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`Santen/Asahi Glass Exhibit 2059
`Micro Labs v. Santen Pharm. and Asahi Glass
`IPR2017-01434
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`

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`Table 1 Forty patients were randomised to one offive
`different treatments with eight patients in each group. The
`baseline characteristics for the different treatment groups are
`shown
` Placebo 0-3 yg lpg 3g 10 yg
`
`
`
`
`HYPERAEMIA
`Number
`8
`8
`8
`8
`8
`Females
`8
`5
`6
`6
`7
`Males
`0
`3
`2
`2
`1
`The degree of hyperaemia was determined from
`Mean age
`58:9
`64-4
`67°6
`58:4
`65:0
`colour photographsand graded onascale from 0
`STD
`10-4
`66
`56
`12:2
`8-0
`to 3 with seven steps, by comparing with four
`Range
`45-73
`56-75
`56-78
`41-72
`54-75
`IOP
`22:4
`22:8
`23-2
`22:8
`23-1
`standard photographs covering the range from
`STD
`2:54
`3-83
`4-40
`2:47
`2-95
`none to pronounced hyperaemia. The average of
`Exfoliations
`3
`4
`6
`0
`3
`Right eyes
`3
`6
`4
`3
`2
`four independent and masked gradings deter-
`
`5 2 4 5Left eyes 6
`
`
`
`
`mined the hyperaemia.
`
`PhXA34 —a prostaglandin F2, analogue. Effect on intraocularpressure in patients with ocular hypertension
`
`215
`
`from each eye alwaysstarting with therighteye.
`The medianvalueof the three readings was taken
`as the true IOP.
`
`.
`
`CELLS AND FLARE
`Theanterior chamberwas examinedbyslit-lamp
`biomicroscopy. Flare was graded none, slight,
`moderate, or severe, and the numberofcells, if
`any, were counted.
`
`SYMPTOMS
`
`Prior to IOP measurements the patients were
`asked in a standardised way about
`local and
`systemic symptoms. Symptomsand discomfort
`were graded mild, moderate, or severe.
`
`DATA ANALYSIS
`All IOP values are presented as means with 95%
`confidence intervals. The IOP values used for
`the dose-responsecurve (Fig 1) are based on the
`IOPdeterminationsat tg and t,2. These two IOP
`values were averaged andthe difference between
`average IOP day | (before treatment) and day 2
`(after treatment) has been used as an estimate of
`drugeffect for each patient. Also the differences
`in IOP for corresponding examination times on
`day 1 and day 2 have beencalculatedforall doses
`including placebo (see Table 2).
`To find statistically significant differences
`between placebo effect and drug effects non-
`
`IOPis expressed as the mean ofpretreatmentdayf, fg, and f2.
`
`pairedt tests have been used. Theeffect on IOP
`expressed as the area under the curve for the
`differences in IOP day 1 and day 2 for each
`treatment group has been calculated using a
`simple numerical estimation of area by the
`trapezoidalrule.’
`The contralateral eyes were a mixed group of
`normal eyes and eyes with ocular hypertension,
`and they havenot been includedin the analysis.
`The estimated hyperaemia is based on the
`difference between the maximum score on day 2
`and the score before examination and IOP
`measurementatlp day 2.
`
`Results
`All patients completed the study. Theresults of
`randomisation are shown in Table 1. Figure 1
`shows the average IOP reductions (mean with
`95% confidenceinterval) for placebo and increas-
`ing doses of PhXA34 8 and 12 hours post-dose.
`
`Table2 IOPin the study eyesfor the different treatment
`groups day I and day 2
`
`Day 2
`
`Change in IOP
`
`IOPreduction
`
`mmHg
`
`etwauadAy
`
`10.0 wg
`
`oernmWeboDNsWDwo
`
`Placebo 0.3 wg
`
`10 y9
`
`3.0 wg
`
`log (dose + 4)
`The effecton IOP and conjunctival hyperaemia of
`Figure 1
`four single doses ofPhXA34 and placebo. The values used to
`express the IOP reduction for each dose are based on the IOP
`determinationsat tg and t,2. These two values were averaged
`and the difference between average IOP day | (before
`treatment) and average IOP day 2 (after treatment) was used
`as an estimate ofdrug effectfor each patient. Hyperaemia was
`estimatedfor each patient as the difference between maximum
`score on day 2 (after treatment) and the registration atto day 2.
`Closedcircles: mean IOP reduction with 95% confidence
`interval; open circles: mean hyperaemia.
`
`Thevalues are means in mm Hgwith 95%confidenceinterval.
`The drug wasgiven topically shortly after % (7 am) on day 2. The
`change in IOPis calculated as IOP day 1 minus IOP day2 at the
`correspondingtimeof the day except for the t.5 value which is
`compared with the IOP just before drug application (t on day 2).
`IOPvaluesf24 on day | are identical to the values ton day 2, but
`listed to make comparison easier. Negative values indicate an
`increase in IOP andpositive values indicate a reduction in IOP.
`There wereeight patientsin each group.
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`Time Day 1
`Placebo
`25-8 (22:5-29-0) —0-9 (2:0- —3-8)
`0
`24-9 (232-266)
`26°8 (24:0-29°5) —1-0(—0-1-—1-9)
`0-5
`20-1 (18-5-21-8)
`0-6 (1:6- —0-4)
`8
`20-8 (192-223)
`— Co
`
`12=21-6 (20-2-23-0) 20-6 (17-9-23-4) 1-0 (2-9- —-0-9)
`
`24
`25-8 (22-5-29-0)
`22-9 (20-2-25°5)
`2:9 (5-4- -0-4)
`PhXA34 0:3 pg
`0
`24-9 (22:1-27°6)
`23-9 (20-1-27-7)
`1-0 (3-4- — 1-4)
`i)
`25:1 (21-8-28-5)
`9-1-3 (1:2- —3-7)
`8
`20-6 (17:7-23:5)
`18-9 (16-9-20-8)
`1-8 (3:7- —0:0)
`12
`19-9 (16:0-23-8)
`3-1 (S:1-
`1-2)
`23-0 (19-8-26:2)
`24
`23-9 (20:1-27-7)
`21-9 (19-3-24-5)
`2:0 (4:7- —0°7)
`PhXA34 1 ug
`0
`25-8 (20-5-31:0)
`245 (21-1-27°9)
`1:3 (4:3-—1°8)
`0-5
`23-4 (18-4-28-4)
`1-1 (3:2-—1-0)
`8
`22-0 (20-5-23:5)
`17-1 (14-8-19-4)
`4-9 (6:5-3:2)
`12
`16-4 (13-1-19-7)
`5°5 (8:6-2°4)
`21-9 (19-3-24-4)
`24
`24-5 (21:1-27-9)
`21-5 (17:4-25-6)
`3-0 (5:5-0-5)
`PhXA34 3 ug
`0
`24-5 (22:1-26°9)
`23-5 (20-8-26-2)
`1-0 (3-2- —1-2)
`0-5
`24-0 (22:1-25:9) —0°5 (2:1- —3°1)
`8
`21-8 (20-6-22-9)
`15-0 (13-0-17-0)
`6°8 (8:-4-5-1)
`12
`14-4 (11-8-16-9)
`7°6 (9:4-5-8)
`22-0 (20-2-23-8)
`24
`23-5 (20-8-26-2)
`20-3 (17:7-22-8)
`3-3 (5:2-1-3)
`PhXA34 10 pg
`0
`24:4 (21-2-27-6)
`24-0 (20-8-27-2)
`0-4 (2:5~ —1-8)
`0:5
`24:9 (21:-4-28-4) —0-9 (1-0- —2°8)
`8
`22-5 (21-0-24:0)
`‘15-5 (14-2-16°8)
`7-0 (8:1-5-9)
`12
`14-5 (13-7-15-3)
`7°9 (10-5-S-2)
`22-4 (20-1-24-7)
`24
`24-0 (20-8-27-2)
`18-6 (17-2-20-0)
`5*4 (8+1-2-7)
`
`
`
`
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`216
`
`Villumsen, Alm
`
`Table3 The degree ofhyperaemia in the study eyes. The
`procedures usedfor the grading are described in the text
`
`Grade of hyperaemia
`0
`0-5
`1
`
`~ al
`
`N
`
`2:5
`
`3
`
`Hwen
`wee
`
`
`
`UNWECWWWWHEN
`
`
`-OoOoONOOO
`NDAROoreo—-nNoo
`
`HNHO
`
`WENO
`PNW
`
`COCOkmNHOH”HOC
`
`08
`
`12
`4
`
`—-WwWaun
`
`
`
`
`
`COCRUNNWNWWYHNWWW
`
`The numbers in each column indicate the numberofeyes with the
`specific grade of hyperaemia.
`The drug wasgivenshortlyafterto.
`*Notifies that the number of photographsin thatrowis 7.
`
`IPR Page 3/4
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`PhXA34 eye drops and project support were supplied by Kabi
`Pharmacia Ophthalmics AB, Uppsala, Sweden. The authors have
`no commercial or proprietary interest in PhXA34 eye drops.
`
`Discussion
`Theresult of randomisation did not show any
`important differences except for an uneven dis-
`tribution of the 16 eyes with exfoliations. The
`high frequency of patients with exfoliations
`reflects the expected distribution in a group of
`patients with ocular hypertension in
`the
`northern part of Sweden.
`A prior study has showna clear dose-related
`IOP reduction in normaleyes.‘ A dose-related
`response wasalso foundin this study with regard
`to IOP reduction; 3 and 10 pg PhXA34 seem to
`be almost equipotent with regard to IOP reduc-
`They were 0:8 (—0-7-2:3), 2:4 (0:-4-4:5), 5:4
`tion based on average IOP reduction 8 and 12
`(3:0-7°8), 7:0 (5:3-8:7) and 7:8 (5-8-9-8)
`hours post dose, but 10 pg appears more potent
`
`mmHg. The_corresponding ~ reductions
`if the IOP reduction 24 hoursafter the doseis
`expressed as a percentage of IOP on day 1 were
`includedas in the values expressed as area under
`4%, 11%, 25%, 32% and 35%.
`the curve. The 8 and 12 hours average IOP
`When comparedwith placebo 1, 3, and 10 pg
`reduction was chosenasthe primary variable for
`PhXA34 weresignificantly better in reducing the
`this dose-response study because it
`is known
`IOP whereas 0:3 pg was not
`significantly
`from prior studies that the maximal effect
`is
`changed from placebo: 0:3 pg p<0-1,
`1 ug
`observed within this period for most doses. In
`p<0-002, 3 pg p<0-001, 10 pg p<0-001; (¢ test
`this study the maximaleffect is seen 12 hours
`for two independent meanswith pooled estimate
`after the dose for all doses of PhXA34, and the
`of commonvariance).
`inclusion ofthe 8-hourvalues thereforeresults in
`Table 2 presents the IOP values on day 1 and
`aslight underestimate of the peak IOP reduction.
`day 2 for the five different treatment groups
`In the contralateral eyes we observed only
`including the differences in IOP between the 2
`minor fluctuations in IOP with a tendency
`days.
`towardsa slight IOP reduction of normally less
`The change in IOPforthe different treatment
`than 1 mm Hg on day 2, and these changes
`groups can also be expressed as area under the
`seemed to be completely unrelated to the dose
`curve and these values were for placebo and
`given in the study eye. Hyperaemia was neg-
`increasing doses of PhXA34: 24 (—15-65), 42
`ligible for doses lower
`than 10 ug PhXA34
`(—12-96), 94 (38-153),
`118 (72-164),
`132
`suggesting that
`the dose-response curve for
`(82-184). Values are means in mm Hg hours
`hyperaemia is displaced to the right of the IOP
`with upper and lowerlimits for the 95% confi-
`denceinterval.
`dose-response curve. This is in contrast to the
`hyperaemia observed after PGF2,-IE whereall
`IOP was measured 30 minutesafter the drug
`effective doses caused some hyperaemia. There
`application on day 2 andat that time nosignifi-
`is also a difference in the timing of the hyperaemia
`cant effect on IOP was found for any dose of
`PhXA34.
`since nonewasvisible for any dose of PhXA34 30
`minutes after application, while PGF>,-IE pro-
`No discomfort wasfelt by any patient before
`duces maximal hyperaemiawithinthe first hour.
`drug application, but mild discomfort was noted
`High doses of PGF2,-IE also caused an initial
`by a total of seven patients at some time during
`increase in IOP, probably due to intraocular
`the remaining part of day 2. Symptomsin both
`vasodilation, something that was not observed
`eyes with no difference between the two eyes
`even with 10 pg PhXA34.
`were felt by three patients. Discomfort in the
`In summary PhXA3¢4is a potent ocular hypo-
`treated eye only, mainly in the form of a mild
`tensive agentalso in patients with ocular hyper-
`foreign body sensation, was reported by four
`tension, where onetopical dose of 3 pg reduce
`patients: one placebo treated, two treated with
`IOP about 32% 8-12 hours after application
`1 pg PhXA34, and one treated with 3 pg
`withoutclinically significantside effects.
`PhXA34. Additionally, headache was reported
`by onepatienttreated with placebo.
`No significant difference
`in hyperaemia
`between study eyes and contralateral eyes was
`
`in any treatment group before drug
`present
`application. No hyperaemia was observed for
`any dose 30 minutesafter drug application, and
`Treatment
`hyperaemia was practically absent for doses
`time
`lower than 10 yg. This dose however produced
`Placebo
`observable hyperaemia grade 1-5-2 in most
`*
`0
`*
`8
`patients
`(Table 3). Photographs were not
`*
`12
`achieved from three patients due to camera
`*
`24
`problems. These patients were treated with
`PhXA34 0-3 pg
`0
`placebo,
`1 pg, and 3 ug PhXA34 respectively,
`*
`8
`12
`and the 8-hour photograph fromapatienttreated
`24
`with 0-3 pg PhXA34 wasnot possible to grade.
`PhXH34 1-0 ug
`No flare or cells were seen in the anterior
`0
`*
`.
`*
`3
`chamber.
`*
`12
`*
`24
`PhXA34 3-0 ug
`~~
`0
`*
`8
`*
`12
`*
`24
`PhXA34 10-0
`
`
`
`
`
`
`
`
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`‘yyBuUAdooAqpayoajoig“ysan6AqgpozAin¢|uo/wos‘fwaqolqy/:dyjyWopapeojumog‘Z66LId|UOpLZ"7'9ZOIG/GELL'OLSepaysiiqndysy:joujeuydO¢4g
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`paper of every kind are badly needed. It has been
`Our readers will probably have noticed the slight
`rather a wrench to cast out copies of old text-books
`difference in texture and tint of the paper used for
`which we used in the days of our studentship. Some
`printing the Journal since the beginning ofthis year.
`of these were at least forty years out of date but had
`Ourstock of paper came to an end in Decemberlast
`a sentimental interestto us.
`and like everybody else we have had to make do
`Those who were broughtupin Victorian dayswill
`with what the controller allows us. In after years it
`be aware of the hoarding propensities of parents in
`may be of interest as dating some of the War years.
`the matter of family and other letters. A great many,
`Deterioration in quality of paper during war is no
`
`but not all, of these are very suitable for salvage.
`new thing. Exactly the same happened in the
`
`Young hopeful’s reiterated appeals from school-for a
`Napoleonic struggle. Much of the paper used in the
`
`hamperor a new cricket bat or even a modest half-
`earlier years of the last century was very poor in
`
`a-crown are not worth keeping, but no onein his
`quality and no one now-a-days would dream of
`
`senses would destroy letters by eminent hands. If, in
`reading suchathingasthe first edition of Waverley
`
`going through bundles of old correspondence, one
`(published 1814), if he could geta later edition.
`
`It behoves us all to contribute as much as we can
`lights upon a letter,
`for instance,
`from the poet
`
`Wordsworth to one’s own grandfatherit will be wise
`to the paper salvage campaign. For ourselves we
`
`to preserve it, for its value may appreciate in post-
`almost tremble to think of the numbers ofgalleys of
`
`
`war times,
`back numbers which we have sent to the pulping
`BrJ Ophthalmol 1942; 26: 225-6.
`machine. Old books, old letters, old receipts and
`
`
`
`
`
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`
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`
`
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`‘\yBuAdooAqpayoajoig*sanbAqgLOzAinrEe}uO/Woo'fqolqy/:dyjyWoypapeojuMog‘ZE6IIudy|UOPLZp'9ZO!Q/9ELLOLSepaysiiqndysuysjoujeuydOfF4g
`
`FIFTY YEARS AGO
`
`Paper Salvage
`
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`PhXA34 a prostaglandin F2, analogue. Effect on intraocularpressure in patients with ocular hypertension
`
`217
`
`1 Kerstetter JR, Brubaker RF, Wilson SE, et al. Prostaglandin
`F,,,-1-isopropylester
`lowers intraocular pressure without
`decreasing aqueousflow. AmF Ophthalmol 1988; 105: 304.
`2 Villumsen J, Alm A. Prostaglandin F2,-isopropylester eye
`drops: effects in normal human eyes. Br¥ Ophthalmol 1989;
`73: 419-26.
`3 Villumsen J, Alm A, Séderstrém M.Prostaglandin F2,-isopro-
`pylester eye drops: effect on intraocular pressure in open
`angle glaucoma. Br7 Ophthalmol 1989; 73: 975-9.
`4 Camras CB, Siebold EC, Lustgarten js, et al. Maintained
`reduction of intraocular pressure by prostaglandin F2,-1-
`isopropylester applied in multiple doses in ocular hyperten-
`
`sives and glaucoma patients. Ophthalmology 1989; 96:
`1329-37.
`5 Villumsen J, Alm A. Theeffect of adding prostaglandin Fig:
`isopropylester
`to timolol
`in patients with open angle
`glaucoma. Arch Ophthalmol 1990; 108: 1102-5.
`6 Alm A,Villumsen J. PhXA34—-a new potent ocular hypotensive
`drug. A study ondose-response relationship on aqueous
`humor dynamics in healthy volunteers. Arch Ophthalmol
`1991; 109: 1564-8.
`7 Rowland M, Tozer TN. In: Clinical pharmacokinetics concepts
`and applications. Philadelphia: Lea and Febiger, 1980: 288.
`
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