents
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`17
`
`Ex1004 at 19, l. 33-20, l. 9; Ex 2022 at ¶¶133-142; Paper 25 at 16, 19-21
`
`

`

`Flink’s Genus Disclosures of Chemicals – Buffers
`
`In a further embodiment of the invention the buffer is selected
`from the group consisting of sodium acetate, sodium
`carbonate, citrate, glycylglycine, histidine, glycine, lysine,
`arginin, sodium dihydrogen phosphate, disodium hydrogen
`phosphate, sodium phosphate, and tris(hydroxymethyl)-
`aminomethane, or mixtures thereof. Each one of these specific
`buffers constitutes an alternative embodiment of the invention.
`
`12 chemicals,
`some of which are
`genuses +
`mixtures
`
`Disodium phosphate dihydrate is not listed in this disclosure
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Ex1004 at 18, ll. 27-33; Ex2022 at ¶¶147-148; Paper 25 at 21-23
`
`18
`
`

`

`At Least 216 Combinations of Buffer and Isotonicity Agent in Flink
`
`NaCl
`
`Propylene
`Glycol
`
`Xylitol Mannitol
`
`Sorbitol
`
`Glycerol
`
`Glucose Maltose
`
`Sucrose
`
`Glycine
`
`Histidine
`
`Arginine
`
`Lysine
`
`Iso-
`leucine
`
`Aspartic
`Acid
`
`Tryptophan
`
`Threonine
`
`Sodium
`Acetate
`Sodium
`Carbonate
`Citrate
`
`1
`
`19
`
`2
`
`20
`
`3
`
`21
`
`4
`
`22
`
`5
`
`23
`
`6
`
`24
`
`7
`
`25
`
`8
`
`26
`
`9
`
`27
`
`10
`
`28
`
`11
`
`29
`
`12
`
`30
`
`48
`
`13
`
`31
`
`49
`
`14
`
`32
`
`50
`
`15
`
`33
`
`51
`
`16
`
`34
`
`52
`
`17
`
`35
`
`53
`
`PEG-
`400
`
`18
`
`36
`
`54
`
`37
`
`55
`
`73
`
`38
`
`56
`
`74
`
`39
`
`57
`
`75
`
`40
`
`58
`
`76
`
`41
`
`59
`
`77
`
`42
`
`60
`
`78
`
`43
`
`61
`
`79
`
`Glycylglycine
`
`Histidine
`
`Glycine
`
`44
`
`62
`
`80
`
`98
`
`45
`
`63
`
`81
`
`99
`
`46
`
`64
`
`82
`
`100
`
`47
`
`65
`
`83
`
`101
`
`66
`
`84
`
`102
`
`67
`
`85
`
`103
`
`68
`
`86
`
`104
`
`69
`
`87
`
`105
`
`70
`
`88
`
`106
`
`71
`
`89
`
`107
`
`72
`
`90
`
`108
`
`Lysine
`
`Arginin
`
`91
`
`109
`
`127
`
`92
`
`110
`
`128
`
`93
`
`111
`
`129
`
`147
`
`94
`
`112
`
`130
`
`148
`
`95
`
`113
`
`131
`
`149
`
`96
`
`114
`
`132
`
`150
`
`97
`
`115
`
`133
`
`151
`
`116
`
`134
`
`152
`
`117
`
`135
`
`153
`
`118
`
`136
`
`154
`
`119
`
`137
`
`155
`
`120
`
`138
`
`156
`
`121
`
`139
`
`157
`
`122
`
`140
`
`158
`
`123
`
`141
`
`159
`
`124
`
`142
`
`160
`
`125
`
`143
`
`161
`
`126
`
`144
`
`162
`
`Sodium
`Dihydrogen
`Phosphate
`Disodium
`Hydrogen
`Phosphate
`Sodium
`Phosphate
`Tris(hydroxy
`methyl)-
`aminomethan
`
`145
`
`146
`
`163
`
`181
`
`199
`
`164
`
`182
`
`200
`
`165
`
`183
`
`201
`
`166
`
`184
`
`202
`
`167
`
`185
`
`203
`
`168
`
`186
`
`204
`
`169
`
`187
`
`205
`
`170
`
`188
`
`206
`
`171
`
`189
`
`207
`
`172
`
`190
`
`208
`
`173
`
`191
`
`209
`
`174
`
`192
`
`210
`
`175
`
`193
`
`211
`
`176
`
`194
`
`212
`
`177
`
`195
`
`213
`
`178
`
`196
`
`214
`
`179
`
`197
`
`215
`
`180
`
`198
`
`216
`
`Omits formulations with no isotonicity agent or with “mixtures” of isotonicity agents or buffers
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Ex1004 at 18, l.27-20, l. 9;
`Paper 45 at 1, 5
`
`19
`
`

`

`At Least 216 Combinations of Buffer and Isotonicity Agent in Flink
`
`NaCl
`
`Propylene
`Glycol
`
`Xylitol Mannitol
`
`Sorbitol
`
`Glycerol
`
`Glucose Maltose
`
`Sucrose
`
`Glycine
`
`Histidine
`
`Arginine
`
`Lysine
`
`Iso-
`leucine
`
`Aspartic
`Acid
`
`Tryptophan
`
`Threonine
`
`Sodium
`Acetate
`Sodium
`Carbonate
`Citrate
`
`1
`
`19
`
`2
`
`20
`
`3
`
`21
`
`4
`
`22
`
`5
`
`23
`
`6
`
`24
`
`7
`
`25
`
`8
`
`26
`
`9
`
`27
`
`10
`
`28
`
`11
`
`29
`
`12
`
`30
`
`48
`
`13
`
`31
`
`49
`
`14
`
`32
`
`50
`
`15
`
`33
`
`51
`
`16
`
`34
`
`52
`
`17
`
`35
`
`53
`
`PEG-
`400
`
`18
`
`36
`
`54
`
`37
`
`55
`
`73
`
`38
`
`56
`
`74
`
`39
`
`57
`
`75
`
`40
`
`58
`
`76
`
`41
`
`59
`
`77
`
`42
`
`60
`
`78
`
`43
`
`61
`
`79
`
`Glycylglycine
`
`Histidine
`
`Glycine
`
`44
`
`62
`
`80
`
`98
`
`45
`
`63
`
`81
`
`99
`
`46
`
`64
`
`82
`
`100
`
`47
`
`65
`
`83
`
`101
`
`66
`
`84
`
`102
`
`67
`
`85
`
`103
`
`68
`
`86
`
`104
`
`69
`
`87
`
`105
`
`70
`
`88
`
`106
`
`71
`
`89
`
`107
`
`72
`
`90
`
`108
`
`Lysine
`
`Arginin
`
`91
`
`109
`
`127
`
`92
`
`110
`
`128
`
`93
`
`111
`
`129
`
`147
`
`94
`
`112
`
`130
`
`148
`
`95
`
`113
`
`131
`
`149
`
`96
`
`114
`
`132
`
`150
`
`97
`
`115
`
`133
`
`151
`
`116
`
`134
`
`152
`
`117
`
`135
`
`153
`
`118
`
`136
`
`154
`
`119
`
`137
`
`155
`
`120
`
`138
`
`156
`
`121
`
`139
`
`157
`
`122
`
`140
`
`158
`
`123
`
`141
`
`159
`
`124
`
`142
`
`160
`
`125
`
`143
`
`161
`
`126
`
`144
`
`162
`
`Sodium
`Dihydrogen
`Phosphate
`Disodium
`Hydrogen
`Phosphate
`Sodium
`Phosphate
`Tris(hydroxy
`methyl)-
`aminomethan
`
`145
`
`146
`
`163
`
`181
`
`199
`
`164
`
`182
`
`200
`
`165
`
`183
`
`201
`
`166
`
`184
`
`202
`
`167
`
`185
`
`203
`
`168
`
`186
`
`204
`
`169
`
`187
`
`205
`
`170
`
`188
`
`206
`
`171
`
`189
`
`207
`
`172
`
`190
`
`208
`
`173
`
`191
`
`209
`
`174
`
`192
`
`210
`
`175
`
`193
`
`211
`
`176
`
`194
`
`212
`
`177
`
`195
`
`213
`
`178
`
`196
`
`214
`
`179
`
`197
`
`215
`
`180
`
`198
`
`216
`
`NO COMBINATIONS ARE SPECIFIC TO THE DIHYDRATE FORM OF DISODIUM HYDROGEN PHOSPHATE
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Ex1004 at 18, l.27-20, l. 9;
`Paper 45 at 1, 5
`
`20
`
`

`

`Illustration of Mylan’s Picking-and-Choosing from Flink
`Isotonic Agents:
`Buffers:
`Pages 19-20: a salt (e.g. sodium chloride), a polyhydric alcohol (e.g.
`propyleneglycol, xylitol, mannitol, sorbitol or glycerol), a monosaccharide
`(e.g. glucose or maltose), a disaccharide (e.g. sucrose), an amino acid
`(e.g. L-glycine, L-histidine, arginine,
`lysine,
`isoleucine, aspartic acid,
`tryptophan, threonine), polyethyleneglycol (PEG400), or mixtures thereof
`Pages 19-20: sodium chloride, glycerol, mannitol,
`glucose, sucrose, L-glycine, L-histidine, arginine,
`lysine or mixtures thereof.
`
`“Long List:”
`
`“Short List:”
`
`Page 18: sodium acetate, sodium carbonate, citrate, glycylglycine,
`histidine, glycine, lysine, arginin, sodium dihydrogen phosphate, disodium
`hydrogen phosphate,
`sodium phosphate, and tris(hydroxymethyl)-
`aminomethane, or mixtures thereof
`
`N/A
`
`Page 20: mannitol and glycerol
`
`Preferred
`Embodiments:
`
`Page 18: glycylglycine, sodium dihydrogen phosphate,
`disodium hydrogen phosphate, or mixtures thereof
`
`Pages 27-35: 55 mannitol and 23 glycerol
`
`Typical
`Formulations:
`
`Pages 27-35: 48 disodium hydrogen phosphate (anhydrous),
`12
`disodium hydrogen
`phosphate/sodium dihydrogen
`phosphate, 12 glycine, 6 glycylglycine
`
`Pages 38-46: 20 mannitol and 10 glycerol
`
`Examples:
`
`Pages 38-46: 12 disodium hydrogen phosphate (anhydrous),
`7
`disodium hydrogen
`phosphate/sodium dihydrogen
`phosphate, 2 glycine, 2 glycylglycine,
`9 disodium hydrogen phosphate dihydrate
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Paper 25 at 16-23; Ex1077 at 80:3-15
`
`21
`
`

`

`Kennametal v. Ingersoll is Inapposite
`
`Kennametal
`Options
`
`1. Tungsten
`2. Iron
`3. Nickel
`4. Ruthenium
`5. Rhenium
`
`X
`
`1. Chemical Vapor
`Deposition
`2. Moderate
`Temperature Chemical
`Vapor Deposition
`3. Physical Vapor
`Deposition
`
`= 15
`
`Flink Options
`
`X
`
`1. Sodium Acetate
`2. Sodium Carbonate
`3. Citrate
`4. Glycylglycine
`5. Histidine
`6. Glycine
`7. Lysine
`8. Arginin
`9. Sodium Dihydrogen Phosphate
`10. Disodium Hydrogen Phosphate
`11. Sodium Phosphate
`12. Tris(hydroxymethyl)-
`aminomethan
`
`1. Sodium Chloride
`2. Propylene Glycol
`3. Xylitol
`4. Mannitol
`5. Sorbitol
`6. Glycerol
`7. Glucose
`8. Maltose
`9. Sucrose
`10. L-glycine
`11. L-histidine
`12. Arginine
`13. Lysine
`14. Isoleucine
`15. Aspartic Acid
`16. Tryptophan
`17. Threonine
`18. PEG400
`
`= 216
`
`Kennametal, Inc. v. Ingersoll Cutting Tool Co., 780 F.3d 1376, 1382 (Fed. Cir. 2015)
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Paper 11 at 32; Paper 25 at 27-30
`
`22
`
`

`

`Wrigley v. Cadbury is Inapposite
`
`Wrigley
`Options
`
`16. Menthone
`17. Alpha-ionone
`18. Ethyl Vanillin
`19. Limonene
`20. Isoamylacetate
`21. Benzaldehyde
`22. Thymol
`23. Ethylbutyrate
`
`1. Anise
`2. Cassia
`3. Clove
`4. Dihydroanethole
`5. Estragole
`6. Eucalyptol
`7. Menthol
`7. Menthol
`8. Spearmint
`9. Peppermint
`10. Oxanone
`Federal Circuit found
`11. Phenyl Ethyl Alcohol
`menthol was “extremely
`12. Sweet Birch
`well known in the prior
`13. Eugenol
`art for its inclusion in a
`cooling gum.”
`14. Methyl Salicylicate
`15. Cinnamic aldehyde
`
`X
`
`1. WS-3
`2. WS-23
`3. TK-10
`
`Flink Options
`
`X
`
`1. Sodium Acetate
`2. Sodium Carbonate
`3. Citrate
`4. Glycylglycine
`5. Histidine
`6. Glycine
`7. Lysine
`8. Arginin
`9. Sodium Dihydrogen Phosphate
`10. Disodium Hydrogen Phosphate
`11. Sodium Phosphate
`12. Tris(hydroxymethyl)-
`aminomethan
`
`1. Sodium Chloride
`2. Propylene Glycol
`3. Xylitol
`4. Mannitol
`5. Sorbitol
`6. Glycerol
`7. Glucose
`8. Maltose
`9. Sucrose
`10. L-glycine
`11. L-histidine
`12. Arginine
`13. Lysine
`14. Isoleucine
`15. Aspartic Acid
`16. Tryptophan
`17. Threonine
`18. PEG400
`
`= 216
`
`Wm. Wrigley Jr. Co. v. Cadbury Adams USA, LLC, 683 F.3d 1356, 1362 (Fed. Cir. 2012)
`
`Paper 11 at 31-32; Paper 25 at 27-30
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`23
`
`

`

`Wrigley Teaches Focus on Preferred Agents
`
`Wm. Wrigley at 1362
`
`• Wrigley teaches use of agents identified
`as “particularly preferred” or “most
`suitable”
`• In Flink, these do not include propylene
`glycol or disodium phosphate dihydrate
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Paper 11 at 31-32; Paper 25 at 27-30
`
`24
`
`

`

`Perricone v. Medicis is Inapposite
`
`Perricone
`Options
`
`1. Retinoic Acid
`2. Retinyl Palmitate
`3. Ascorbic Acid
`4. Ascorbyl Palmitate
`5. Tocopherol
`6. Tocopherol acetate
`7. Pyroglutamic acid
`8. Amino Acids
`9. Sunscreens
`10. Hyaluronic acid
`11. Perfluoropolyether
`12. Hydrocortisone acetate
`13. A 2-hydroxyalkanoic acid
`14. Mixtures thereof
`
`= 14
`
`Flink Options
`
`X
`
`1. Sodium Acetate
`2. Sodium Carbonate
`3. Citrate
`4. Glycylglycine
`5. Histidine
`6. Glycine
`7. Lysine
`8. Arginin
`9. Sodium Dihydrogen Phosphate
`10. Disodium Hydrogen Phosphate
`11. Sodium Phosphate
`12. Tris(hydroxymethyl)-
`aminomethan
`
`1. Sodium Chloride
`2. Propylene Glycol
`3. Xylitol
`4. Mannitol
`5. Sorbitol
`6. Glycerol
`7. Glucose
`8. Maltose
`9. Sucrose
`10. L-glycine
`11. L-histidine
`12. Arginine
`13. Lysine
`14. Isoleucine
`15. Aspartic Acid
`16. Tryptophan
`17. Threonine
`18. PEG400
`
`= 216
`
`Perricone v. Medicis Pharmaceutical Corp., 432 F.3d 1368, 1376 (Fed. Cir. 2005)
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Paper 25 at 27-30
`
`25
`
`

`

`Flink Teaches Using Mannitol at pH 7.4
`
`Example 4
`
` Flink teaches
`formulations with
`mannitol at different pH
`values, including 7.4
` 6 exemplary formulations
`of Flink use mannitol at
`pH 7.4
`
`Paper 11 at 40-41; Ex2022 at ¶218
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Ex1004 at 41
`
`26
`
`

`

`Claim 14 of Flink Does Not Anticipate the ’833 Patent Claims
`Petitioners’ Flink Claim 14 Chain of Dependencies
`Claim 5: A pharmaceutical formulation comprising an aqueous solution of a GLP-1 compound, and a buffer, wherein
`said GLP-1 compound is GLP-1 (7-37) or an analogue thereof wherein an amino acid residue of the parent peptide
`has a lipophilic substituent attached optionally via a spacer, wherein said GLP-1 compound is present in a
`concentration from 0.1 mg/ml to 100 mg/ml, and wherein said formulation has a pH from 7.0 to 10; provided that if
`an isotonic agent is present and pH is 7.4 then mannitol or NaCl is not the isotonic agent.
`Claim 6: The formulation according to claim 5, wherein said GLP-1 compound is present in a concentration from 1
`mg/ml to 100 mg/ml.
`Claim 8: The formulation according to any one of claims 4 and 6, wherein said formulation has a pH from 7.5 to 10.
`Claim 10: The formulation according to any one of claims 2, 4, 6 and 8, wherein the GLP-1 compound is present in a
`concentration from 1mg/ml to 80mg/ml, 1mg/ml to 50mg/ml, 1mg/ml to 20mg/ml, 1mg/ml to 10mg/ml, typically
`from 1-5mg/ml.
`Claim 11: The formulation according to any one of claims 1-10, further comprising a preservative.
`Claim 12: The formulation according to claim 11 , wherein said preservative is present in a concentration from
`0.1mg/ml to 20mg/ml.
`Claim 13: The formulation according to any one of claims 1-12, further comprising an isotonic agent.
`Claim 14: The formulation according to claim 13, wherein said isotonic agent is present in a concentration from
`1mg/ml to 50mg/ml.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Ex1002 at ¶149; Paper 11 at 19-25; Paper 25 at 18
`
`27
`
`

`

`Claim 14 of Flink Does Not Anticipate the ’833 Patent Claims
`Contrast to Claim 1 of the ’833 Patent
`Petitioner’s Flink Claim 14 Chain of Dependencies
`In Claim 14
`Chain?
`
`’833 Claim 1 Limitations
`
`A pharmaceutical formulation
`comprising at least one GLP-1 agonist,
`
`a disodium phosphate dihydrate buffer
`
`and propylene glycol
`wherein said propylene glycol is present in said
`formulation in a final concentration of from about 1
`mg/ml to about 100 mg/ml
`and wherein said formulation has a pH of from about
`7.0 to about 10.0.
`
`NO
`NO
`
`NO
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Ex1002 at ¶149; Paper 11 at 19-25; Paper 25 at 18-23, 31-32
`
`28
`
`

`

`The Web of Dependencies Stemming From Claim 14 of Flink
`
`There are 60
`possible chains of
`dependency
`stemming from claim
`14 of Flink
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Ex1004 at claims 1-14; Paper 11 at 19-25; Paper 45 at 1
`
`29
`
`

`

`No Teaching in Flink that Propylene Glycol and Disodium Phosphate
`Dihydrate are Compatible
`
`“However, the prohibition from picking, choosing, and combining
`disclosures involves scenarios where those combined disclosures
`are not directly related to each other by the teachings of the cited
`reference.”
`
`Paper 13, at 16-17
`
`Example 7
`• Directed to use of stabilizers
`• Petitioners combine this with a
`disclosure that is “not directly
`related”
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Ex2022 at ¶¶150, 152; Paper 25 at 24-27; Paper 45 at 10
`
`30
`
`

`

`Flink Does Not Disclose a Concentration of Propylene Glycol
`
`Ex1001 at col. 22, claims 3-4
`
`“Q: And there’s no description
`in Flink of a particular
`concentration for propylene
`glycol because propylene
`glycol is only mentioned a
`single time in Flink, right?
`A. Well, it’s not necessary to
`give the exact
`concentration…he doesn’t give
`the concentration.”
`
`From the Deposition of Dr. Laird Forrest
`Ex 2079 at 119:20-120:17; Paper 25 at 31
`
`Ex 2022 at ¶¶142-144; Paper 25 at 30-32
`
`31
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`

`

`Flink Does Not Render Claims 1-15 of the ’833 Patent Obvious
`
`1. Flink does not motivate a POSA to select propylene glycol as an
`isotonicity agent
`2. Flink encourages a POSA to choose mannitol or glycerol as an
`isotonicity agent
`3. Flink does not motivate a POSA to select disodium phosphate
`dihydrate as a buffer
`4. Flink’s focus is on the stability of the active ingredient through
`pH and amino acid stabilizers
`
`Ex2022 at ¶¶176-192; Paper 25 at 35-43
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`32
`
`

`

`Commonly Used Isotonicity Agents in 2003
`Prior art taught using other compounds as isotonic agents – not propylene glycol
`
`Tonicity Agent
`Dextrose
`Glycerin
`Mannitol
`Potassium Chloride
`Sodium Chloride
`
`Ex2015 at 5-6
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Ex2022 at ¶¶58-60; Paper 25 at 7
`
`33
`
`

`

`Commonly Used Isotonicity Agents in 2003
`Prior art taught using other compounds as isotonic agents – not propylene glycol
`
`Ex1023 at 9
`
`Ex1023 at 12
`
`Ex1023 at 17
`
`Ex2022 at ¶¶58-60; Paper 25 at 7
`
`34
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`

`

`Propylene Glycol’s Membrane Permeability
`
`Patel & Newsham (Ex2039)
`
` Membrane permeability is
`why propylene glycol causes
`hemolysis
` No FDA-approved drug in the
`prior art using propylene
`glycol as an isotonicity agent
`
`Paper 25 at 8-9; Ex2022 at ¶¶68-79
`
`Ex2039 at 2; Ex2022 at ¶73
`Dr. Forrest’s Declaration:
`“Not all isosmotic solutions are also isotonic. For example, if
`a solute can freely diffuse through the membranes of red blood
`cells (RBCs), the osmolarity will rise within in the RBCs
`causing the swelling and possible rupture.” Ex1002 at ¶61; see also Ex2022 at ¶75
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`35
`
`

`

`Obviousness Based On Flink Requires Hindsight
`
`Without hindsight, a skilled artisan would not have:
`
`• Varied the isotonicity agents of Flink
`
`•
`
`•
`
`Ignored Flink’s 9 specific agents and 2 preferred agents
`(mannitol and glycerol)
`
`Ignored Flink’s list of preferred buffers that did not include
`disodium phosphate dihydrate
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Paper 25 at 20, 41-45
`
`36
`
`

`

`Petitioners’ References Regarding Mannitol Crystallization All Relate to
`Supersaturated Mannitol Solutions
`
`Epperson (Ex1009)
`
`Jacobs (Ex1011)
`
`Ex1009 at 1
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`37
`
`Ex1011 at 6
`
`Ex 2022 at ¶79; Paper 25 at 52-53; Paper 45 at 13-14
`
`

`

`Petitioners’ References Regarding Mannitol Crystallization All Relate to
`Supersaturated Mannitol Solutions
`
`Robblee (Ex1114)
`
`Jeffrey (Ex1115)
`
`Ex1115 at 1
`
`Ex1114 at 2
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`“Robblee and
`Jeffrey alone are
`very pertinent
`prior art that a
`POSA would
`consider.”
`
`Jan. 21, 2021 Deposition Transcript of
`Dr. Laird Forrest (Ex2096) at 148:25-149:11
`
`Paper 25 at 52-53; Paper 45 at 13-14
`
`38
`
`

`

`Propylene Glycol Was Unexpectedly the Best Candidate
`
`Isotonicity Agent
`
`Drop Test
`
`Clogging
`Test
`
`Simulated
`Filling Test
`
`Reducing
`Saccharide
`
`Physical Stability
`Test
`
`Chemical
`Stability Test
`
`Antimicrobial
`Preservative Test
`
`X
`X
`X
`
`Propylene Glycol
`Mannitol
`Arginine
`Myo-inositol
`Maltose
`Lactose
`Dimethylsulfon
`Glycine
`Sucrose
`Sorbitol
`Glucose
`Glycerol
`Xylitol
`PEG 400
`
`X
`X
`X
`X
`X
`X
`X
`X
`X
`X
`X
`X
`X
`
`X
`X
`X
`
`X
`X
`X
`X
`X
`
`X
`
`X
`X
`
`X
`X
`
`X = negative finding
`
`Ex2022 at ¶¶104-105; Paper 25 at 10-13, 45-48
`
`X
`
`X
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`39
`
`

`

`The Combination of Flink and Betz Does Not Render Claims 1-31 of
`the ’833 Patent Obvious
`
`Flink
`
`Betz
`
`Focus of the reference Prolonged GLP-1 stability
`during storage
`GLP-1 - a smaller, more flexible
`peptide
`Does not direct a POSA to use
`propylene glycol
`
`API Characteristics
`
`Propylene Glycol
`
`Preventing crystallization of hGH
`
`hGH - a larger, more rigid protein
`
`Directs a POSA to use propylene
`glycol as a stabilizer
`
`Mention of reduction
`of deposits/clogging? No
`pH of formulations
`pH of 7.0-10.0
`
`No
`
`pH of 6.1-6.3
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Ex2022 at ¶¶117-127, 211-222, 241;
`Paper 25 at 35-40, 52-58, 60-62
`
`40
`
`

`

`Betz Does Not Teach Any Problems with Mannitol
`
`Betz teaches mannitol as a preferred specific isotonicity
`agent
`
`Betz teaches propylene glycol as a stabilizer
`
`Example 2 does not show a replacement of mannitol with
`propylene glycol, let alone solve any problems by doing so
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Ex1005 at 6, 11, 17-18; Ex2022 at ¶¶117-127, 211-222; Paper 25 at 52-55
`
`41
`
`

`

`Example 2 of Betz
`Table 2: Composition of the final pharmaceutical formulations
`1
`2
`3
`4
`5
`6
`6.67 mg/ml
`6.67 mg/ml
`6.67 mg/ml
`6.67 mg/ml
`6.67 mg/ml
`6.67 mg/ml
`
`7
`6.67 mg/ml
`
`8
`6.67 mg/ml
`
`0.49 mg/ml
`
`0.49 mg/ml
`
`0.49 mg/ml
`
`0.49 mg/ml
`
`0.49 mg/ml
`
`0.49 mg/ml
`
`0.89 mg/ml
`
`0.89 mg/ml
`
`1.29 mg/ml
`
`1.29 mg/ml
`
`1.29 mg/ml
`
`1.29 mg/ml
`
`1.29 mg/ml
`
`1.29 mg/ml
`
`1.05 mg/ml
`
`1.05 mg/ml
`
`9.0 mg/ml
`
`9.0 mg/ml
`
`9.0 mg/ml
`
`9.0 mg/ml
`
`9.0 mg/ml
`
`9.0 mg/ml
`
`9.0 mg/ml
`
`9.0 mg/ml
`
`2.00 mg/ml
`
`2.00 mg/ml
`
`2.00 mg/ml
`
`2.00 mg/ml
`
`2.00 mg/ml
`
`2.00 mg/ml
`
`2.00 mg/ml
`
`2.00 mg/ml
`
`27.4 mg/ml
`
`25.0 mg/ml
`
`22.5 mg/ml
`
`15.2 mg/ml
`
`8.1 mg/ml
`
`---
`
`---
`
`---
`
`---
`1.0 mg/ml
`
`---
`2.0 mg/ml
`
`---
`3.0 mg/ml
`
`---
`6.0 mg/ml
`
`---
`9.0 mg/ml
`
`---
`12.4 mg/ml
`
`---
`15 mg/ml
`
`7.5 mg/ml
`7.5 mg/ml
`
`6.2
`
`6.2
`
`6.2
`
`6.2
`
`6.2
`
`6.2
`
`6.2
`
`6.2
`
`Formulation
`
`hGH
`Na2HPO4 x 7 H2O
`
`Na2HPO4 x 2 H2O
`
`Benzyl Alcohol
`
`Poloxamer 188
`
`Mannitol
`
`Glycine
`1,2-Propylene Glycol
`pH
`
`“The formulations stored at 2°C-8°C do not show crystallization during the test period, which is e.g. 3 months
`for formulations 1 and 3, 12 months for formulations 4, 5, and 6, and 18 months for formulation 2.”
`Ex1005 at 17-18; Ex2022 at ¶¶117-127; Paper 25 at 53-55
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`42
`
`

`

`Conclusions
`
`The claims of the ’833
`patent are not
`anticipated by Flink
`
`The claims of the ’833
`patent are not obvious
`over Flink alone or in
`view of Betz
`
`Propylene glycol
`demonstrated
`unexpected results in
`the formulations of the
`’833 patent
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Paper 25 at 2-4
`
`43
`
`

`

`IPR2020-00324
`Patent 8,114,833 B2
`
`CERTIFICATE OF SERVICE
`
`Pursuant to 37 C.F.R. § 42.6(e), I hereby certify that on March 24, 2021, the
`
`foregoing document is being served by filing this document through the Patent Trial
`
`and Appeal Board End to End System, as well as delivering a copy via electronic
`
`mail upon the following attorneys of record for the Petitioners:
`
`Brandon M. White (Reg. No. 52,354)
`Perkins Coie LLP
`700 Thirteenth Street, N.W., Suite 600
`Washington, D.C., 20005
`Telephone: (202) 654-6206
`Fax: (202) 654-9681
`BMWhite@perkinscoie.com
`White-ptab@perkinscoie.com
`
`Lara Dueppen (Reg. No. 65,002)
`Perkins Coie LLP
`1888 Century Park East
`Suite 1700
`Los Angeles, CA 90067
`Telephone: (310) 788-3349
`Fax: (310) 788-3399
`LDueppen@perkinscoie.com
`Dueppen-ptab@perkinscoie.com
`Liraglutide@perkinscoie.com
`
`Emily J. Greb (Reg. No. 68,244)
`Perkins Coie LLP
`33 East Main Street, Suite 201
`Madison, WI 53703
`Telephone: (308) 663-7494
`Fax: (608) 283-4494
`greb-ptab@perkinscoie.com
`
`i
`
`

`

`IPR2020-00324
`Patent 8,114,833 B2
`
`Thomas J. Meloro (Reg. No. 33,538)
`Michael W. Johnson (Reg. No. 63,731)
`Willkie Farr & Gallagher LLP
`787 Seventh Avenue
`New York, NY 10019
`Telephone: (212) 728-8428
`Fax: (212) 728-8111
`tmeloro@willkie.com
`mjohnson1@willkie.com
`amoore@willkie.com
`mao-ny@willkie.com
`
`Date: March 24, 2021
`
`Respectfully submitted,
`
`/Jeffrey J. Oelke/
`Jeffrey J. Oelke (Reg. No. 37,409)
`Lead Counsel
`
`ii
`
`