MICRO LABS LIMITED AND MICRO LABS USA INC.
`Petitioners,
`v.
`SANTEN PHARMACEUTICAL CO., LTD. AND ASAHI GLASS CO., LTD.
`Patent Owners.
`
`IPR2017-01434
`U.S. Patent No. 5,886,035
`Petitioners’ Demonstrative Exhibits
`Oral Argument
`September 6, 2018
`
`DEMONSTRATIVE EXHIBIT—NOT EVIDENCE
`
`
`Petitioners,
`v.
`SANTEN PHARMACEUTICAL CO., LTD. AND ASAHI GLASS CO., LTD.
`Patent Owners.
`
`IPR2017-01434
`U.S. Patent No. 5,886,035
`Petitioners’ Demonstrative Exhibits
`Oral Argument
`September 6, 2018
`
`DEMONSTRATIVE EXHIBIT—NOT EVIDENCE
`
`
`
`The ’035 Patent Claims
`Independent Claims: Claim 1
`
`Ex. 1001-17, Claim 1; Paper 1 at 44; Ex. 1027, ¶¶ 86-101
`
`# 2 (DEMONSTRATIVE EXHIBIT—NOT EVIDENCE)
`
`
`
`The ’035 Patent Claims
`Independent Claims: Claim 12
`
`The isopropyl ester of this is
`Tafluprost.
`
`Ex. 1001-17, Claim 12; Paper 1 at 60-61; Ex. 1027, ¶¶ 86-101
`
`# 3 (DEMONSTRATIVE EXHIBIT—NOT EVIDENCE)
`
`
`
`Lead Compound and Tafluprost Are Structurally Similar
`With The Only Difference Being The 2 Fluorine Substituents at C-15 Carbon
`
`(Klimko)
`
`Paper 1 at 11, ; Ex. 1027, ¶ 41
`
`# 4 (DEMONSTRATIVE EXHIBIT—NOT EVIDENCE)
`
`
`
`Instituted Grounds
`
`Ground 1:
`Claims 1-14 are obvious over Klimko, Kishi, and Ueno
`
`Ground 2:
`Claims 1-14 are obvious over Klimko, Kishi, Bezuglov 1982
`and/or Bezuglov 1986, and Ueno
`
` Klimko (Ex. 1003) was never considered by the Examiner during
`prosecution.
`
`Paper 11 at 20; Paper 1 at 1.
`
`# 5 (DEMONSTRATIVE EXHIBIT—NOT EVIDENCE)
`
`
`
`A POSA Would Have Chosen Compound C As A Lead Compound
`
` Longer-lasting IOP-reducing efficacy
` Superior IOP-reducing effectiveness
`relative to commercially available drug
`latanoprost
` Any potential side effects can be
`reduced or eliminated by further
`modification
`
`(16-phenoxy-17,18,19,20-
`tetranorprostaglandin F2α)
`
`Paper 1 at 19, 46-49; Ex. 1003-15 (Klimko)
`
`# 6 (DEMONSTRATIVE EXHIBIT—NOT EVIDENCE)
`
`
`
`Klimko: Compound C Has Long-lasting and Superior IOP-reducing Efficacy
`
`Paper 1 at 26-29, 46-49; Ex. 1003-15, Table 2; Ex. 1027, ¶¶ 57-65; Ex. 1028, ¶¶ 52-59; Paper 24 at 1-2
`# 7 (DEMONSTRATIVE EXHIBIT—NOT EVIDENCE)
`
`
`
`Klimko: Compound C Has Long-lasting and Superior IOP-reducing Efficacy
`
`Paper 1 at 30; 46-49; Ex. 1003-18, Table 4; Ex. 1027, ¶ 59; Ex. 1028, ¶ 53; Paper 24 at 1-2
`# 8 (DEMONSTRATIVE EXHIBIT—NOT EVIDENCE)
`
`
`
`Klimko: Compound C Has Long-lasting and Superior IOP-reducing Efficacy
`
`Latanoprost
`
`Compound C
`
`Compound A
`Compound B
`Compound D
`
`Paper 1 at 31-32; 46-49; Ex. 1003-30, Fig. 2; Paper 24 at 2-3; Ex. 1027 at ¶¶ 61-63; Ex. 1028 at ¶¶ 56-57,
`# 9 (DEMONSTRATIVE EXHIBIT—NOT EVIDENCE)
`63; Paper 24 at 1-2
`
`
`
`Klimko: Compound C Has Long-lasting and Superior IOP-reducing Efficacy
`Dr. deLong 1st Depo Tr:
`
`Paper 1 at 46-49; Paper 39 at 14-15; Ex. 2025 at 146:18-147:2; 150:9-10; Paper 24 at 1-2;
`# 10 (DEMONSTRATIVE EXHIBIT—NOT EVIDENCE)
`Ex. 1027 at ¶¶ 64-65; Ex. 1031 at ¶ 13
`
`
`
`Compound C Continues to Lower IOP More Than 6 hours After Dosing
`
`Compound C
`
`Paper 24 at 3-4; Ex. 1031 at ¶¶ 15-16; Ex. 1003-30, Fig. 2; Ex. 1040 at 8
`
`# 11 (DEMONSTRATIVE EXHIBIT—NOT EVIDENCE)
`
`Untreated Patients Exhibit
`Highest IOP b/w 6 am – 8 am
`
`
`
`Kishi: Removal of C-15 Hydroxyl Group Can Improve Stability and Eliminate Side Effects
`
`Paper 1 at 35-37, 49-51; Ex. 1005-3 at 1:63-2:15
`
`# 12 (DEMONSTRATIVE EXHIBIT—NOT EVIDENCE)
`
`
`
`A POSA Would Be Motivated to Replace C-15 Hydroxyl Group
`With A Substituent Other than Hydrogen
`Compound 8:
`
`Kishi (Ex. 1005)
`
`C: PGF2α isopropyl ester
`
`The only difference between Compound 8 and C is the
`substitution at C-15.
`
` Replacing C-15 hydroxyl group with a hydrogen
`would result in some loss of IOP-reducing activity.
`
`Paper 1 at 51; Ex. 1005-9 at 14:12-24; Ex. 1005-24, Table 1; Ex. 1027, ¶¶ 72-76
`
`# 13 (DEMONSTRATIVE EXHIBIT—NOT EVIDENCE)
`
`
`
`Ueno Specifically References Kishi’s Teaching Regarding Removing C-15 Hydroxyl Group
`
`Ueno (Ex. 1006/1029)
`
`Kishi (Ex. 1005)
`
`PCT/JP91/00305 published
`as WO 91/13869
`
`“[T]he researcher/inventor R.
`Ueno himself was well known in
`the prostaglandin/antiglaucoma
`field.”
`(deLong Supp. Decl. at ¶ 66)
`
`Paper 1 at 38; Ex. 1006/1029 at [0007]; Ex. 1005 at 1:7-12; Ex. 1031 at ¶¶ 65-66; Paper 24 at 17
`# 14 (DEMONSTRATIVE EXHIBIT—NOT EVIDENCE)
`
`
`
`Ueno Teaches 15,15-difluorinated PG Compounds Can Be Used to Treat Conjunctivitis
`
`Ueno (Ex. 1006/1029)
`
`Paper 1 at 37-38; Ex. 1006/1029 at [0008], [0012], [0087]; Claims 5-6
`
`# 15 (DEMONSTRATIVE EXHIBIT—NOT EVIDENCE)
`
`
`
`Additional Motivation to Make a Difluorination Substitution
`
`Dr. DeLong
`
` Easier to manufacture and
`analyze
` Improve economic efficiency &
`corresponding regulatory
`efficiency
`
`Paper 1 at 52-54; Ex. 1027 at ¶¶ 116-119
`
`# 16 (DEMONSTRATIVE EXHIBIT—NOT EVIDENCE)
`
`
`
`Ground II: Bezuglov 1982 Teaches That Substitution of the C-15 Hydroxyl
`with Fluorine Improves Stability and Maintains Activity
` Kishi also teaches that removing C-15
`hydroxyl increases stability by
`preventing degradation enzyme attack
` Maintain activity characteristic of PG
`compounds but with prolonged
`activity
`
`Paper 1 at 35, 39-40, 50, 63; Ex. 1007/1030 at 7-10; Ex. 1027 at ¶¶ 74, 77-79, 111; 124-126
`Paper 24 at 15; Ex. 1031 at ¶ 57
`# 17 (DEMONSTRATIVE EXHIBIT—NOT EVIDENCE)
`
`
`
`Ground II: Bezuglov 1986 Teaches Monofluorine Substitution of C-15 Hydroxyl
` Increase stability by preventing
`degradation enzyme attack
`prolonged activity
` Increase selectivity
`
`Paper 1 at 63; Ex. 1008 at 5-6; Ex. 1027, ¶¶ 80-81, 124-126
`
`# 18 (DEMONSTRATIVE EXHIBIT—NOT EVIDENCE)
`
`
`
`Ground II: Bezuglov 1982 and/or Bezuglov 1986 Motivates a POSA
`To Replace the Hydroxyl at C-15 with Fluorine
`
` Enhance and prolong the IOP-reducing activity of the lead compound
` At a minimum, restore any reduction in IOP-reducing activity resulting from the
`removal of the hydroxyl group
`
` Exchange of fluorine for hydroxyl represents the most incremental change in
`structure that can be made.
` Proximity of Fluorine to Oxygen on the periodic table
` High electronegativity
` Hydrogen-bond acceptor capability
` A known substitution in prostaglandin derivatives
`
`Paper 1 at 63-64; Ex. 1027 at ¶¶ 77-82, 124-126; Paper 24 at 14-16; Ex. 1031 at ¶¶ 55-61
`# 19 (DEMONSTRATIVE EXHIBIT—NOT EVIDENCE)
`
`
`
`Ground II: A POSA Would Prefer Difluorination Over Monofluorination at C-15
`
` Ueno:
` references Kishi’s teaching about removing C-15 hydroxyl group
` teaches difluorinated PG compounds can be used to treat inflammation diseases
`such as conjunctivitis
`
` Advantages over monofluorination
` Avoid a stereogenic center
` Reduce regulatory workload and streamline manufacture
`
`Paper 1 at 65; Ex. 1006/1029 at [0008],[0012],[0087]; Ex. 1027 at ¶¶ 116-119.
`
`# 20 (DEMONSTRATIVE EXHIBIT—NOT EVIDENCE)
`
`
`
`A POSA Would Not Be Taught Away by Klimko’s Self-Serving Statements
`
`In order to obtain a patent, Klimko “must
`assert or claim that these compounds
`somehow had certain advantages over the
`already disclosed compound C.”
`(DeLong Suppl. Decl. at ¶¶ 19-20).
`
`Paper 24 at 1, 6, 20; Ex. 1003 at 3:35-44, 15, Table 2; Ex. 1031 at ¶¶ 19-20
`
`# 21 (DEMONSTRATIVE EXHIBIT—NOT EVIDENCE)
`
`
`
`The Underlying Scientific Data:
`Stjernschantz Reports Only Moderate Hyperemia for Compound C
`
` Dr. Stjernschantz characterizes 2.0 ± 0.3 out of 4 as “only
`modest”:
`
` Dr. deLong:
`
`Paper 24 at 5-6, 12; Ex. 2017 at 10, 15; Ex. 1031 at ¶¶ 21-23; Ex. 1032 at ¶ 31.
`
`# 22 (DEMONSTRATIVE EXHIBIT—NOT EVIDENCE)
`
`
`
`The Underlying Scientific Data:
`Stjernschantz Reports Compound C Has Superior IOP-Lowering Efficacy
`
`Paper 24 at 6, 12; Ex. 2017 at 11, ll. 8-9; 16-17, Table V; Ex. 1031 at ¶¶23, 44;
`Ex. 1032 at ¶¶ 34, 52
`
`# 23 (DEMONSTRATIVE EXHIBIT—NOT EVIDENCE)
`
`
`
`The Underlying Scientific Data:
`Stjernschantz Reports Compound C Has Very Little Ocular Irritation At High Dose
`
`Dr. DeLong
`
`Paper 24 at 6; Ex. 2017 at 14; Ex. 1031 at ¶ 23; Ex. 1032 at ¶ 35
`
`# 24 (DEMONSTRATIVE EXHIBIT—NOT EVIDENCE)
`
`
`
`The Underlying Scientific Data:
`Klimko Reports Only Moderate Hyperemia with Compound C
`
` None had a score of 4, even
`at high dose (1.0 µg)
` 62% had only a score of 2 at
`the dose of 0.3 µg
`
`Paper 24 at 5; Ex. 1003 at 16, Example 5; at 17, Table 3; Ex. 1031 at ¶¶ 24-26; Ex. 1032, ¶ 46
`# 25 (DEMONSTRATIVE EXHIBIT—NOT EVIDENCE)
`
`
`
`Compound C Has Superior IOP-reduction Efficacy at a Dose of 0.3 µg
`
`Compound C
`
`Paper 24 at 3, 5-8; 12-13; Ex. 1031 at ¶¶ 15-16; Ex. 1003-30, Fig. 2; Ex. 1032, ¶¶ 38-40;
`# 26 (DEMONSTRATIVE EXHIBIT—NOT EVIDENCE)
`Paper 1 at 31-32, 49; Ex. 1027 at ¶ 65; Ex. 1028 at ¶ 58
`
`
`
`Moderate Hyperemia Would Not Discourage A POSA
`from Selecting Compound C as A Lead Compound
`
`Dr. DeLong
`
`Paper 24 at 4-5; Ex. 1031 at ¶¶ 24-26; Ex. 1032, ¶¶ 42-44
`
`# 27 (DEMONSTRATIVE EXHIBIT—NOT EVIDENCE)
`
`
`
`Moderate Hyperemia Would Not Discourage A POSA
`from Selecting Compound C as A Lead Compound
`
`Ex. 2062, Dr. Rose 2nd Depo Tr. at 55:9-17:
`
`Paper 40 at 9; Ex. 2062 at 55:9-17; Paper 24 at 4-5; Ex. 1031 at ¶¶ 24-26; Ex. 1032, ¶¶ 42-44
`# 28 (DEMONSTRATIVE EXHIBIT—NOT EVIDENCE)
`
`
`
`Moderate Hyperemia Would Not Discourage A POSA
`from Selecting Compound C as A Lead Compound
`
`Ex. 1011
`
`Paper 24 at 4-5; Ex. 1011 at 2; Ex. 1031 at ¶ 26; Ex. 1032, ¶¶ 42-44, 61
`
`# 29 (DEMONSTRATIVE EXHIBIT—NOT EVIDENCE)
`
`
`
`Moderate Hyperemia Would Not Discourage A POSA
`from Selecting Compound C as A Lead Compound
`Ex. 1037
`
`Dr. Rose
`
`Ex. 1036
`
`Paper 24 at 4-5; Ex. 1032, ¶44; Ex. 1037 at 3; Ex. 1036 at 8; Paper 39 at 4
`
`# 30 (DEMONSTRATIVE EXHIBIT—NOT EVIDENCE)
`
`
`
`The Erroneous Alleged “Initial Increase in IOP” in Klimko
`
` Dr. Macdonald:
` “The increase in IOP is reported as a decrease in
`percent IOP reduction from 30.2±4.4 (before the
`fifth dose) to 25.3±4.5 (2 hours after the fifth
`dose) to 23.6±3.8 (4 hours after the fifth dose). Id.
`at 18:28-50 (Table 4). At 6 hours after the fifth
`dose, the IOP appears to be returning to the
`treated baseline level prior to administration of
`the fifth dose. Id.”
`
` Dr. Fechtner:
` “Klimko reports a decrease in mean % IOP reduction (increase in IOP) from 30.2±4.4 (before the fifth
`dose) to 25.3±4.5 (2 hours after the fifth dose) to 23.6±3.8 (4 hours after the fifth dose). Id. at 18:28-
`50 (Table 4). Even at 6 hours after administration of the fifth dose, the mean % IOP reduction
`(28.9±3.0) has not returned to the level reported for 16 hours after the fourth dose (30.2±4.4).”
`Ex. 1003-18, Table 4; Paper 22 at 38; Ex. 2001 at ¶ 87; Ex. 2002 at ¶¶ 33-34; Paper 24 at 8-9
`# 31 (DEMONSTRATIVE EXHIBIT—NOT EVIDENCE)
`
`
`
`The Erroneous Alleged “Initial Increase in IOP” in Klimko
`
` Dr. Macdonald’s misinterpretation of Ex. 2003 to explain “initial increase
`in IOP”
`
`Ex. 2028 at ¶ 7 (citing Ex. 2003); Paper 22 at 38-39; Paper 24 at 8-9
`
`# 32 (DEMONSTRATIVE EXHIBIT—NOT EVIDENCE)
`
`
`
`The True Meaning of “Initial Increase in IOP”
`As Understood by the POSA
`Ex. 2003
`(Camras 1977)
`
`Dr. Macdonald’s flawed understanding of what is
`meant by “an initial increase in IOP” is not even
`supported by the prior art reference he relies on.
`
`Paper 24 at 8-9; Ex. 2003 at 4-5, Fig. 3; Ex. 1031 at ¶ 31; Ex. 1032, ¶¶ 39-40
`
`# 33 (DEMONSTRATIVE EXHIBIT—NOT EVIDENCE)
`
`
`
`The True Meaning of “Initial Increase in IOP”
`As Understood by the POSA
`
`Ex. 1009
`(Camras 1981)
`
`Paper 24 at 8-9; Ex. 1009 at 2, Table 1; Ex. 1031 at ¶ 32
`
`# 34 (DEMONSTRATIVE EXHIBIT—NOT EVIDENCE)
`
`
`
`The True Meaning of “Initial Increase in IOP”
`As Understood by the POSA
`Ex. 1044
`
`Ex. 1044 at 2-3, Fig. 1; Paper 24 at 8-9; Ex. 1031 at ¶ 33.
`
`# 35 (DEMONSTRATIVE EXHIBIT—NOT EVIDENCE)
`
`
`
`The True Meaning of “Initial Increase in IOP”
`As Understood by the POSA
`
`Ex. 2013
`
`Ex. 2013 at 5-6, Fig. 2; Paper 24 at 8-9; Ex. 1031 at ¶ 33
`
`# 36 (DEMONSTRATIVE EXHIBIT—NOT EVIDENCE)
`
`
`
`No “Initial Increase in IOP” Observed In Klimko
`for Compound C
`
`ALL IOPexp – IOPbaseline < 0
`
`Compound C
`
`Paper 24 at 9-10; Ex. 1031 at ¶ 37
`
`# 37 (DEMONSTRATIVE EXHIBIT—NOT EVIDENCE)
`
`
`
`Expert Explanation for the Decrease in Percent IOP Reduction Observed In Klimko
`
`Dr. DeLong
`
`Ex. 1031 at ¶ 39; Paper 24 at 10-11
`
`# 38 (DEMONSTRATIVE EXHIBIT—NOT EVIDENCE)
`
`
`
`No “Initial Increase in IOP” Reported for Compound C In Stjernschantz
`
` The corresponding control group (group “C”) also exhibited an increase in the IOP.
` Table IV in Stjernschantz reports statistical significances, however, no statistical significance was
`indicated with the IOP at 1-2 hours data point.
`
`Ex. 2017 at 16-17, Table V; Ex. 1031 at ¶ 41; Paper 24 at 10-11; Ex. 1032 at ¶¶ 30-33
`
`# 39 (DEMONSTRATIVE EXHIBIT—NOT EVIDENCE)
`
`
`
`No “Initial Increase in IOP” Reported for Compound C In Stjernschantz
`
`Ex. 2034
`(Wang)
`
`No initial ocular hypertension was observed when the IOPs from both
`the control group and the experimental group shows an increase.
`
`Ex. 2034 at 2-3, Fig. 3; Ex. 1031 at ¶ 41; Paper 24 at 10-11.
`
`# 40 (DEMONSTRATIVE EXHIBIT—NOT EVIDENCE)
`
`
`
`Any Observable Initial Increase in IOP Would Not Discourage A POSA
`From Selecting Compound C As A Lead Compound
`
`Ex. 2003
`
`Reason 1: Initial increase in IOP was known to be dose-
`dependent and can be mitigated or eliminated by dose
`reduction.
`
` The alleged initial increase in IOP for compound C
`from Stjernschantz was at a high dose of 5 µg. Klimko
`reports that compound C has superior IOP-lowering
`effect on monkeys with a low dose of 0.3 µg.
`
`Paper 24 at 1, 7, 12-13; Ex. 2003 at Fig. 3; Ex. 1031 at ¶ 30, 42-44; Ex. 1032 at ¶¶ 31-33
`# 41 (DEMONSTRATIVE EXHIBIT—NOT EVIDENCE)
`Paper 1 at 49; Ex. 1027 at ¶ 65; Ex. 1028 at ¶ 58
`
`
`
`Any Observable Initial Increase in IOP Would Not Discourage A POSA
`From Selecting Compound C As A Lead Compound
`Reason 2: Latanoprost was developed despite
`showing an initial increase in IOP.
`
`Ex. 1046 at 2-4, Fig. 3; Paper 24 at 12-13; Ex. 1031 at ¶ 43.
`
`# 42 (DEMONSTRATIVE EXHIBIT—NOT EVIDENCE)
`
`
`
`Any Observable Initial Increase in IOP Would Not Discourage A POSA
`From Selecting Compound C As A Lead Compound
`Reason 3: Kishi teaches how to eliminate both hyperemia and an initial increase in IOP.
`
`Paper 1 at 50-51; Ex. 1005 at 2:4-10; Paper 24 at 13-14; Ex. 1031 at ¶ 45
`
`# 43 (DEMONSTRATIVE EXHIBIT—NOT EVIDENCE)
`
`
`
`Reasonable Expectation: Difluorination Substitution Mimics the Tetrahedral
`Geometry Essential for IOP-Reducing Efficacy
`
`Ex. 1047
`(Resul 1993)
`
`A POSA would recognize that the tetrahedral
`geometry (i.e., stereochemical configuration) of
`the carbon at C-15 is essential for maintaining the
`potent and selective binding to FP receptors, which
`plays the defining role in IOP-reducing effect.
`
`Ex. 1047 at 1-2; Paper 24 at 15-16; Ex. 1031 at ¶ 49
`
`# 44 (DEMONSTRATIVE EXHIBIT—NOT EVIDENCE)
`
`
`
`Reasonable Expectation: Difluorination Substitution Mimics the Tetrahedral
`Geometry Essential for IOP-Reducing Efficacy
`
`Ex. 1048
`(Skuballa 1978)
`
`Paper 24 at 15-16; Ex. 1048 at 1; Ex. 1031 at ¶¶ 49-50
`
`# 45 (DEMONSTRATIVE EXHIBIT—NOT EVIDENCE)
`
`
`
`Reasonable Expectation: Difluorination Substitution Mimics the Tetrahedral
`Geometry Essential for IOP-Reducing Efficacy
`
`Ex. 1048
`(Skuballa 1978)
`
`15, 15-ethylene ketals (cyclic ketals) PGF2α
`has an increased biological activity.
`
`Paper 24 at 15-16; Ex. 1048 at 1; Ex. 1031 at ¶¶ 49-50
`
`# 46 (DEMONSTRATIVE EXHIBIT—NOT EVIDENCE)
`
`
`
`Reasonable Expectation: Difluorination Substitution Mimics the Tetrahedral
`Geometry Essential for IOP-Reducing Efficacy
`
`Kishi (Ex. 1005)
`
`Ex. 1049 (Bito)
`
`15-keto PGF2α has less
`potency of IOP-reducing
`activity.
`(deLong Suppl. Decl. at ¶ 50)
`
`Paper 24 at 14-16; Ex. 1005-3 at 1:46-50; Ex. 1049 at 3; Ex. 1031 at ¶ 50
`
`# 47 (DEMONSTRATIVE EXHIBIT—NOT EVIDENCE)
`
`
`
`Reasonable Expectation: Difluorination Substitution Mimics the Tetrahedral
`Geometry Essential for IOP-Reducing Efficacy
`
`15-keto PGF2α has less potency,
`but 15, 15-ethylene ketals (cyclic
`ketals) PGF2α has more potency.
`
`15-keto replacement
`disrupts the tetrahedral
`geometry at C-15
`
`Dr. DeLong
`
`Ex. 1048 at 1; Paper 24 at 15-16; Ex. 1031 at ¶ 50
`
`# 48 (DEMONSTRATIVE EXHIBIT—NOT EVIDENCE)
`
`
`
`Substituting the C-15 Hydroxyl Group With Fluorine Atoms
`Would Have Been A Natural And Obvious Choice For A POSA
`
`Checklist for a proper surrogate for the C-15 hydroxyl group
` Must maintain or mimic the tetrahedral geometry of the groups
`attached at the C-15 position
` Similar “C-X” bond length as “C-O”
`
` Relatively small atomic size (to avoid steric hindrance)
`
` Can serve as a hydrogen-bond acceptor, but not hydrogen-bond
`donor (to minimize chemical and biological lability, i.e., resistance to
`enzymatic attack)
`
` Enhance lipophilicity
`
`Paper 24 at 14-16, 18; Ex. 1031 at ¶¶ 55-61
`
`# 49 (DEMONSTRATIVE EXHIBIT—NOT EVIDENCE)
`
`
`
`Substituting the C-15 Hydroxyl Group With Fluorine Atoms
`Would Have Been A Natural And Obvious Choice For A POSA
`
`Bezgluv 1986
`(Ex. 1008)
`
`Paper 24 at 14-16, 18; Ex. 1008 at 3-4; Ex. 1031 at ¶¶ 55-61
`
`# 50 (DEMONSTRATIVE EXHIBIT—NOT EVIDENCE)
`
`
`
`Reasonable Expectation: Fluorination at C-15 Would Improve Compound C’s
`Therapeutic Profile
`
`Bezgluv 1986
`(Ex. 1008)
`
`Paper 24 at 14-16, 18; Ex. 1008 at 5-6; Ex. 1031 at ¶¶ 55-61, 66
`
`# 51 (DEMONSTRATIVE EXHIBIT—NOT EVIDENCE)
`
`
`
`Reasonable Expectation: Fluorination at C-15 Would Improve Compound C’s
`Therapeutic Profile
`Bezuglov 1982 teaches fluorination substitution at C-15
`not only maintains the activity but also has a prolonged
`activity
`
`Ex. 1007/1030
`(Bezuglov 1982)
`
`Paper 1 at 39-40; Paper 24 at 14-16; Ex. 1007/1030 at 7-10; Ex. 1031 at ¶¶ 55-61
`
`# 52 (DEMONSTRATIVE EXHIBIT—NOT EVIDENCE)
`
`
`
`Reasonable Expectation: Difluorination Substitution Mimics the Tetrahedral
`Geometry Essential for IOP-Reducing Efficacy
`
`Dr. DeLong
`
`Paper 24 at 15-16, 18; Ex. 1031 at ¶ 59
`
`# 53 (DEMONSTRATIVE EXHIBIT—NOT EVIDENCE)
`
`
`
`Klimko’s ’671 Application Reflects the State of the Art At the Filing Date of the ’035 Patent
`
`Fluorination at C-15
`
` Klimko’s ’671 Application claims
`15-fluoro PGF2α analogs which
`replace C-15 hydroxyl group with
`fluorine.
`
` In re Hogan, 559 F.2d 595, 605 &
`n. 17 (C.C.P.A. 1977) (non-
`statutory prior art is relevant “as
`evidence of the state of the art
`existing on the filing date of an
`application.”).
`
`Earlier than the priority date of the
`’035 patent: December 26, 1996
`
`Paper 1 at 21-22; Paper 24 at 16; Ex. 1012 at p. 1-7; Ex. 1027 at ¶¶ 44-47
`
`# 54 (DEMONSTRATIVE EXHIBIT—NOT EVIDENCE)
`
`
`
`Alleged Secondary Considerations
`Do Not Rebut Prima Facie Obviousness
`
`Paper 24 at 18; Ex. 1031 at ¶¶ 77-98; Ex. 1032 at ¶¶ 54-73
`
`# 55 (DEMONSTRATIVE EXHIBIT—NOT EVIDENCE)
`
`
`
`Tafluprost Has Not Achieved Any Commercial Success
` Patent Owners relied on “Forecasts” of a global sales of
`Tapros.
` Dr. deLong: “a global sales of only $150 million in 2017 is far
`from what could be described as a commercial success as I
`understand the term to mean the total glaucoma market of
`these regions (global regions listed above excluding the U.S.
`market) is estimated to be ~ $2.6 billion (and at least ~ $1.3
`billion just for prostaglandin analogues (PGA)).”
`
`Patent Owners
`
`Ex. 2030
`
`Paper 24 at 19-20; Paper 22 at 66; Ex. 2030 at 10; Ex. 1031 at ¶ 82.
`
`# 56 (DEMONSTRATIVE EXHIBIT—NOT EVIDENCE)
`
`
`
`Tafluprost Has Not Achieved Any Commercial Success:
`Very Small Market Share
`
`Eight years after being launched in Japan:
`
`• The market share of latanoprost is 19% ~ 20%.
`•
`Latanoprost stills accounts for approximately 65% of PG-analog prescriptions even after tafluprost was launched.
`
`Paper 24 at 19-20; Ex. 1031 at ¶¶ 83, 92
`
`# 57 (DEMONSTRATIVE EXHIBIT—NOT EVIDENCE)
`
`
`
`Alleged Copying by Generics Is Not Evidence of Commercial Success
`
`Paper 24 at 20
`
`# 58 (DEMONSTRATIVE EXHIBIT—NOT EVIDENCE)
`
`
`
`No Nexus Between Any Alleged Commercial Success and the Patent Claims
`
`Paper 24 at 19-20; Ex. 1031 at ¶ 86; Ex. 1060 at 36, 50; Ex. 1032, ¶¶ 69-70
`
`# 59 (DEMONSTRATIVE EXHIBIT—NOT EVIDENCE)
`
`
`
`No Unexpected Results for Tafluprost
`
` Kishi teaches that removal of the C-15 hydroxyl of compound C would
`reduce hyperemia and ameliorate any initial increase in IOP
`
` Bezuglov 1982/1986, Ueno, and common sense knowledge of the POSA
`teaches that difluorination at the C-15 position of compound C would be
`expected to improve the therapeutic profile of compound C by
`maintaining IOP-lowering activity while reducing side effects.
`
`Paper 24 at 20-21; Ex. 1031 at ¶¶ 17-39; 47-57
`
`# 60 (DEMONSTRATIVE EXHIBIT—NOT EVIDENCE)
`
`
`
`No Long-Felt But Unmet Need That Was Met by Tafluprost
`
`Dr. Rose
`
`Paper 24 at 21; Ex. 1031 at ¶ 91; Ex. 1032 at ¶¶ 55-62
`
`# 61 (DEMONSTRATIVE EXHIBIT—NOT EVIDENCE)
`
`
`
`No Long-Felt But Unmet Need That Was Met by Tafluprost
`
`Dr. deLong
`
`Paper 24 at 21; Ex. 1031 at ¶ 91; Ex. 1032 at ¶¶ 55-62
`
`# 62 (DEMONSTRATIVE EXHIBIT—NOT EVIDENCE)
`
`
`
`Dr. deLong
`
`No Evidence of Failure of Others
`Ex. 1036
`
`Paper 24 at 21-22; Ex. 1031 at ¶¶ 92-93; Ex. 1036 at 2
`
`# 63 (DEMONSTRATIVE EXHIBIT—NOT EVIDENCE)
`
`
`
`Alleged Secondary Considerations Are Not Commensurate With the Scope of Claims
`Claims of the ’035 patent cover a broad
`range of compounds other than tafluprost.
`
`Paper 24 at 22-23; Ex. 1031 at ¶¶ 94-98; Ex. 1001-17, Claims 1, 12, Paper 1 at 44
`
`# 64 (DEMONSTRATIVE EXHIBIT—NOT EVIDENCE)
`
`
`
`Alleged Secondary Considerations Are Not Commensurate With the Scope of Claims
`Ex. 2012
`Dr. deLong
`
`Paper 24 at 22-23; Ex. 1031 at ¶¶ 94-98; Ex. 2012 at 1, Abstract
`
`# 65 (DEMONSTRATIVE EXHIBIT—NOT EVIDENCE)
`
`
`
`Alleged Secondary Considerations Are Not Commensurate With the Scope of Claims
`Ex. 1061
`Dr. deLong
`
`Paper 24 at 22-23; Ex. 1031 at ¶¶ 94-98; Ex. 1061 at 15:27–61
`
`# 66 (DEMONSTRATIVE EXHIBIT—NOT EVIDENCE)
`
`
`
`Dr. Timothy Macdonald
`
` Expert in the field of “the medicinal
`chemistry and molecular
`pharmacology of lipid signaling
`systems”
`
` Only relevant experience: worked for
`Allergan as a technical consultant on
`the discovery and evaluation of novel
`compounds, allegedly including
`prostaglandin analogs
`
` No scientific publication or patent in
`the area of prostaglandin analogs
`
`V.
`
`Dr. Mitchell deLong
`
` A medicinal chemist with decades of
`specific experience in developing
`prostaglandin derivative compounds for
`treatment of glaucoma or ocular
`hypertension
`
` Successfully developed netarsudil
`(Rhopressa®) for the treatment of elevated
`IOP in glaucoma patients via Aerie
`Pharmaceuticals, and bimatoprost
`(Latisse®) for the treatment of
`hypotrichosis of eyelashes
`
` Many scientific publications and
`patents/patent applications in the area of
`prostaglandin analogs, including the use for
`the treatment of glaucoma.
`
`Paper 24 at 11-12; Ex. 1031 at ¶ 7; Paper 30 at 7; Ex. 1027 at Appd’x B.
`
`# 67 (DEMONSTRATIVE EXHIBIT—NOT EVIDENCE)
`
`
`
`DeLong’s Testimony in the Canadian Proceeding Is Irrelevant
`
` Issue in this proceeding: “what a POSA would have chosen to select as a
`lead compound and modify [in view of Kishi or any other prior art]… in
`December 1996.” (Ex. 1031, deLong Suppl. Decl. ¶ 74)
`
` Issue in the Canadian proceeding: whether a POSA in August 1993,
`would have considered compound C as a therapeutic agent for direct
`“human testing” and whether the compound would accordingly
`anticipate the claims of the Canadian patent at issue in that case
`
`Paper 44 at 1; Ex. 1031 at ¶ 74; Paper 24 at 7; Paper 30 at 3-4
`
`# 68 (DEMONSTRATIVE EXHIBIT—NOT EVIDENCE)
`
`
`
`DeLong’s Testimony in the Canadian Proceeding Is Irrelevant
`
` A compound that causes moderate hyperemia may not be considered as
`having an acceptable therapeutic profile for direct use as a therapeutic
`drug, but it may be the best candidate for a lead compound if further
`modification is expected to reduce the side effects.
`
` Neither Kishi nor the ’856 publication (Ex. 1004) was ever referenced in the
`Canadian proceeding, nor was there any reason to because in the Canadian
`case the issue was not modification of compound C in view of any prior art
`reference, including Kishi, but direct human testing of compound C
`
`Paper 44 at 1-2; Ex. 1031 at ¶¶ 72-74; Paper 30 at 3-4; Paper 24 at 7-8
`
`# 69 (DEMONSTRATIVE EXHIBIT—NOT EVIDENCE)
`
`
`
`DeLong’s Testimony in the Canadian Proceeding Is Irrelevant
`
`Ex. 2027 at [9], [337]; Paper 44 at 1-2; Ex. 1031 at ¶¶ 72-74; Paper 30 at 3-4; Paper 24 at 7-8
`# 70 (DEMONSTRATIVE EXHIBIT—NOT EVIDENCE)
`
`
`
`Statistical Significance
`
`Dr. deLong 2nd Depo. Tr:
`
`Paper 39 at 14-15; Ex. 2061 at 69:21-70:4; 12:7-13
`
`# 71 (DEMONSTRATIVE EXHIBIT—NOT EVIDENCE)
`
`
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