lnt<rnn1ional Juurn,11 of l)~rm.11olo1tr. Vol. H , No. 8, Augu>i 1995
`
`llFV!EW
`
`Cbu t/llcv~
`
`EXHIBIT NO._
`
`EVOLVING ROLE OF N ON DERMATOPHYTE
`l N ONYCHOMYCO I
`
`DONAL.I) L.. GRL· l· R. P11.D.
`
`-
`
`Onychomycosis is the term given lO 3ny fung3l infec(cid:173)
`tion of the n::iil :ind represents one of the more common
`superfici31 funga l infections.1 Grearer mcdic:il attention
`needs to be placed on the idemiCic::11ion, cv3lu::ition, ::ind
`m::inagcmcm of 1he pa1hogens th::11 underlie 1his disease.
`There is increasing aw::ircness of nail infection:.. Also,
`nonpathogenic fungi, not normally associated with nail
`disease, may be emerging as pathogens by taking advan(cid:173)
`rnge of the imp.tired resistance of m3n)' of today's pa(cid:173)
`tients. In pnrricular, a number of species of yc::ISL in the
`genus Candida h3ve been described 3S the etiologic
`:igencs of dyslrophic n3ils and cases of nondcrm<Hophyt(cid:173)
`ic molds h:ive been documented as nail parhogens. Like(cid:173)
`wise, rhe increasing frequency of mixed infections, from
`which dcrma1ophyres, yc3Sts, and/or molds, or a combi(cid:173)
`nation rhcreof have been isolated, has important i111pli(cid:173)
`ca1ions for the future managemenl of onychomycosis; 2- 7
`however, one should remember, that the mt:re isolation
`of 311 orga111sm from an infection site is not proof thnr ic
`is chc c::iusnrive pathogen. Thus, although for many
`years yeasts nod molds have been culnired from nails,
`rhey have been considered either comamin::inrs or com(cid:173)
`mensab and, therefore, ignored as 1he eriology of nail
`disease. A positive potassium hydroxide (KOi i) prepar::1-
`t1on, showing hyphae, pseudohyphae, or yea t, is need(cid:173)
`ed to prove a fungal etiology. Hisropathological exami(cid:173)
`nation showing uwasion of the fungus in a nail pl::irt:
`will posittvcly confirm the etiology. Accumul:uing diag(cid:173)
`nos1ic evidence suggests rhar nonderm;irophy1es can no
`longer be discounted as a potential cause of nail disease.
`
`DIAGNOSIS
`
`Until recently, because the etiology of cut:rncous fungal
`inCecrions was thought to be limited ro dcrmamphytcs,
`
`horn the Dcparuncnis of Pathology, Dcrmntology, nnd Mi·
`crolnology, Lmusmn:i Slate U01vcr:.1t} 1\lcdic:il Ccmcr, Ne\\
`Orleans, Lou1S1nna.
`
`Supported m p.lrt hy :in unrcsmctcd education.ti granc from
`Jnnsscn Pharmaceuuca.
`
`Sc.:c also pages 525- 530.
`
`Addrc~s for correspondence: Donald L. Greer, Ph.D., l ouis1ano
`Stnte Uruvcr~ity Medical Center, 1542 Tul,111c Avenue, New
`Orleam, I A 70122 2822.
`
`saprophytic organisms were nor recognized as primary
`pathogens; 1hese organ isms were 1hough1 10 be sec(cid:173)
`onda ry ro dermatophylic infections. Furt hermore, clin(cid:173)
`icians were noc moriv:11cd ro confirm the cltnical diag
`nosis with approprinre bbor:itory ces1ing; however.
`rcccm studie!l> have shown that clin1cal diagnosis alone
`is often i11:1ccurate. In one large-scale study, involving
`2750 cases of onychoparhy, 70% were diagnosed clini(cid:173)
`cally as fungal infccrions; of lhese, on!) 40°/o could be
`confirmt:d as fungal in origin by direct examination
`and culcurc.s A similar srudy ai Louisiana State Um(cid:173)
`versity found char the clinical diagnosis could not be
`confirmed in 57% of cases.9
`Direcr microscopic examination using a kerarin(cid:173)
`clcaring agem, such as 1o:o11 or chlornzol black £, is
`necessary to detect che presence of fungal clemenrs. Al(cid:173)
`though more labor-intensive, histologic ex3mination of
`the nai l place showing hyphal invasion provides defini-
`1ivc proof of a fungal etiology nnd may be necessnry to
`confirm infections due to nonderm;Hophytic agents.
`This is essenrial because of chc high incidence of false(cid:173)
`nega11ve cultures. In one study, 28% of negalive cul(cid:173)
`rnres were found co be positive on hisrologic examina(cid:173)
`tion. 8 In order to minimize folse-neg.nivc results on
`culrure, microscopic, and histologic exammarion, ir is
`imponam that rhe debris be collecred as proximal ro
`the cuticle as possible. The debris from 1h1s area will
`have rhe highesr number of fungal organisms.
`The type of medium on which the isolate ts grown
`can have an impact on the results, as well as limit the
`idc111ificarion of the causative org:111ism(s). I l1storical(cid:173)
`ly, cycloheximide has been used in dcrmatologic media
`ro prevent the growrh of nondcrm:itophyrcs. Unfortu(cid:173)
`nate!)', use of media co111aining cyclohcximide inhibits
`the identification of many "saprophytes" that may be
`potential pathogens. These include some species of
`Candida, Scop11lariopsis l1rt'v1ca 11/is, Scytalidmm
`di1111d1at1t111 (1 ie11dc1so1111la 10111/oidcn),
`. hyalm11111,
`:md ~<>me species of As/1crgill11s. It is imperative that
`1hc medical mycology reference labora1orics culture all
`nail amples using both a cyclohc.x11nide free medium
`(i.e., Sabouraud's agar), and C) clohcx1midc-supplcment(cid:173)
`ed med1a,'O such as derma1ophytc 1esr medium (IHM),
`l\ lycosel, or tycobiotic agar (nm 1 BJlrimorc, l\ID).
`Gentamicm may be :1dded lO • nbour:iud's agar ro
`prevent bacreria l overgrowth. The identification of a
`nondermatoph)•Cc mold or yeast as the pathogen re-
`
`52 1
`
`CFAD v. Anacor, IPR2015-01776, CFAD EXHIBIT 1077 - Page 1 of 5
`
`

`
`1ntrrnot inn::il Journal of l>crm:uolosy
`Vol. 34, No, 8, Augu\l 1995
`
`quires stringent criteria. 11·12 The criteria arc as follows:
`1) a bsence o f any dermaLOphytc on cultu re; 2) KO i i
`positivity; showing the presence or fi l:i ments (hyphac),
`pscudohyphae, or yensr in the subungual keratin; and
`3) pure cultu re; five cultu rn l sites o ut o f 20 must be
`positive for rhe nondermatophyte only.
`These criteri:i eliminate the possibility of diagnosing
`" mixed infections" of d1e nail (i.e., that more than one
`organism may be the cause of the infection). This poten(cid:173)
`tial siwarion requires differcnr techniques to analyze the
`infected nail.
`In a Belgian laboratory, the technique of immunohis(cid:173)
`t0chemis1 ry and flow cytomctry was developed to study
`fungal nail dystrophy. This laboratory hns unequivoca l(cid:173)
`ly identified cases where different species o f fungi arc
`present in a nail plare.13 In addition, the now cytomctry
`technique enables identification of individual genera and
`species of fungi.14 These new methods are providing evi(cid:173)
`dence that mi xed infections do occur and, furthermore,
`that nondermarophytic molds and yeasts can invade the
`na il and cause primary infections in nails.1 ~
`
`ETIO l.OGY
`
`Evolving Shift of Pathogens
`
`The etiology of onychomycosis, as well as that of other
`superficia l fungal infections of the hair and skin, appears
`to be fl uctu:i ting. Factors, such as l ) the emergence of
`new org:inisms, 2) the variety of diagnostic techniques,
`3) the definiuon of "what IS a pathogen," and 4) the var(cid:173)
`ious geographic locations of the indi vidual studies, all
`combine to inAuencc the wide range of dcrmatophytes,
`yeasts, and molds that have been rep orted in the litera(cid:173)
`ture (Table I). Allhough organisms va ry according to the
`regional site, 1•16-20 dermatophytes account for the majori(cid:173)
`ty o f fungi isolated as the causntive pathogen in ony(cid:173)
`chomycosis, ranging from 328 to 90.7% .IO
`Dermatophytes arc far more likely to cause in fec(cid:173)
`tions in toenails than fingernails.J.B,1M,1 9 By comparison,
`onychomycoses in the fingernails of women arc usunlly
`caused by yeast inf cctions. s,17,18
`
`Table l. T ypes of Fungi Found in Onychomycosis ( % )
`y
`Study (Ycar)R'f. No.
`N Mixed
`N
`/)
`11
`44 .3 29.2 15.5
`1844
`NR
`13
`11
`56
`373
`NR
`66
`1098
`32
`2
`
`Mcinhof ( 1962)H
`Wa lshe and English 1~
`Achtcn :ind
`Wancc-Roua rd ( 1978)8
`Clayton ( J 992)21
`Greer (1993)
`unpublished
`N .: number of n.1ils; 0 = dcrmntophytc; Y "' yeast; N = nondcrmn10·
`phyte molds; NR - noi reported.
`
`669
`431
`
`8 1
`23
`
`17
`63
`
`2
`4
`
`N R
`8
`
`Among the clermatophytes, Trichop/J yto11 m bm111 is
`the most prevalent pa thogen in both temperate and
`tro pica l cl imates.3•8·10•17 O:i ta were compiled fro m a
`routine diagnostic mycology laborato ry in Engla nd . lt
`was found that 462 of 539 (85%) derma tophytes iso(cid:173)
`lated from nails were T. mlu 11111 , fo llowed by Tri(cid:173)
`c!J0/1hyto11 111e11tagrop/Jytes var i11terdigitale, at 13 %.21
`All data included b0th positive KOi i preparations and
`culture. In :inothcr report,1 also usmg do.ta from both
`KO i i a nd cultures, 3626 ski n and nail samples were
`taken from 2507 patients. Derm:i toph yrc infections
`were demon strated in 700 p:i tie nt~ (824 specimen s),
`77% of which involved the fee1. The most common
`pa thoge n idenrified was T. mbmm, acco unting fo r
`66% of the derm:itophyte infect io ns. T. 111e11tagro(cid:173)
`fJbytes was isola ted from 33.2 % of a II patients and, as
`expected, w:is more frequently found in toenails than
`in fingernails.
`Similarly, in a retrospective ~Ludy over :i 20-year pcri
`od in the Nethcrlands,u 2079 superfici:il fungal infec(cid:173)
`tions were diagnosed. T he rel:itivc incidence of dermato(cid:173)
`phytes was found to remain fairly constant at 66%; 3 15
`( 15%) of the infections were from nails, wirh T. rulm1111
`a nd T. m c11tag rophy tes the most prevalent <lcrmato(cid:173)
`phytes isolated (57% and 18% , respectively). Interest(cid:173)
`ingl y, whereas T. rubmm was isol:ited predominantly in
`t0enails (88% ), T. 111e11tagrop/Jytes was isolnred only in
`toenails. It is not surprising that the re lat ivc incidence of
`yeasts (:ind, in particular, Candida n/bica11s) remained
`fairl y com1ant at 25% . Candida species :ire normal
`Aora of rhe human host. Lasdy, it wns noted that Sco/J11-
`lariopsis brcvica11/is was the most frequent nondermaro(cid:173)
`phytic mold causing infection of nails.22
`YcastS arc often present in cutaneous 111ycoses,i,i7,i i-n
`especially in paronychi:il infections in women. In one
`reporr on pnronychia l infections, it was found that
`Candida spp, particularly C. albicans, were the cause
`of 79% of fingernail infections in women, but only of
`22% of fingernail infections in men.21
`In o ne study , usin g d a ta from bo th KO ii and
`culture,8 yeasts were identified in 66% of onychomy(cid:173)
`coscs; C. albicans was isolated in 72 % of those cases.
`In n Canadian repon that also combined l<O l I and cul(cid:173)
`ture data, over 4000 specimens of fungal infections o f
`the nails, soles, and palms were studied.1° I lcre, it was
`found that C. albica11s was the third most prevalent or(cid:173)
`g:rni sm from all sources, and the most predominant
`yeast isolated. Likewise, in another study of I 0-ye::irs'
`duration, of 986 fungal nail infections in Western Aus(cid:173)
`tralia, 17 C. albicn11s accoumcd for the majority of yeasts
`in fingernail infections (58.6%), but was less prevalent
`among toenail infeCLions ( 17. 1 %). On rhe other hand,
`Ca11rl1da parapsilosrs was isolated in 40 % of toen::iil in
`fcc tio ns a nd 24.6 % of fin gern ail infections. Even
`though this yeast was the second moi.t common fungus
`idemified by Achten and Wanct-Rouard ,8 the signifi(cid:173)
`cance or these isolates could not be determined.
`
`522
`
`CFAD v. Anacor, IPR2015-01776, CFAD EXHIBIT 1077 - Page 2 of 5
`
`

`
`No1ufo1 m.itt>ph)•tc' 11\ On1·,hoon1 CO\I\
`Greer
`
`It is now cle~u that nondermatophytic molds isolated
`from dystrophic nails2•16•17 •22•24 may be rruc patho1,Zcns.
`Onychomycosi~ caused b} nonderm:uophync molds,
`111cludc Sco/111lnrio/1sis breuica11/is, '.l.2t.H Aspergil/11s
`spp,2.1.111,i .71.n Scytalidi11111 hyali1111111,14 and S. di1111dia(cid:173)
`t11111. In fact, 111 one study, rhe third most common 1so
`bte wns S. lm•u1cn11/is, which was identified 111 233 of
`3626 specimens (7%); 1 it was the fourth most common
`pathogen of the nail ( L.6%) in ycr nnorhcr study. 10
`In 1987, the first case of I le11derso1111/a torulorden
`( cytalirli11111 di1111dint11111) infection in the Un1ted St:Hes
`was reponed.26 Since rhen, additional cases h:ive been
`rcpcmed in £urope27·2'1 and elsewhere in the United
`Stntes.24•10 This dcmntiaccous fungu s nnd n rclnted hy:i
`. /Jya/i1111111, are proven cnuses of onycho(cid:173)
`line species,
`mycos1s, tinea pedis, and tinca manuum.24 Documented
`cases h.we been reported predominantly from tropical
`and subtropical areas where this mold is endemic (1.e.,
`rhe C:mbbean, Africa, lndin, and the Fnr Enst)."·32
`
`Mixed In fections
`
`Another complicat111g aspect of onychomyco is is the
`prcv:ilcnce of "mixed fungal infccnons," when more
`than one type of fungus is found within :111 infected
`nail. In the post, mixed infections went l::irgely unrcc·
`ognizcd because the tendency hos been to ignon: the
`nondermat0phytes, whenever :l dcrmatophyte was pre
`sent. A number of studies have clinically evaluated the
`111cidence of mixed infections (Table 2).1·3,H
`It w:ts found thar, of 69 l infected nails cultured
`(646 roenaib and 45 fingernails), a s111glc oqpni m was
`1 olatcd from 58% (23% derm:uophytc, 24% yc;.1s1,
`11 % mold). 1 The other 42 % of the cultures were
`polymicrobic (fig. I). Other reports do nm support
`such a high incidence of mixed cultures; these r:mged
`from almost 017 LO J l %. 15 This vari::irion renects the
`d1Hiculry of proving the etiology of such infcctionsl 111
`addiuon to the geographic area, sample types, and pa(cid:173)
`ticnti.' variations in the different srudies. For example,
`one report shows that lOcnails arc more prone w 111fcc(cid:173)
`cion with 11011dcrma cophyric species rha n (i ngern•li ls,
`probably because of frcquenc trnumn nnd d1t• humid en(cid:173)
`vironment rclntcd LO the daily wearing of :.hoes. 17 Re
`port~ confirm thnt nondermatophyuc molds :irt• mort•
`
`Dormotophy10, Yoast,
`ondMold
`
`Figure L.
`
`~ illc1mcn-
`
`lnciclcncc of mi"cd cultures tn n:lils.
`
`prevalent in nail infccrions m the hot :md humid trop1-
`a l :ind subtropical parts of rhe world. 1 ~ Thus, the
`ource of nail samples may inAuencc the O\ erall etio(cid:173)
`logic picture produced b)' studies of tnfected nails.
`
`IMPI !CATION roR TRLATMl.NT
`
`1 he divcrsit> of ct1ologic ngents associated w1rh ony(cid:173)
`chomycosis has 1mporranl implications for the man(cid:173)
`agement of fungal nail infections, n di~case entity that
`h,1s been nocon ousl) difficulr to treat. Griseofulvin has
`been the most commonl y used ornl amifungal treat(cid:173)
`ment for onychomycoses; however, it is effective only
`against dermatophyric infections. It s high relapse rate
`ma)' be due to infections c:rnscd by yeasr and molds.'-'
`Fortunately, recent adv:inces have taken pbcc 111 the
`a nrifungal armament:mum wnh the development of
`broader spectrum drugs, nuconnzole, cerbtn:ifinc, and
`itr:iconazolc. ltracona7.olc, 111 particul:ir, has ac11v1ry
`again r mosr fungal pathogens of the nail (dermatoph' res,
`ye:lSl. nnd molds) :ind has been as~oci:ucd with good
`chmcal resulrs;5•14·H however, no annfunizal agcnr has vet
`to be found effective ag::11nsr II. torulordeo.4·26.2" 11
`
`ONCt USIO
`
`Although derm:uophyttc fungi :uc srill the matn cno(cid:173)
`logtc agents of onychomycoscs, some species of non(cid:173)
`dcrrnatophync molds ond yeasts <He also capable of
`111\ading 1he nails. Reports 111 rhc current literature 111-
`dtcatc that nor onl} ts the awarC'ness of onychomycosts
`1ncrcas1ng, but nntl diseases caused hy nondcrmaro(cid:173)
`phytcs and mixed infccnons :ire becoming more preva(cid:173)
`lent. There 1s ;l nerd ro changt• d1agno~tic labor:uor)
`rrocedures to account for the new ev1dencc thnt non(cid:173)
`dcrm:nophytes and yc.lsts arc imporc.rnr 111 che euology
`of onychomycoses. Spcc1f1c:illy, rfuc; includes the con
`s1:.tent use of appropn:nc m1croscop1c evaluatron. 111
`con1u 11ction w1th the culturing of .111 specimens on
`both cyclohc;...1midc frel' and cy lohe'\.1mide-contai11111g
`11icd1a. l forologic exam111a11on can lw used ro verify
`the rnva sion b) a nondermatophyte fungu<>. l n addi(cid:173)
`tion, histochemica l technique:. have been developed
`
`TAhlc 2. Mi~cd Fung:ll Jnfcctio1h {~ .. )
`D+I) D~Y D+M D~Y+M )'t) )iAI M+Af
`6.4 4.7
`
`7.4
`
`9. 1
`
`1•1.8 33.9 23.7
`
`S111,/y
`Budak ct ,11. 1
`(N= ISI 3)
`(,ngor111 ct Al. 11 11
`(N-872)•
`W11lc1mcn 1
`(N 69 1)
`D
`l1cr111111ophy1c.,; M No11dcrm;11nphy1c mo(J.,;)
`nu1 1cpom·d, only mcnnils.
`
`11.S 12.2
`
`9.6
`
`6.7 15
`
`NK 2~
`
`6
`
`9
`
`NR 5
`
`14
`
`NR
`
`\ c.1\1'; NR
`
`513
`
`CFAD v. Anacor, IPR2015-01776, CFAD EXHIBIT 1077 - Page 3 of 5
`
`

`
`hnun.1111111.11 Jnurn.11 uf l>rrnrntnltJKY
`Vol l4, No. II, A111111'1 19'1~
`
`that foci lirntc uccurnte iclentifica1ion of fung:tl p:11h
`ogens and hence avoid the problems of fobc-positivc
`and false negative test results.
`Onychomycot1c infections present a diagnostic
`dilemm::i tc> chc clinician, frequently leading ro empirical
`treatment of the disease. With the recen t development of
`broad-spectrum amifungal agems, clinicians can now
`have [he confidence that dermarophync, as well as non
`dermat0phy1ic pathogens will be eradicaccd cffcc1ively.
`l)lllJC NAMES
`
`Ouconazolc: Di Oucon
`griseofulvin: rulvicin, Crifulvin V, Grisacrin
`itracon.11ole: Spomnox
`rerbin:irine: La misil
`
`llfFFRl.:.NCLS
`
`14.
`
`15.
`
`16.
`
`17.
`
`18.
`
`19.
`
`20.
`
`21.
`
`22.
`
`23.
`
`24.
`
`25.
`
`26.
`
`27.
`
`28.
`
`29.
`
`30.
`
`3 1.
`
`32.
`
`33.
`
`34.
`
`35.
`
`36.
`
`Arrcsc j E, Syne11 D, Goris A, Pit:rartl GE. Identification
`immunohistochimiquc des Aspcrgillus par l'anticorps
`monoclonal l<B Al. Ann Dcrmatnl 1?90; 9:•113-414.
`Picrnrd <..F, Ancsc JE, Pic1re S, ct al. Apport de l'cxam(cid:173)
`cn hisculog1q uc ct de l.t microscopic confoc.1le /11 111110
`d.ms lcs onychomycoscs. Ann Ocrmatol Vcncrcol 1994;
`121 :25-29.
`/.a1;1s N, Oertel I, Elliott DJ·. l•u11g1 in tocn;tils. J Invest
`Dcrmarnl 1%9; 53:140-142.
`MtAlccr R. Fungal infccuons of the nails in Western
`Ausrraha. Mycop.nhologia 1981; 73; 1 15 120.
`Andre J, Actcn G. Onycho111ycos1s. Int J Dcrmatol
`1987; 26:48 1-490.
`Sinski j1, Flcmras K. A survey of dcrmntophyces isol:u(cid:173)
`cd from hum.Ill p.incnrs in the United Swtcs from 1979
`to l Y81 with chronolog1cal liblings of worldwide inci(cid:173)
`clcncc of five de1 matophytcs often isolated in the United
`States. Mycopathologia 1985; 85:97-J 20.
`Znias N. Cl1 n1c,\l manifestations of onychomycosis.
`Uin Fxp Dcrmatol 1992; J 7(Suppl I ):6-7.
`Cl.tyton Y. Cl1111c.ll and mycolo1-11c.tl d1ngnost1c aspects
`of onychomycoscs nnd dcrm.11omyco~c~. Clin Exp Dcr(cid:173)
`maml 1992; J 7(Suppl l ):37-40.
`.s, ct al. Vcr(cid:173)
`1 an CS, Wintcrmans RGI<, Del loog
`schuivingcn 111 1he sooncmpcctrum van mycosen in
`Nederland in her rijclvnk 1970- 1990. Ned Tijclschr Gc(cid:173)
`nccskd 1992; 136:631-637.
`C:irctta G, DclFrote G, Picco AM , Mang1arott1 AM. Su(cid:173)
`perficial mycoscs in lrn ly. Mycopnthologi.t l 98 1; 76:
`27-32.
`Flewsk1 HE, Greer DL. I lc11dcrso1111/a tomlo1dc11 nnd
`Sryt11/id111111 /1yali1111111-a review and updntc. Arch Dcr(cid:173)
`matol 199 1; 127:1041- 1044.
`Mcinhof W. Kntischc. Auswcrtung dcr griscofulvinbc(cid:173)
`hnndlung von Onychomykoscn untcr besondcrer
`Jkr~1cksichtigung des Rcsistcn1.problems. In: Got:t 11 ,
`ed. Die griscofulvinbchnndlung clcr Dcrmncomykmcn.
`New York, NY: Springer Verlag, l 962:29.
`<..rccr DL, Gutierre1. MM. Tinea pcclis cnu\cd by l-lc11-
`dcrso111rla toruloid£•t1: a new problem in dermatology. J
`Am Acad Dermatol 1987; 16: 1111 I l 15.
`Abramson C. Atblctc'i. foo1 and OJ1ychomy1:osis caused
`by I fo11der~o1111l11 torrtloidaa. Cu us I 990; 4 6: l 28-1 32.
`Moore MK. Hc11dcrso1111/a torulo1dl!fl and Scyt11/id111111
`hyuli1111111 infccLiun' i11 London, England. J Med Vet
`Mycol 1986; 24:219-230.
`Moore MK, P:ibc10-Hcrnarn AD, Lopez-Gomez S. ~CY·
`111/1d111111 hya/11111111 111fcction diagnosed in Spain. J Med
`Vc1 Mycol l 984; 22:243-245.
`Rippon JW. Medical mycology: the palhogcnic fungi
`and the pa1 hogen1c act inomycctc~. Philndclph1a: WB
`Saunder~, 1988.
`Kong nl 11>, Kap1co I., I .cc I\. Kt:r<1t111 invasion b) I lcm(cid:173)
`cforso111rlr1 to111/01dc•a: :t tropic:tl pathogenic fungu~ rc(cid:173)
`~i~tan1 to 1herapy. Int j Dcrmnrol 1984; 2 3:65-66.
`Kcnra1aras R, Chongsath1cn !:>, Ro1anavan1ch V, ct nl.
`l-/c11derscm11la torrtloidcn infection 1n 1 hailand. Int J
`Dcrmntol 1988; 27:39 1-395.
`Grigonu A, Grigoriu 0, Dclncrc111z J. 1),,, 7us.1mmen(cid:173)
`wirkcn von Pili.trten bci I lau1krank hc11cn. Mykoscn
`1985; 28:U9-569.
`( anwcnlwrgh G, Dcgrccf 11, l lcykants J, ct :ii. Ph:irma(cid:173)
`cokinctic profile of orally admims1crecf itraconawlc in
`hu111nn skin. J J\m Acnd Dcrniatol 1988; 18:263-268.
`W1llcm~en M, DeDonckcr P, Willems j, ct nl. PoM
`treatment itraconnzole ll•vcls 111 the nnil. J Am Acnd
`Dcnnatol 1992; 26:73 1-735.
`W.tlshe MM, Engh\h MP. Fungi 111 na1b. llr J Dcrmatol
`J 966; 78: 198-207.
`
`524
`
`1.
`
`3.
`
`4.
`
`6.
`
`7.
`
`I. Willemsen M. Changing patterns rn ~upcrficial 111ft:c(cid:173)
`t1on~: focus on 011ychomycos1s. J Lur Acad Dcnnatol
`Vcncreol 199 3; 2:$6-S I I.
`I !:inckc I:.. l•unga l 111fccrions of the 11::111. Scmin Derma·
`ml 1991; 10:41-53.
`f\udak A, Macura AB, Mazur 1, L.1skow11icka Z. Fun(cid:173)
`ga l species isolated from skin and nail les1on1> of the
`h.tnd\ and feet of pauents su~pccted of mycotic mfcc(cid:173)
`tion. Mykoscn 1987; 30:4 34-439.
`11.t> RJ, Clayton YM, Moore MK, Midgley C. An cv,tl(cid:173)
`uanon or irrncon•l7ole in the management of ony
`chomycosis. llr j Ocrmntol l 988; 11 9:359-366.
`5. M,nthu:u 1., OeDonckcr P, C:rnwenbcrgh C., ct al. lrrn
`conazole penetrate.\ the nail v10 the n<til matrix and 1he
`nail bed. A11 invcstigauon 111 onychomycos1~. Clin Exp
`Dernrntol l 99 1; 16;374-376.
`Pierard GI., Arrcsl' JE, Piernrd l'nlllchimon1 C. Trent
`mcnr of onychomycos1s-crnd1riona l approaches. J Am
`Acad Ocrrmuol 1993; 29:S4 l-S4 5.
`\V;1rnock DW. Phamrncolog1cal iswcs in amifungnl
`therapy. Pre~cntcd at " I ssue~ in the modern manage
`menr of onychomycos1s. new apprn:ichc\ to d1agnu~i\
`and chcrapy " Monte Carlo, April I 2, 1993.
`8. Achtcn C., W::inet-Rouard j . Onychomycoscs in chc lab
`or.uory. Mykoscn Suppl 1978; 23{Suppl 1):l25-127.
`9. Greer DI.. l:.r1ology of onychomycosii;: review of the lit·
`er.1turc Prc\cntcd at: "l,~ues in the modern mnnage(cid:173)
`ment of onychomycos1s: nc" approaches to diagnosis
`and therapy." Monte Carlo, April 1-2, 1991.
`10. Summerbell RC, Kane J, Kra1den 5 Onychom)'Cm1•.,
`ttnc:;i pcdi~ •. 111d tinca m<tnuum caused br nondern1,110
`ph)•tic filamentous fungi. Mycoscs 1989; 32:609-619.
`rnghsh l\lP Nails .ind fu11g1. Br I Dcrmaiol 1976; 94:
`697 701.
`12. hnglish MP. The saprophytic growth or 11011kcralino
`ph1l1c fungi in kcr;H11117.cd substratt and a comparison
`with kcraunophilic fungi. l rnns Hr Myeol Soc 1965;
`48·2 19-224.
`1\rrc~c JI·, Picr.ud I ranth1mont C, C,rc1mcrs R, Picrard
`GL l·ung1 1n onychomycm1~. A 'tudy m 1mmunohi\lo
`chl·mistry <tnd clu,11 no\\ cytomctry J hur Acnd Derma
`tol Vcnerrol 1995, 4: 123-130.
`
`11.
`
`13.
`
`CFAD v. Anacor, IPR2015-01776, CFAD EXHIBIT 1077 - Page 4 of 5
`
`

`
`f
`
`This document is a scanned copy of a printed document. No warranty is given about
`the accuracy of the copy. Users should refer to the original published version of the
`material.
`
`CFAD v. Anacor, IPR2015-01776, CFAD EXHIBIT 1077 - Page 5 of 5