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`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
`v.
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`ALLERGAN, INC.
`Patent Owner
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`Case IPR2016-01131
`Patent 8,648,048
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`PATENT OWNER ALLERGAN, INC.’S
`RESPONSE
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`

`

`Case IPR2016-01131
`Attorney Docket No: 13351-0008IP5
`
`
`TABLE OF CONTENTS
`
`
`
`I. 
`II. 
`
`Introduction .......................................................................................... 1 
`Background of the ‘048 Patent ............................................................. 6 
`A. 
`Lack of Tear Production is a Hallmark of Dry Eye Disease .... 6 
`B. 
`Prior Treatments for Dry Eye Disease ...................................... 9 
`C. 
`Allergan’s Development of RESTASIS® .............................. 10 
`III.  The ASSERTED PRIOR ART REFERENCES ................................. 12 
`A. 
`The Ding ‘979 Patent .............................................................. 12 
`B. 
`The Sall Paper ......................................................................... 13 
`IV.  The ‘048 Patent ................................................................................... 16 
`V.  Argument ............................................................................................ 17 
`Increasing The Amount Of Castor Oil Vehicle In The
`A. 
`Emulsion Would Be Expected To Reduce The Amount of CsA
`Reaching The Lacrimal Gland............................................................ 22 
`PK Data Predicted That The Claimed 0.05%
`B. 
`Cyclosporin/1.25% Castor Oil Vehicle Emulsion Would Have Been
`Less Effective Than The 0.10% Cyclosporin/1.25% Castor Oil
`Vehicle Emulsion At Increasing Tear Production .............................. 24 
`The Claimed Emulsion Is More Effective At Increasing Tear
`C. 
`Production Than The Ding ‘979 Emulsions ....................................... 28 
`The Increased Tear Production Is Not Due To Balancing Or
`D. 
`Optimizing The Concentration Of The Castor Oil Vehicle ............... 30 
`The Differences Between The Claimed Emulsion And The
`E. 
`Ding ‘979 Emulsions Are Differences In Kind, Not Degree ............. 34 
`F. 
`Objective Evidence Of Non-Obviousness .............................. 36 
`1.  There was a long-felt need and unmet need for a dry eye
`treatment that increased tear production .................................. 36 
`2.  The claimed emulsions unexpectedly were more effective at
`increasing tear production than the Ding ‘979 prior art
`emulsions .................................................................................. 37 
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`Case IPR2016-01131
`Attorney Docket No: 13351-0008IP5
`3.  The claimed emulsions were commercially successful
`because they increased tear production .................................... 38 
`Allergan Did Not Admit That The Claims Were
`G. 
`Unpatentable ....................................................................................... 40 
`Claims 11 And 21 Would Not Have Been Obvious Over
`H. 
`Ding ‘979 Plus Sall And Acheampong. ............................................. 41 
`Claim 15 Would Not Have Been Obvious Over Ding ‘979 Plus
`I. 
`Sall And Glonek. ................................................................................ 41 
`VI.  Claim Construction ............................................................................. 43 
`VII.  Conclusion .......................................................................................... 44 
`
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`
`iii
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`Case IPR2016-01131
`Attorney Docket No: 13351-0008IP5
`LIST OF EXHIBITS
`
`EX. 2002
`EX. 2003
`
`EX. 2004
`EX. 2005
`EX. 2006
`EX. 2007
`EX. 2008
`EX. 2009
`
`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)
`
`EX. 2010
`EX. 2011
`
`EX. 2012
`
`EX. 2013
`
`EX. 2014
`
`iv
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`Case IPR2016-01131
`Attorney Docket No: 13351-0008IP5
`das Neves et al., “ Mucosal Delivery of Biopharmaceuticals:
`Biology, Challenges and Strategies,” Springer Science (2014)
`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”
`
`EX. 2015
`
`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
`
`v
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`

`

`EX. 2031
`EX. 2032
`
`EX. 2033
`
`EX. 2034
`
`EX. 2035
`EX. 2036
`
`EX. 2037
`
`EX. 2038
`EX. 2039
`
`EX. 2040
`
`EX. 2041
`EX. 2042
`
`EX. 2043
`EX. 2044
`EX. 2045
`EX. 2046
`EX. 2047
`
`Case IPR2016-01131
`Attorney Docket No: 13351-0008IP5
`Allergan – NYSE: AGN – Company Profile
`Drugs@FDA: FDA Approved Drug Products,
`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
`
`vi
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`

`EX. 2048
`
`EX. 2049
`
`EX. 2050
`
`EX. 2051
`EX. 2052
`
`EX. 2053
`EX. 2054
`EX. 2055
`EX. 2056
`
`EX. 2057
`
`EX. 2058
`EX. 2059
`EX. 2060
`
`EX. 2061
`EX. 2062
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`EX. 2063
`
`EX. 2064
`
`EX. 2065
`
`Case IPR2016-01131
`Attorney Docket No: 13351-0008IP5
`Allergan Inc., Buckingham Research Group Equity Research
`Report, Feb 5, 2003
`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
`
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`Case IPR2016-01131
`Attorney Docket No: 13351-0008IP5
`“Sales-Units_2011-2016_AllData_NSP_Feb-19-
`2017_RESTASIS.xlsx”
`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
`
`EX. 2066
`
`EX. 2067
`EX. 2068
`
`EX. 2069
`
`EX. 2070
`
`EX. 2071
`
`EX. 2072
`EX. 2073
`EX. 2074
`
`
`
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`Case IPR2016-01131
`Attorney Docket No: 13351-0008IP5
`
`I.
`
`INTRODUCTION
`
`RESTASIS® is the first and only FDA-approved product indicated for
`
`increasing tear production in patients suffering from a serious eye condition known
`
`as dry eye disease.1 Dry eye is a chronic condition with no known cure in which
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`the eyes do not make enough tears. EX. 1007 (Sall et al.) at 631. Left untreated,
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`this condition can cause severe pain, as well as increased risk of ocular surface
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`damage and ocular infection. Id.
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`Before RESTASIS®, the most common treatments for dry eye were
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`artificial tears and lubricants that provided temporary comfort but did not treat the
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`immune-based inflammatory processes responsible for the disease. RESTASIS®
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`created an entirely new treatment for the disease, and was the first therapy
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`approved by FDA to actually treat the underlying disease.
`
`The challenged patent, U.S. Patent No. 8,648,048 (“the ‘048 patent), covers
`
`this groundbreaking product, and covers Allergan’s discovery that the formulation
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`of RESTASIS® is uniquely suited to enhancing the production of tears in dry eye
`
`
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`1 The precise FDA-approved indication for RESTASIS® is for increasing
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`tear production in patients with keratoconjunctivitis sicca. EX. 2008
`
`(RESTASIS® Label) at 1. Keratoconjunctivitis sicca (“KCS”) is a type of dry eye
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`disease. See EX. 2024 (Sheppard), ¶¶ 18-19.
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`1
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`Case IPR2016-01131
`Attorney Docket No: 13351-0008IP5
`patients. The active ingredient in RESTASIS® is cyclosporin A (“CsA”). CsA is
`
`an immunosuppressant that, when delivered to the lacrimal gland, suppresses the
`
`inflammatory processes that lead to lack of tear production. EX. 1007 (Sall et al.)
`
`at 631-32.
`
`Because CsA has limited solubility in water, it cannot be delivered in a
`
`traditional aqueous ophthalmic solution. Instead, it must be combined with a
`
`lipophilic material, such as castor oil, in a vehicle to deliver it to the eye. See EX.
`
`1006 (Ding ‘979), 1:40-53. RESTASIS® thus is an emulsion that contains 0.05%
`
`by weight CsA in a liquid vehicle that includes 1.25% by weight castor oil,
`
`polysorbate 80, and other excipients. EX. 2008 (RESTASIS® Label) at 3-4; EX.
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`2001 (NDA 21-023) at 256.
`
` The claims of the ‘048 patent specifically recite this combination of 0.05%
`
`CsA/1.25% castor oil vehicle that makes RESTASIS® work. As demonstrated in
`
`Allergan’s Phase 3 clinical trials, this particular combination of 0.05% CsA/1.25%
`
`castor oil vehicle is unique and has unexpected therapeutic effects in increasing
`
`tear production. Specifically, the claimed emulsion unexpectedly increases tear
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`production much better than an emulsion containing twice the amount of CsA and
`
`the same amount of castor oil vehicle (0.10% CsA/1.25% castor oil vehicle)—the
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`opposite of what a person of ordinary skill would have expected.
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`Case IPR2016-01131
`Attorney Docket No: 13351-0008IP5
`The 0.10% CsA/1.25% castor oil emulsion is disclosed in Allergan’s Ding
`
`‘979 patent (EX. 1006, 4:30-45, Example 1, composition E), the closest prior art
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`relied upon by Mylan and the same art the Examiner rejected the claims over
`
`during original prosecution. After reviewing data comparing the efficacy of the
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`claimed formulation and the prior art formulation, the Examiner correctly
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`concluded that the claimed formulation “is surprisingly critical for therapeutic
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`effectiveness in the treatment of dry eye or keratoconjunctivitis sicca,” and
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`therefore, “demonstrate[s] surprising and unexpected results.” EX. 1004 (Notice
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`of Allowability) at 473.
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`The Examiner’s conclusion was well taken. A person of ordinary skill in the
`
`art, applying basic thermodynamic principles, would have expected that a
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`formulation containing more castor oil relative to CsA would make the lipophilic
`
`CsA less likely to separate from the lipophilic castor oil vehicle and travel to the
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`ophthalmic tissues and, specifically, the lacrimal gland. EX. 2025 (Loftsson), ¶¶
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`37-40. Allergan’s pharmacokinetic (“PK”) data is consistent with that expectation
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`and showed that, with increased castor oil concentration, less CsA, in fact, traveled
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`to the tissues. As a result, a person of ordinary skill would have expected that with
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`less CsA reaching the tissues, the claimed emulsion (0.05% CsA/1.25% castor oil)
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`would have been less effective for increasing tear production than the prior art
`
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`Case IPR2016-01131
`Attorney Docket No: 13351-0008IP5
`0.10% CsA/1.25% castor oil vehicle emulsion disclosed in the Ding ‘979 patent.
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`EX. 2025 (Loftsson), ¶¶ 41-44; EX. 2027 (Allergan PK-09-074 Report).
`
`Surprisingly, Phase 3 clinical data demonstrated the opposite. The claimed
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`emulsion (0.05% CsA/1.25% castor oil) resulted in a statistically significant
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`improvement in tear production compared to the castor oil vehicle alone (i.e., with
`
`no CsA) after three months, as measured by the Schirmer’s tear test, whereas the
`
`Ding ‘979 prior art emulsion (0.10% CsA/1.25% castor oil) did not. EX. 2025
`
`(Loftsson), ¶¶ 33-34; EX. 2024 (Sheppard), ¶¶ 40-42; EX. 1007 (Sall et al.), Fig.
`
`2. And even after six months, when the Ding ‘979 prior art emulsion showed
`
`some effect, the claimed emulsion continued to outperform it. Id. Accordingly,
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`the unique combination of 0.05% CsA with the 1.25% castor oil vehicle, with half
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`the active ingredient as the prior art emulsion, was unexpectedly more effective
`
`than the Ding ‘979 prior art emulsion.
`
`In its Institution Decision, the Board, relying on Mylan’s Petition, postulated
`
`that the claimed castor oil concentration might result from “optimiz[ing] the castor
`
`oil concentration” by “balancing the need to minimize any undesirable effects
`
`associated with castor oil” to “take advantage of the ‘substantial palliative benefits’
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`of castor oil.” IPR2016-01131, Paper 8, at 17-18. This is incorrect. The same
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`Phase 3 testing described above showed that patients given the 1.25% castor oil
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`vehicle alone actually experienced reduced tear production. EX. 2025 (Loftsson),
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`Case IPR2016-01131
`Attorney Docket No: 13351-0008IP5
`¶ 35; EX. 2024 (Sheppard), ¶ 41; EX. 1007 (Sall et al.), Fig. 2. Thus, whatever
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`“palliative” benefits might result from the claimed castor oil concentration,
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`increased tears is not one of them.
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`The Schirmer tear test results demonstrate that—contrary to the Board’s
`
`supposition in its Institution Decision—a person of ordinary skill would not have
`
`contemplated any “balancing” or “optimizing” of the castor oil concentration at all,
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`because there was nothing to balance. When tested in a rigorous Phase 3 clinical
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`trial by itself, the 1.25% castor oil vehicle simply did not increase tear production.
`
`Based on the available art, including the Sall paper, a person of skill would have
`
`understood that it was only the CsA, not the castor oil vehicle, that increased tear
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`production, and would have expected that using half the amount of CsA (0.05%)
`
`disclosed in the closest prior art formulation (0.10%) would have made things
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`worse, not better.
`
` Accordingly, the specific combination of 0.05% CsA/1.25% castor oil
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`vehicle found in RESTASIS® and recited in each of the ‘048 patent claims is
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`critical for increasing tear production in the lacrimal gland, and operates in a
`
`different way—less CsA is delivered to the ophthalmic tissues but results in better
`
`efficacy—compared to the emulsions described in the Ding ‘979 patent. EX. 2025
`
`(Loftsson), ¶ 36; EX. 2024 (Sheppard), ¶ 45. Under controlling Federal Circuit
`
`precedent, this formulation is not the result of “optimizing” anything, but instead is
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`Case IPR2016-01131
`Attorney Docket No: 13351-0008IP5
`a unique combination that produces exceptional results for patients that were
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`wholly unexpected. See Galderma Laboratories, L.P. v. Tolmar, Inc., 737 F.3d
`
`731, 739 (Fed. Cir. 2013) (“Unexpected results that are probative of
`
`nonobviousness are those that are different in kind and not merely in degree from
`
`the results of the prior art.”). It is manifestly not obvious.
`
`Objective evidence of non-obviousness supports this conclusion. To this
`
`day, despite incredible market incentives for others to compete with it,
`
`RESTASIS® remains the only FDA-approved product indicated for increasing tear
`
`production. RESTASIS® created a market for the treatment of the underlying
`
`disease by increasing tear production. The growth and expansion of that market
`
`demonstrate RESTASIS®’s commercial success.
`
`The ‘048 claims would not have been obvious over the Ding ‘979 patent in
`
`combination with any of the secondary references included in Mylan’s grounds for
`
`unpatentability. Allergan respectfully requests that the Board confirm the
`
`patentability of the challenged claims.
`
`II. BACKGROUND OF THE ‘048 PATENT
`A. Lack of Tear Production is a Hallmark of Dry Eye Disease
`
`Dry eye disease is a disease affecting the ocular surface, tear film, and
`
`related ocular tissues and organs. EX. 2024 (Sheppard), ¶ 19. It is generally
`
`characterized by reduced tear production, tear evaporation, and/or an imbalance in
`
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`Case IPR2016-01131
`Attorney Docket No: 13351-0008IP5
`tear film components. Keratoconjunctivitis sicca (“KCS”) is a type of dry eye
`
`disease. See id., ¶¶ 18-19. Dry eye occurs when the lacrimal glands are unable to
`
`produce enough tears to keep the eyes moist and healthy. See id., ¶¶ 19-23.
`
`Symptoms of dry eye can include ocular grittiness, burning, irritation,
`
`photophobia, and blurred vision. Id., ¶ 19. Left untreated, the disease can damage
`
`the ocular surface and increase the risk of ocular infection. Id.
`
`The exact mechanism underlying dry eye disease is not fully known. Id., ¶
`
`23. Nevertheless, current evidence suggests that dry eye results from multifactorial
`
`etiologies that result in a common immune-based inflammation of the lacrimal
`
`glands and ocular surface. Id.
`
`Two distinct triggers for dry eye disease have been idenitfied. Id., ¶ 24. In
`
`one variation, a localized autoimmune event occurs in the ocular tissues, which
`
`results in a loss of normal hormonal support to the lacrimal tissues. Id. This
`
`results in a local environment that facilitates initiation of the inflammatory process,
`
`in which activated T-cells are recruited to the ocular surface and lacrimal glands of
`
`dry eye patients. Id.; EX. 1021 (Small et al.) at 411-12. These T-cells play an
`
`important role in the inflammatory response through cytokine synthesis, which in
`
`the case of dry eye disease results in repeated inflammation and further T-cell
`
`activation that ultimately destroys the lacrimal glands. EX. 2024 (Sheppard), ¶ 23;
`
`EX. 1021 (Small et al.) at 411-12.
`
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`Case IPR2016-01131
`Attorney Docket No: 13351-0008IP5
`Alternatively, chronic physical irritation to the ocular surfaces may occur,
`
`for example, as a result of environmental factors such as wind, low humidity, or
`
`increased abrasive forces from blinking over an ocular surface with an inadequate
`
`tear film. EX. 2024 (Sheppard), ¶ 25. The result of the irritative inflammatory
`
`response is immune activation. Id.
`
`Dry eye is commonly diagnosed using the Schirmer tear test with anesthesia.
`
`Id., ¶ 20. The Schirmer tear test evaluates whether the eye produces enough tears
`
`to keep it moist. Id. In addition to diagnosing dry eye, it is used to determine
`
`whether a given treatment, such as RESTASIS®, is working to increase a patient’s
`
`tear production. Id.
`
`Clinicians perform the Schirmer tear test by numbing the eye with a local
`
`anesthetic and then placing a small strip of test paper inside the lower eyelid. Id., ¶
`
`21. The anesthetic ensures that only basal tears, i.e., the tears produced by the
`
`lacrimal gland, are measured, rather than reflexive tears, which are produced in
`
`response to an irritant such as the test paper.2 Id. The test can also be conducted
`
`without anesthesia. This variation, however, fails to isolate the relevant basal tear
`
`production from reflexive tear production. Id., ¶ 43.
`
`
`
`2 Unless explicitly stated, all references to Schirmer tests are with anesthesia.
`
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`Case IPR2016-01131
`Attorney Docket No: 13351-0008IP5
`After insertion of the paper, the eyes are then closed for five minutes, after
`
`which the paper is removed and the amount of moisture absorbed on the paper is
`
`measured. Id., ¶ 21. A healthy person normally moistens about 15 mm of each
`
`paper strip after five minutes. Id. Patients with mild dry eye will moisten
`
`approximately 14-9 mm of the paper after five minutes, whereas severe dry eye
`
`patients will moisten less than 4 mm in the same timeframe. Id.
`
`B.
`
`Prior Treatments for Dry Eye Disease
`
`Before the development of RESTASIS®, the most common products used to
`
`treat the symptoms of dry eye disease consisted of topical application of artificial
`
`tears and lubricants. Id., ¶ 27; EX. 1012 (Kunert et al.) at 1490. For example,
`
`Allergan marketed a castor oil-only emulsion as an artificial tear product under the
`
`tradename, REFRESH ENDURA®, for the temporary relief of burning, irritation,
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`and discomfort due to dryness of the eye.3 Although artificial tears may provide
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`temporary comfort to the eye, they do not mediate the immune-based inflammatory
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`process responsible for dry eye disease and are not indicated to enhance tear
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`production. See EX. 2024 (Sheppard), ¶ 27.
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`
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`3 Refresh Endura Lubricant Eye Drops (Allergan), Theodora,
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`http://www.theodora.com/drugs/refresh_endura_lubricant_eye_drops_allergan.htm
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`l (last visited Mar. 19, 2017).
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`Steroids were also used to treat dry eye. However, steroids generally were
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`recommended only for short-term use because prolonged use could result in
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`adverse events including ocular infection, glaucoma, and cataracts. EX. 2024
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`(Sheppard), ¶ 28; EX. 2011 (Agarwal & Rupenthal) at 1.
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`Additional measures for treating dry eye disease included the use of punctal
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`plugs to restore tear volume. EX. 2024 (Sheppard), ¶ 29; EX. 1020 (Murphy) at 2-
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`3; EX. 1007 (Sall et al.) at 631. Punctal plugs, which are small devices temporarily
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`or permanently inserted into the eye, alleviate the symptoms of dry eye disease by
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`preventing tears from draining from the eyes. EX. 2024 (Sheppard), ¶ 29; EX.
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`1007 (Sall et al.) at 631. Another option was dry eye surgery, in which the tissue
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`at the opening of the punctum is cauterized, sealing the eye’s fluid drainage system
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`permanently. EX. 2024 (Sheppard), ¶ 29.
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`Until RESTASIS® entered the market in 2003, there was no medication or
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`treatment on the market that increased tear production or directly impacted the
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`underlying immunological cause of dry eye disease. Id.
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`C. Allergan’s Development of RESTASIS®
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`RESTASIS® is formulated as an emulsion containing 0.05% by weight
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`CsA, 1.25% by weight castor oil, and 1% by weight polysorbate 80, along with
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`other excipients. EX. 2008 (RESTASIS® Label) at 3-4; EX. 2001 (NDA 21-023)
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`at 256, tbl.3.3.2.1-1. RESTASIS® is different from any other drug prescribed for
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`dry eye disease. Its active ingredient, CsA, is a drug with immunomodulatory and
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`anti-inflammatory properties. EX. 2024 (Sheppard), ¶ 32; EX. 1007 (Sall et al.) at
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`631-32. RESTASIS® treats dry eye disease by delivering CsA to the lacrimal
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`gland, where it inhibits activation of T-cells, thereby preventing the production of
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`inflammatory cytokines. EX. 2024 (Sheppard), ¶ 34. The disruption in
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`inflammation, via inhibition of T-cell activation and down-regulation of
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`inflammatory cytokines in the conjunctiva and lacrimal gland, is believed to result
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`in enhanced tear production. Id., ¶ 34; EX. 1011 (Kaswan) at 650.
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`In late 2002, FDA approved RESTASIS®, the first prescription ophthalmic
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`emulsion ever approved, “to increase tear production in patients whose tear
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`production is presumed to be suppressed due to ocular inflammation associated
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`with keratoconjunctivitis sicca.” EX. 2008 (RESTASIS® Label) at 1. FDA relied
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`upon the Schirmer tests with anesthesia in approving RESTASIS®, as reflected on
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`the FDA approved product label:
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`EX. 2008 (RESTASIS® Label) at 5.
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`To this day, RESTASIS® remains the only FDA-approved product indicated
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`for increasing the eye’s production of natural tears, even 15 years after its original
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`approval and despite a substantial commercial incentive for developing dry eye
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`treatments. EX. 2028 (Maness), ¶¶ 43-71. For example, just last year Shire
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`obtained approval and began marking XIIDRA® (liftegrast ophthalmic solution
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`5%) for the treatment of dry eye. EX. 2038 (LeCause Dep.) at 120:7-122:3. In
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`contrast to RESTASIS®, XIIDRA® is only indicatedfor treating the signs and
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`symptoms of dry eye, and not for enhancing tear production. Id. at 62:17-63:14.
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`III. THE ASSERTED PRIOR ART REFERENCES
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`The two primary references that Mylan relies upon for its obviousness
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`challenge are the Ding ‘979 patent (EX. 1006) and the Sall paper (EX. 1007).
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`A. The Ding ‘979 Patent
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`The Ding ‘979 patent is an Allergan patent. It describes the difficulty in
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`formulating CsA and proposes a combination of oil, excipient (including, for
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`example, an emulsifier), and dispersing agent to create emulsions containing CsA
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`that are both stable and have low irritation potential. See, e.g., EX. 1006 (Ding
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`‘979) at 6:3-8. Example 1 of the Ding ‘979 patent describes five different CsA-
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`containing emulsions. Id. at 4:32-42. Each emulsion combines CsA with a vehicle
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`that includes castor oil. Formulation D includes 0.01% CsA and 1.25% castor oil,
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`while Formulation E includes 0.05% CsA and 0.625% castor oil. Id. Formulations
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`A, B, and C include higher amounts of both CsA and castor oil. Id.
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`The Ding ‘979 patent further describes animal studies showing that each of
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`these emulsions potentially could be used to deliver CsA to ocular tissues. Id. at
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`5:14-25. Importantly, however, the Ding ‘979 patent does not disclose any testing
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`concerning the ability of any of these formulations to actually increase tear
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`production. And none of the formulations described in the Ding ‘979 patent
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`includes the 0.05% CsA/1.25% castor oil vehicle formulation claimed in the ‘048
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`patent.
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`B.
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`The Sall Paper
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`Sall describes the pivotal Phase 3 clinical studies that Allergan conducted to
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`secure approval of RESTASIS®. Two CsA-containing emulsions were tested:
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`0.05% and 0.10% CsA. EX. 1007 (Sall et al.) at 631. Sall compares the
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`performance of both emulsions to an emulsion that included only the vehicle. Id.
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`at 632. Both the CsA emulsions and the vehicle-only emulsion were castor oil-in-
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`water emulsions, but the precise formulations were kept proprietary. Id.
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`Petitioner does not dispute that Sall fails to disclose the composition of the
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`proprietary formulations used, except only to note that it includes CsA and castor
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`oil. See id. Therefore, a person of ordinary skill, reading Sall, would not have
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`known the amount or relative percentages of castor oil in any of the Sall vehicles.
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`EX. 2024 (Sheppard), ¶ 38; EX. 2025 (Loftsson), ¶ 32. Only later did the ‘048
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`patent disclose that the vehicle for each formulation in Sall contained 1.25% castor
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`oil. See EX. 1001, 14:14-34 (“These compositions are employed in a Phase 3,
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`double-masked, randomized, parallel group study for the treatment of dry eye
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`disease.”); EX. 2024 (Sheppard), ¶ 39; EX. 2025 (Loftsson), ¶ 32.
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`The efficacy measures used in the Phase 3 study included several objective
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`and subjective parameters. EX. 1007 (Sall et al.) at 633. In particular, one of the
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`objective efficacy measures was the Schirmer tear test, which, as described above,
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`measures basal tear production. Id. Figure 2 of Sall, reproduced below, shows the
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`results of the Schirmer tear test on the three test formulations in the pivotal Phase 3
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`trials:
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`
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`The asterisks in Figure 2 denote a statistically significant result compared to
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`vehicle (P ≤ .05). As shown in Figure 2, at month three there was a significant
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`worsening of tear production in the vehicle group (i.e., the castor oil-only
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`emulsion). As for the CsA-containing emulsions, at month three only the CsA
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`0.05% emulsion showed increased tear production compared to vehicle, despite
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`having less active ingredient than the CsA 0.10% emulsion. Id. at 635-36. At
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`month six, the CsA 0.05% emulsion continued to outperform the CsA 0.10%
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`emulsion, which did show some increased tear production at that point in time. As
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`for the castor oil-only emulsion, at month six it continued to show no statistical
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`improvement in tear production and numerically worse tear production than
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`baseline. Id. Sall interpreted the Schirmer tear test results as suggesting that CsA
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`treatment was affecting baseline tearing and not reflexive tearing. Id. at 637.4
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`Based on these results, the authors concluded that CsA treatment is not
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`purely palliative and represented the first therapeutic treatment specifically for dry
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`eye, and a significant breakthrough in the management of this common and
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`frustrating condition. Id. at 7-8.
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`IV. THE ‘048 PATENT
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`The ‘048 patent is one of several patents covering Allergan’s RESTASIS®
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`product and its use to treat dry eye disease by increasing tear production. It
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`contains 23 claims, each directed towar