`
`
`
`
`
`
`
`SENJU EXHIBIT 2267
`LUPIN v SENJU
`IPR2015-01099
`
`
`
`#151142-203.01 Letter Final Report
`
`
`
`
`Page 2 of 65
`
`
`
`
`ADDENDUM 1
`
`
`
`
`Protocol #15! 142-203
`
`Protocol Deviation Recording Forms (Form No. 99—QA-004)
`
`
`
`
`
`
`
`
`CONFIDENTIAL
`
`
`PROL0337790
`
`
`
`PAGE 2 OF 65
`
`PAGE 2 OF 65
`
`
`
`
`
`H511-=i2~20J.Dl M111.-r Final Report
`
`
`
`
`Page 3 of65
`
`
`
`
`
`
`
`
`
`
`Novembet 23. 2015
`
`
`
`
`
`PROTOCOL #lSI 142-203
`
`
`
`A NON-GLP ANTIMICROBIAL PRESERVAHVES EFFECTIVENESS EVALUATION OF SIX
`
`
`
`
`
`
`
`PRODUCTS WHEN CHALLENGED WITH FOUR MICROORGANISM SPECIES BASED ON
`
`
`
`
`
`
`
`
`
`EUROPEAN PHARMACOPOEIA METHOD 5.1.3.
`
`
`
`
`
`
`
`
`icon
`
`
`
`SSCI (SPONSOR)
`
`
`3065 Kent Avenue
`
`
`
`Was! Lafayefle, IN 47909
`
`
`
`
`
` 3
`
`
`
`
`
`
`
`
`BIOSCIENCE LABORATORlESfi'lNC. (TESTING FACIUTY)
`I755 South 19 Menu:
`
`
`
`
`Bozemsn, Montana 59718
`
`
`
`(406) 587-5735
`
`
`
`PRUIOCDL I ISI I42-203
`
`Page I of II
`
`
`
`BIOSCIENCE U\BOR4KT0RlI3.$. INC.
`
`
`
`
`CONFIDENTIAL
`
`
`
`PAGE 3 OF 65
`
`pR0|_0337-(91
`
`
`
`PAGE 3 OF 65
`
`
`
`
`
`M51 I42-203.0] l.e11erFimI Report
`
`
`
`
`
`Page 4 M65
`
`
`
`
`CONFIDENTIAL
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`This Document has been copyrighted by Bioscience Laboratories, Imc., and is considered
`
`
`
`
`
`
`
`
`
`
`
`confidential between Biosoienee Laboratories, Inc. (Testing Facility) and SSCI (Sponsor). This
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`is not
`to be shown, given to, or used by anyone except SSCI without written
`document
`
`
`
`
`
`
`
`
`
`
`
`
`permission from Biosoience Laboratories. Inc. Pennission to release the Protocol and Study
`
`
`
`
`
`
`
`
`
`
`
`
`
`Results to the United States Foot} and Drug Administration (FDA) is explicitly granted.
`
`PROTOCOL M51141-203
`
`
`
`rm 2 of 1|
`
`BIOSCIENCE LABORATORIES. INC.
`
`
`
`
`
`CONFIDENTIAL
`
`
`
`PAGE 4 OF 65
`
`pRo|_o3377g2
`
`
`
`PAGE 4 OF 65
`
`
`
`
`
`|‘l I I2 IN "1 I.-tut I nu] R»[‘\'ll
`P32.‘ 5' u[ 4-.‘
`
`IA l!l_.§_(_)F C()NT|-I.\T$
`
`CONFIDENTIAL
`
`PRQL0337793
`
`PAGE 5 OF 65
`
`
`
`I ‘ I I4?-201 HI lcncr Filul Rap-\r1
`|’:|gu () .-|‘<'~5
`
`I-mge -1 ufl I
`lil(>S("H-‘htlj I.AH(.’sR.\ I l.)i{H 5, W1]
`
`CONFIDENTIAL
`
`PROLO337794
`
`PAGE 6 OF 65
`
`
`
`I5? I-1'.‘ 203 (ll I cllcr I-‘inn! Ilcpnrl
`Page 7 nI'(v5
`
`|’RC=TOC0l.H I5! I4}.-Z03
`Pagc 5 of TI
`Bl(.)S(‘|EhCl‘ LABOR/\'I'f)R1I€5.
`
`INIQ
`
`CONFIDENTIAL
`
`PROL0337795
`
`PAGE 7 OF 65
`
`
`
`.
`
`I5? I-1'.‘ 203 (ll I cllcr I-‘inn! Ilcpnrl
`Pug: § nI'(v5
`
`Pngc 6 01:1 I
`HI(’.-s«._‘I:r.LL L.\(!ORAT()RIES‘ :r~.'(.‘
`
`CONFIDENTIAL
`
`PROL0337796
`
`PAGE 8 OF 65
`
`
`
`I5? I-1'.‘ 203 (ll I cllcr I-‘inn! Rcpnrl
`Pug: ‘J nI'(v5
`
`FROIUCCI. M51 542-20]
`Page 7 cl" I
`I
`.'>!l()SF|I—N(‘l>-
`I .I\H(Hl;\TUR|F§, |N('
`
`CONFIDENTIAL
`
`PROL0337797
`
`PAGE 9 OF 65
`
`
`
`I<I I I: 2»! HI
`
`I .-am 1 um] R.,‘.-n
`l'.::u H.~..u.5
`
`1I‘.('
`
`1.
`
`.
`
`UILN ll ‘HT
`
`P.
`
`‘
`r
`
`.
`
`5
`
`.
`v
`b L)! 1|
`€(>RA'l(‘:Rll\‘
`
`CONFIDENTIAL
`
`PRQL0337798
`
`PAGE 10 OF 65
`
`
`
`1.‘! HI-I1" ‘II
`
`I mu ['In.n{ R-;[u-II
`l‘,1::c H ul t-5
`
`CONFIDENTIAL
`
`PROL0337799
`
`PAGE 11 OF 65
`
`
`
`|‘l I I: IN "1 lulu 1 HM] R»[‘\'ll
`l'.::.' E: ull-5
`
`r1 I il I-13-201
`l‘RL)l(K‘( I.,
`l‘;u_:c 10 ul‘ 1'.
`lLN(‘l
`I Al()R/\T(‘)|{I|’S_ NI’
`
`[\l().\‘(
`
`CONFIDENTIAL
`
`PROLO337800
`
`PAGE 12 OF 65
`
`
`
`H1112 I'W|*| l~l!.'rl nu! Ehp--:1
`1'4-.'\: I501!-5
`
`PROTOLOL IISH-42~Z03
`I‘
`I
`I of II
`lHC3}(,'!F.NC‘E .. BOK/\'i'0I7.lFS INC
`
`CONFIDENTIAL
`
`PROL0337801
`
`PAGE 13 OF 65
`
`
`
`l‘|| 83-.‘v.v\nI
`
`|_u.r I "Lil Rupurl
`l’.|~;; Hut 1-.‘
`
`CONFIDENTIAL
`
`PROL0337802
`
`PAGE 14 OF 65
`
`
`
`r ‘mm ._.mm
`hm
`inh mm nun
`F‘:--;m.1.u\
`H
`.1\JI|.:l‘1'.'.
`'1): ~J:\\h~w|_ u».t‘\L m
`I‘.-‘I
`Im \ cnrnmncd mm: and mu.
`(->nI>xIcIm.:2 ;v.'.~pr:cI.n~. ml‘-xv an-n .-I M1-v\:;-n.L I
`IV7I\)1hvl
`.! uvlxmlz-u!
`--I <.‘1s!r1'mu«| ml‘y«u:‘ II‘\ run
`. n.\':nl
`IJlllvl‘IN-'l"C!‘-(‘X’l2\|l1d\I(‘<|1|IXIII.|)H[X3\‘ Ilu .ln\‘d.:|\1.I;.‘L‘\.'l)\1|\‘~\C*- cwl um: hcrclrun
`~
`(u|\\x1t,'||'. 2' I4 ;'-
`Ii: -\w.-2 xc I 4!’ mm 11¢». Inc
`I am Nu 'r"1(‘)\-ml
`‘Ix 1
`
`1
`
`CONFIDENTIAL
`
`337803
`
`PAGE 15 OF 65
`
`
`
`I5? I-1'.‘ ZLV (ll
`
`I cllcr I-‘inn! Ilcpnn
`l’;:gc |<~ nI'(v5
`
`V
`|)_ H. W U.
`|r\£\ r ‘.3 Ion Nu! for v’I.1H cmm‘.
`Pnvpr ‘(ar_\
`Nu L‘
`x:f.1Hc,
`\;~.c\l, m.n!:
`In-1 Lm u'1:~\IUsL‘J_
`\I1I'v:n1.JHu:: nl T\':u\ cn-.c l;ut‘.w.'J(=vr:.\.
`In;
`.x
`cm '1lu:1c(l hurt uv
`m.x.
`(.~nI'z!cn:x.:'.‘ p:.‘prIcI.1r_\
`J :1‘-|:.;nu!_ w xl\|fl'VL|1L‘rI‘\‘.I1|1Hll1|l>[!1L‘l’ m.'x.»'~l }:|1I1rcIuuh~<':'\: ‘inn
`.rL‘.\L!l1nl1uh‘lm ‘1;n\d'.~In:u.'c.\ nu! In-xL'.\ ‘c»u|.:n,: }:x:u.l}mr
`I If 1 4 '1) Hm. U'.'H\‘L'
`I ah \7T1l.:r1<.‘a
`Inc
`I
`-nn N.» m(_1\|H'1
`RL"-
`«
`('n§1‘1~I
`
`CONFIDENT AL
`
`PROL0337804
`
`PAGE 16 OF 65
`
`
`
`I-1'.‘ 203 (ll I cllcr I
`
`II Ilcpnrl
`I7 nl'('5
`
`cIcz1u'
`[in
`1n!v n‘.u.1Im'x ml‘
`-yum.‘
`‘H’
`('*nl'I
`'.\1l|m.JlIl\;1 nu uuxsmx
`‘r :1 .\'.nl‘-.&
`.9: plzumi,
`V <’u;“ym_'h1 3 !-1 iv. Hw\.1 .x.ci .I}‘A'l,1(v\!\L‘\, In.‘
`H; _;
`
`Pr my uv.\r_\‘ lnfn -nixlum . .\mIlv.vrI'I.l"h.'ul1-II
`
`CONFIDENT AL
`
`PROL03 78 5
`
`PAGE 17 OF 65
`
`
`
`I5? I-1'.‘ 203 (ll I cllcr I-‘inn! Ilcpnrl
`l’;xgc |I\ nI'(v5
`
`xx1w<'nl~n-un-vn
`in!‘ nu: u n
`Impn-_-:.u;.
`‘.1«.~nu
`;1'.);|.xilc
`Im \ 0 m:n".L'd ':Crc am! nu. ml by dmix C1, mod m
`c 1.1M.‘
`10:
`Ii:-~.\_
`(\:r)IM m.xl1n.~;~uc:,|r\ 1|\Innn.1.'1«~n nl
`A Iplun ‘I vrr <.x~:n*»L'.'.u1
`11
`H |‘.\;T1Ur ;.uw:x1L Muinru in nhw'r\s.'IlI).\1i‘.d) .'C\'L\l \n'n;ah:11|jr
`r>!a1\x!.n
`‘o .Ar,Lf Iunux *
`:1 mg f‘,L‘1L'|I-Yfl
`4‘ llvpyu W ‘V H I) I5’: -.\uv.~1c« I
`.: mm ncx Km
`I-um »'-
`‘W (_)\—
`-1) ‘J
`J“.
`1
`1
`
`CONFIDENT AL
`
`PROL0337
`
`PAGE 18 OF 65
`
`
`
`#151142-203.01 Leiief Final Report
`
`
`
`
`Page 19 of 65
`
`
`
`
`ADDENDUM 2
`
`
`
`Data Tables 1 Through 18
`
`
`
`
`
`
`
`CONFIDENTIAL
`
`
`
`PROL0337807
`
`
`
`PAGE 19 OF 65
`
`PAGE 19 OF 65
`
`
`
`
`
`=-151 I-1'.?—2fJ_1 HI
`
`
`
`1 on-:: I-'in:.I Ih-p.~r1
`
`
`E‘agu:2'.J ut‘(:5
`
`
`
`
`
`F'1'0[:_'ul_'I'.s]:‘“C-‘1li12-2|r.1._:-
`
`
`Fag‘.
`I 0!‘ 15
`
`
`
`
`
`
`
`
`CONFIDENTIAL
`
`
`
`PROLOSBYBOS
`
`
`
`PAGE 20 OF 65
`
`
`
`
`
`
`
`=-151 I-1'.?—3!fJ_1 HI
`
`1 on-:: I-'in:.I Ih-p.~r1
`
`
`Pa~-:21-nt‘(:5
`
`
`
`
`
`Prolc-col #151 H2-EU}
`
`
`l’:1,t_r_L‘2c1i'15
`
`
`
`
`
`
`
`
`CONFIDENTIAL
`
`
`
`PROLOSBTBOQ
`
`
`
`
`PAGE 21 OF 65
`
`
`
`
`
`
`
`=-151 I-1?-2fJ_1 I1!
`
`1 vtt-:I I-'in:nI Rqn-r1
`. ,. av
`,.‘
`a
`
`
`
`
`
`
`
`I-‘Iutc.-::::| H151 1<I2—2(}3
`
`
`Pagt‘3rJ1']S
`
`
`
`
`
`
`
`CONFIDENTIAL
`
`
`
`F’ROL0337810
`
`
`
`PAGE 22 OF 65
`
`
`
`
`
`
`
`=-151 I-1'.?—2fJ_1 HI
`
`
`
`1 on-:: I-'in:.I Ih-p.~r1
`
`
`E‘agu:2_\ ..t‘(:5
`
`
`
`
`
`Protocol #]5]112—203
`
`Page 4 of IS
`
`
`
`
`
`
`
`CONFIDENTIAL
`
`
`
`PROLOSBYB11
`
`
`
`
`PAGE 23 OF 65
`
`
`
`
`
`
`
`= 1.‘-1 I-1?-I_'.f.'.ZI.1 HI
`
`1
`
`.:-t_1_.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`CONFIDENTIAL
`
`
`
`PROLOSBTB12
`
`
`
`PAGE 24 OF 65
`
`
`
`
`
`
`
`#151142-203.01 Lefier Final Report
`
`
`
`
`Page 25 of 65
`
`
`
`
`Protocol #151 142203
`
`January 07. 2015
`
`
`
`
`
`
`
`
`TM IA.B_L.E_I
`Test Product #3: Prolensa
`bromfenac ophthalmic solution 0.07%.
`
`
`
`
`
`
`
`
`Bron-rfenac Sodium (unstressed)
`
`
`
`Lot Numbers 240031
`
`
`
`
`
`
`Test Product #4: Prolensam bromfenac ophthalmic solution 0.07% (wfv)
`
`
`
`
`
`
`
`
`Bromfenar: Sodium (4 weeks @ 60°C})
`
`
`
`
`
`Lot Number 249031
`
`
`
`
`
`
`Challenge
`
`Microorganism
`
`(ATCC #)
`
`
`Initial
`
`Population
`
`
`(CFU:‘n:L
`
`
`
`
`
`Fgayfiig
`
`Inoculation
`
`
`
`Aspergfllus bmslflensls
`
`(ATCC #16404}
`
`
`
`
`
`5
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`8.6818 x10
`
`
`
`
`aflflztrigg
`
`(Cl?U!rnL)
`
`
`
`
`
`
`Acceptance
`
`Criteria
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`0European Pharmacopoeia '?.0. 5.1.3. EFFACACY OF ANTIMICROBIAL PRESERVATION. 01.-’20l l:S0l{]3. Acceptance Criteria,
`
`
`
`
`
`
`
`
`
`
`
`Table 5.1.3.1, Parenteral preparations, eye preparations. Intrauterine preparations and inrramammary preparations: The criteria for
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`fungi is a 2 103:1} reduction following 7 days of exposure to the test product with no recovered Colony Forming Units (CFU) recovered
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`aflnr 28 days: nfexpnsure tn the product.
`
`
`
`
`
`
`
`
`
`Protocol #151142-203
`Page 6 of 15
`
`
`
`
`
`
`
`CONFIDENTIAL
`
`
`
`PROL0337813
`
`
`
`PAGE 25 OF 65
`
`PAGE 25 OF 65
`
`
`
`
`
`#151142-203.01 Letter Final Report
`
`
`
`
`Page 26 of 65
`
`
`
`
`Protocol #15 I 142-203
`
`January 0?, 2016
`
`
`
`
`
`
`
`TABLE 8
`
`
`Test Product #3: Prolensam bromfenac ophthalmic solution 0.07%.
`
`
`
`
`
`
`
`Bromfenac Sodium (unstressed)
`
`
`
`Lot Number 240031
`
`
`
`
`
`
`Test Product #4: Prolcnsam bromfenac ophthalmic solution 0.07% (w.’v}
`
`
`
`
`
`
`
`
`
`Bromfenac Sodium (4 weeks @ 60°C)
`
`
`
`
`
`Lot Number 240031
`
`
`
`
`Challenge
`
`Microorggnism
`
`
`(ATCC #)
`
`
`
`I it! I
`
`Poplimtion
`
`{CFUML
`
`of Product)
`
`
`
`Day(s-)
`
`
`Following
`
`Inoculation
`
`Candida efbicans
`
`
`
`
`
`
`5
`:r?L
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`(ATCC #10231]
`
`
`
`
`
`
`
`.
`Population
`
`
`Recovered
`
`(CFU.-"n1L)
`
`
`
`
`
`A
`
`t
`gggefiau
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`0Europ-can Pharmacopoeia 7.0. 5.1.3. EFFACACY OF ANTIMICROBIAL PRESERVATION. 0Ir‘20II:50I03. Acceptance
`
`
`
`
`
`
`
`
`
`
`Criteria, Table 5.1.3.1, Parenrerm’ preparations, eye preparations, intrauterine preparations and fnrramammary preparations:
`
`
`
`
`
`
`
`
`
`
`
`
`The criteria for fungi is a 2 logic reduction foilow-ing '7 days of exposure to the test product with no recovered Coiony Forming
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Units {CFU} recovered alter 28 days of exposure to the product...
`
`
`
`
`
`
`
`
`
`
`
`
`Protocol #151142-203
`
`
`Page '1' of 15
`
`
`
`
`CONFIDENTIAL
`
`
`
`PROL0337814
`
`
`
`PAGE 26 OF 65
`
`PAGE 26 OF 65
`
`
`
`
`
`#151142-203.01 Lefiet Final Report
`
`
`
`
`Page 2'? of 65
`
`
`
`
`Protocol #151 142-203
`
`
`January 07, 2016
`
`
`
`
`
`TABLE 9
`
`Test Product #3: Prolensam bmmfenac ophthalmic solution 0.07%.
`
`
`
`
`
`
`
`Bromfenac Sodium (unstressed)
`
`
`
`Lot Number 240031
`
`
`
`
`
`
`
`Test Product #4: Proiensam brornfcnac ophthalmic solution 0.07% (w.’v}
`
`
`
`
`
`
`
`
`
`Bromfenac Sodium (4 weeks @ 60°C)
`
`
`
`
`
`Lot Number 24003}
`
`
`
`
`
`C“'"°"g°
`
`Microorganism
`(ATCC #)
`
`
`Initial
`
`Population
`
`(CF"U2'mI.
`
`
`of Product)
`
`
`
`Dayts)
`
`Foliowing
`
`Inoculation
`
`
`Pseudamonas aemginoxa
`
`{ATCC #902?)
`
`
`
`
`
`
`
`1.7070 x [0
`
`6
`
`
`
`
`
`
`
`
`
`
`
`3.§.3
`
`
`
`
`
`Ofiumpean Phannacopoeia 7.0. 5.1.3. EFFACACY OF ANTIMICROBIAL PRESERVATION. {]lf2011:5UlO3. Acceptance Criteria,
`
`
`
`
`
`
`
`
`
`
`
`Table 5.1.3.1, Parenteral preparations, eye preparations, intrauterine preparations and lmmmammary preparations: Criteria A for
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`bacteria is a 3 log"; reduction following 24 hours of exposure to the test product with no recovered Colony Forming Unilo (CFU)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`recovered after 28 days of exposure to the product.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Population
`
`Recovered
`
`(CFU."mL)
`
`
`.55
`
`Reduction
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`<l.{J0x10'
`
`¢I.D0x 10'
`
`<I.{)0x 10'
`
`
`-=1.00x 10'
`
`
`c1.00x 10'
`
`<1.00 x 10'
`
`<1.00 :4; 10'
`
`<l.00 x 10'
`
`H
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`5.232
`5.2322
`
`5.2322
`
`5.2322
`
`5.2322
`
`
`
`
`
`
`
`
`
`
`
`5.2322
`
`
`5.2322
`
`
`
`
`
`5.2322
`
`
`
`
`
`Acceptance
`Criteria
`
`
`
`
`YE
`
`YES
`
`
`
`
`
`YES
`
`YES
`
`
`
`YES
`
`
`YES
`
`
`
`YES
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`99 999494’
`
`99.999404.
`
`99.999494.
`
`YES
`
`99.99949/o
`
`Protocol #15] 142-203
`Page 8 of IS
`
`
`
`
`
`
`
`CONFIDENTIAL
`
`
`
`PROL0337815
`
`
`
`PAGE27OF65
`
`PAGE 27 OF 65
`
`
`
`
`
`#151142-203.01 Lefier Final Report
`
`
`
`
`Page 28 of 65
`
`
`
`
`Protocol #151142-203
`
`January 0'7, 2016
`
`
`
`
`
`
`
`TABLE. II!
`
`
`leg; Egodygg Q3: Prulensa' " bromfenac ophthalmic solution 0.07%.
`
`
`
`
`
`
`
`
`Bromfenac Sodium (unstressed)
`
`
`
`Lot Number 240031
`
`
`
`
` : Prolensam bromfenac ophthalmic solution 0.07% {w/V)
`
`
`
`
`
`
`
`
`
`Bromfenac Sodium (4 weeks @ 60°C)
`
`
`
`
`
`Lot Number 240031
`
`
`
`
`
`
`Challenge
`
`Microorganism
`(“CC 3’
`
`
`
`
`
`
`i’o::1!ltaiI:on
`
`CFU, L
`
`o{f ProdT1‘ct
`
`
`
`
`Day(s)
`
`Following
`
`Inoculation
`
`
`
`
`
`Prague‘
`
`
`
`Population
`Recovered
`
`
`
`l‘
`
`E?3
`
`
`
`
`
`(CFU.-"mL)
`=o
`
`
`
`
`
`Staphyfococcu: aw-ens
`
`{ATCC #6538}
`
`
`
`
`
`
`5
`
`
`
`1.9767 x 10
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`<1.010'
`
`<l.0Dx 10'
`
`<1.0Dx 10'
`
`
`
`(1 '00 " 10'
`-:1.00x 10'
`
`<1.00 1: 10'
`
`
`I
`
`
`
`
`
`
`
`
`
`5.2959
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`5.2959
`
`5.2959
`
`5.2959
`
`5.2959
`
`
`
`
`
`
`
`YES
`
`was
`
`was
`
`
`YES
`<1.oo x 10'
`
`
`
`
`
`0European Pharmacopoeia 7.0. 5.1.3. EFFACACY OF ANTIMICROBIAL PRESERVATION. 0ll201l:5(}203. Acceptance Criteria,
`
`
`
`
`
`
`
`
`
`
`
`Table 5.1.3.1, Parenteral preparations, eye preparations, intrauterine preparations and intramammary preparations: Criteria A for
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`bacteria is a 3 10310 reduction following 24 hours of exposure to the test product with no recovered Colony Fanning Units (CFU)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`recovered alter 28 days of exposure to the product.
`
`
`
`
`
`
`
`
`
`
`<1.00x 10'
`
`Acceptance
`
`Criteria
`
`
`
`
`
`
`
`S
`
`YES
`
`
`
`YES
`
`YES
`
`
`
`99.999596 I
`
`99.999596
`
`99.999598
`
`99.9995%
`
`
`
`99.9995%
`
`99.999596
`
`99.999593
`
`
`
`
`
`
`
`99.999596
`
`Protocol #151142-203
`
`
`Page 9 of I 5
`
`
`
`
`
`
`CONFIDENTIAL
`
`
`
`PROL0337816
`
`
`
`PAGE 28 OF 65
`
`PAGE 28 OF 65
`
`
`
`
`
`#151142-203.01 Lefiet Final Report
`
`
`
`
`Page 29 of 65
`
`
`
`
`Protocol #151142-203
`
`January 07, 2016
`
`
`
`
`
`11
`T
`
`
`Neutralization Evaluation -— Results
`
`
`jljest Egguct #3: Prolenmm bromfenac ophthalmic solution 0.07%.
`
`
`
`
`
`
`Bromfenac Sodium (unstressed)
`
`
`
`Lot Numbers 240031
`
`
`
`
`
`
`.
`
`
`
`.
`
`
`
`
`
`
`
`
`
`Microbial Recovery
`
`
`
`
`
`Aspergiflus bmriliensls
`
`
`
`16404
`
`
`
`Candida olbicans
`
`
`
`10231
`
`
`Pseudamonas aeruginosa
`
`
`
`902'?
`
`
`
`Staphylococcus aureus
`
`
`
`6533
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`0
`
`
`
`
`
`
`
`
`
`
`
`
`
`TEST
`
`
`OThe counts (Average CFU:'Plate) observed for the TEST sample do not vary by more than a factor of
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`5 from those recovered from the respective CONTROL sample; hence, the neutralizing media are considered to be
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`effective.
`
`
`
`
`Results
`
`
`
`
`Pass
`
`
`
`Pass
`
`
`
`Pass
`
`
`
`Pass
`
`
`
`
`
`
`TABLE 12
`
`Neutraiization Evaluation — Results
`
`
`Test Pmguct #4: Prolensam bromfenac ophthalmic solution 0.07% (w!v}
`
`
`
`
`
`
`
`
`Bmrnfenao Sodium (4 weeks @ 60°C}
`
`
`
`
`
`Lot Number 24003!
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Aspergiflus brasiliertsix
`
`
`
`16404
`
`
`Candida albiccms
`
`
`
`Pseudomanas aerugittosa
`
`
`
`10231
`
`
`
`9027
`
`
`
`Staphylococcus mrreus
`
`
`
`
`6538
`
`
`.
`
`.
`
`
`
`
`
`
`
`TEST
`
`
`CONTROL
`
`
`TEST
`
`CONTROL
`
`
`TEST
`
`
`CONTROL
`
`
`
`Microbial Recovery
`
`
`
`
`T
`
`213.50
`
`
`Results
`
`
`Pass
`
`
`
`
`
`
`
`
`Pass
`
`
`
`IE!
`
`
`
`30.00
`
`36.00
`
`30.50
`
`35.50
`
`24.00
`
`20.00
`TEST
`
`
`0 The counts (Average CFUfPlale] observed for the TEST sample do not vary by more than a factor of
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`5 from those recovered fi'om the respective CONTROL sample; hence, the neutralizing media are considered
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`to be effective.
`
`
`
`
`
`
`Protocol #151142-203
`
`
`Page 10 of 15
`
`
`
`
`
`CONFIDENTIAL
`
`
`
`PROL0337817
`
`
`
`PAGE29OF65
`
`PAGE 29 OF 65
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`REDACTED
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`cb"NFiDEN"fIAL
`
`
`
`PAGE 30 OF 65
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`PROL"633?'é'1'§"'";
`
`
`PAGE 30 OF 65
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`REDACTED
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`cb"NFiDEN"fIAL
`
`
`
`PAGE 31 OF 65
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`PROL"633?'é'1'§""'";
`
`
`PAGE 31 OF 65
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`REDACTED
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`cb"NFiDEN"fIAL
`
`
`
`PAGE 32 OF 65
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`'"i5iiE3L"6§§?'é§6""":
`
`
`PAGE 32 OF 65
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`REDACTED
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`cb"NFiDEN"fIAL
`
`
`
`PAGE 33 OF 65
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`'"i5fi6E6§§?'é§T'"""j
`
`
`PAGE 33 OF 65
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`REDACTED
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`cb"NFiDEN"fIAL
`
`
`
`PAGE 34 OF 65
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`'""i5iiE3L"6§§?'駧""'":
`
`
`PAGE 34 OF 65
`
`
`
`
`
`#151142-203.01 Letter Final Report
`
`
`
`
`Page 33 of65
`
`
`
`
`ADDENDUM 3
`
`
`
`Neutralization Data Sheets For Antimicrobial Preservative Effectiveness Testingk
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`_¥:l%cu1um Population Data Sheets For Antimicrobial Preservative Effectiveness Testing
`Antimicrobial Effectiveness Testing Data Sheets
`'
`
`
`
`
`
`
`
`
`CONFIDENTIAL
`
`
`PROL0337823
`
`
`
`PAGE 35 OF 65
`
`PAGE 35 OF 65
`
`
`
`
`
`HI I-13-I01 HI
`
`I cllcr I-'in.ul R.-purl
`Pugs 36 vi (-5
`
`CONFIDENTIAL
`
`PROL0337824
`
`PAGE 36 OF 65
`
`
`
`HI I-13-I01 HI
`
`I cllcr I-'in.ul R.-purl
`l’;ugc 37 vi (-5
`
`CONFIDENTIAL
`
`PROL0337825
`
`PAGE 37 OF 65
`
`
`
`I ‘ I I4?-201 HI lcncr Filul Rap-\r1
`Page 38 ul‘ (R5
`
`CONFIDENTIAL
`
`PROLO337826
`
`PAGE 38 OF 65
`
`
`
`I ‘ I I4?-201 HI lcncr Filul Rap-\r1
`
`CONFIDENTIAL
`
`PROLO337827
`
`PAGE 39 OF 65
`
`
`
`HI I-13-I01 HI
`
`I cllcr I-'in.:l R.-purl
`Pugc -10 I‘! (-5
`
`CONFIDENTIAL
`
`PROL0337828
`
`PAGE 40 OF 65
`
`
`
`|‘l I I2 IN "1 I .-tut l nu] (hp.-:1
`
`CONFIDENTIAL
`
`PROLO337829
`
`PAGE 41 OF 65
`
`
`
`
`
`
`
`
`
`
`
`
`ooz_u_amz:>rvmorommwmmo
`
`
`
`
`
`..__“___fi.m_.___..__:_.....:
`
`
`56F024EGP
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 56F034EGP
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`ooz_u_amz:>rnmorommwmmg
`
`
`
`_.»_Iva::__r.:
`
`
`
`.1_,n.u...:.__r.:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`REDACTED
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`cb"NFiDEN"fIAL
`
`
`
`PAGE 46 OF 65
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`'""i5iiE3L"6§§?'é§Z""'":
`
`
`PAGE 46 OF 65
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`REDACTED
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`cb"NFiDEN"fIAL
`
`
`
`PAGE 47 OF 65
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`'""i5iiE3L"6§§?'駧""'":
`
`
`PAGE 47 OF 65
`
`
`
`
`
`
`
`
`
`..__“___fi.m_.___..__:_.....:
`
`56F084EGP
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`ooz_u_amz:>rnmorommummm
`
`
`
`
`
`
`
`
`
`
`
`
`ooz_u_amz:>rnmorommummu
`
`
`
`
`
`..__“___fi.m_.___..__:_.....:
`
`56F094EGP
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`:3:u.~_..»:_—r.:r.
`
`
`
`_.»_Iva::__r.:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`REDACTED
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`cb"NFiDEN"fIAL
`
`
`
`PAGE 52 OF 65
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`'""i5iiE3L"6§§?'éZ6""'":
`
`
`PAGE 52 OF 65
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`REDACTED
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`cb"NFiDEN"fIAL
`
`
`
`PAGE 53 OF 65
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`'"i5fi6E6§§?'éZT'"""j
`
`
`PAGE 53 OF 65
`
`
`
`
`
`
`
` 56F01....5EGP
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`ooz_u_amz:>rvmorommwmam
`
`
`
`
`
`
`
`
`
`
`
`
`
`OOZ_n_U_mZ4._.P_uvmorommwmgu
`
` 56F055EGP
`
`
`
`
`
`.1_,n.u...:.__r.:
`
`
`
`:3:u.~_..»:_—r.:r.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`REDACTED
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`cb"NFiDEN"fIAL
`
`
`
`PAGE 58 OF 65
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`'""i5iiE3L"6§§?'éZé""'":
`
`
`PAGE 58 OF 65
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`REDACTED
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`cb"NFiDEN"fIAL
`
`
`
`PAGE 59 OF 65
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`'"i5iiE3L"6§§?'éZ?""":
`
`
`PAGE 59 OF 65
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`ooz_u_amz:>rvmorommwmam
`
`
`
`
`
`..__“___fi.m_.___..__:_.....:
`
`56F0mEGP
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`..__“___fi.m_.___..__:_.....:
`
`
`56F016EGP
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`ooz_u_amz:>rvmorommumam
`
`
`
`_.»_Iva::__r.:
`
`
`
`_.»_Iva::__r.:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`REDACTED
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`cb"NFiDEN"fIAL
`
`
`
`PAGE 64 OF 65
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`'"i5iiE3L"6§§?'é'§§""":
`
`
`PAGE 64 OF 65
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`REDACTED
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`cb"NFiDEN"fIAL
`
`
`
`PAGE 65 OF 65
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`'"i5iiE3L"6§§?'é'§§""":
`
`
`PAGE 65 OF 65