UNITED STATES PATENT AND TRADEMARK OFFICE
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`MYLAN PHARMACEUTICALS INC.,
`Petitioner
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`v.
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`ALLERGAN, INC.
`Patent Owner
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`Case IPR2016-011321
`Patent 9,248,191
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`PATENT OWNER’S SURREPLY
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`1 Cases IPR2017-00586 and IPR2017-00601 have been joined with this
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`proceeding.
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`MYLAN PHARMACEUTICALS INC.,
`Petitioner
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`v.
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`ALLERGAN, INC.
`Patent Owner
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`Case IPR2016-011321
`Patent 9,248,191
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`PATENT OWNER’S SURREPLY
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`1 Cases IPR2017-00586 and IPR2017-00601 have been joined with this
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`proceeding.
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`Case IPR2016-01132
`Attorney Docket No: 13351-0008IP6
`
`EXHIBIT LIST
`
`EX. 2002
`EX. 2003
`
`EX. 2004
`EX. 2005
`EX. 2006
`EX. 2007
`EX. 2008
`EX. 2009
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`EX. 2010
`EX. 2011
`
`EX. 2012
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`EX. 2013
`
`Exhibit No. Description
`EX. 2001
`NDA 21-023 Cyclosporine Ophthalmic Emulsion 0.05%, Original
`NDA Filing, Vol. 1 (Feb. 24, 1999)
`U.S. Pat. No. 4,839,342
`Said et al., Investigative Ophthalmology & Visual Science, vol. 48,
`No. 11 (Nov. 2007):5000-5006
`Alba et al., Folia Ophthalmol. Jpn. 40:902-908 (1989)
`Stedman’s Medical Dictionary, definition of therapeutic
`Dorland’s Illustrated Medical Dictionary, definition of therapeutic
`Stedman’s Medical Dictionary, definition of palliative
`RESTASIS® label
`Murphy, R., “The Once and Future Treatment of Dry Eye,” Review
`of Optometry, pp. 73-75 (Feb. 15, 2000)
`RESERVED
`Agarwal, Priyanka and Ilva D. Rupenthal, “Modern Approaches to
`the Ocular Delivery of Cyclosporine A,” Drug Discovery Today,
`vol. 21, no. 6 (June 2016)
`Damato et al., “Senile Atrophy of the Human Lacrimal Gland: The
`Contribution of Chronic Inflammatory Disease,” British Journal of
`Ophthalmology (1984)
`Higuchi, “Physical Chemical Analysis of Percutaneous Absorption
`Process From Creams and Ointments,” Seminar, New York City
`(1959)
`Lallemand et al., “Cyclosporine a Delivery to the Eye: A
`Pharmaceutical Challenge,” European Journal of Pharmaceutics
`and Biopharmaceutics (2003)
`das Neves et al., “ Mucosal Delivery of Biopharmaceuticals:
`Biology, Challenges and Strategies,” Springer Science (2014)
`
`EX. 2014
`
`EX. 2015
`
`i
`
`
`
`EX. 2016
`
`EX. 2017
`EX. 2018
`
`EX. 2019
`
`EX. 2020
`
`EX. 2021
`
`EX. 2022
`
`EX. 2023
`EX. 2024
`EX. 2025
`EX. 2026
`EX. 2027
`EX. 2028
`EX. 2029
`
`EX. 2030
`EX. 2031
`EX. 2032
`
`Case IPR2016-01132
`Attorney Docket No: 13351-0008IP6
`Power et al., “Effect of Topical Cyclosporin A on Conjunctival T
`Cells in Patients with Secondary Sjögren’s Syndrome,” Cornea
`12(6): 507-511 (1993)
`Schaefer et al., “Skin Permeability,” Springer-Verlag (1982)
`Stern et al., “The Pathology of Dry Eye: The Interaction Between
`the Ocular Surface and Lacrimal Glands,” Cornea 17(6): 584-589
`(1998)
`Wepierre, Jacques and Jean-Paul Marty, “Percutaneous Absorption
`of Drugs,” Elsvier/North-Holland Biomedical Press (1970)
`Williamson et al., “Histology f the Lacrimal Gland in
`Keratoconjunctivitis Sicca,” Brit. F. Ophthal /91973)
`“Approved Drug Products with Therapeutic Equivalence
`Evaluations,” U.S. Department of Health and Huma Services, 37th
`Edition (2017)
`Lemp, Michael A., “ Report of the National Eye Institute/Industry
`Workshop on Clinical Trials in Dry Eyes,” CLAO Journal, vol. 21,
`no. 4 (October 1995)
`Deposition transcript of Mansoor Amiji, Ph.D
`Declaration of John D. Sheppard, M.D., M.M.Sc.
`Declaration of Dr. Thorsteinn Loftsson, Ph.D.
`Declaration of Eric Rubinson
`Allergan PK-98-074 Report
`Declaration of Robert S. Maness, Ph.D.
`DiMasi, “Risks in New Drug Development: Approval Success
`Rates for Investigational Drugs,” Clinical Pharmacology and
`Therapeutics, May 2001
`FDA Review, “The Drug Development and Approval Process”
`Allergan – NYSE: AGN – Company Profile
`Drugs@FDA: FDA Approved Drug Products,
`
`ii
`
`
`
`EX. 2033
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`EX. 2034
`
`EX. 2035
`EX. 2036
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`EX. 2037
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`EX. 2038
`EX. 2039
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`EX. 2040
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`EX. 2041
`EX. 2042
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`EX. 2043
`EX. 2044
`EX. 2045
`EX. 2046
`EX. 2047
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`EX. 2048
`
`Case IPR2016-01132
`Attorney Docket No: 13351-0008IP6
`http://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=ov
`erview.process&ApplNo=021023
`Drugs@FDA: FDA Approved Drug Products, Restasis Approved,
`http://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/21-
`023_Restasis_Approv.PDF
`Drugs@FDA: FDA Approved Drug Products,
`http://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=ov
`erview.process&ApplNo=050790
`Facts About Dry Eye, https://nei.nih.gov/health/dryeye/dryeye
`Christopher Glenn, “New Thinking Spurs New Products,” Review
`of Ophthalmology, February 15, 2003
`Mark B. Abelson, MD and Jason Casavant, “Give Dry Eye a One-
`two Punch,” Review of Ophthalmology, March 15, 2003
`Deposition of David LeCause, February 17, 2017
`Joan-Marie Stiglich ELS, “Restasis: the road to approval,” Ocular
`Surgery News, March 1, 2003
`Lynda Charters, “Increased Tear Production,” Ophthalmology
`Times, February 1, 2003
`RESERVED
`Jonathan R. Pirnazar, MD, “Taking a Custom Approach to Dry Eye
`Treatment,” Ophthalmology Management, February 1, 2004
`RESERVED
`FDA label for Xiidra®
`RESERVED
`Restasis Strategic Plan Forecast 2009-2013
`Allergan Inc., Credit Suisse First Boston Equity Research Report,
`Jan 30, 2003
`Allergan Inc., Buckingham Research Group Equity Research
`Report, Feb 5, 2003
`
`iii
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`
`
`EX. 2049
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`EX. 2050
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`EX. 2051
`EX. 2052
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`EX. 2053
`EX. 2054
`EX. 2055
`EX. 2056
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`EX. 2057
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`EX. 2058
`EX. 2059
`EX. 2060
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`EX. 2061
`EX. 2062
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`EX. 2063
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`EX. 2064
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`EX. 2065
`EX. 2066
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`Case IPR2016-01132
`Attorney Docket No: 13351-0008IP6
`Allergan Inc., SalomonSmithBarney Equity Research Report, Feb
`12, 2003
`Allergan Inc., Morgan Stanley Equity Research Report, Jan 30,
`2003
`Restasis P&L (US Only excl. Canada and Puerto Rico)
`Allergan Inc., Morgan Stanley Equity Research Report, Apr 30,
`2004
`Allergan Inc., JP Morgan Equity Research Report, Nov 1, 2005
`RESERVED
`“commercial Restasis Formulary June 2006.xls”
`“NOVEMBER 2006 input MHC Report Restasis Playbook
`data.ppt”
`Restasis® 2013 Managed Markets Tactics & Preliminary Budget,
`August 8, 2012
`RESERVED
`RESERVED
`“Allergan Inc. (AGN) - Q4 2002 Financial Release Conference Call
`Wednesday, January 29, 2003 11:00 am” Fair Disclosure Financial
`Network
`Restasis Launch Marketing Plan, dated February 12-13, 2003
`Allergan Dry Eye, “Dry Eye Franchise 2014 Business Plan,” 2014
`U.S. Eye Care Sales & Marketing Plan, September 9, 2013
`Allergan Eye Care, “US Dry Eye Strat Plan Narrative: Summary
`Version,” April 16, 2011
`Kline, Kate, “Restasis Professional Critical Issues,” Allergan Dry
`Eye, 2010
`Allergan Dry Eye, “Restasis Business Update,” August 16, 2010
`“Sales-Units_2011-2016_AllData_NSP_Feb-19-
`2017_RESTASIS.xlsx”
`
`iv
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`Case IPR2016-01132
`Attorney Docket No: 13351-0008IP6
`
`RESERVED
`Iazuka and Jin, “The Effect of Prescription Drug Advertising on
`Doctor Visits,” Journal of Economics and Management Strategy,
`2007
`Bradford, Kleit, Nietert, et al, “How Direct-to-Consumer Television
`Advertising for Osteoarthritis Drugs Affect Physicians’ Prescribing
`Behavior,” Health Affairs, 2006
`Calfee, Winston, and Stempski, “Direct-to-Consumer Advertising
`and the Demand for Cholesterol Reducing Drugs,” Journal of Law
`and Economics, 2002
`Bradford, Kleit, Nietert, et al, “Effects of Direct-to-Consumer
`Advertising of Hydroxymethylglutaryl Coenzyme A Reductase
`Inhibitors or Attainment of LDL-C Goals,” Clinical Therapeutics,
`2006
`Restasis NPA Monthly
`Restasis Projects, Global R&D Cost
`Refresh Endura Lubricant Eye Drops (Allergan), Theodora
`Declaration of Jonathan Singer in support of Petitioner’s Motion for
`Pro Hac Vice Admission
`Memorandum Opinion and Order, Allergan, Inc. v. Teva
`Pharmaceuticals USA, Inc., et al., Case No. 2:15-cv-1455-WCB
`Nussenblatt, R. et al. Local Cyclosporine Therapy for Experimental
`Autoimmune Uveitis in Rats. Arch Ophthalmology, Volume 103,
`October 1985.
`Medical Officer’s Review of NDA 21-023
`Correction to Sall article (Ex. 1007), Opthalmology, Vol. 107, No.
`7, July 2000.
`GraphPad Calculation of Bloch Table 2 – 3 mo. B vs A.
`GraphPad Calculation of Bloch Table 2 – 3 mo. C vs A.
`
`EX. 2067
`EX. 2068
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`EX. 2069
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`EX. 2070
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`EX. 2071
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`EX. 2072
`EX. 2073
`EX. 2074
`EX. 2075
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`EX. 2076
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`EX. 2077
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`EX. 2078
`EX. 2079
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`EX. 2080
`EX. 2081
`
`v
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`
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`Case IPR2016-01132
`Attorney Docket No: 13351-0008IP6
`
`
`I. Introduction
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`
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`The fundamental issue in this IPR proceeding is whether the claimed
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`emulsions containing 0.05% CsA and 1.25% castor oil vehicle work differently
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`and are unexpectedly more effective in increasing tear production than the closest
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`prior art emulsions containing 0.1% CsA and 1.25% castor oil vehicle. In its
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`Patent Owner’s Response, Allergan demonstrated that the results of the Schirmer
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`Tear Test (“STT”) with anesthesia shown in Fig. 2 of Sall, a peer-reviewed paper
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`summarizing the results of Allergan’s Phase III clinical studies submitted to FDA,
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`proved that the claimed emulsions were, in fact, better and performed differently
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`than the prior art emulsions. Allergan further demonstrated that this result was
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`unexpected based upon thermodynamic principles confirmed by pharmacokinetic
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`and bioavailability studies that predicted the opposite result.
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`Mylan’s reply improperly introduces brand new theories and arguments,
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`straying from the arguments made in their Petition. To do so, Mylan relies on
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`declarations from three new witnesses: a clinician (Dr. Calman), a statistician (Dr.
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`Bloch), and an economist (Mr. Hofmann). Collectively, the declarations total over
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`170 pages to support a 26 page reply—an attempt to circumvent the word count
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`limitation constraining the reply. In addition to being improper, Mylan’s evidence
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`is flawed and fails to prove that the claimed emulsions do not work differently than
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`the prior art regarding tear production.
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`1
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`Case IPR2016-01132
`Attorney Docket No: 13351-0008IP6
`Neither Dr. Calman nor Dr. Bloch challenges what a person of ordinary skill
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`would have expected based upon thermodynamic principles. Rather, both Dr.
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`Calman and Dr. Bloch attack the pharmacokinetic/bioavailability data confirming
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`the thermodynamic predictions, as well as Sall’s tear production data. However,
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`Dr. Calman and Dr. Bloch’s analyses are based upon scientifically unsound
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`methodologies that rely on “inferring” numbers from the bar chart presented in Sall
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`Fig. 2. In other words, to challenge the findings in a peer-reviewed paper, Drs.
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`Calman and Bloch resort to estimation and guesswork. The Board should give
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`these flawed analyses no weight, especially because both Dr. Calman and Dr.
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`Bloch ignore that FDA approved RESTASIS® because it was statistically superior
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`to the prior art 0.1% CsA/1.25% castor oil vehicle emulsion for increasing tear
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`production in particular populations of dry eye patients.
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`Mylan’s economist, Mr. Hofmann, does not dispute that RESTASIS®’s
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`sales and revenues demonstrate commercial success, and his argument of a lack of
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`nexus between that success and the claims misstates the prior art, the relevant
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`market, and the features that drive RESTASIS® sales.
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`The claimed emulsion containing 0.05% CsA/1.25% castor oil vehicle
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`performs differently and is more effective in increasing tear production than the
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`0.1% CsA/1.25% castor oil vehicle emulsion, a result that was unexpected by
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`persons of skill in the art at the time of the inventions. The peer-reviewed Sall
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`2
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`Case IPR2016-01132
`Attorney Docket No: 13351-0008IP6
`paper and FDA’s analysis confirm that the claimed formulation is critical to
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`increasing tear production. Because Mylan has failed to demonstrate otherwise,
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`the Board should confirm the patentability of the challenged claims.
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`II. The Claimed Emulsion Is Critical For Increasing Tear Production And Is
`Unexpectedly More Effective Than the Closest Prior Art Emulsion
`The closest prior art emulsion is the 0.1% CsA/1.25% vehicle emulsion
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`identified in Ding ’979 as Composition 1D. EX. 1006 at 4:35-43. This and the
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`claimed 0.05% CsA/1.25% vehicle emulsion were the two emulsions selected for
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`Phase III clinical studies. EX. 1001 at 13:40-62; EX. 2024 at ¶ 39.
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`In the Phase III studies, the Schirmer Tear Test (“STT”), both with and
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`without anesthesia, was used to evaluate tear production. EX. 1007 at 635-636.
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`The primary test used for measuring tear production—STT with anesthesia—
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`measures basal tear production. EX. 2024 at ¶¶ 20-21; EX. 1035 at 16:14-25.
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`Basal tears are the tears produced by the lacrimal gland that continuously moisten
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`and lubricate the eyes. EX. 2024 at ¶ 21. They are chemically different from
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`reflexive tears, which are produced as a spurt in response to an irritant.
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`Ophthalmologists treating dry eye aim to increase basal tear production. EX. 1037
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`at 261:17-262:19. While some patients with dry eye are also unable to produce
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`reflexive tears, increasing reflexive tear production alone is not the goal when
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`treating dry eye because a patient cannot expect to moisten his eyes on a regular
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`basis by, for example, chopping onions to induce tearing.
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`3
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`Case IPR2016-01132
`Attorney Docket No: 13351-0008IP6
`The STT with anesthesia data presented in Fig. 2 of Sall demonstrate that the
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`0.05% CsA emulsion resulted in a statistically significant change in tear production
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`compared to vehicle at 3 months, whereas the 0.1% CsA emulsion did not. EX.
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`1007 at 635. After 6 months, the 0.05% CsA emulsion increased tear production to
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`a greater extent than the 0.1% CsA emulsion. Id. In contrast, the castor oil vehicle
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`alone reduced tear production after both 3 and 6 months.2 Id.
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`On the other hand, the STT without anesthesia data in Sall shows that the
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`vehicle itself, as well as the 0.05% CsA and 0.1% CsA emulsions, increased
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`overall tear production. EX. 1007 at 635-636. STT without anesthesia measures
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`both basal tear production and reflexive tear production without distinguishing
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`between the two. EX. 2024 at ¶ 43. While such information is useful, the STT
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`with anesthesia, which measures only basal tear production, is more clinically
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`significant for patients suffering from dry eye disease, as shown in Sall Fig. 2. EX.
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`1007 at 635; EX. 2024 at ¶ 42; see also EX. 1035 at 17:19-21 (“[I]f I wanted what
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`has come to be believed to be the best single measure, I would pick with
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`anesthesia.”). In fact, FDA relied on STT with anesthesia when approving
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`RESTASIS®. EX. 2078 at 26, 29. This underscores the fact that increasing tear
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`2 Consistent with this data is the fact that Allergan’s ENDURA® product, which
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`contains only castor oil vehicle (and not CsA), is not indicated for tear production.
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`4
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`Case IPR2016-01132
`Attorney Docket No: 13351-0008IP6
`production requires, at a minimum, increasing basal tear production. Sall’s STT
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`with anesthesia data, specifically Fig. 2, show that the vehicle alone does not
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`increase basal tear production, and that the 0.05% CsA emulsion outperforms the
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`0.1% CsA emulsion. EX. 1007 at 635.
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`Despite Mylan’s extensive reliance on Sall in its Petition, Dr. Bloch now
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`criticizes the STT with anesthesia data presented in Sall’s Fig. 2. EX. 1040 at ¶¶
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`41-46. While Dr. Bloch does not dispute that the 0.05% CsA emulsion is
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`numerically more effective than the 0.1% CsA emulsion at both 3 and 6 months, he
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`argues that there is no statistical difference between the two emulsions. EX. 1040
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`at ¶ 46. Dr. Bloch’s analysis is flawed for several reasons.
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`First, Dr. Bloch bases his statistical analysis on numbers that he “gleaned”
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`(in other words, estimated) from Sall. EX. 1040 at ¶¶ 26, 44. This is scientifically
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`unsound. The numbers that Dr. Bloch used as the basis for his statistical analysis
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`are, at best, educated guesses and therefore unreliable. They cannot form the basis
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`of a rigorous statistical analysis from which meaningful conclusions can be drawn.
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`Second, whether there is a “statistical” difference between the two emulsions
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`with respect to tear production is of no consequence to a clinician when treating
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`patients. Dr. Rhett Schiffman, an investigator in the Phase III clinical trials,
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`testified that “for an agency, you may be required to hit a certain p-value, but for
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`the purpose of making decisions about how formulations are performing or what
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`5
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`Case IPR2016-01132
`Attorney Docket No: 13351-0008IP6
`appears to have a better effect than the other, a p-value is not necessarily relevant
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`to that discussion at all.” EX. 1035 at 56:17-22; see also id. at 61:16-62:3.
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`Additionally, as Dr. Sheppard testified, the numerical results shown in Fig. 2 alone
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`show that the 0.05% CsA emulsion is more effective than the 0.1% CsA emulsion.
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`EX. 1037 at 202:15-203:22. This difference is particularly true at 3 months, an
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`important milestone for patients suffering from dry eye, who need relief as soon as
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`possible. At 3 months, the 0.05% CsA emulsion yielded a statistical improvement
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`in tear production relative to baseline whereas the 0.1% emulsion did not. EX.
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`1007 at 635. At 6 months, the 0.05% CsA emulsion was numerically more
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`effective at increasing tear production as compared to the 0.1% CsA emulsion. Id.
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`These differences3 are meaningful to a clinician treating patients with dry eye
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`disease, and inform the clinician that the 0.05% CsA emulsion was more effective
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`at increasing tear production than the 0.1% CsA emulsion.
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`Third, FDA concluded that the 0.05% CsA emulsion was statistically better
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`at increasing tear production, as measured by STT with anesthesia, than both the
`
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`3 In addition, other testing reported in Sall confirmed a meaningful difference
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`between the 0.05% CsA emulsion and the 0.1% CsA emulsion – for example, in
`
`corneal staining (Fig. 1), blurred vision (Fig. 3), and artificial tear use (Fig. 4).
`
`EX. 1007 at 635-636; see also EX. 2079 at 1.
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`6
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`Case IPR2016-01132
`Attorney Docket No: 13351-0008IP6
`0.1% CsA emulsion and vehicle for certain patient populations.4 EX. 2078 at 26.
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`On this basis, FDA approved RESTASIS® for increasing tear production. Id. at
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`29-30; see also EX. 2008 at 1. As FDA found, there is a real, statistically
`
`significant, and clinically meaningful difference between the two emulsions with
`
`respect to tear production. EX. 2078 at 26.
`
`Dr. Calman also criticizes and discounts the tear production results shown
`
`in Sall Fig. 2, despite Mylan’s reliance on Sall in its Petition. But his arguments
`
`likewise fail. First, Dr. Calman criticizes the study for using categorized Schirmer
`
`scores rather than individual Schirmer scores. EX. 1039 at ¶ 66. However, FDA
`
`requested and relied on categorized Schirmer scores in approving RESTASIS®.
`
`EX. 2078 at 26, 29. The use of categorized Schirmer scores, therefore, is
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`scientifically sound. Second, Dr. Calman attempts to “infer” raw Schirmer scores
`
`from the categorized Schirmer scores disclosed in Sall. EX. 1039 at ¶ 68. On the
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`basis of these “putative conversions,” Dr. Calman then proceeds to concoct an
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`elaborate analysis that purportedly shows no real difference in tear production
`
`versus baseline for either the 0.05% or 0.1% CsA emulsions, and thus no real
`
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`4 FDA found responder rates were statistically significant favoring the 0.05% CsA
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`emulsion in the “Intent-To-Treat – anti-inflammatory Rx and punctal plugs” and
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`“Sjogrens – anti-inflammatory Rx and punctal plugs” populations. EX. 2078 at 26.
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`7
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`Case IPR2016-01132
`Attorney Docket No: 13351-0008IP6
`difference between the two emulsions. Id. at ¶¶ 68-71.
`
`Like Dr. Bloch’s analysis, Dr. Calman’s analysis is scientifically unsound.
`
`It is based upon “inferred” Schirmer scores rather than actual scores. EX. 1039 at
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`¶ 68. These “inferred” scores—which Dr. Calman concedes are not to be
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`“interpreted as literal conversions”—are unreliable educated guesses. Id. They are
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`no substitute for a rigorous scientific analysis and cannot rebut what Sall, a peer-
`
`reviewed paper reporting Phase III clinical studies, shows and what FDA found.
`
`III. The Increased Amount of Castor Oil Vehicle in the Claimed Emulsion
`Would Be Expected to Reduce the Amount of CsA Reaching the Lacrimal
`Gland
`
`
`
`Dr. Loftsson explained why, based upon thermodynamic principles, a person
`
`of ordinary skill would expect that the amount of CsA reaching the lacrimal gland
`
`in a 0.05% CsA/1.25% castor oil vehicle emulsion would be less than for the 0.1%
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`CsA/1.25% castor oil vehicle emulsion disclosed in Ding ’979 (Composition 1D).
`
`EX. 2025 at ¶¶ 40-41. As Dr. Loftsson explained, lipophilic substances like CsA
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`prefer to remain in the lipophilic vehicle. Id. at ¶ 40. Therefore, increasing the
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`amount of castor oil would impede the lipophilic CsA from diffusing from the
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`vehicle into the ocular tissues, including the lacrimal gland. Id. at ¶ 41.
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`Pharmacokinetic and bioavailability studies conducted by Allergan confirmed the
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`thermodynamic predictions. EX. 2027 at 13 (“Mean Cmax and AUC0-12 in all
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`ocular tissues were higher after 0.1% treatment than 0.05% treatment”); see also
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`8
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`Case IPR2016-01132
`Attorney Docket No: 13351-0008IP6
`EX. 2026 at 16. More CsA, in fact, reached the lacrimal gland in the 0.1%
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`CsA/1.25% vehicle emulsion than the 0.05% CsA/1.25% vehicle emulsion. EX.
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`2027 at 25; see also EX. 2026 at 28.
`
`
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`Dr. Loftsson’s testimony regarding thermodynamic principles stands
`
`unrebutted. In fact, Mylan’s experts implicitly agree that thermodynamic
`
`principles predict that increasing the amount of castor oil vehicle relative to CsA
`
`will result in less CsA reaching aqueous ocular tissues, including the lacrimal
`
`gland. Instead, both Drs. Calman and Bloch resort to attacking the
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`pharmacokinetic/bioavailability data. Once again, these attacks fail.
`
`
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`EX. 2027 shows the amount of CsA reaching the lacrimal gland for both a
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`0.05% CsA/1.25% castor oil vehicle emulsion and a 0.1% CsA/1.25% castor oil
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`vehicle emulsion. Id. This data, which Allergan included in its submission to
`
`FDA, shows that the 0.1% CsA/1.25% castor oil vehicle emulsion resulted in more
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`CsA reaching the lacrimal gland, consistent with thermodynamic principles. Id.
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`Dr. Bloch criticizes this data on the basis of an analysis he performed that allegedly
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`shows no statistical difference between the two emulsions. EX. 1040 at ¶¶ 55-56.
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`However, Dr. Bloch’s analysis is flawed. The sample set was too small to permit
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`meaningful statistical analysis. EX. 2027 at 16; see also EX. 2026 at 19. The
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`results were based upon the eyes of a mere two rabbits at each time point. EX.
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`2027 at 19-20; see also EX. 2026 at 22-23. Indeed, Allergan’s principal scientist
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`who worked on the preclinical studies, Dr. Attar, noted that it would have been
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`unethical to try to obtain enough data points for a meaningful statistical analysis
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`because it would have required sacrificing hundreds of rabbits, and was
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`unnecessary to demonstrate the point when other data was already available. EX.
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`1038 at 168:15-169:24.
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`Dr. Calman’s attack on the pharmacokinetic/bioavailability results is equally
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`unavailing. Dr. Calman opines that any difference between the two emulsions is
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`irrelevant because in both cases, the amount of CsA reaching the lacrimal gland
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`was above a “therapeutic threshold.” EX. 1039 at ¶ 81. To support his opinion,
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`Dr. Calman relies upon the Kaswan and Oellerich papers, as well as statements in
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`Sall regarding the lack of a “dose-response” relationship. Id. at ¶ 79.
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`
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`The Kaswan paper examines the use of topically applied CsA to treat ocular
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`disorders, and examines the concentration of CsA in various ocular tissues. EX.
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`1011 at 650. The concentrations of CsA are expressed in units of ng CsA/g tissue.
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`Id. at 651. Kaswan states that “[t]issue concentrations in excess of minimal
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`therapeutic levels (50 to 300 ng CsA/g tissue)6 were achieved within one hour and
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`maintained for at least 24 hours in the cornea, anterior, and posterior sclera.” Id. at
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`652. Dr. Calman concludes from this statement that the “therapeutic threshold” for
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`treating dry eye is 50 to 300 ng CsA/g tissue. EX. 1039 at ¶¶ 78-79. However, a
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`closer reading reveals that Dr. Calman’s conclusion is inaccurate.
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`Kaswan cites a paper by Nussenblatt for the minimal therapeutic range. EX.
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`
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`1011 at 652. Nussenblatt, however, reports a level of 50-300 ng CsA/mL, not 50-
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`300 ng CsA/g. EX. 2077 at 1562. The reference to units of ng per mL is a
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`reference to serum (blood) levels, not tissue concentrations. Id. (“[T]opical
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`therapy seemed predictably effective only if serum cyclosporine levels entered
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`what is considered the therapeutic range of 50 to 300 ng/mL.” (emphasis added)).
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`Kaswan simply misquoted Nussenblatt. Moreover, there is no known correlation
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`between serum levels and tissue concentration for increasing tear production with
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`CsA, nor is there a known dose response curve. EX. 1038 at 112:20-113:2. The
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`claimed invention results in no CsA in the blood of the patient, and thus reliance
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`on serum levels of CsA is even more inappropriate. Therefore, there is no basis for
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`asserting that the “therapeutic threshold” for increasing tear production to treat dry
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`eye was even known, let alone was in the range of 50-300 ng CsA/g tissue.
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`
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`Dr. Calman also relies on a paper by Oellerich to support his theory.5 EX.
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`1039 at ¶ 79. Oellerich, however, concerns the use of systemic CsA to minimize
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`rejection in organ transplant patients. EX. 1058 at 643. It is unrelated to dry eye
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`5 Allergan notes that the Oellerich paper is new art, not previously cited by Mylan,
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`and objects to its insertion in the case at this juncture.
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`disease and thus reveals nothing regarding a supposed “therapeutic threshold” of
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`CsA in the context of dry eye and tear production.
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`
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`Dr. Calman’s reliance on Sall’s statement regarding the lack of a “dose-
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`response” relationship is also ill-founded. EX. 1039 at ¶ 80. In making that
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`statement, Sall was addressing overall efficacy, not tear production. EX. 1007 at
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`631. In the context of tear production—the indication for which FDA approved
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`RESTASIS®—Sall shows a critical difference between the 0.05% and 0.1% CsA
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`emulsions. Id. at 635. FDA acknowledged this difference when it approved
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`RESTASIS®, finding statistically significant tear production responder rates for
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`certain patient populations, favoring the 0.05% CsA emulsion over both the vehicle
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`and the 0.1% CsA emulsion. EX. 2078 at 26.
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`IV. The Commercial Success of RESTASIS® is Evidence of Non-Obviousness
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` Mylan does not dispute that the substantial sales and revenues achieved by
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`RESTASIS® demonstrate that the product is commercially successful. EX. 2028
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`at ¶¶ 38-39, 40, 44-46, 53-60. Mylan’s argument that Allergan relies solely on a
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`presumption of nexus is wrong. Reply at 24. Allergan also provided evidence that
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`RESTASIS® is marketed as the first and only product approved to increase the
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`production of natural tears, which further demonstrates a nexus between the
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`claimed features and RESTASIS®’s commercial success. EX. 2028 at ¶¶ 72-76.
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`Moreover, the features that drive commercial success—the particular formulation
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`of RESTASIS® and the clinical properties of the formulation—are not present in
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`the prior art Kaswan ’342 and Ding ’979 patents. EX. 1034 at 250:10-251:9,
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`251:24-252:21. Apportionment of RESTASIS®’s success to these references is
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`therefore inappropriate, and these references do not diminish the nexus between
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`the claims at issue and commercial success. Apportionment of RESTASIS®’s
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`success to specific patents or claims at issue (Reply at 24-25) is also inappropriate,
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`because the claimed features that drive commercial success are recited across the
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`claims at issue—there is a nexus between each of the claims and commercial
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`success. EX. 1034 at 202:5-205:5; EX. 2028 at ¶¶ 72-76.
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`
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`Although Mylan criticizes Allergan for failing to analyze the relevant market
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`(Reply at 25), Mylan’s expert, Mr. Hofmann, does not define a relevant market or
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`identify which products are in that market. EX. 1041 at ¶¶ 43-55. As Dr. Maness
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`testified, RESTASIS® was the first product to treat dry eye disease by increasing
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`natural tear production, and created a market where none existed previously. EX.
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`2028 at ¶¶ 61-71. RESTASIS® sales are also not attributable to excessive
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`marketing. EX. 2028 at ¶¶ 84-99. Marketing and promotional expenses for
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`RESTASIS® have decreased over time, indicating that the product features, not
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`marketing, drive sales. EX. 2028 at Appendix F. Therefore, the commercial
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`success of RESTASIS® supports a finding of non-obviousness over the prior art.
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`V. Mylan’s New Arguments In Reply Deprive Allergan Of Due Process
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`While Allergan acknowledges and appreciates the opportunity to present a
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`surreply, significant due process concerns remain. Mylan’s Reply raises issues and
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`relies upon three declarations that are entirely different than, and in certain cases
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`even contradict, the statements made in its IPR Petition. Far from being confined
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`to the arguments and evidence raised in its Petition, Mylan relies upon three new
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`declarants from three new disciplines, who now critique and contradict the very
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`evidence Mylan relied upon initially.
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`For example, in its Petition Mylan relied heavily on Sall, stating that “Sall
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`teaches either concentration of CsA is ‘therapeutically effective’ in increasing tear
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`production and treating dry eye disease/KCS,” and that based on Sall, “it would
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`have been a routine matter for a skilled artisan to make and then confirm the
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`efficacy of the emulsion comprising 1.25% castor oil and 0.05% CsA.” Petition at
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`39, 41. But in the Reply, Mylan dismisses Sall’s findings of efficacy, stating that
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`“Sall Figure 2 reports a very small average improvement in tearing for both the
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`0.10% and 0.05% CsA formulations, meaning that the average patient started
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`treatment and ended treatment with severe dry eye,” and that the improvement in
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`both formulations “is simply too small to be clinically meaningful.” Reply at 11-
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`12 (emphasis in original). Mylan should not be permitted this complete change of
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`course, undercutting the very prior art it relied upon for its initial arguments.
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`If the Board permits Mylan's new arguments to stand, Allergan’s due
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`process rights will be violated, as Allergan cannot meaningfully respond to these
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`new arguments—which essentially amount to a new petition—without submitting
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`rebuttal declarations from, at minimum, a clinician and a biostatistician. Mylan
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`cannot be allowed to ignore its original petition and present entirely new
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`arguments simply because Allergan presented an effective response to the
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`arguments raised in the Petition. Thus, Allergan respectfully requests the Board
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`give no weight to Mylan’s new arguments and evidence.
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`VI. The Constitutionality of the IPR Process Has Been Challenged
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`The Supreme Court has agreed to hear certain arguments in the petition for
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`certiorari in Oil States Energy Services, LLC v. Greene’s Energy Group, LLC, No.
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`16-712 (U.S. cert. granted June 12, 2017). If the Court accepts those arguments
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`after full briefing, then the Board lacks jurisdiction under the Constitution to
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`consider issues of invalidity in the instant proceeding. Therefore, Patent Owner
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`respectfully submits that the Petition should be denied—or at least stayed pending
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`disposition of the Oil States appeal. If the Board would like additional briefing on
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`the issue, Patent Owner can provide it on terms specified by the Board.
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`VII. Conclusion
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`For at least the foregoing reasons, Mylan has not proven the challenged
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`claims are unpatentable.
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`Respectfully submitted,
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`
`
`/Susan Morrison Coletti/
`Susan Morrison Coletti, Reg. No. 56,332
`Attorney for Allergan, Inc.
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