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`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`_____________________________
`
`
`MYLAN PHARMACEUTICALS INC., TEVA PHARMACEUTICALS USA,
`INC. and AKORN INC.,1
`Petitioners,
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`v.
`
`ALLERGAN, INC.
`Patent Owner.
`
`_____________________________
`
`Case IPR2016-01127 (US 8,685,930 B2)
`Case IPR2016-01128 (US 8,629,111 B2)
`Case IPR2016-01129 (US 8,642,556 B2)
`Case IPR2016-01130 (US 8,633,162 B2)
`Case IPR2016-01131 (US 8,648,048 B2)
`Case IPR2016-01132 (US 9,248,191 B2)
`_____________________________
`
`PETITIONERS’ REPLY
`37 C.F.R. §42.24(c)
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`
`
`1 Cases IPR2017-00576 and IPR2017-00594, IPR2017-00578 and IPR2017-
`00596, IPR2017-00579 and IPR2017-00598, IPR2017-00583 and IPR2017-00599,
`IPR2017-00585 and IPR2017-00600, and IPR2017-00586 and IPR2017-00601,
`have respectively been joined with the captioned proceedings. The word-for-word
`identical paper is filed in each proceeding identified in the caption pursuant to the
`Board’s Scheduling Order (Paper 10).
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`PROTECTIVE ORDER MATERIAL
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`I.
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`INTRODUCTION .............................................................................................. 1
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`TABLE OF CONTENTS
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`II.
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`LEGAL STANDARDS ....................................................................................... 3
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`III. ALLERGAN ABANDONED ITS CLAIMED SUPERIORITY OVER DING 1E. ............... 4
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`IV. SALL DOES NOT DEMONSTRATE SUPERIORITY OF THE 0.05% CSA
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`FORMULATION ............................................................................................... 6
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`V. NEITHER THERMODYNAMIC PRINCIPLES NOR PK STUDIES SUPPORT
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`“CRITICALITY,” UNIQUE MECHANISM OF ACTION, OR UNEXPECTED RESULTS.. 14
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`VI. ALLERGAN LABELS CASTOR OIL AS TOXIC AND UNDESIRABLE AND IGNORES
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`ITS FAVORABLE PROPERTIES ........................................................................ 18
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`VII. THE CLAIMED DIFFERENCES ARE NOT DIFFERENCES IN KIND ....................... 20
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`VIII. NO NEXUS BETWEEN CLAIMS AND ALLEGED SATISFACTION OF LONG-FELT,
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`UNMET NEED............................................................................................... 22
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`IX. NO NEXUS BETWEEN CLAIMS AND SALES FIGURES ....................................... 24
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`X.
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`CLAIM CONSTRUCTION ................................................................................ 26
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`XI. CONCLUSION ............................................................................................... 26
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`-i-
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`PROTECTIVE ORDER MATERIAL
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`I.
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`INTRODUCTION
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`It is undisputed that the claimed formulation falls squarely within the ranges
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`disclosed in the prior art Ding ’979 patent. Allergan attempts to weave a tale of
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`unexpected results and criticality of the claimed formulation based on an alleged
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`superiority, but none has been demonstrated. The prior art Sall reference
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`demonstrates therapeutic equivalence between the 0.05% and 0.10% CsA
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`formulations. Allergan conjures a theory that the ratio of CsA-to-castor oil is
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`critical to therapeutic efficacy. But the very ratio used in the claimed formulation is
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`already disclosed in Ding ’979, and nothing in the record indicates that using this
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`ratio for a 0.05% CsA formulation changes its therapeutic efficacy. Allergan’s
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`arguments are not only unsubstantiated entirely, they are repeatedly and soundly
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`contradicted by the evidence of record.2
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`Allergan’s criticality arguments hinge on an alleged improvement in
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`categorized Schirmer Tear Test (“STT”) scores in Sall Figure 2 for the 0.05% CsA
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`formulation over the 0.10% CsA formulation. Allergan’s arguments contradict the
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`2 Because of the near-identity of issues in each of the IPRs addressing the
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`related ’930, ’111, ’556, ’162, ’048, and ’191 patents (“patents-at-issue”),
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`Petitioners’ Reply is identical in each IPR and provides citations to the page
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`numbers in IPR2016-01127 as exemplary citations for all six proceedings.
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`-1-
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`PROTECTIVE ORDER MATERIAL
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`teachings of Sall, Stevenson (EX1015 reporting Phase 2 results), and the shared
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`specification of the patents-at-issue. Sall, in fact, demonstrates substantially
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`equivalent therapeutic efficacy between the two formulations. EX1007, 634-36.
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`Any alleged difference between the two formulations is neither significant nor
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`material. Unexpected equivalent efficacy (or even potentially marginally increased
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`efficacy) between the two formulations does not demonstrate a difference in kind.
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`Allergan’s thermodynamic theory is so theoretical its experts never even
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`bothered to attempt to quantify it. Allergan’s suggestion that a thermodynamic
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`effect would be large enough to render the claimed formulation inoperative is
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`directly contradicted by Ding ’979’s teachings that its emulsions had “reasonably
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`high thermodynamic activity,” and that “the therapeutic level of cyclosporin was
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`found in the tissues of interest after dosage.” EX1006, 3:25-28, 5:15-24.
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`Allergan’s two PK studies confirm that any theoretical thermodynamic
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`effect was not large enough to matter, demonstrating each formulation delivered
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`well-above-therapeutic levels of CsA to the tissues. Further, Allergan’s employee,
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`Dr. Attar, compared these two, completely different types of studies (steady-state,
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`measuring tissue concentrations after 9.5 days of twice-daily 50 µL doses, versus
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`single-dose, measuring tissue concentrations after just one 28.5 µL dose), and still
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`failed to demonstrate a statistically significant difference in CsA delivery to the
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`lacrimal glands, the “most important” target tissue.
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`PROTECTIVE ORDER MATERIAL
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`Allergan’s remaining alleged objective indicia of non-obviousness fail for
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`lack of nexus. Allergan’s Orange Book listing of both U.S. Patent No. 4,839,342
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`(EX2002) and Ding ’979 render it impossible to attribute commercial sales to any
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`allegedly novel features of the claims. EX1032, ADA36. Allergan forcefully drove
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`sales through heavy direct-to-consumer marketing and other strategic initiatives.
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`Thus, Allergan’s sales numbers provide no information about any alleged relative
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`benefit from or criticality of the claimed formulation as compared to the prior art
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`alternatives. Moreover, the alleged objective indicia are not relevant to the
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`formulation claims because those are also anticipated.
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`II. LEGAL STANDARDS
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`Allergan must show that a POSA would have expected the claimed
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`formulation to lack therapeutic efficacy or operate differently for treating dry
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`eye/KCS. Paper 8, 17-19. Allergan must also produce evidence of objective indicia
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`of nonobviousness to rebut Petitioners’ evidence of obviousness. Prometheus
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`Labs., Inc. v. Roxane Labs., Inc., 805 F.3d 1092, 1101-02 (Fed. Cir. 2015).
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`Objective indicia require “a nexus to establish that the evidence relied upon traces
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`its basis to a novel element in the claim and not to something in the prior art.”
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`Biomarin Pharmaceutical Inc. v. Genzyme Therapeutic Products L.P., IPR2013-
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`00537, Paper 79, 22; Institute Pasteur & Universite Pierre et Marie Curie v.
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`Focarino, 738 F.3d 1337, 1347 (Fed. Cir. 2013); Ormco Corp. v. Align
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`Technology, Inc., 463 F.3d 1299, 1311-12, n.14 (Fed. Cir. 2006); Paper 8, 12-13.
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`III. ALLERGAN ABANDONED ITS CLAIMED SUPERIORITY OVER
`DING 1E.
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`Allergan falsely complains that Mylan failed to inform the Board that
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`Allergan attempted to retract its admission that the claimed formulation is squarely
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`within the prior art. Paper 16 (“POR”), 42-43. As Mylan explained in the petition
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`(1-4, 48; EX1002, ¶¶18-19; EX1005, 0434-37), Allergan conceded to the USPTO
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`on June 15, 2009 that the POSA “would readily envisage” the formulation of
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`Restasis® from Ding ’979 Example 1. Ding ’979, slated to expire on May 17, 2014,
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`was one of two patents Allergan listed in the FDA’s Orange Book in 2009 as
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`covering Restasis®. EX1032, ADA36. The second, U.S. Patent No. 4,839,342 to
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`Kaswan, broadly claimed “A method for enhancing or restoring lacrimal gland
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`tearing comprising topically administering cyclosporin to the eye in a
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`pharmaceutically acceptable vehicle. EX2002, claim 1. The ’342 patent expired on
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`August 2, 2009, leaving Ding ’979 as the sole patent covering Restasis®. EX1032,
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`ADA36.
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`In August 2013 when the Ding ’979 patent was close to expiration, Allergan
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`referred back to its June 2009 admissions and informed the USPTO that “Since
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`these comments have been filed, the Applicants have collected evidence that
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`supports the patentability of the pending claims.” Petition, 1-4, 48 (citing EX1004,
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`0007). Allergan stripped error bars from the prior art results of its Phase 3 clinical
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`trials, copied them wholesale from the Sall reference (including inaccuracies), and
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`submitted them to the USPTO through two then-Allergan employees, Drs.
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`Schiffman and Attar. EX1002, ¶¶127-29; EX1035, 54:7-61:12 (same data just
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`stripped error bars, including duplication of Figure 3), 18:23-19:7, 76:25-77:3;
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`EX1038, 14:2-7, 39:1-42:7; EX1039, ¶62. Notably, none of these exhibits was
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`based on data collected after June 15, 2009. EX1038, 145:13-22, 161:21-24;
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`EX1035, 58:10-61:12 (Schiffman exhibits copied from Sall); EX1036, 204:20-
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`205:7 (data reported in Sall not collected after June 15, 2009).
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`Drs. Schiffman and Attar both use nearly verbatim language to proclaim that
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`the claimed formulation is “critical for therapeutic effectiveness in the treatment of
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`dry eye/keratoconjunctivitis sicca.” POR, 21 (citing inclusive of EX1004, 0203
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`(Schiffman ¶20) and 0227-28 (Attar ¶14). These conclusions (including a
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`purported comparison between the claimed formulation and the Ding 1E
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`formulation) were based on exhibits for which Allergan refused to produce the
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`underlying data, leading the Board to order that these exhibits and the conclusions
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`based on them be entitled to no weight. EX1004, 0199-0203 (¶¶5-8, 14-20,
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`Exhibits B, D-F), 0225-0228 () ¶¶5, 9-14, Exhibits C-D); EX1038, 51:19-55:14
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`(adopted “the clinical stuff” without independent analysis); Paper 33, 3. In
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`abandoning these exhibits and testimony, Allergan disclaims its prior assertion that
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`the claimed formulation provides superior clinical efficacy over Ding 1E.
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`These declarations were not, however, without effect on the Patent Office,
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`and this alleged new evidence led to the issuance of the patents-at-issue. Petition,
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`4-5. Dr. Attar wrote that gaining “additional patent protection” for Restasis® was a
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`“major accomplishment” of hers. EX1038, 30:17-31:3; 50:24-51:10; EX1033, 1.
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`Dr. Bloch, a biostatistician who reviewed Dr. Attar’s data and attended her
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`deposition, describes how she adopted apparently false testimony during her
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`deposition in order to paint a more favorable picture of her analysis. EX1040,
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`¶¶58-68.
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`IV. SALL DOES NOT DEMONSTRATE SUPERIORITY OF THE 0.05%
`CSA FORMULATION
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`Allergan enlisted Drs. Loftsson and Sheppard in an attempt to establish that
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`the claimed formulation was surprisingly critical to and unique in increasing basal
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`tear production in dry eye/KCS patients. Instead of obtaining testimony from a
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`wholly independent clinician, Allergan turned to an expert who is “loyal” to it and
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`the Restasis® brand. EX1128, 9.
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`Despite insisting that they never spoke to one another, Drs. Loftsson and
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`Sheppard recited conspicuously similar conclusory opinions that “the ability of
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`RESTASIS® to increase tear production is unique and unexpected, and was critical
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`to the FDA’s approval of RESTASIS®”, “acts differently than a 0.1% CsA/1.25%
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`castor oil vehicle formulation, and the formulation of RESTASIS® is critical to
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`increasing tear production and treating dry eye disease.” EX2024, ¶¶46-47;
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`EX2025, ¶¶33-37, 46; EX1037, 265:12-21.
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`However, “critical” as used by Allergan’s experts does not mean necessary
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`or essential to increasing tear production, unique does not mean exclusive, and
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`“acts differently” does not mean that Restasis® increases tear production using a
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`different mechanism of action than Ding 1D. EX1039, ¶¶52-57. It is undisputed
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`that Sall establishes that both the 0.01% CsA formulation (Ding 1D) and the 0.05%
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`CsA formulation (Restasis®) are therapeutically effective for treating dry eye
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`disease, provide a statistically significant improvement as compared to baseline
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`and vehicle for STT with anesthesia (and compared to baseline for STT without
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`anesthesia), and that they share the very same therapeutic mechanism of action.
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`For example, Dr. Loftsson agreed that when he used the word critical, he
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`just meant that the 0.05% CsA formulation “appears” to be “somewhat better than
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`the 0.1 percent formulation” but that he would want to see the underlying data to
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`make a proper evaluation. EX1036, 224:14-227:18. Dr. Loftsson also agreed that
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`Sall reported the 0.1% CsA formulation also increased tear production in patients
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`with dry eye, that the 0.1% and 0.05% CsA formulations “were both effective,”
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`and that there was “no dose response effect.” Id., 212:21-215:4, 217:5-12 (Dr.
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`Loftsson simply “assume[d] the 0.05 percent is better”); EX1037, 175:22-176:17
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`(agreeing Sall concluded both formulations “were safe and effective”).
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`Dr. Sheppard agreed it would be wrong to conclude based on Sall that only
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`one of the two CsA formulations was safe and effective, and stressed “the most
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`appropriate presentation is to include them together” in that conclusion. EX1037,
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`177:7-179:22. Drs. Sheppard and Loftsson agreed that they failed to perform any
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`statistical analysis to determine whether there was any actual difference between
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`the CsA formulations in Sall Figure 2. EX1037, 174:8-175:21; EX1036, 214:16-
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`216:3; EX1040, ¶29.
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`Dr. Sheppard agreed the patents-at-issue teach that Restasis® “provides
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`overall efficacy in treating dry eye disease substantially equal to that” of Ding 1D.
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`EX1037, 182:12-186:9. Dr. Sheppard also agreed that Sall teaches that both the
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`0.05% and 0.10% CsA formulations significantly increased tear production as
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`compared to baseline and vehicle at month 6, and that both formulations “were
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`safe and effective in the treatment of moderate to severe dry eye disease.” Id. Dr.
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`Sheppard incorrectly believed that Sall was “not statistically powered” to make
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`comparisons between the two CsA groups. Id., 186:10-193:21; EX1040, ¶31.
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`Although Dr. Sheppard believed that the 0.05% CsA formulation “acts differently”
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`than the 0.10% CsA formulation, he explained “there’s not a cause and effect”
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`between acting differently and the criticality of the formulation “to increasing tear
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`production and treating dry eye disease” because, as explained in the patents-at
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`issue, the therapeutic efficacy of the two formulations is “substantially equal.” Id.,
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`187:6-188:4. Dr. Sheppard also agreed that Restasis® and the Ding 1D formulations
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`each shared the same mechanism of action. EX1037, 290:6-295:4.
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`Allergan’s claim to improved clinical efficacy of Restasis® over Ding 1D
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`also ignores all eight measures of clinical efficacy, except one, to focus exclusively
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`on the STT with anesthesia. Dr. Calman, an accomplished ophthalmologist also
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`having a Ph.D., in Immunology, testifies that Allergan’s clinician errs by focusing
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`on the STT with anesthesia. EX1039, ¶¶1-6, 37-48; EX1042. Even Dr. Sheppard
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`had to admit that STT with anesthesia is not really the primary means for
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`diagnosing patients with dry eye. EX1037, 99:13-103:3 (uses corneal staining to
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`diagnose at least 90% of his dry eye patients); EX1039, ¶¶15-16, 37-48; EX1047,
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`12; EX1048, 9; EX1061, 462-66 (no reliable objective test for dry eye, STT has
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`“notorious variability”).
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`Contrary to Allergan’s assertions, there is no significant or meaningful
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`difference between the STT results for the two formulations in Sall Figure 2. As
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`explained by Dr. Bloch, Professor Emeritus of Biostatistics at Stanford, the Phase 3
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`studies reported in Sall were adequately powered to make statistical pairwise
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`comparisons between treatment groups (Restasis® , Ding 1D, Ding 2C). EX1040,
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`¶¶1-20, 31-32, 40, EX1043. Sall Figure 2 teaches that each of the 0.05% and
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`0.10% CsA formulations had changes in categorized STT scores, as compared to
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`their baseline measurements, that were statistically significantly better than that
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`observed for the vehicle, but no statistically significant difference was observed in
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`Sall Figure 2 between the two CsA formulations. EX1040, ¶¶42-47. Dr. Bloch
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`testifies that Sall reports no statistically significant difference between the two CsA
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`formulations for any of the efficacy measures he evaluated. Id., ¶¶28-30, 33-47.
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`Thus, from a statistical standpoint, no significance can be drawn between the two
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`CsA formulation from Sall Figure 2.
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`Dr. Calman also testifies that Sall reports no significant or material
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`improvement in therapeutic efficacy between the 0.05% and 0.10% CsA
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`formulations. EX1039, ¶¶65-71. Dr. Calman explains that Allergan’s experts’
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`(Sheppard and Loftsson) analysis of Sall Figure 2 overlooks the fact that perceived
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`differences between the two CsA formulations are small enough to be caused by
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`chance variation. Id. In addition, Allergan’s experts’ analysis ignores the clinical
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`context of Sall’s Figure 2 results. Dr. Calman testifies that Sall concluded both
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`formulations “were safe and effective in the treatment of moderate-to-severe dry
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`eye disease,” and both gave statistically “significantly (P ≤ 0.05) greater
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`improvement than vehicle in two objective signs of dry eye disease (corneal
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`staining and categorized Schirmer values).” EX1039, ¶¶58-59, 75; EX1007, 631.
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`Further, Sall states that “[t]here was no dose-response effect.” Id. Thus, Figure 2 of
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`Sall discloses that both CsA formulations were therapeutically effective in
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`increasing tear production as compared to baseline values, and as compared to
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`vehicle. EX1039, ¶¶58, 65.
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`Dr. Calman also testifies that, contrary to Allergan’s assertions, a reported
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`difference of 0.1-0.2 in the observed change in STT Score from baseline for the
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`two formulations is not a significant difference, and he notes that such a difference
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`does not reflect a clinically meaningful or materially superior result. EX1039,
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`¶¶47, 67-71. Notably, a similar difference in STT Scores (2.11-1.94=0.17) existed
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`between treatment groups before treatment even started and Sall noted that this
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`difference was not significant or meaningful. EX1007, 635. Sall explained that the
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`same STT score was used for measurements differing by as much as 4mm “to
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`reduce overall within-patient variability known to occur for Schirmer wetting
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`scores.” Id., 633; EX1037, 169:10-25 (“[Q.] [Is]…a difference in Schirmer’s score
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`of approximately 3 to 4 millimeters…a small enough difference that it may simply
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`be due to within patient variability? [Objection]. THE WITNESS: I don’t think you
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`can even say that because somebody could be a category 3, and today they’re 7
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`millimeters, tomorrow they’re 6 millimeters, now they category 2. It’s only a 1-
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`millimeter difference.”).
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`Dr. Calman observes that Sall Figure 2 reports a very small average
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`improvement in tearing for both the 0.10% and 0.05% CsA formulations, meaning
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`that the average patient started treatment and ended treatment with severe dry eye.
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`EX1039, ¶¶67-71; EX1037, 209:14-18. Moreover, Dr. Calman testifies the
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`possible increase in average STT wetting score is small even compared to the 3
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`mm in within-patient variability expected in the Sall trial. EX1039, ¶¶67-71;
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`EX1037, 165:18-166:24. Dr. Sheppard confirms that it would not be unexpected
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`for any given patient’s STT wetting score to change from a 3 to 6 mm even if
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`simply taken on different days without any treatment at all. Id. He explained that
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`the categorized scale was adopted because “it’s hard for me to say that somebody
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`that’s 3 is any different than 4 or 5 but they may be different than 6 or 7.” Id.,
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`167:7-168:11. Thus, the average improvement reported in Sall Figure 2 is simply
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`too small to be clinically meaningful. EX1039, ¶¶67-72.
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`Even if the difference were large enough to be meaningful, the results of
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`Figure 2 are less informative than other measures (e.g., corneal staining, STT
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`without anesthesia) because Figure 2 has relatively few time points. EX1039, ¶¶46,
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`60-61. Because it’s only “two points in time” it is “far less informative than
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`multiple time points.” EX1037, 176:14-23; EX1007, 633 (measuring corneal
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`staining and STT without anesthesia at four different time points). As Dr. Calman
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`testified, Drs. Sheppard’s and Loftsson’s exclusive focus on STT with anesthesia
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`overlooks other more informative measures. EX1039, ¶¶37-47, 55, 59-61, 73.
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`Allergan also argues that the 0.1-0.2 difference in relative STT scores
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`observed in Sall Figure 2 was “critical” to obtaining FDA approval of Restasis.
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`POR, 5-6, 17-19, 21-22, 28, 34-37. Notably, however, the Restasis® label
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`(EX2008) describes the clinical trial results that supported FDA approval, and
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`nowhere does it mention the results provided in Sall Figure 2. To the contrary, the
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`label indicates that approval was predicated on material improvements (≥10mm) in
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`a small subset (15%) of patients, and a demonstration that this material
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`improvement occurred statistically significantly more frequently when the CsA
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`formulation was given than when the vehicle was given alone (5%). EX1039, ¶¶63,
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`72-73; EX2008. Notably, Allergan has produced no comparable data for the 0.1%
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`CsA Ding 1D, 0.05% CsA Ding 1E, or any other formulations, despite including
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`the Ding 1D formulation in the very same phase 3 study. As each of these
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`formulations share the same mechanism of action as Restasis® (EX1037, 294:10-
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`295:4), and were shown to be substantially therapeutically equivalent to Restasis®
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`in phase 2 and phase 3 trials, the absence of FDA approval for the admittedly prior
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`art emulsions appears to have more to do with Allergan’s marketing decisions than
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`with any technical obstacle.
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`V. NEITHER THERMODYNAMIC PRINCIPLES NOR PK STUDIES
`SUPPORT “CRITICALITY,” UNIQUE MECHANISM OF ACTION,
`OR UNEXPECTED RESULTS.
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`Allergan argues that the alleged therapeutic improvement of the 0.05% CsA
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`formulation is surprising because a POSA would have expected the 0.10% CsA
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`formulation—containing twice as much active drug—to deliver more active drug
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`into the target tissues and therefore have the potential to further increase
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`therapeutic efficacy. POR, 20-24. For this theory, Allergan relies on its prior art
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`PK studies.
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`As explained above, Sall reports substantially equivalent efficacy between
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`the two CsA formulations. Allergan’s allegations of superiority for the 0.05% CsA
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`formulation are unsupported and contrary to the evidence. EX1039, ¶¶74-75. Even
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`if theoretical principles suggest that doubling CsA concentration or maintaining a
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`ratio of CsA-to-CO of 0.08 instead of 0.04 would positively impact CsA delivery,
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`both Stevenson and Sall teach that there is no dose-response effect at these
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`concentrations (0.05 and 0.10% CsA), and that both concentrations are
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`therapeutically efficacious. EX1007, 631; EX1015, 967. Moreover, Ding ’979
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`expressly teaches that its formulations were efficacious for enhancing and restoring
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`tears in dry eye patients regardless of whether the CsA-to-CO ratio was 0.08, as in
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`Example 1C, or was 0.04, as in Example 1B. Ding ’979 teaches that its
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`formulations had sufficient thermodynamic potential to achieve therapeutic levels
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`of CsA in the tissue of interest. EX1006, 5:19-25. Dr. Loftsson agreed that Ding
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`achieved “therapeutic concentrations” with her example formulation. EX1036,
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`146:6-22.
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`Allergan’s own evidence indicates that both formulations delivered levels of
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`CsA well above the required therapeutic threshold. As Dr. Calman testifies, the PK
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`studies disclose actual tissue concentrations in the cornea and conjunctiva well
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`above therapeutic levels for each of the 0.05% and 0.10% CsA. EX1039, ¶78;
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`EX2026, 21-24; EX1027, 26-27; EX1028-EX1031; EX1011, 652-53; EX1058.
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`Indeed, Dr. Calman testifies that even the 0.01% CsA formulation achieved
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`therapeutic levels in the tissues examined by Dr. Attar. EX1039, ¶¶77-79.
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`As Dr. Calman explained, Dr. Attar’s presentation of “relative AUC” ratios
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`instead of actual tissue concentrations effectively divorced the data portrayed in
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`Dr. Attar’s Exhibit B from its therapeutic context. Id. As a consequence, Exhibit B
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`conveys an incorrect impression that the differences in bar graph height
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`represented a significant and material difference in CsA concentration in the
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`tissues.
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`Dr. Calman also testifies that Dr. Attar’s relative AUC comparison shown in
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`her Exhibit B is analytically defective because of significant differences between
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`how the two studies were performed. Id.; EX1027, 16; EX2027, 6. Dr. Attar also
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`purported to be disclosing in her Exhibit B the PK values obtained from the Ding
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`1E formulation. EX1038, 70:20-71:2 (Composition I is Ding 1D), 71:14-75:14,
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`70:25-71:18. But the 0.05% CsA/0.625% CO formulation described is not Ding
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`1E, which contains 1.0% polysorbate 80, but instead contained only 0.5%
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`polysorbate 80. EX1027, 12 (Formulation B). Dr. Attar testified that a formulation
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`with only half of the required polysorbate 80 was no more Ding 1E than would a
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`formulation be Restasis® that had half the required amount of CsA, CO, or
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`polysorbate 80. EX1038, 65:16-69:15. Thus, Dr. Attar’s Exhibit B never compared
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`either the claimed formulation or Ding 1D to the Ding 1E formulation. Dr. Attar’s
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`declarations to the USPTO did not disclose the substantial differences between the
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`two PK studies. EX1004, 0225-28.
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`Because neither of the two PK studies Dr. Attar relied upon to make her
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`Exhibit B (and the identical Schiffman Exhibits C) actually contain data for the
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`Ding 1E formulation, Allergan has failed to make any comparison in terms of any
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`unexpected results to what it itself has called the “closest prior art.” POR, 3, 5, 28,
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`39. Dr. Bloch testifies that no statistical comparisons between CsA formulations
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`are possible based on the Stevenson graphs, which do not even disclose STT
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`results with anesthesia. EX1040, ¶¶26-27. Thus, with Dr. Schiffman’s exhibits
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`disclaimed and lacking underlying data, there is no data of record permitting a
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`comparison of tear production between the claimed formulation and Ding 1E.
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`Allergan’s failure to provide any STT data for the Ding 1E formulation that is
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`amenable to scientific comparison undermines its unexpected results case. In re
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`Baxter Travenol Labs., 952 F.2d 388, 392 (Fed. Cir. 1991) (showing of unexpected
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`results requires comparison of the claimed invention with the closest prior art); In
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`re Merchant, 575 F.2d 865, 869 (CCPA 1978).
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`Dr. Bloch also analyzed the PK data and found that the errors in the readings
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`were so large that the lacrimal gland CsA concentrations measured after
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`administering the different CsA formulations were not statistically significantly
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`different from one another. EX1040, ¶¶48-57, Table 3, Appendix A; EX1036,
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`194:4-19 (did not statistically analyze PK data). Dr. Loftsson testified that the
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`lacrimal glands were the “most important” target tissue. EX1036, 147:23-148:25,
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`239:19-24. In other words, Allergan’s PK studies fail to establish that the observed
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`values reflect actual differences in the key tissue of interest. Id. Notably, the PK
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`study Dr. Loftsson relies upon (EX2026/2027) to support his thermodynamic
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`opinions (EX2025, ¶¶43-44) fails to satisfy his own criteria for appropriate study
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`design because only two rabbits at each time point were tested. EX1038, 140:19-
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`143:18 (2 rabbits); EX1036, 151:23-153:17, 174:22-175:20 (calling for “at least
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`five” rabbits at each time point).
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`During prosecution, Dr. Attar’s declaration argued that her PK studies
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`mattered because, without effective drug delivery, there could not be therapeutic
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`efficacy. EX1004, 0225-26. Although she refused to accept the logic during her
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`deposition (EX1038, 122:23-128:20), it must also necessarily be true that because
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`there was therapeutic efficacy (as demonstrated in Stevenson and Sall), there must
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`have been effective drug delivery. EX1039, ¶¶77-81. Thus, the PK studies are truly
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`immaterial because all available evidence, including the prior art Sall reference
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`that Allergan relies upon to demonstrate “unexpected results,” teaches
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`unequivocally that the 0.05% CsA formulation was therapeutically effective, and
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`therefore was not so thermodynamically restrained as to render it inactive.
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`EX1007, 631; EX1015, 967; EX1006, 5:18-24; EX1036, 133:25-134:19.
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`VI. ALLERGAN LABELS CASTOR OIL AS TOXIC AND
`UNDESIRABLE AND IGNORES ITS FAVORABLE PROPERTIES
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`Allergan contends that a POSA would have used the minimum amount of
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`castor oil (“CO”) that would dissolve 0.05% CsA because of CO’s alleged
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`“toxicity,” “undesired properties” and “side effects,” and because Sall Figure 2
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`allegedly demonstrated that CO “had a negative impact on tear production” and
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`“no beneficial effect” at all. POR, 31; POPR, 11-12, 19; EX1036, 122:3-25,
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`139:11-140:7.
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`First, Allergan exaggerates CO’s deficiencies. POPR, 4, 6-7, 11-12, 19, 31
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`(arguing CO toxicity based on EX2003, published in 2007 and a reference EX2004
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`discussing a different composition, polyoxyethylene CO, also known as
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`Cremophor EL, EX1132, 591); EX1006, Abstract, 5:15-18 (5% CO safe and non-
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`toxic); EX1036, 88:14-89:3 (“Ding is using very low concentrations”).
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`PROTECTIVE ORDER MATERIAL
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`Second, Allergan errs by assuming that the POSA must be motivated by the
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`same thing (increased basal tear production) that allegedly motivated the claimed
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`invention. Par Pharm., Inc. v. TWI Pharm., Inc., 773 F.3d 1186, 1197 (Fed. Cir.
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`2014); Alcon Research, Ltd. v. Apotex Inc., 687 F.3d 1362, 1368 (Fed. Cir. 2012).
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`Third, Allergan incorrectly assumes that a POSA would ignore CO’s
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`favorable properties. The CO vehicle in Sall provided a statistically significant
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`improvement from baseline in both objective and subjective measures of dry eye
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`disease. EX1007, 634-36; EX1039, ¶¶48, 58; EX2008, 5 (noting ≥10mm
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`improvement in basal tear production for 5% of vehicle-treated patients); EX1036,
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`207:23-208:16 (agreeing Sall teaches the vehicle improved corneal staining).
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`Allergan’s exclusive focus on basal tear production ignores the fact that reflexive
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`tearing is also lacrimal gland tearing, which is important to preventing damage and
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`irritation to the eye (thereby reducing dry eye), and was a critical diagnostic
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`criteria for inclusion in the Sall study. EX1039, ¶¶34, 37, 44, 64; EX1037, 155:19-
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`156:10 (reflexive lacrimal tearing), 76:5-15 (tearing in response to physical
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`irritation is a hallmark of dry eye); EX1049-51 (reflexive tearing is clinically
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`significant). Allergan even markets a 2.5% CO emulsion RefreshEndura® as a dry
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`eye tear supplement. EX1037, 276:15-277:2; POR, 33 (RefreshEndura® embodies
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`the Ding ’607 emulsions); EX1057 (RefreshEndura® on the market).
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`PROTECTIVE ORDER MATERIAL
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`Fourth, Allergan’s “minimum solubility” arguments are internally
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`inconsistent. Dr. Loftsson testified that he didn’t know the solubility of CsA in CO
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`or the minimum amount of CO sufficient to dissolve 0.05% CsA, and that Ding
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`’979’s more preferred CsA-to-CO ratios permitted even less CO for 0.05% CsA
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`than was used in Ding 1E. EX1036, 46:10-47:17, 134:22-139:4, 140:10-143:25. He
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`admitted that Ding Examples 1B-1C used more CO than was needed simply to
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`dissolve the given CsA. Id.; see also id., 170:20-174:21, 179:18-24. The
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`formulations taught by Ding ’979 had adequate bioavailability, were comfortable,
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`non-irritating, and did not cr
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