MICRO LABS LIMITED AND
`MICRO LABS USA INC., Petitioner,
`v.
`SANTEN PHARMACEUTICAL CO., LTD. AND
`ASAHI GLASS CO., LTD., Patent Owner.
`
`Patent Owner’s Demonstratives
`September 6, 2018
`
`Case IPR2017-01434
`Patent No. 5,886,035
`
`
`MICRO LABS USA INC., Petitioner,
`v.
`SANTEN PHARMACEUTICAL CO., LTD. AND
`ASAHI GLASS CO., LTD., Patent Owner.
`
`Patent Owner’s Demonstratives
`September 6, 2018
`
`Case IPR2017-01434
`Patent No. 5,886,035
`
`
`
`Tafluprost Differs from 2 Commercially Available
`PG Analogs in 3 Ways
`
`• Only tafluprost has 2 Fs at 15 position (v. OH)
`• Only tafluprost has phenoxy at 16 position
`
`Paper 22 (POR), 2-3, 15
`
`DEMONSTRATIVE EXHIBIT—NOT EVIDENCE
`
`2
`
`
`
`Medicinal Chemistry of Prostaglandins Highly Unpredictable
`
`• Medicinal chemistry of prostaglandins highly unpredictable as of
`December 1996 (and remains so today)
`
`Ex. 1003 (Klimko), 15:54-56
`
`Paper 22 (POR), 5-6, 11, 34, 52-53
`
`DEMONSTRATIVE EXHIBIT—NOT EVIDENCE
`
`3
`
`Ex. 1003 (Klimko), 15:1-50 (Table 2)
`
`
`
`Petitioner’s Proposed Trajectory from Compound C to
`Tafluprost Made in Hindsight
`
`Proposed Scheme
`
`Asserted Prior Art
`
`Compound C as lead compound
`
`Ex. 1003 (Klimko), 15:1-50 (Table 2)
`
`Replace 15-OH with 15-H to
`diminish side effects
`
`Replace 15-H with 15-F to
`mimic (removed) 15-OH
`
`• Klimko (Ex. 1003)
`
`• Kishi (Ex. 1004)
`
`• Bezuglov 1982 (Ex. 1007)
`• Bezuglov 1986 (Ex. 1008)
`• Ueno Japan (Ex. 1006)
`
`Hindsight
`• Not a Suitable Lead
`Compound
`• Other Compounds Are
`Superior
`• Intolerable Side Effects
`(Hyperemia)
`• Unfavorable IOP Profile
`(Initial Increase in IOP)
`• No “Longer –Lasting
`Efficacy”
`
`• Change Associated with
`Reduced IOP-Lowering
`Activity
`
`• Change Made with
`Hope of Restoring
`IOP-Lowering Activity
`But Not Intolerable
`Side Effects
`
`Inserting 2Fs at C15
`
`Paper 22 (POR), 4-7, 28-46, 51-65
`
`• Ueno Japan (Ex. 1006)
`
`• 2Fs ≠ 1F ≠ 1OH
`
`DEMONSTRATIVE EXHIBIT—NOT EVIDENCE
`
`4
`
`
`
`Petitioner Picked Compound C as Lead Based on Hindsight
`
`• The standard:
`
`Paper 22 (POR), 27-28 (citing Otsuka Pharm. Co. v. Sandoz, Inc., 678 F.3d
`1280, 1292 (Fed. Cir. 2012))
`• But Petitioner’s expert, Dr. deLong, worked backwards from
`tafluprost to get to Compound C:
`
`Paper 22 (POR), 27-28, 46-47
`
`Ex.2025 (deLong Tr.),
`79:13-22
`
`DEMONSTRATIVE EXHIBIT—NOT EVIDENCE
`
`5
`
`
`
`Petitioner Picked Compound C as Lead Based on Hindsight
`
`• The standard:
`
`Paper 22 (POR), 27 (citing Takeda Chem. Indus., Ltd. v. Alphapharm Pty., Ltd., 492 F.3d
`1350, 1357 (Fed. Cir. 2007))
`
`• But Petitioner’s expert, Dr. deLong, on what makes a lead
`compound:
`
`Ex.2025 (deLong Tr.), 80:8-9
`
`Ex.2025 (deLong Tr.), 88:1-3
`
`Ex.2025 (deLong Tr.), 90:3-4
`
`Paper 22 (POR), 27, 46-47
`
`DEMONSTRATIVE EXHIBIT—NOT EVIDENCE
`
`6
`
`
`
`Petitioner’s Proposed Trajectory from Compound C to
`Tafluprost Made in Hindsight
`
`Proposed Scheme
`
`Asserted Prior Art
`
`Compound C as lead compound
`
`Ex. 1003 (Klimko), 15:1-50 (Table 2)
`
`Replace 15-OH with 15-H to
`diminish side effects
`
`Replace 15-H with 15-F to
`mimic (removed) 15-OH
`
`• Klimko (Ex. 1003)
`
`• Kishi (Ex. 1004)
`
`• Bezuglov 1982 (Ex. 1007)
`• Bezuglov 1986 (Ex. 1008)
`• Ueno Japan (Ex. 1006)
`
`Hindsight
`• Not a Suitable Lead
`Compound
`• Other Compounds Are
`Superior
`• Intolerable Side Effects
`(Hyperemia)
`• Unfavorable IOP Profile
`(Initial Increase in IOP)
`• No “Longer –Lasting
`Efficacy”
`
`• Change Associated with
`Reduced IOP-Lowering
`Activity
`
`• Change Made with
`Hope of Restoring
`IOP-Lowering Activity
`But Not Intolerable
`Side Effects
`
`Inserting 2Fs at C15
`
`Paper 22 (POR), 4-7, 28-46, 51-65
`
`• Ueno Japan (Ex. 1006)
`
`• 2Fs ≠ 1F ≠ 1OH
`
`DEMONSTRATIVE EXHIBIT—NOT EVIDENCE
`
`7
`
`
`
`Compound C of Klimko Not Preferred by Stjernschantz
`
`Stjernschantz Compound
`
`Most Preferred?
`
`Type
`
`YES
`
`NO
`
`YES
`
`YES
`
`17-phenyl-18,19,20-trinor analog
`
`16-phenoxy-17,18,19,20-tetranor analog
`
`17-phenyl-18,19,20-trinor analog
`
`17-phenyl-18,19,20-trinor analog
`
`YES
`(commercialized)
`
`17-phenyl-18,19,20-trinor analog
`
`1 2 3
`
`4
`(Compound C of Klimko (Ex. 1003))
`
`5 6
`
`7
`
`8 9
`
`(latanoprost)
`10
`20
`
`Paper 22 (POR), 31, 33
`
`Ex.2017 (Stjernschantz), 4:8-20, 4:13, 4:21-24; Ex.2001 (Macdonald Decl.), ¶75
`DEMONSTRATIVE EXHIBIT—NOT EVIDENCE
`
`8
`
`
`
`Klimko Teaches Away from Compound C as Lead Compound
`
`Compound C of Klimko (Ex. 1003) = Compound (4) of Stjernschantz (Ex. 2017)
`
`• Petitioner’s experts did not address this passage in
`their opening declarations
`
`Ex.1003 (Klimko), 3:39-44
`
`Paper 22 (POR), 30-32
`
`DEMONSTRATIVE EXHIBIT—NOT EVIDENCE
`
`9
`
`
`
`Klimko Teaches Away from Compound C as Lead Compound
`
`Ex. 1003 (Klimko), 15:1-50 (Table 2)
`• Compounds other than Compound C identified as having
`excellent IOP reduction without significant side effects
`
`Paper 22 (POR), 32-34
`
`Ex. 1003 (Klimko), 3:48-53
`DEMONSTRATIVE EXHIBIT—NOT EVIDENCE
`
`10
`
`
`
`At Deposition, Petitioner’s Experts Disagree with
`Conclusions of Klimko Primary Prior Art
`
`Ex. 1003 (Klimko), 3:39-44
`
`Paper 22 (POR), 30-31, 40-41
`
`Ex. 2026 (Rose Tr.), 61:12-62:8
`DEMONSTRATIVE EXHIBIT—NOT EVIDENCE
`
`11
`
`
`
`At Deposition, Petitioner’s Experts Disagree with
`Conclusions of Klimko Primary Prior Art
`
`Ex. 1003 (Klimko), 3:39-44
`
`Ex.2025 (deLong Tr.), 63:7-10
`
`Ex.2025 (deLong Tr.), 61:25-62:11
`
`Ex. 2025 (deLong Tr.), 63:11-15
`
`Paper 22 (POR), 30-31, 40-41
`
`DEMONSTRATIVE EXHIBIT—NOT EVIDENCE
`
`12
`
`
`
`Klimko Teaches Away from Compound C as Lead Compound
`
`Ex. 2025 (deLong Tr.), 141:23-142:3
`
`Paper 22 (POR), 28-29
`
`Ex. 2025, (deLong Tr.), 143:11-18
`
`DEMONSTRATIVE EXHIBIT—NOT EVIDENCE
`
`13
`
`
`
`Klimko Teaches Away from Compound C as Lead Compound
`
`Ex.2026 (Rose Tr.), 60:22-61:5
`
`Paper 22 (POR), 28-29
`
`DEMONSTRATIVE EXHIBIT—NOT EVIDENCE
`
`14
`
`
`
`Klimko Compared IOP Lowering Activity and
`Side Effects of 5 Compounds
`
`Ex. 1003 (Klimko), 17:1-55 (Table 3)
`
`Ex. 1003 (Klimko), 15:1-50 (Table 2)
`
`Paper 22 (POR), 33-38
`
`Ex. 1003 (Klimko), 18:28-50 (Table 4)
`DEMONSTRATIVE EXHIBIT—NOT EVIDENCE
`
`15
`
`
`
`Klimko Singled Out Compound C with
`Highest Conjunctival Hyperemia Side Effect
`
`E
`
`BA
`
`D
`
`C
`
`Ex. 1003 (Klimko), 17:1-55 (Table 3)
`
`Ex. 1003 (Klimko), 29 (Fig. 1)
`
`Ex. 1003 (Klimko), 17:57-18:1
`
`Paper 22 (POR), 33-36
`
`Ex. 1003 (Klimko), 18:1-6
`DEMONSTRATIVE EXHIBIT—NOT EVIDENCE
`
`16
`
`
`
`Petitioner’s Experts Disagree with
`Studies and Conclusions of Klimko Primary Prior Art
`
`E
`
`BA
`
`D
`
`C
`
`Ex. 1003 (Klimko), 17:1-55 (Table 3)
`
`Ex. 1003 (Klimko), 29 (Fig. 1)
`
`Paper 22 (POR), 33-36, 40
`
`Ex. 2025 (deLong Tr.),
`126:22-127:8
`DEMONSTRATIVE EXHIBIT—NOT EVIDENCE
`
`17
`
`
`
`Canadian Testimony of Petitioner’s Expert, Dr. deLong,
`Directly Contradicts His Testimony Here
`
`Compound C of Klimko (Ex. 1003) = Compound (4) of Stjernschantz (Ex. 2017)
`
`Here:
`
`But in Canada, re validity of Klimko
`counterpart:
`
`Ex. 2025 (deLong Tr.), 63:7-10
`
`Ex. 2027 (CA Court Decision), ¶ 314
`
`Paper 22 (POR), 47-51
`
`Ex. 2027 (CA Court Decision), ¶ 315
`
`DEMONSTRATIVE EXHIBIT—NOT EVIDENCE
`
`18
`
`
`
`Petitioner’s Expert Admits That Hyperemia was a
`Highly Undesirable Side Effect at the Time of the Invention
`
`Ex. 1028 (Rose Decl.), ¶ 39
`
`Paper 22 (POR), 34
`
`DEMONSTRATIVE EXHIBIT—NOT EVIDENCE
`
`19
`
`Ex. 1028 (Rose Decl.), ¶ 40
`
`
`
`Hyperemia was Highly Undesirable Side Effect at
`Time of Invention
`
`• Petitioner:
`
`• But state of the art:
`
`Paper 24 (Reply), 4
`
`Ex. 1036 (Alm 2014), 2
`
`Ex. 1036 (Alm 2014), 8
`
`Ex. 1036 (Alm 2014), 9
`
`Paper 34 (Mtn. for Observation – deLong), 3 (citing Ex. 2061, 126:16-131:14); Paper 22 (POR), 34, 69
`
`Ex. 1036 (Alm 2014), 9
`DEMONSTRATIVE EXHIBIT—NOT EVIDENCE
`
`20
`
`
`
`Early PG Analogs Had Clinically Unacceptable Hyperemia
`
`• Dr Rose:
`
`Ex. 1032 (Rose Suppl. Decl.), ¶ 26
`• But state of the art regarding early PGF2α analogs:
`
`Ex. 2015 (Camras), 1
`
`Ex. 2062 (Rose Tr.), 15:7-12
`
`* * *
`
`Paper 35 (Mtn. for Observation – Rose), 1-2 (citing Ex. 2062, 14:19-23, 15:4-16:13);
`Paper 22 (POR), 10-13
`
`Ex. 2015 (Camras), Abstract
`
`DEMONSTRATIVE EXHIBIT—NOT EVIDENCE
`
`21
`
`
`
`Early PG Analogs Had Clinically Unacceptable Hyperemia
`
`• Dr Rose:
`
`Ex. 1032 (Rose Suppl. Decl.), ¶ 26
`
`Ex. 1032 (Rose Suppl. Decl.), ¶ 24
`• But state of the art regarding early PGF2α analogs:
`
`Ex. 2058 (Rulo 1994)
`
`Ex. 2058 (Rulo 1994), 4, FN 18
`
`Ex. 2058 (Rulo 1994), 3, FN 9
`
`Ex. 2058 (Rulo 1994), 2
`
`Paper 35 (Mtn. for Observation – Rose), 2 (citing Ex. 2062, 18:18-23, 19:6-23, 20:16-25, 21:7-12);
`Paper 22 (POR), 10-13
`
`DEMONSTRATIVE EXHIBIT—NOT EVIDENCE
`
`22
`
`
`
`Early PG Analogs Had Clinically Unacceptable Hyperemia
`
`• Dr Rose:
`
`Ex. 1032 (Rose Suppl. Decl.), ¶ 24
`• But state of the art regarding early PGF2α analogs:
`
`Ex. 1033 (Kerstetter), 1
`
`Paper 35 (Mtn. for Observation – Rose), 2-3 (citing Ex. 2062, 22:6-10, 22:23-23:3, 24:15-23);
`Paper 22 (POR), 10-13
`
`DEMONSTRATIVE EXHIBIT—NOT EVIDENCE
`
`23
`
`Ex. 1033 (Kerstetter), 3
`
`
`
`Early PG Analogs Had Clinically Unacceptable Hyperemia
`
`• Dr Rose:
`
`• But Stjernschantz:
`
`Ex. 1032 (Rose Suppl. Decl.), ¶ 26
`
`Ex. 2017 (Stjernschantz),
`2:45-52
`
`* * *
`
`Ex. 2062 (Rose Tr.), 79:3-8
`
`Paper 35 (Mtn. for Observation – Rose), 3-4 (citing Ex. 2062, 77:8-78:9, 79:3-8); Paper 22 (POR), 10-13
`
`DEMONSTRATIVE EXHIBIT—NOT EVIDENCE
`
`24
`
`
`
`Dr. deLong Misstates Level of Hyperemia Acceptable
`for Latanoprost
`
`• Dr. deLong makes bare assertion:
`
`• But Xalatan (latanoprost) label:
`
`Ex. 1031 (deLong Suppl. Decl.), ¶ 73
`
`Paper 34 (Mtn. for Observation – deLong), 4 (citing Ex. 2061, 34:5-15)
`
`DEMONSTRATIVE EXHIBIT—NOT EVIDENCE
`
`25
`
`Ex. 2037 (Xalatan label), 4 (Table 1)
`
`
`
`Klimko Singled Out Compound C with
`Highest Conjunctival Hyperemia Side Effect
`
`Compound C of Klimko (Ex. 1003) = Compound (4) of Stjernschantz (Ex. 2017)
`
`• Compound C caused a
`high degree of hyperemia:
`
`Ex. 1003 (Klimko), 3:39-44
`• Compound (4) not identified in
`Stjernschantz as among the
`5 compounds described as
`“advantageous” for having
`less hyperemia
`Ex. 2017 (Stjernschantz), 10:48-53
`
`Paper 22 (POR), 30-32;
`Paper 34 (Mtn. for Observation – deLong), 11-12 (citing Ex. 2061, 52:16-22, 55:12-16, 57:5-10);
`Paper 35 (Mtn. for Observation – Rose), 10-11 (citing Ex. 2062, 85:2-86:25, 87:20-88:6)
`
`Ex. 2017 (Stjernschantz), 15:1-42 (Table IV)
`26
`DEMONSTRATIVE EXHIBIT—NOT EVIDENCE
`
`
`
`Compound C of Klimko Not Preferred by Stjernschantz
`
`• At deposition, Petitioner’s
`expert agreed that “most
`promising” compounds
`advanced to human testing:
`
`• No human test data reported for
`compound (4) of Stjernschantz =
`Compound C of Klimko:
`
`Ex. 2061 (deLong Tr.), 44:7-10
`
`Ex. 2061 (deLong Tr.), 41:14-24
`
`Paper 34 (Mtn. for Observation – deLong), 10 (citing Ex. 2061, 41:14-24, 43:20-44:2, 44:7-10);
`Paper 22 (POR), 31, 33
`
`DEMONSTRATIVE EXHIBIT—NOT EVIDENCE
`
`27
`
`
`
`Klimko Singled Out Compound C with
`Highest Conjunctival Hyperemia Side Effect
`
`Ex. 1003 (Klimko), 17:1-54 (Table 3)
`• Petitioner’s expert on Compound C’s ~10X hyperemia than
`Compound B:
`
`Paper 34 (Mtn. for Observation – deLong), 9 (citing Ex. 2061, 29:6-32:19); Paper 22 (POR), 33-36
`
`DEMONSTRATIVE EXHIBIT—NOT EVIDENCE
`
`28
`
`Ex. 2061 (deLong Tr.), 32:17-19
`
`
`
`Klimko Singled Out Compound C with
`Highest Conjunctival Hyperemia Side Effect
`
`Ex. 1003 (Klimko), 16:9-15
`
`Paper 34 (Mtn. for Observation – deLong), 8-9 (citing Ex. 2061, 22:6-15);
`Paper 35 (Mtn. for Observation – Rose), 8 (citing Ex. 2062, 53:23-54:10, 57:10-17);
`Paper 22 (POR), 33-36
`
`Ex. 1003 (Klimko), 17:1-54 (Table 3)
`
`DEMONSTRATIVE EXHIBIT—NOT EVIDENCE
`
`29
`
`
`
`Klimko Singled Out Compound C with
`Highest Conjunctival Hyperemia Side Effect
`
`• In his declaration, Petitioner’s expert described Compound C’s
`hyperemia as moderate, mild/moderate, or mild/modest:
`
`Ex. 1031 (deLong Suppl. Decl.), ¶ 25
`
`Ex. 1031 (deLong Suppl. Decl.), ¶ 27
`
`• But at deposition,
`Petitioner’s
`expert said:
`
`Paper 34 (Mtn. for Observation – deLong), 8-9 (citing Ex. 2061, 22:6-15);
`Paper 22 (POR), 33-36
`
`* * *
`
`Ex. 2061 (deLong Tr.), 22:6-15
`
`DEMONSTRATIVE EXHIBIT—NOT EVIDENCE
`
`30
`
`
`
`Klimko Singled Out Compound C with
`Highest Conjunctival Hyperemia Side Effect
`
`• In his declaration, Petitioner’s expert described Compound C’s
`hyperemia as modest:
`
`Ex. 1032 (Rose Suppl. Decl.), ¶ 46
`• But at deposition, Petitioner’s expert said:
`
`* * *
`
`* * *
`
`Ex. 2062 (Rose Tr.), 57:10-17
`
`Ex. 2062 (Rose Tr.), 53:23-54:10
`
`Paper 35 (Mtn. for Observation – Rose), 8 (citing Ex. 2062, 53:23-54:10, 57:10-17);
`Paper 22 (POR), 33-36
`
`DEMONSTRATIVE EXHIBIT—NOT EVIDENCE
`
`31
`
`
`
`Klimko’s Compound C Had Unacceptable Initial Increase in IOP
`
`Compound C of Klimko (Ex. 1003) = Compound (4) of Stjernschantz (Ex. 2017)
`
`Ex. 1003 (Klimko), 3:39-44
`
`* * *
`
`* * *
`
`Paper 22 (POR), 30-32
`
`DEMONSTRATIVE EXHIBIT—NOT EVIDENCE
`
`32
`
`Ex. 2017 (Stjernschantz), 16:1-17:55 (Table V)
`
`
`
`Klimko’s Compound C Had Unacceptable Initial Increase in IOP
`
`• Impossible to reach definitive conclusions based on Klimko IOP
`experiment, e.g., no disclosure of statistical significance
`
`Ex. 2025 (deLong Tr.),
`81:25-82:2
`• With above qualifications, Klimko IOP data for Compound C
`consistent with Klimko’s characterization of Stjernschantz data
`
`E
`
`BA
`
`CD
`
`Ex. 1003 (Klimko), 18:28-50 (Table 4)
`
`Ex. 1003
`(Klimko), 30 (Fig. 2)
`
`Paper 22 (POR), 36-40
`
`DEMONSTRATIVE EXHIBIT—NOT EVIDENCE
`
`33
`
`
`
`Klimko’s Compound C Had Unacceptable Initial Increase in IOP
`
`E
`
`BA
`
`CD
`
`• Petitioner explains increase as due to
`metabolism, absorption, and level of
`drug in eye at different time points:
`
`Ex. 1031 (deLong Suppl. Decl.), ¶ 39
`• At deposition, Dr. deLong confirmed Klimko
`does not report on metabolism, absorption,
`and level of drug in eye at different time points:
`
`* * *
`
`* * *
`
`* * *
`
`Ex. 2061 (deLong Tr.), 16:2-9
`
`Ex. 1003 (Klimko), 30 (Fig. 2)
`
`Ex. 2061 (deLong Tr.), 18:13-16
`
`Ex. 2061 (deLong Tr.), 16:12-24
`Paper 34 (Mtn. for Observation - deLong), 7-8 (citing Ex. 2061, 16:2-9, 16:12-17:11, 18:13-16);
`Paper 22 (POR), 36-40
`
`Ex. 2061 (deLong Tr.), 16:25-17:11
`
`DEMONSTRATIVE EXHIBIT—NOT EVIDENCE
`
`34
`
`
`
`Modifying to Overcome Undesirable Initial Increase in IOP
`Associated with Less Efficacy
`
`• Petitioner: decreasing dose
`addresses undesirable initial
`increase in IOP
`
`• But petitioner’s expert at deposition:
`
`Paper 24 (Reply), 12-13
`
`Ex. 2062 (Rose Tr.), 103:14-24
`
`Ex. 2003 (Camras
`1977), 4 (Fig. 3);
`Ex. 2001
`(Macdonald Decl.),
`¶ 7
`
`Paper 35 (Mtn. for Observation – Rose), 4-5 (citing Ex. 2062, 101:8-12, 102:12-25, 103:2-24);
`Paper 22 (POR), 39
`
`DEMONSTRATIVE EXHIBIT—NOT EVIDENCE
`
`35
`
`
`
`Petitioner’s Comparison of Stjernschantz Cat Model to
`Klimko Monkey Model
`
`• Petitioner would compare doses of Compound C in Stjernschantz
`cat model to Klimko monkey model:
`
`• At deposition, Petitioner’s
`experts testified:
`
`* * *
`
`Ex. 2062 (Rose Tr.), 68:20-25
`
`Paper 24 (Reply), 13
`
`* * *
`
`Ex. 2061
`(deLong Tr.),
`39:14-40:5
`
`Paper 34 (Mtn. for Observation – deLong), 9-10; (Ex. 2061, 36:14-37:3, 39:14-40:13);
`Paper 35 (Mtn. for Observation – Rose), 8-9 (citing Ex. 2062, 67:15-25, 68:20-25)
`
`DEMONSTRATIVE EXHIBIT—NOT EVIDENCE
`
`36
`
`
`
`Petitioner Cherrypicks Klimko Data to Argue
`Longer-Lasting IOP-Lowering for Compound C
`
`E
`
`BA
`
`CD
`
`• Petitioner extrapolates:
`
`Ex. 1003 (Klimko), 30 (Fig. 2)
`• Petitioner concedes there is no
`actual data showing longer-lasting
`efficacy for Compound C
`Ex.2001, ¶ 91; Ex.2002, ¶ 38; Ex.2025, 146:18-147:2, 147:24-25;
`Ex.2026, 109:2-6, 111:3-11
`
`Paper 22 (POR), 37, 41-44
`
`DEMONSTRATIVE EXHIBIT—NOT EVIDENCE
`
`37
`
`Paper 1 (Petition), 48
`
`
`
`At Deposition, Petitioner’s Experts Disagree with Conclusions
`of Klimko Primary Prior Art
`
`Paper 22 (POR), 40, n. 11
`
`Ex.2025 (deLong Tr.), 150:19-151:16
`DEMONSTRATIVE EXHIBIT—NOT EVIDENCE
`
`38
`
`
`
`Canadian Testimony of Petitioner’s Expert, Dr. deLong,
`Directly Contradicts His Testimony Here
`
`Here:
`
`But in Canada, re validity of Klimko
`counterpart:
`
`Ex.2027 (CA Court Decision), ¶ 434
`
`Ex.1027 (deLong Decl.), ¶ 64
`
`Ex.2027 (CA Court Decision), ¶ 432
`
`Paper 22 (POR), 47-51
`
`DEMONSTRATIVE EXHIBIT—NOT EVIDENCE
`
`39
`
`
`
`Petitioner Cherrypicks Klimko Data (First Data Point)
`
`• Petitioner argues Compound C exhibited superior IOP-lowering
`at 16/4 datapoint:
`
`Paper 1 (Petition), 49
`
`Paper 22 (POR), 44-45
`
`DEMONSTRATIVE EXHIBIT—NOT EVIDENCE
`
`40
`
`
`
`Petitioner Cherrypicks Klimko Data (First Data Point)
`
`• But error bars overlap at 16/4 (16 hours after administration of
`the fourth dose) datapoint
`
`E
`
`B
`A
`
`CD
`CD
`
`Ex. 1003 (Klimko), 18:28-50 (Table 4)
`
`Paper 22 (POR), 37, 42-43
`
`Ex. 1003 (Klimko), 30 (Fig. 2)
`DEMONSTRATIVE EXHIBIT—NOT EVIDENCE
`
`41
`
`
`
`Petitioner Cherrypicks Klimko Data
`
`Ex. 2025 (deLong Tr.), 82:15-17
`
`* * *
`
`Paper 22 (POR), 42-43, n. 13
`
`DEMONSTRATIVE EXHIBIT—NOT EVIDENCE
`
`42
`
`Ex. 2026 (Rose Tr.), 103:3-13
`
`
`
`Klimko Does Not Disclose Superior IOP-Lowering Efficacy by
`Compound C (First Data Point)
`
`• Dr. deLong conceded at deposition that he could not determine
`significant difference between Compounds C, D, and A at
`first 16/4 datapoint
`
`E
`
`B
`A
`
`CD
`
`Ex. 2025 (deLong Tr.), 104:8-16
`
`Paper 22 (POR), 44-45
`
`Ex. 2025 (deLong Tr.),104:21-105:2
`
`Ex. 1003 (Klimko), 30 (Fig. 2)
`
`DEMONSTRATIVE EXHIBIT—NOT EVIDENCE
`
`43
`
`
`
`Petitioner Cherrypicks Klimko Data (Last Data Point)
`
`E
`
`BA
`BA
`
`CD
`CD
`
`Ex. 1003 (Klimko), 18:28-50 (Table 4)
`
`Paper 22 (POR), 37, 44-45
`
`Ex. 1003 (Klimko), 30 (Fig. 2)
`
`DEMONSTRATIVE EXHIBIT—NOT EVIDENCE
`
`44
`
`
`
`Petitioner Cherrypicks Klimko Data (Last Data Point)
`
`• Undisputed A-D similar at last time point
`Ex. 2001 (Macdonald Decl.), ¶ 91; Ex. 2002 (Fechtner Decl.), ¶ 38; Ex. 2025 (deLong Tr.), 109:19-110:2; Ex. 2026 (Rose Tr.), 106:1-19
`
`Ex. 1003 (Klimko), 19:29-30
`
`E
`
`BA
`
`CD
`
`Ex. 2025 (deLong Tr.), 109:19-110:2
`
`Paper 22 (POR), 37, 42-43
`
`Ex. 1003 (Klimko), 30 (Fig. 2)
`DEMONSTRATIVE EXHIBIT—NOT EVIDENCE
`
`45
`
`
`
`Petitioner’s Experts Disagree with
`Studies and Conclusions of Klimko Primary Prior Art
`
`Ex. 1003 (Klimko), 19:29-30
`
`* * *
`
`Ex.2025 (deLong Tr.), 106:17-24
`
`Paper 22 (POR), 40, n. 11, 43
`
`DEMONSTRATIVE EXHIBIT—NOT EVIDENCE
`
`46
`
`
`
`Canadian Testimony of Petitioner’s Expert, Dr. deLong,
`Directly Contradicts His Testimony Here
`
`Here, Dr. deLong opines Compound C
`has better IOP-lowering profile than
`Cloprostenol-IE (Compound A) and
`Fluprostenol-IE (Compound B):
`
`But in Canada, Dr. deLong opined Compound C
`has comparable IOP-lowering profile:
`
`Ex. 1027 (deLong Decl.), ¶ 64
`
`Ex. 2027 (CA Court Decision), ¶ 233
`
`Paper 22 (POR), 50-51
`
`DEMONSTRATIVE EXHIBIT—NOT EVIDENCE
`
`47
`
`
`
`Petitioner Cherrypicks Klimko Data (Last Data Point)
`
`E
`
`BA
`
`CD
`
`Ex. 1003 (Klimko), 18:28-50 (Table 4)
`
`Ex. 1003 (Klimko), 30 (Fig. 2)
`• But last time point reflects return to level of first data time point
`Ex. 2001 (Macdonald Decl.), ¶ 90; Ex. 2002 (Fechtner Decl.), ¶ 36
`
`Paper 22 (POR), 37, 42-43
`
`DEMONSTRATIVE EXHIBIT—NOT EVIDENCE
`
`48
`
`
`
`Petitioner Cherrypicks Klimko Data (Last Data Point)
`
`E
`
`BA
`
`D
`C
`
`Ex. 1003 (Klimko), 18:28-50 (Table 4)
`
`Paper 22 (POR), 37, 42-43, n. 13
`
`Ex. 2026 (Rose Tr.), 108:21-109:1
`
`DEMONSTRATIVE EXHIBIT—NOT EVIDENCE
`
`49
`
`Ex. 1003 (Klimko), 30 (Fig. 2)
`
`
`
`Petitioner Cherrypicks Klimko Data (Compound D)
`
`BA
`
`CD
`
`Ex. 1003 (Klimko), 18:28-50 (Table 4)
`
`Ex. 1003 (Klimko), 30 (Fig. 2)
`• Compound D has highest mean percent IOP reduction at
`last time point
`• Compound D has greatest mean percent IOP reduction overall
`
`Paper 22 (POR), 37, 42-43
`
`DEMONSTRATIVE EXHIBIT—NOT EVIDENCE
`
`50
`
`
`
`Compound D Has Higher Peak IOP Reduction Than
`Compound C
`
`• Petitioner contends POSA would have chosen Klimko Compound C as
`lead compound over Compound D with higher peak IOP reduction
`Ex. 1032 (Rose. Suppl. Decl.), ¶ 47; Paper 24 (Reply), 2
`
`• Petitioner’s expert on significance of peak IOP reduction:
`
`* * *
`
`* * *
`
`Ex. 2062 (Rose Tr.), 45:16-46:4
`
`Ex. 2062 (Rose Tr.), 46:9-18
`
`Paper 35 (Mtn. for Observation – Rose), 5-6 (citing Ex. 2062, 39:16-22,
`41:16-23, 45:12-14, 45:16-46:4, 46:9-18, 47:9-48:2); Paper 22 (POR), 42-43
`
`DEMONSTRATIVE EXHIBIT—NOT EVIDENCE
`
`51
`
`
`
`Petitioner Cherrypicks Klimko Data (Compound D)
`
`• Compound D has higher peak IOP reduction than Compound C
`
`E
`
`BA
`
`CD
`
`Ex. 1003 (Klimko),
`18:28-49 (Table 4)
`
`* * *
`
`Ex. 2062 (Rose Tr.), 47:9-48:2
`
`Ex. 1003 (Klimko), 30 (Fig. 2)
`
`Paper 35 (Mtn. for Observation – Rose), 5-6 (citing Ex. 2062, 39:16-22,
`41:16-23, 45:12-14, 45:16-46:4, 46:9-18, 47:9-48:2); Paper 22 (POR), 37, 42-43
`
`DEMONSTRATIVE EXHIBIT—NOT EVIDENCE
`
`52
`
`
`
`Petitioner Cherrypicks Klimko Data
`
`• Petitioner: POSA would pick lead compound with later peak
`IOP-lowering effect
`
`Ex. 1031 (deLong Suppl. Decl.), ¶ 15
`Ex. 1031 (deLong Suppl. Decl.), ¶ 16
`• But Stjernschantz picked latanoprost (compound 9) for
`development with earlier peak effect than compound 2:
`
`Paper 35 (Mtn. for Observation – Rose), 9 (citing Ex. 2062, 73:2-4, 75:7-11, 75:25-76:12, 76:20-23)
`
`DEMONSTRATIVE EXHIBIT—NOT EVIDENCE
`
`53
`
`Ex. 2017 (Stjernschantz),
`18 (Table VI)
`
`
`
`No Motivation to Pursue or Reasonable Expectation of
`Success for Convoluted Scheme
`
`Proposed Scheme
`Compound C as lead compound
`
`Ex. 1003 (Klimko), 15:1-50 (Table 2)
`
`Replace 15-OH with 15-H to
`diminish side effects
`
`Replace 15-H with 15-F to
`mimic (removed) 15-OH
`
`Inserting 2Fs at C15
`
`Paper 22 (POR), 4-7, 28-46, 51-65
`
`Asserted Prior Art
`
`Hindsight
`
`• Klimko (Ex. 1003)
`
`• Kishi (Ex. 1004)
`
`• Bezuglov 1982 (Ex. 1007)
`• Bezuglov 1986 (Ex. 1008)
`• Ueno Japan (Ex. 1006)
`
`• Not a Suitable Lead Compound
`• Other Compounds Are Superior
`• Intolerable Side Effects
`(Hyperemia)
`• Unfavorable IOP Profile
`(Initial Increase in IOP)
`• No “Longer –Lasting Efficacy”
`
`• Change Associated with
`Reduced IOP-Lowering Activity
`
`• Change Made with Hope of
`Restoring IOP-Lowering Activity
`But Not Intolerable Side Effects
`
`• Ueno Japan (Ex. 1006)
`
`• 2Fs ≠ 1F ≠ 1OH
`
`DEMONSTRATIVE EXHIBIT—NOT EVIDENCE
`
`54
`
`
`
`Petitioner’s Proposed Trajectory from Compound C to
`Tafluprost Made in Hindsight
`
`Proposed Scheme
`
`Asserted Prior Art
`
`Compound C as lead compound
`
`Ex. 1003 (Klimko), 15:1-50 (Table 2)
`
`Replace 15-OH with 15-H to
`diminish side effects
`
`Replace 15-H with 15-F to
`mimic (removed) 15-OH
`
`• Klimko (Ex. 1003)
`
`• Kishi (Ex. 1004)
`
`• Bezuglov 1982 (Ex. 1007)
`• Bezuglov 1986 (Ex. 1008)
`• Ueno Japan (Ex. 1006)
`
`Hindsight
`• Not a Suitable Lead
`Compound
`• Other Compounds Are
`Superior
`• Intolerable Side Effects
`(Hyperemia)
`• Unfavorable IOP Profile
`(Initial Increase in IOP)
`• No “Longer –Lasting
`Efficacy”
`
`• Change Associated with
`Reduced IOP-Lowering
`Activity
`
`• Change Made with
`Hope of Restoring
`IOP-Lowering Activity
`But Not Intolerable
`Side Effects
`
`Inserting 2Fs at C15
`
`Paper 22 (POR), 4-7, 28-46, 51-65
`
`• Ueno Japan (Ex. 1006)
`
`• 2Fs ≠ 1F ≠ 1OH
`
`DEMONSTRATIVE EXHIBIT—NOT EVIDENCE
`
`55
`
`
`
`POSA Would Not Remove 15-OH from
`Klimko’s Compound C Based on Kishi
`
`latanoprost
`
`E
`
`BA
`
`D
`
`C
`
`Ex. 1003 (Klimko), 15:1-50 (Table 2)
`
`Ex. 1003 (Klimko), 29 (Fig. 1)
`
`Paper 22 (POR), 3, 13-14, 34, 36, 45-46
`
`DEMONSTRATIVE EXHIBIT—NOT EVIDENCE
`
`56
`
`
`
`POSA Would Not Remove 15-OH from
`Klimko’s Compound C Based on Kishi
`
`• Undisputed that single 15-OH believed to be crucial for
`IOP-lowering activity
`
`Paper 1 (Petition), 36
`
`Ex.2025 (deLong Tr.), 204:21-205:7
`
`Paper 22 (POR), 3, 13-14 , 45-46
`
`Ex.2025 (deLong Tr.), 205:25-206:2
`
`DEMONSTRATIVE EXHIBIT—NOT EVIDENCE
`
`57
`
`
`
`POSA Would Not Remove 15-OH from
`Klimko’s Compound C Based on Kishi
`
`• No reasonable expectation of success removing Compound C’s
`15-OH with Kishi 15-H
`Ex. 2001 (Macdonald Decl.), ¶ 98
`
`Ex. 1003 (Klimko), 15:54-56
`
`Paper 22 (POR), 34, 45-46, 51-53
`
`Ex. 1003 (Klimko),
`15:1-50 (Table 2)
`DEMONSTRATIVE EXHIBIT—NOT EVIDENCE
`
`58
`
`
`
`Canadian Testimony of Petitioner’s Expert, Dr. deLong,
`Directly Contradicts His Testimony Here
`
`Here, Dr. deLong testified POSA could
`predict IOP-lowering activity:
`
`But in Canada, re validity of Klimko
`counterpart:
`
`Ex. 2027 (CA Court Decision), ¶ 432
`
`Ex. 2025 (deLong Tr.), 209:24-210:2
`
`Ex. 2025 (deLong Tr.), 210:12-15
`
`Paper 22 (POR), 47-51
`
`DEMONSTRATIVE EXHIBIT—NOT EVIDENCE
`
`59
`
`
`
`POSA Would Not Remove 15-OH from
`Klimko’s Compound C Based on Kishi
`• Significant structural difference between Kishi compounds and
`Klimko’s Compound C
`Ex. 2001 (Macdonald Decl.), ¶ 98
`• Kishi only discloses PGs where omega chain is a 6-12 carbon chain;
`no 16-phenoxy as with Compound C
`Ex. 2001 (Macdonald Decl.), ¶ 98
`
`Ex. 1003 (Klimko), 15:1-50 (Table 2)
`
`• Kishi discloses replacing 15-OH with
`15-H for PGs that do not include
`Compound C
`
`Ex. 2001 (Macdonald Decl.), ¶ 98; Ex. 2025
`(deLong Tr.), 218:18-24, 219:23-220:7
`
`Paper 22 (POR), 30, 51-52
`
`Ex. 1005 (Kishi), Abstract
`
`DEMONSTRATIVE EXHIBIT—NOT EVIDENCE
`
`60
`
`
`
`Modifying to Overcome Undesirable Initial Increase in IOP
`Associated with Less Efficacy
`• Petitioner: POSA would make Kishi modification (15-OH to 15-H) to
`eliminate undesirable initial increase in IOP
`
`Paper 24 (Reply), 13
`• But modified Kishi compounds 6 and 8 (without 15-OH) less effective at
`reducing IOP than control compounds B and C Ex. 2061 (deLong Tr.), 95:13-96:10
`Compound B
`
`Compound 6
`
`Paper 22 (POR), 10
`Ex. 1005 (Kishi), 49:60-67
`‒ Compound C is the isopropyl
`‒ Compound 8 is the isopropyl
`ester of Compound 6
`ester of Compound B
`Paper 34 (Mtn. for Observation – deLong), 2-3 (citing Ex. 2061, 95:13-96:10)
`
`Ex. 1005 (Kishi), 45:20-33 (Table 4)
`
`DEMONSTRATIVE EXHIBIT—NOT EVIDENCE
`
`61
`
`
`
`Canadian Testimony of Petitioner’s Expert, Dr. deLong,
`Directly Contradicts His Testimony Here
`• Petitioner: Dr. deLong’s Canadian Testimony irrelevant because Kishi (Ex. 1005)
`not available to POSA as of invention date of Canadian Klimko counterpart
`Ex. 1031 (deLong Suppl. Decl.), ¶ 74; Paper 24 (Reply), 7
`• But European Patent Application to Kishi (Ex. 1004) with essentially identical
`disclosure to Kishi (Ex. 1005) published before Canadian Klimko counterpart’s
`invention date
`• Petitioner admits that Kishi References (Ex. 1004 and Ex. 1005) interchangeable:
`
`Paper 34 (Mtn. for Observation – deLong), 1-2 (citing Ex. 2061, 119:6-24,
`122:4-123:5, 123:17-123:24, 125:5-18); Paper 22 (POR), 47-51
`
`DEMONSTRATIVE EXHIBIT—NOT EVIDENCE
`
`62
`
`Paper 1 (Petition), 34, n. 6
`
`
`
`Petitioner’s Proposed Trajectory from Compound C to
`Tafluprost Made in Hindsight
`
`Proposed Scheme
`
`Asserted Prior Art
`
`Compound C as lead compound
`
`Ex. 1003 (Klimko), 15:1-50 (Table 2)
`
`Replace 15-OH with 15-H to
`diminish side effects
`
`Replace 15-H with 15-F to
`mimic (removed) 15-OH
`
`• Klimko (Ex. 1003)
`
`• Kishi (Ex. 1004)
`
`• Bezuglov 1982 (Ex. 1007)
`• Bezuglov 1986 (Ex. 1008)
`• Ueno Japan (Ex. 1006)
`
`Hindsight
`• Not a Suitable Lead
`Compound
`• Other Compounds Are
`Superior
`• Intolerable Side Effects
`(Hyperemia)
`• Unfavorable IOP Profile
`(Initial Increase in IOP)
`• No “Longer –Lasting
`Efficacy”
`
`• Change Associated with
`Reduced IOP-Lowering
`Activity
`
`• Change Made with
`Hope of Restoring
`IOP-Lowering Activity
`But Not Intolerable
`Side Effects
`
`Inserting 2Fs at C15
`
`Paper 22 (POR), 4-7, 28-46, 51-65
`
`• Ueno Japan (Ex. 1006)
`
`• 2Fs ≠ 1F ≠ 1OH
`
`DEMONSTRATIVE EXHIBIT—NOT EVIDENCE
`
`63
`
`
`
`No Reasonable Expectation of Success
`Replacing 15-H with 15-F to Mimic 15-OH
`
`• C15-fluorinated compounds not allowed in Klimko description of
`invention
`Ex. 2028 (Macdonald Suppl. Decl.), ¶ 16; Ex. 2025 (deLong Tr.), 144:10-145:3
`
`* * *
`
`* * *
`
`Ex. 1003 (Klimko), 4:14-40
`
`Paper 22 (POR), 53-54
`
`DEMONSTRATIVE EXHIBIT—NOT EVIDENCE
`
`64
`
`
`
`No Motivation or Reasonable Expectation of Success
`Replacing 15-H with 15-F to Mimic 15-OH
`
`• Petitioner:
`
`• But POSA would have expected replacing 15-OH with 15-F to
`significantly change properties of PG:
`
`Paper 1 (Petition), 64
`
`Paper 22 (POR), 53-54
`
`DEMONSTRATIVE EXHIBIT—NOT EVIDENCE
`
`65
`
`Ex. 2021 (Klimko 2004), 1
`
`
`
`No Motivation or Reasonable Expectation of Success
`Replacing 15-H with 15-F to Mimic 15-OH
`• Petitioner:
`
`• But state of the art:
`
`Paper 24 (Reply), 15
`
`Ex.1050 (Howard), Abstract
`
`Paper 34 (Mtn. for Observation – deLong), 4-5 (citing Ex. 2061, 98:21, 99:13); Paper 22 (POR), 55
`
`DEMONSTRATIVE EXHIBIT—NOT EVIDENCE
`
`66
`
`Ex.1050 (Howard), 9
`
`
`
`No Motivation or Reasonable Expectation of Success
`Replacing 15-H with 15-F to Mimic 15-OH
`• 15-OH and 15-F have fundamentally different properties:
`
`Ex.2028
`(Macdonald Suppl. Decl.), ¶ 17
`
`Ex.2028 (Macdonald Suppl. Decl.), ¶ 19
`
`Ex.2028 (Macdonald Suppl. Decl.), ¶ 21
`
`Ex.2028 (Macdonald Suppl. Decl.), ¶ 18
`
`Ex.2028 (Macdonald Suppl. Decl.), ¶ 20
`
`Paper 22 (POR), 54-56
`
`Ex.2028 (Macdonald Suppl. Decl.), ¶ 22
`
`Ex.2028 (Macdonald Suppl. Decl.), ¶ 23
`DEMONSTRATIVE EXHIBIT—NOT EVIDENCE
`
`67
`
`
`
`No Motivation or Reasonable Expectation of Success
`Replacing 15-H with 15-F to Mimic 15-OH
`
`• Bezuglov 1982 and 1986 are not directed to fluorination in
`context of IOP lowering
`Ex. 2001 (Macdonald Decl.), ¶ 100; Ex. 2025 (deLong Tr.), 221:21-222:5
`
`• Unpredictability of 15-F Replacing 15-OH in Bezuglov 1982 and 1986:
`
`… When the 15-hydroxyl group is replaced with fluorine, the activity is generally
`reduced in a test of contraction of the smooth muscle of the intestines. Meantime, the
`effect on blood pressure either increases or remains unchanged. …
`
`Ex. 1007 (Bezuglov 1982), 10
`
`Ex. 1007 (Bezuglov 1982), 9-10
`
`Paper 22 (POR), 54-57
`
`Ex. 1008 (Bezuglov 1986), 6
`
`DEMONSTRATIVE EXHIBIT—NOT EVIDENCE
`
`68
`
`
`
`Petitioner’s Proposed Trajectory from Compound C to
`Tafluprost Made in Hindsight
`
`Proposed Scheme
`
`Asserted Prior Art
`
`Compound C as lead compound
`
`Ex. 1003 (Klimko), 15:1-50 (Table 2)
`
`Replace 15-OH with 15-H to
`diminish side effects
`
`Replace 15-H with 15-F to
`mimic (removed) 15-OH
`
`• Klimko (Ex. 1003)
`
`• Kishi (Ex. 1004)
`
`• Bezuglov 1982 (Ex. 1007)
`• Bezuglov 1986 (Ex. 1008)
`• Ueno Japan (Ex. 1006)
`
`Hindsight
`• Not a Suitable Lead
`Compound
`• Other Compounds Are
`Superior
`• Intolerable Side Effects
`(Hyperemia)
`• Unfavorable IOP Profile
`(Initial Increase in IOP)
`• No “Longer –Lasting
`Efficacy”
`
`• Change Associated with
`Reduced IOP-Lowering
`Activity
`
`• Change Made with
`Hope of Restoring
`IOP-Lowering Activity
`But Not Intolerable
`Side Effects
`
`Inserting 2Fs at C15
`
`Paper 22 (POR), 4-7, 28-46, 51-65
`
`• Ueno Japan (Ex. 1006)
`
`• 2Fs ≠ 1F ≠ 1OH
`
`DEMONSTRATIVE EXHIBIT—NOT EVIDENCE
`
`69
`
`
`
`No Motivation or Reasonable Expectation of
`Success to Insert 2Fs at 15 Position
`
`• Ueno not directed to IOP lowering
`Ex. 2001 (Macdonald Decl.), ¶¶ 69, 105
`• Ueno does not test any compound for IOP lowering
`Ex. 2001 (Macdonald Decl.), ¶ 107; Ex. 2025 (deLong Tr.), 183:11-17
`• Ueno does not suggest applying its compounds to IOP
`lowering
`Ex. 2001 (Macdonald Decl.), ¶ 107
`• Ueno does not assess or disclose ocular side effects for its
`compounds
`Ex. 2001 (Macdonald Decl.), ¶ 108
`
`Paper 22 (POR), 57-61
`
`DEMONSTRATIVE EXHIBIT—NOT EVIDENCE
`
`70
`
`
`
`No Motivation or Reasonable Expectation of
`Success to Insert 2Fs at 15 Position
`• Ueno directed to allergy
`and inflammatory diseases
`and treating liver and
`biliary tract disease
`
`• Ueno only tests compounds
`for inhibition of histamine
`activity and acute liver injury
`
`Ex. 1006 (Ueno), 48
`
`Ex. 1006 (Ueno), 48
`
`Ex. 1006 (Ueno), 65 (Table 2)
`
`Paper 22 (POR), 57-61
`
`Ex. 1006 (Ueno), 64-65 (Table 1)
`
`DEMONSTRATIVE EXHIBIT—NOT EVIDENCE
`
`71
`
`
`
`No Motivation or Reasonable Expectation of
`Success to Insert 2Fs at 15 Position
`
`• Ueno examples involve 15-dehydroxy PGE (v. PGF2α like tafluprost) with diflourination
`Ex. 1006, 54-57, 59-65; Ex. 2025 (deLong Tr.), 166:21-167:13, 171:8-179:10
`
`• Ueno examples feature C16 or C17 diflourination (v. C15 like tafluprost)
`Ex. 1006, 54-57, 59-65; Ex. 2025 (deLong Tr.), 166:21-167:13, 171:8-179:10
`
`• Ueno does not test any C15 flourinated or C15 diflourinated compounds
`Ex. 2001, ¶107
`
`Paper 22 (POR), 9, 59-60
`
`DEMONSTRATIVE EXHIBIT—NOT EVIDENCE
`
`72
`
`
`
`No Motivation or Reasonable Expectation of
`Success to Insert 2Fs at 15 Position
`
`• Petitioner argues practical considerations (ease of manufacture
`and analysis) provide motivation to insert 2Fs at C15 (i.e. with
`no stereogenic center):
`
`Paper 22 (POR), 61-63
`
`DEMONSTRATIVE EXHIBIT—NOT EVIDENCE
`
`73
`
`Paper 1 (Petition), 52-53
`
`
`
`No Motivation or Reasonable Expectation of
`Success to Insert 2Fs at 15 Position
`
`• But FDA-approved and marketed latanoprost has a stereogenic
`center at C15
`Ex. 2001 (Macdonald Decl.), ¶¶ 70, 104, 110
`
`Paper 22 (POR), 3
`
`Paper 22 (POR), 3, 61-63
`
`DEMONSTRATIVE EXHIBIT—NOT EVIDENCE
`
`74
`
`
`
`No Motivation or Reasonable Expectation of
`Success to Insert 2Fs v. 1F at 15 Position
`
`• Petitioner points to no support for interchangeability of
`2Fs and 1F
`Ex. 2001 (Macdonald Decl.), ¶¶ 70, 104, 111
`• Lipophilicity of C15 2F derivative of Compound C predicted to
`be 2.5 times higher than C15 F
`Ex. 2001 (Macdonald Decl.), ¶ 112
`• Too much lipophilicity (measured by logP) known to decrease
`permeability of compound across lipid-based membranes in
`the eye, impacting efficacy
`
`Paper 22 (POR), 61-63
`
`DEMONSTRATIVE EXHIBIT—NOT EVIDENCE
`
`75
`
`
`
`Tafluprost More Lipophilic (Has Higher logP) Than Latanoprost
`
`• Petitioner: POSA motivated to choose difluorinated over
`monofluorinated compounds
`Ex. 1031 (deLong Suppl. Decl.), ¶ 69
`
`• But Dr. deLong compared logP values with different methods:
`Ex. 2061 (deLong Tr.), 107:7-14
`Algorithm
`Tafluprost
`Latanoprost
`
`Dr. deLong
`
`Dr. MacDonald
`
`X
`
`X
`
`Paper 34 (Mtn. for Observation – deLong), 5 (citing Ex. 2061, 107:7-14)
`
`DEMONSTRATIVE EXHIBIT—NOT EVIDENCE
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`76
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`Tafluprost More Lipophilic (Has Higher logP) Than Latanoprost
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`• Pe
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