MYLAN - EXHIBIT 1056
`Mylan Pharmaceuticals Inc. et al. v. Allergan, Inc.
`IPR2016-01127, -01128, -01129, -01130, -01131, & -01132
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`[338
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`MMdat
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`substitute tear instillation or photophobia. Objective tests include teat: production
`(Schirmer I test <55 mntlS min), break up time [BUT < '.I‘ sec), positive staining of the
`infcfior exposed ocular surface with I‘ll: Lissaminc green {Van Bjstcrveld score scale}? In
`addition. the distinction between patients with Sjogren and non-Sjogren dry eyes was
`determined by serologic‘ and clinicalT evaluation for the presence of collagen or
`inflammatory disease. The subjects who suffered from oondry eye related inflatrunation of
`the ocular surface, such as allergicai, viral or bacterial conjunctivitis and ocular surgery.
`were excluded from the study. Specifically. patients with Rosacea. staphylococcal
`htcpharitis and meibomian glands diseases were excluded.
`Impression cytology was performed in both eyes of each patient following the Tseng‘I
`modification of the technique originally described by Nelson.‘ The results were classified
`according to the criteria outline by Tscng.D In lieu of their previous substitute [car therapy.
`patients were treated with unpreserved Diclofenac 0.1% (Velma-en Ofia monodose. Ciba
`Vision. Ilaly) in one eye and unprescnred 0.3% hydrosypiopylmethyloetluiosc with 0.1%
`dextran substitute tears (Dacr'tosol monodotse. Alcoa. Italy) in the controlateral eye. 4 times
`a day for IS consecutive days. A visual analogue scale WAS) made up from a 10 cm line
`on which the patient could mark the lever of his symptoms (Fig. i}. II was used to evaluate
`the changes in the symptoms in each eye from the beginning I0 the end of the study in each
`patient. Lissamine green staining and impression cytology tests were repeated at the end of
`the study. '111e Mann-Whitney statistical tes: was used to analyse the results.
`
`i——-—-—t—I
`Woes:
`Better
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`Figure l. Visual Analogue Scale Eltlli.i mm}.
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`3. RESULTS
`
`The results of VAS. Lissamine green staining and impression cytology are
`summarized in Fig. 2. Analysis of the subjective syrnptcu'rt results indicates that Diclofeuac
`(It's: significantly improved the symptoms of 1025 (P = 0.03}. The ocular sutface
`condition. evaluated by Lissaminc green staining. was also significantly improved after
`treatment {P = 0.05}. Although not statistically significant. visual inspection of the
`impression cytology resulLs also suggested an improvement after treatment. There were no
`significant differences between Sjogren and non-Sjogren patients.
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`impression cytology and Lissarnine green
`Figure 2. Dll'terences from hastilne some: lot symptoms.
`staining oi lhc ocular surface. Unpresemd I13“! hydroxypropylmclhylcellutose with 0.1% dexlran {any
`liars}: Uni-reserved D. 1% Ditluienuc {black burst.
`
`4. DISCUSSION
`
`In our study U'DB short-lean topical use of unpreserved {1.1% Dictafenae was effective
`in improving symptoms and. signs of KCS. This therapy was used in a group of patients
`where Ihe therapy will'i substitute tears did not efieelively improve the chronic ocular
`dimmfort. and. consequently. the quality of life of the patient. After 2 weeks of treatment
`we noticed an appreciable impmvemenl (P: 0.03) in symploms and therefore. in quality
`of life of Ihe patients.
`Lissarnine greeu staining is an indicator of conjunctiva] epithelium damage.” After 2
`weeks of therapy. Lissarnine green staining indicated that treatment with Dietofenac
`improved Ihe condition of the coniunctivat epithelium and therefore the ocular surface.
`Pflugfelder' previously reported that there is decreased goblet cell density in the temporal
`hfllbar conjuncriva in ICES. At the end 0|~ our study we noticed an increase of goblet cell
`density in this area. even if not stalistically significant.
`The ralienale for the use of Diclofcnac in KCS is related to recently published
`information on the palhogenesis ofthc disease. Inflammation of the ocular surface is either
`the Origin of injury or can exacerbate an existing injury in eyes with PICS." The primary
`insult thal gives rise lo inflammation is unclear. However, me inflammatory cascade
`results in the expression of high levels of pro-inflammatory cytoltine mRNA in
`conjunctival eelis or palients wilh Sjogren syndrome” and in general with dry eye.""
`Corticosteroid Ireatmenl improves symptoms of [hese diseases appreciably. probably by
`inlerrupling the inflammatory cascade. Chronic ucalment with these drugs. however,
`resulted in important side effects as pointed out in this and other studies.‘
`Dielufenac. like olher non-steroidal anliainflammatnry drugs. acts by inhibiting the
`activity of cyclooxygenase on arachidonit: acid" that in Iurn inhibils the production of pro—
`inflammatory cytokines on the ocular surface. The use or a singie dose unpreserveci
`treatmenl regimen avoids the well known and harmful effects of benzalkocniurn chloride on
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`the ocular wrface.“ Although rate paths-logic ocular surface changes as resth nt' tepieally
`administered non-steroidal anti-inflammatory drugs alter ocular surgery have been recently
`described." The number ofpatients in our study is too small to assess the complete safety
`(If such a treatment in dry eyes. However. dry eye patients treated with topically
`administered nanvstemidal anti-inflammatory drugs should be monitored for the
`appearance of corneal changes. Although further studies are necessary to establish the
`safety and the efficacy of long term therapy, the results of this study are encouraging and
`indicate that Diclofenat: in association with tear substitutes can be effective for the
`mannenl of patients with KCS.
`
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