MYLAN - EXHIBIT 1056
`Mylan Pharmaceuticals Inc. et al. v. Allergan, Inc.
`IPR2016-01127, -01128, -01129, -01130, -01131, & -01132
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`1238
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`M. Rolando ef al,
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`substitute tear instillation or photophobia. Objective tests include tear production
`(Schirmer [ test <5.5 mm/5 min), break up time (BUT < 7 sec), positive staining of the
`inferior exposed ocular surface with 1% Lissamine green (Van Bjsterveld score scale). In
`addition, the distinction between patients with Sjogren and non-Sjogren dry eyes was
`determined by serologic’ and clinical’ evaluation for the presence of collagen or
`inflammatory disease. The subjects who suffered from non-dry eye related inflammation of
`the ocular surface, such as allergical, viral or bacterial conjunctivitis and ocular surgery,
`were excluded from the study. Specifically, patients with Rosacea, staphylococcal
`blepharitis and meibomian glands diseases were excluded.
`Impression cytology was performed in both eyes of each patient following the Tseng?
`modification of the technique originally described by Nelson." The results were classified
`accordingto the criteria outline by Tseng.” In lieu of their previous substitute tear therapy,
`patients were treated with unpreserved Diclofenac 0.1% (Voltaren Ofta monodose, Ciba
`Vision, Italy) in one eye and unpreserved 0.3% hydroxypropylmethyleellulose with 0.1%
`dextran substitute tears (Dacricsol monodose, Alcon,Italy) in the controlateral cye, 4 times
`a day for 15 consecutive days. A visual analogue scale (VAS) made up from a 10 cm line
`on which the patient could mark the level of his symptoms (Fig. 1). It was used to evaluate
`the changes in the symptoms in cach eye from the beginning to the end of the study in each
`patient. Lissamine green staining and impression cytology tests were repeated at the end of
`the study. The Mann-Whitneystatistical test was used to analyze the results.
`
`=Worse Better
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`Figure 1. Visual Analogue Scale (100 mm).
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`3. RESULTS
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`The results of VAS, Lissamine green staining and impression cytology are
`summarized in Fig. 2. Analysis of the subjective symptom results indicates that Diclofenac
`0.1% significantly improved the symptoms of KCS (P = 0.03). The ocular surface
`condition, evaluated by Lissamine green staining, was also significantly improved after
`treatment (P = 0.05). Although not statistically significant, visual inspection of the
`impression cytology results also suggested an improvementafter treatment. There were no
`significant differences between Sjogren and non-Sjogrenpatients.
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`f symotore
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`average 5 _———
`score
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`Monersoncytology©sTamEne green
`differences from basoling
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`impression cytology and Lissamine green
`Figure 2. Differences from baseline scores for symptoms.
`staining of the ocular surface. Unpreserved 0.3% hydroxypropylmethyloellulose with 0.1% dexwan (gray
`bars); Unpreserved 0.1% Diclofenac (black bars).
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`4, DISCUSSION
`
`In our study the short-term topical use of unpreserved 0.1% Diclofenac was effective
`in improving symptoms and signs of KCS. This therapy was used in a group of patients
`where the therapy with substitute tears did not effectively improve the chronic ocular
`discomfort, and consequently, the quality of life of the patient. After 2 weeks of treatment
`we noticed an appreciable improvement (P = 0.03) in symptoms and therefore, in quality
`oflife of the patients.
`Lissamine green staining is an indicator of conjunctival epithelium damage." After 2
`weeks of therapy, Lissamine green staining indicated that treatment with Diclofenac
`improved the condition of the conjunctival epithelium and therefore the ocular surface.
`Pflugfelder’ previously reported that there is decreased goblet cell density in the temporal
`bulbar conjunctiva in KCS. At the end of our study we noticed an increase of goblet cell
`density in this area, even if mot statistically significant.
`The rationale for the use of Diclofenac in KCS is related to recently published
`information on the pathogenesis of the disease. Inflammation of the ocular surface is either
`the origin of injury or can exacerbate an existing injury in eyes with KCS,'! The primary
`insult that gives rise to inflammation is unclear. However, the inflammatory cascade
`results in the expression of high levels of pro-inflammatory cytokine mRNA in
`conjunctival cells of patients with Sjogren syndrome” and in general with dry eye."
`Corticosteroid treatment improves symptoms of these diseases appreciably, probably by
`interrupting the inflammatory cascade, Chronic treatment with these drugs, however,
`resulted in important side effects as pointed out in this and other studies."
`Diclofenac, like other non-steroidal anti-inflammatory drugs, acts by inhibiting the
`activity of cyclooxygenase on arachidonic acid" that in turn inhibits the production of pro-
`inflammatory cytokines on the ocular surface. The use of a single dose unpreserved
`treatment regimen avoids the well known and harmful effects of benzalkonium chloride on
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`Ni. Mead ef ae
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`the ocular surface."* Although rare, pathologic ocular surface changes asresult oftopically
`administered non-steroidal anti-inflammatory drugs after ocular surgery have been recently
`described.'° The numberof patients in our study is too small to assess the complete safety
`of such a treatment
`in dry eyes. However, dry eye patients treated with topically
`administered non-steroidal 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 Diclofenac in association with tear substitutes can be effective for the
`treatmentof patients with KCS.
`
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