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`Case IPR2017-01434
`US Patent No. 5,886,035
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`UNITED STATES PATENT AND TRADEMARK OFFICE
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`____________
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`____________
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`MICRO LABS LIMITED AND MICRO LABS USA INC.
`Petitioners,
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`v.
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`SANTEN PHARMACEUTICAL CO., LTD. AND ASAHI GLASS CO., LTD.
`Patent Owners.
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`____________
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`Case IPR2017-01434
`U.S. Patent No. 5,886,035
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`____________
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`PATENT OWNERS' MOTION FOR OBSERVATION
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`REGARDING CROSS-EXAMINATION OF PETITIONERS' EXPERT,
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`DR. MITCHELL A. DELONG
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`Case IPR2017-01434
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`US Patent No. 5,886,035
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`Pursuant to the Scheduling Order in this proceeding (Paper 12), and the
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`Office Patent Trial Practice Guide, Patent Owners Santen Pharmaceutical Co., Ltd.
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`and Asahi Glass Co., Ltd. (together, "Patent Owners"), respectfully submit this
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`Motion for Observation Regarding Cross-Examination of Dr. Mitchell A. deLong,
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`the Reply declarant of Petitioners Micro Labs Limited and Micro Labs USA Inc.
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`(together "Micro Labs" or "Petitioner"). The full transcript of Dr. deLong's July
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`12, 2018 cross-examination is being filed concurrently as Ex. 2061.
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`Observation # 1: In Ex. 2061 at 119:6-24, Dr. deLong agreed that
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`Petitioners' Ex. 1004 (a European patent application listing Kishi as the first named
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`inventor) was published February 26, 1992. Dr. deLong agreed that Ex. 1004
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`contains "the same" disclosure as Tables 1 and 3 (and the conclusions
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`accompanying those tables) in the asserted Kishi prior art reference in this
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`proceeding (Ex. 1005). Id. at 122:4-123:5, 123:17-124:24. Notably, Dr. deLong
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`agreed that Ex. 1004 discloses the teaching of the asserted Kishi reference (Ex.
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`1005) that he and Petitioners rely on in this proceeding: "Ex. 1004 discloses 15-
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`deoxy PG derivatives with fewer side effects than PGF2alpha, which has a 15-
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`hydroxyl group." Id. at 125:5-18. The above testimony is relevant to Dr. deLong's
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`opinions in a previous Canadian proceeding (Ex. 2027). Dr. deLong's testimony
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`refutes his and Petitioners' assertion that his contradictory testimony in that
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`US Patent No. 5,886,035
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`previous Canadian proceeding (see Patent Owners' Response (Paper 22) at 47-51)
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`should be ignored; Dr. deLong's testimony contradicts his position that the
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`teachings of Kishi (Ex. 1005) were allegedly unavailable to a person of ordinary
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`skill in the art ("POSITA") as of the relevant invention date in the Canadian
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`proceeding, i.e., August 3, 1993. Ex. 1031, ¶ 74; Reply (Paper 24) at 7. Instead,
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`Dr. deLong’s testimony above is consistent with Petitioners' admission in the
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`Petition that Exs. 1004 and 1005 "share nearly-identical disclosures and are
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`interchangeable for purposes of Petitioners' Grounds 1 and 2 and reliance on
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`Kishi therein." Petition (Paper 1) at 34 n. 6 (emphasis added).
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`Observation # 2: In Ex. 2061 at 95:13-96:10, Dr. deLong agreed that the
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`modified Compounds 6 and 8 disclosed in Kishi (Ex. 1005) "show[] less reduction
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`in IOP compared to the baseline than the controls B [i.e., PGF2ɑ] and C [i.e.,
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`PGF2ɑ-IE]" and "show[] less reduction in IOP compared to the control [eyes] than
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`Compounds B and C." Dr. deLong's testimony demonstrates that, to the extent
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`Kishi's modified compounds lack the undesirable initial increase in IOP of the
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`PGF2ɑ and PGF2ɑ-IE controls, they are also much less effective at reducing IOP
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`than the PGF2ɑ and PGF2ɑ-IE controls. This is consistent with the opinion of
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`Patent Owners' expert, Dr. Macdonald, that overcoming an undesirable initial
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`increase in IOP of a prostaglandin analog is associated with decreased efficacy.
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`Ex. 2028, ¶ 7. Dr. deLong's testimony regarding the decreased efficacy of the
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`Kishi compounds also contradicts his and Petitioners' argument that a POSITA
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`would turn to Kishi's modifications to eliminate an undesirable initial increase in
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`IOP. Ex. 1031, ¶ 45; Reply (Paper 24) at 13-14.
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`Observation # 3: In Ex. 2061, Dr. deLong testified that he had read
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`Petitioners' Ex. 1036 in its entirety "many times" (id. at 126:16-127:2), and that it
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`teaches the following in 2014: 1) PGF2ɑ-IE causes "unacceptable foreign body
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`sensation and conjunctival hyperemia" (id. at 127:3-20); 2) conjunctival hyperemia
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`"is the most frequently reported side effect of the PG analogs and is commonly a
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`cause of treatment discontinuation" (id. at 127:21-130:8); 3) hyperemia "is a
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`significant contributor to treatment discontinuation with the PG analogs" that
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`"account[s] for stopping or changing medication in 63 percent of patients in whom
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`changes were made due to side effects" (id. at 130:9-131:3); and 4) "the per-patient
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`cost of treating hyperemia-free patients [is] U.S. dollars 73.67 compared with U.S.
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`dollars 140.02 in those who discontinued treatment due to hyperemia" (id. at
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`131:4-131:14). Dr. deLong's testimony contradicts his and Petitioners' assertion
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`that, by December 26, 1996, the field had come to view conjunctival hyperemia as
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`a minor cosmetic side effect of prostaglandin analogs. Ex. 1031, ¶ 73; Reply
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`(Paper 24) at 4, 6-7.
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`Observation # 4: In Ex. 2061 at 34:5-15, Dr. deLong testified that, for
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`FDA-approved Xalatan (branded latanoprost), "[t]he percent adverse reaction
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`incidence is noted [in Ex. 2037, the package insert for Xalatan,] as 8 percent and
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`less than 1 percent required discontinuation of therapy because of intolerance to
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`that hyperemia." Id. (emphasis added). This testimony contradicts Dr. deLong's
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`declaration testimony relating to the level of hyperemia that would be acceptable
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`for a prostaglandin analog (and specifically latanoprost) as of December 26, 1996.
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`In particular, Dr. deLong makes the bare assertion in his declaration (Ex. 1031,
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`¶ 73 (emphasis added))—without citing supporting evidence—that "clinical studies
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`show that latanoprost induced an increase in conjunctival hyperemia in more than
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`30% of treated patients; however, this prostaglandin derivative drug was still
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`developed by researchers and received approval from the FDA in 1996."
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`Observation # 5: In Ex. 2061 at 98:21-24, Dr. deLong agreed that "Ex.
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`1050 teaches that a fluorine accepts hydrogen bonds at less than half the strength
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`of an oxygen." Dr. deLong also agreed that Ex. 1050 discloses: "These examples
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`suggest that F is replacing OH, possibly in its role as a hydrogen bond acceptor.
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`However, such successful examples are few and more often than not the
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`substitution proves detrimental to the binding affinity or the kinetics of turnover."
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`Id. at 98:25-99:13. Dr. deLong's testimony contradicts his and Petitioners'
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`contention that a POSITA as of December 26, 1996 would have expected fluorine
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`to mimic the hydrogen bond acceptor ability of the hydroxyl at the C15 position of
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`a prostaglandin analog. Ex. 1031, ¶¶ 55-56; Reply (Paper 24) at 15. Instead, Dr.
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`deLong's deposition testimony is consistent with the opinion of Patent Owners'
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`expert, Dr. Macdonald, that one of the many differences between fluorine and
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`hydroxyl is that fluorine "is only a very poor hydrogen bond acceptor," and "a
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`POSITA would have doubted that fluorine could mimic the C15 hydroxyl group of
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`a prostaglandin analog." Ex. 2028, ¶¶ 17-24.
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`Observation # 6: In Ex. 2061 at 107:7-14, Dr. deLong agreed that, with
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`respect to calculations of logP to assess lipophilicity, he only calculated the logP
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`of latanoprost; he did not calculate the logP of tafluprost. Instead, Dr. deLong
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`compared his calculation for latanoprost against Dr. Macdonald's calculation using
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`a different method for tafluprost. Id. Dr. deLong's testimony demonstrates the
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`flawed basis for his assertion that latanoprost was even more lipophilic (had a
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`higher logP) than difluorinated tafluprost (and that a POSITA would not have been
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`concerned about excessive lipophilicity with tafluprost). Ex. 1031, ¶ 69.
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`Observation # 7: In Ex. 2061 at 113:17-115:10, Dr. deLong agreed that,
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`using the same ALOGPS prediction algorithm for both tafluprost and latanoprost,
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`Ex. 20561 (at 4) discloses a predicted logP value of 4.46 for tafluprost, while Ex.
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`2057 (at 4) discloses a lower predicted logP value (less lipophilicity) of 4.16 for
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`latanoprost. Using the same ChemAxon prediction algorithm for both tafluprost
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`and latanoprost, Dr. deLong agreed that Ex. 2056 (at 4) discloses a predicted logP
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`value of 4.29 for tafluprost, while Ex. 2057 (at 4) discloses a lower predicted logP
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`value (less lipophilicity) of 3.98 for latanoprost. Id. Dr. deLong's testimony
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`contradicts his assertion in his declaration that latanoprost was even more
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`lipophilic (had a higher logP) than difluorinated tafluprost; instead, when
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`comparing logP values using the same algorithm, the opposite is true. Ex. 1031,
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`¶ 69.
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`Observation # 8: In Ex. 2061 at 9:13-11:7, Dr. deLong testified that, with
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`respect to the IOP reduction data for Compound C in Table 4 of Klimko (Ex. 1003
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`at 18), "you can't take a mean without understanding the standard error or standard
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`1 Because some text of Exs. 2056 and 2057 (unrelated to the logP predictions
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`discussed in the deposition) was inadvertently cut off in those exhibits, Patent
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`Owners have also filed replacement documents as Exs. 2063 and 2064,
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`respectively.
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`US Patent No. 5,886,035
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`deviation"; "you have to look at the error bars" and "see how much overlap if any
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`there is in the error bars." Dr. deLong testified that, for Compound C, there is a
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`"pretty significant overlap" between the IOP reduction at 16 hours after the fourth
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`dose and 2 hours after the fifth dose. Id. Dr. deLong concluded: "So I don't think,
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`looking at these numbers in the actual context, with understanding what they
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`represent[] is the average[,] that one can really say there's really a difference
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`between these two numbers." Id. Dr. deLong's testimony contradicts his and
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`Petitioners' argument that Compound C displayed an "observable trend at 2, 4 and
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`6 hours after administration of the fifth dose" that demonstrates a longer duration
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`of action than Compounds A, B and D. Reply (Paper 24) at 3; Ex. 1031, ¶ 13.
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`Observation # 9: In Ex. 2061 at 16:2-9, Dr. deLong testified that, with
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`respect to the IOP lowering data in Table 4 of Klimko (Ex. 1003), he did not know
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`"how long it would take for the mean IOP reduction to drop from 30 to 0 in
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`relation to Compound C," because "[e]very compound is metabolized and
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`processed differently." Dr. deLong testified that "you would need to do a study
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`where you dose the compound and then you stop dosing and then you measure the
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`length of time it takes to go back to baseline." Id. at 16:12-24. Dr. deLong
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`testified that Klimko (Ex. 1003) "doesn't report that exact study." Id. at 16:25-
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`17:11. Dr. deLong also testified that he was "not aware" of any "data in Klimko
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`regarding the level of active drug in the eye at different time points." Id. at 18:13-
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`16. Dr. deLong's testimony confirms that Klimko (Ex. 1003) does not provide any
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`data that would link the initial increase in IOP observed with Compound C to its
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`metabolism, absorption, and levels in the eye. This testimony contradicts Dr.
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`deLong's opinion that the initial increase in IOP for Compound C "is likely only
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`because a trough level (i.e., the lowest concentration) of compound C was reached
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`at that period based on how compound C is metabolized and absorbed in the tested
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`animals." Ex. 1031, ¶ 39.
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`Observation # 10: In Ex. 2061 at 22:6-15, Dr. deLong would not agree
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`that, with respect to the hyperemia scoring scale disclosed in Klimko (Ex. 1003 at
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`16), "a compound associated with a score of 3 has moderate hyperemia." Rather,
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`Dr. deLong testified that the terms "mild" and "moderate" are "not defined in this
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`[Klimko] chart." (Emphasis added). Dr. deLong's testimony contradicts his and
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`Petitioner's argument that Klimko's reported hyperemia scores for Compound C
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`(e.g., 38% incidence of a score of 3 for a 0.3 ug dose, and 63% incidence of a score
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`of 3 for a 1.0 ug dose) indicated only "mild/modest," "mild/moderate" or "only
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`moderate" hyperemia. Ex. 1031, ¶ 27 (emphasis added); Reply (Paper 24) at 5
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`(emphasis added). It also contradicts Dr. deLong's testimony in his declaration that
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`"[C]ompound C only caused at most moderate conjunctival hyperemia in the
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`tested guinea pigs" in Klimko (Ex. 1003). Ex. 1031, ¶ 25 (emphasis in original);
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`see also Reply (Paper 24) at 5, 8.
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`Observation # 11: In Ex. 2061 at 30:4-31:6, Dr. deLong testified that, in
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`the hyperemia data disclosed in Klimko (Ex. 1003), the recorded incidence of a
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`score of 3 was 38 percent for Compound C, and 4 percent for Compound B, i.e.,
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`there was a nearly tenfold greater incidence of a hyperemia score of 3 (the highest
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`recorded score) for Compound C compared to Compound B. Dr. deLong refused
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`to concede that even this nearly tenfold difference was outside the margin of error
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`of the assay. Id. at 32:17-19; see also id. at 29:6-:32:16. Patent Owners
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`respectfully submit that Dr. deLong's extreme position raises questions about his
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`credibility and objectivity in assessing the hyperemia data reported for Compound
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`C in Klimko (Ex. 1003).
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`Observation # 12: In Ex. 2061 at 36:14-37:3, Dr. deLong testified that the
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`IOP-lowering experiment in Stjernschantz (Ex. 2017) with respect to Compound 4
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`(Compound C of Klimko (Ex. 1003)) was conducted in cats, not monkeys. Dr.
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`deLong testified that when he "was doing prostaglandin research, in one model, we
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`found one compound was 10 times worse than a second compound, say A was
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`tenfold less potent than B in one animal model. We tested it in the other animal
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`model and it was a thousand times more potent than the other compound. So going
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`from species to species, no, in general in prostaglandins you can't do an assay and
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`know that even the rank order will be the same unless, you know, you have a lot of
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`other information." Id. at 39:14-40:13. Dr. deLong's testimony contradicts
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`Petitioners' and Dr. Rose's argument that a POSITA would compare the doses of
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`Compound C used in the cat IOP lowering experiment in Stjernschantz (Ex. 2017)
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`with the monkey IOP lowering experiment in Klimko (Ex. 1003) to determine
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`whether the dose in either species could be lowered. Reply (Paper 24) at 13; see
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`also Ex. 1032, ¶ 32.
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`Observation # 13: In Ex. 2061 at 41:14-24, Dr. deLong agreed that "the
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`most promising compounds at the minimum are advanced from animal testing to
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`human testing." Dr. deLong also agreed that Table 6 of Stjernschantz (Ex. 2017)
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`reports human testing and that "table 6 does not report data for Compound 4,
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`which is Compound C of Klimko." Id. at 43:20-44:2, 44:7-10. Dr. deLong's
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`testimony contradicts his and Petitioners' argument that Stjernschantz discloses a
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`favorable therapeutic profile for Compound 4 (Compound C of Klimko (Ex.
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`1003)). Ex. 1031, ¶ 23; Reply at 6-7.
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`Observation # 14: In Ex. 2061 at 44:11-45:13, Dr. deLong testified that,
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`with respect to the IOP-lowering data in Table 6 of Stjernschantz (Ex. 2017), "[w]e
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`don't know" whether "[t]he peak IOP lowering for Compound 2 [is] 8 hours or
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`more." He testified that "it's hard to say that 6 and 8 [hours after administration]
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`are actually statistically different," and "it's very difficult without doing continuous
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`measurements, which were not available at the time of these data, to get the exact
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`peak." Id. Table 4 of Klimko (Ex. 1003 at 18) does not include continuous
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`measurements of IOP; thus, Dr. deLong's testimony establishes that Klimko also
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`does not provide enough data to reliably determine the time of peak IOP lowering
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`for Compounds A-D. This testimony contradicts his and Petitioners' argument that
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`the data of Klimko discloses different peak IOP reductions for Compound C vs.
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`Compounds A, B and D. Ex. 1031, ¶¶ 14-16; Reply (Paper 24) at 3.
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`Observation # 15: In Ex. 2061 at 52:16-22 and 55:12-16, Dr. deLong
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`agreed that Stjernschantz (Ex. 2017) at 10:48-53 called out five compounds as
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`"being of particular significance" because they had considerably less or very little
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`conjunctival hyperemia. Dr. deLong testified that Compound 4 (Compound C of
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`Klimko (Ex. 1003)) is "not called out as being particularly advantageous as in -- in
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`this particular paragraph." Id. at 57:5-10. Dr. deLong's testimony contradicts his
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`and Petitioners' argument that Stjernschantz discloses a favorable therapeutic
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`profile for Compound 4 (Compound C of Klimko (Ex. 1003)). Ex. 1031, ¶ 23;
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`Reply at 6-7.
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`Dated: July 26, 2018
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`Respectfully submitted,
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`
`/ Arlene Chow /
`Arlene L. Chow
`Registration No. 47,489
`Eric J. Lobenfeld
`(pro hac vice)
`Ernest Yakob
`Registration No. 45,893
`Hogan Lovells US LLP
`875 Third Avenue
`New York, New York 10022
`Telephone: (212) 918-3000
`Fax: (212) 918-3100
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`Counsel for Patent Owners
`Santen Pharmaceutical Co., Ltd.
`and Asahi Glass Co., Ltd.
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`Case IPR2017-01434
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`US Patent No. 5,886,035
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`CERTIFICATE OF SERVICE
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`
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`The undersigned hereby certifies that a copy of the foregoing PATENT
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`OWNERS' MOTION FOR OBSERVATION REGARDING CROSS-
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`EXAMINATION OF PETITIONERS' EXPERT, DR. MITCHELL A. DELONG
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`was served on July 26, 2018, by filing this document through the Patent Trial and
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`Appeal Board End to End System as well as delivering a copy via electronic mail
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`upon the following attorneys of record for the Petitioner:
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`Cedric C.Y. Tan, Reg. No. 56,082
`H. Keeto Sabharwal, pro hac vice
`Yun Wei, Reg. No. 70,744
`Alton L. Hare, Reg. No. 68,638
`PILLSBURY WINTHROP SHAW PITTMAN LLP
`1200 Seventeenth Street, NW
`Washington, DC 20036
`Tel.: (202) 663-8000
`Fax.: (202) 663-8007
`Email: cedric.tan@pillsburylaw.com
`Email: keeto.sabharwal@pillsburylaw.com
`Email: sophie.wei@pillsburylaw.com
`Email: alton.hare@pillsburylaw.com
`
`Sean M. Weinman, Reg. No. 69,515
`PILLSBURY WINTHROP SHAW PITTMAN LLP
`1650 Tysons Boulevard, 14th Floor
`McLean, VA 22102
`Tel.: (703) 770-7511
`Fax.: (703) 770-4856
`Email: sean.weinman@pillsburylaw.com
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`MicroLabsIPR@pillsburylaw.com
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`Dated: July 26, 2018
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`Case IPR2017-01434
`US Patent No. 5,886,035
`/ Arlene Chow /
`
`Arlene L. Chow
`Registration No. 47,489
`Hogan Lovells US LLP
`875 Third Avenue
`New York, New York 10022
`Telephone: (212) 918-3000
`Fax: (212) 918-3100
`
`Counsel for Patent Owners
`Santen Pharmaceutical Co., Ltd.
`and Asahi Glass Co., Ltd.
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`
`14
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