CFAD V. Anacor, |PR20’|5-01776
`ANACOR EX. 2161 - “I/7
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`
`CFAD v. Anacor, IPR2015-01776
`ANACOR EX. 2161 - 1/7
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`MARCH 20x 5
` COPYRIGHT © 2015
`
`223
`VOLUME 14 - ISSUE3
`OR'*IG_INA flu-1-wmw-v--nu .
`.. ,
` ARTIGEES‘
`
`
`
`JOURNAL or DRUGS IN DERMATOLOGY
`
`Onychomycosis: Epidemiology, Diagnosis, and
`Treatment in a Changing Landscape
`
`Theodore Rosen MD,“ Sheila Fallon Friedlander MD,” Leon Kircik MD,‘ Matthew]. Zirvvas MD,“
`Linda Stein Gold MD,‘ Neal Bhatia MD,fAditya K. Gupta MD PhD MBAg
`"Department of Dermatology, Baylor College ofMedicinc, Houston,TX
`"Department of Pediatrics and Medicine (Dermatology), School of Medicine, University of California and Rady Children’s Hospital, San Diego, CA
`“Department of Dermatology, Icalm School of Medicine at Mount Sinai, NewYork, NY; Indiana University School ofMcdicine,
`Indianapolis, IN; Physicians Skin Care, PLLC, Louisville, KY
`“Division of Dermatology,The Ohio State University Medical Center, Columbus, OH
`“Department ofDermatology, Henry Ford Health Systems, Detroit, MI
`‘Division of Dermatology, I-Iarbor UCLA Medical Center, Los Angeles, CA
`*'Department of Medicine, University ofToronto,Toronto, ON
`
`
`
`
`?ABsTR?’A'GT:fl
`
`Onychomycosis is an often overlooked and/or undertreated disease.This may be in part due to an under appreciation among both
`physicians and patients of its impact on quality of life and the potential for significant complications, from tinea corporis and cru— I
`ris, to bacterial superinfection. Some health care providers are unaware of the effective low—risk treatments currently available.
`Changing demographic characteristics such as the relative aging of the population; the increasing prevalence of diabetes and
`peripheral vascular disease, and widespread iatrogenic immunosuppression; and changes in lifestyle practices such as earlier
`and greater participation in sports, are likely to lead to an increased prevalence of onychomycosis in both adults and children. Two
`topical onychomycosis treatments, efinaconazole 10% solution, and tavaborole 5% solution were recently approved by the FDA.
`This article reviews the state of knowledge and describes, briefly, these new treatment options.
`
`l
`
`i
`l
`
`J Drugs Dermato/. 2015;14(3):223-228.
`
`lINTRODUGTIONl
`
`early half (48%) of nail abnormalities result from docu-
`
`Nmented onychomycosis,‘ with toenails affected most
`
`often (toenail-fingernail ratio: 10.6)? In addition to its
`cosmetic impact, onychomycosis can be painful and thereby
`significantly affect patients’ quality of life (QoL).°"‘ These effects
`increase with disease duration and extent and/or number of toe-
`
`nails affected.The average number of toenails involved is 5, with
`approximately 15% of patients having all 10 affected.‘ Spontane-
`ous resolution is rare and disease duration is often >5 years.“
`
`Treatment paradigms will likely shift due to the introduction of
`new topical agents and the increasing recognition that all ages
`are at risk for fungal nail infections.This paper will review the
`epidemiology, diagnosis, and management of onychomycosis
`in the context of these new developments.
`
`medical office visits, or unselected/general population). Preva-
`lence is clearly higher in males and increases with age.‘-5*’
`
`Risk factors for onychomycosis include tinea pedis,“ nail
`trauma,“ diabetes,“ peripheral vascular disease (PVD),5'3'”"3
`and personal/family history of onychomycosis.” Significant
`associations also exist for psoriasis.” These conditions may
`contribute to onychomycosis susceptibility via slower/poor nail
`growth (due to age or poor circulation), immune suppression,
`and/or nail trauma (diabetic neuropathy, psoriatic nail changes).
`Vasoconstriction and/or hypoxemia due to nicotine exposure or
`PVD may further increase the risk of onychomycosis."
`
`The incidence of onychomycosis will likely rise due to projected
`increases in important risk factors such as age, diabetes, and PVD.
`
`Epidemiology
`Disease prevalence estimates vary widely across studies; how-
`ever, a recent meta-analysis calculated a rate of approximately
`4% in North America/Europe? Between-study variation may be
`due to differences in study location (prevalence varies with ge-
`ography/cultural practices), study methodology, and population
`source (ie, patients with nail complaints, mycological samples,
`
`Diabetes
`
`Approximately half (46-50%) of patients with diabetes have
`toenail abnormalities?“ of which 57-65% are due to onycho-
`mycosis” (13-30% prevalence9"5"‘"’). Similar to the general
`population, older age,” male gender,9 PVD,9 and family his-
`tory of onychomycosis” are all significant risk factors among
`diabetics. Further risk factors include immunosuppressionf’
`
`:: ayzmyvg-r a\v(l I
`
`
`This rnatie-rial was {an-pied
`at the N LM and may be
`Sulajetzt Uiztls-pyright Laws
`
`CFAD v. Anacor, |PR20‘l5-01776
`ANACOR EX. 2161 - 2/7
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`

`
` T. Rosen, S. F. Friedlander, L. Kircik, et al.
`JOURNAL or DRUGS IN DERMATOLOGY
`MARCH 2015 - VOLUME 14 -
`ISSUE 3
`
`224
`
`neuropathy,” duration of hyperglycemia,“ and severity of dia-
`betic nail changes.”
`
`Inappropriately managed onychomycosis has the potential to
`lead to serious complications in diabetic patients,
`including
`cellulitis" and foot u|cers.‘3The latter conditions may result in
`
`additional morbidity including the need for amputation.
`
`Per/,0hera/ Vascu/ar D/sease
`
`Chronic venous insufficiency is associated with nail abnormalities
`in 61-84% of patients, and of these, 59-75% are onychomycosis‘9»‘°
`(36% prevalence‘9).The relationship between onychomycosis and
`peripheral arterial disease is less clear.”"3
`
`Psor/as/s
`
`The majority (78-82%) of psoriasis patients have some nail
`abnormalities,“-22 of which 19-31% are related to onYCh0mYC0'
`sis.m“The prevalence of toenail onychomycosis is 5-13% among
`Us/Euiopean psoriasis patients.” Male gender,”-2‘ older age,”
`and use of certain psoriasis therapies“ are significant onycho-
`mycosis risk factors, although the duration of psoriasis is not.”
`
`Pediatrics
`
`Nail abnormalities are present in 0.4-1.8% of pediatric patients,25‘2“
`representing approximately 5% of all nail abnormalities regard-
`'93s of 399-293” Among children with nail abnormalities, 10-49%
`are confirmed to be onychomycosis.2"'29-3‘ A recent retrospective
`review of all pediatric patients presenting to a large academic
`dermatology practice noted an incidence of approximately 3%;
`however, referral bias has likely inflated this number somewhat.“
`Like the adult population, the prevalence of onychomycosis in-
`creases with age“-28'3‘r33 and is at least as common in boys as
`girls.2“"9i3‘-“The prevalence of, or at least awareness of, onycho-
`mV00SiS appears to be rising in the pediatric popu|ation.33'3"This
`may be due to greater surveillance, ’perfect progeny’ attitudes
`among parents, earlier and increased participation in sports
`(leading to greater exposure to fomites and/or more toenail trau-
`ma). and/or commonplace use of occlusive shoes.
`
`
`
`"Dermatophytes are the primary
`causative agent in the majority of
`patients (65% worldwide, 82% in North
`America) with T mbmm being the
`
`most common species."
`
`Diagnosis
`Many health care providers frequently diagnose onychomyco-
`sis based solely on clinical examination; however, this can be
`misleading due to overlapping clinical signs and extensive dif-
`ferential diagnosis (Table 1).
`
`TABLE 1.
`
`Nail Trauma
`
`Psoriasis
`
`Lichen Planus
`
`Paronychia
`Bacterial Infection
`
`Pachyonychia Congenita
`
`Yellow Nail Syndrome
`Phlebitis
`
`Twenty Nail Dystrophy
`
`Alopecia Areata
`Nail BedTumors and Verrucae
`
`Contact/Atopic Dermatitis
`
`idiopathic Onycholysis
`
`Nail Changes Associated with Systemic Disease or Nail Cosmetics
`
`Presence of unilateral dystrophy involving 22 toenails and dys-
`trophy of both the first and fifth toenails on the same foot are
`predictive of onychomycosis.“ When onychomycosis is sus-
`pected based on clinical examination, the presence of plantar
`desquamation is also predictive of fungal infection.35 Dystrophy
`of a single toenail or of all 10 toenails were neither supportive
`nor contraindicative of onychomycosis.5
`
`lateral subungual onychomycosis (DLSO; 86%) is the
`Distal
`most commonly observed subtype, followed by superficial
`onychomycosis (SO; 14%) and proximal subungual onychomy-
`cosis (PSO; O.23%).‘Total dystrophic onychomycosis (TDO) and
`endonyx onychomycosis (E0) are uncommon. In some cases, a
`mixture of infective patterns is observed, so called mixed pat-
`tern onychomycosis (MPO).
`
`Dermatophytes are the primary causative agent in the major-
`ity of patients (65% worldwide, 82% in North America) with T
`rubrum being the most common species (45% worldwide, ap-
`proximately 59% in North America)?
`
`Spec/'a/ Populations
`The pattern of causative agents in patients with diabetes‘°'“"“ or
`PVD‘9 is similar to the general population. In patients with pso-
`riasis, the pattern is also similar,“ although the proportion of
`nondermatophyte molds and yeasts may be greater in patients
`with psoriasis, most likely due to the increased likelihood of
`fingernail infections where nondermatophyte mold and yeast
`infections are more common.“r3‘5
`
`Similar to adults, dermatophytes are the most common patho-
`gens present in the toenails of pediatric patients,27'29-33 and the
`most common morphology is DLSO.”-33 in pediatric patients
`
`Th is material wasw-pied
`at the N LM and may be
`5ul:ijes:t US Copyright Laws
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`

`225
` JOURNAL on DRUGS IN DERMATOLOGY
`T. Rosen, S. F. Friedlander, L. Kircik, et :11.
`MARCH 2015 - VOLUME 14 -
`ISSUE3
`
`the latter is not FDA-approved for onychomycosis. A study
`comparing all three agents for dermatophyte infections dem-
`onstrated clinical (>75% reduction in onycholysis, subungual
`hyperkeratosis, and percentage of nail involvement) and my-
`cological (KOH and culture negative) cure rates at the end of
`9 months (3 months treatment, 6 months follow-up) that were
`81% and 75% with terbinafine (250 mg OD), 78% and 61% with
`itraconazole (200 mg BID, first week each month), and 38% and
`31% with fluconazole (150 mg once weekly), respectively, with
`terbinafine and itraconazole being statistically betterthan fluco-
`nazole.42The use of these systemic treatments is often limited
`by safety concerns such as liver toxicity with terbinafine and
`fluconazole“-4‘ or ventricular disfunction with itraconazole.“
`
`Potential drug-drug interactions also limit their use (Table 2).
`
`TABLE 2.
`
`
`
`r-.-»g;;a;~y«-v—~onmr;'~namnwI':uvzs«anwaw:vn.araw-‘:—-w~-
`
`
`ug Int
`....-_.
`..
`...i .......-
`_,,.,__,_j
`
`
`Antiarrhythmics
`
`Antiarrhythmics
`Statins
`
`Antiarrhythmics
`
`Antipsychotics
`
`overall, toenails are the most common site of infection27'29'3‘;
`however, the fingernail-toenail ratio and causative agent profile
`shifts over pediatric age groups.Thus, yeast infections of the
`fingernails are most prevalent in infants and pre—schoo|—aged
`children but in patients older than 6 years, dermatophyte toe-
`nail infections are most common.2933
`
`Diagnostic Tests
`Since onychomycosis is caused by different genera of fungus,
`it is important to confirm clinical diagnoses utilizing a combi-
`nation of mycologic culture and microscopy (KOH staining)
`or histomycology (PAS staining). However, newer PCR tech-
`niques have several advantages over these more traditional
`methods — results are available quickly (days instead of weeks
`with culture); it is less susceptible to contamination, sampling
`technique, fungal viability, and morphologic/phenotypic differ-
`ences; and it is better adapted to identifying mixed infections.”
`
`Treatment
`
`Until recently, onychomycosis treatments have been disap-
`pointing in terms of efficacy and tolerability.Topical treatments
`have been largely ineffective due to poor nail bed penetration,
`and dependent on lacquer-based vehicles and debridement.
`Systemic treatments have been more effective but potential
`drug-drug interactions and other adverse effects limit their use.
`
`The efficacy of an antifungal therapy can be assessed by sev-
`eral measures. Mycological cure is usually defined as negative
`microscopy (KOH) and negative culture results. Complete cure,
`defined as a completely clear/normal nail (0% nail involvement)
`and mycological cure, is the FDA’s preferred endpoint for the
`evaluation of antifungal efficacy, although a completely normal
`nail may be unattainable due to matrix damage. Endpoints like
`‘almost complete cure’ (35% nail involvement and mycological
`cure) and ‘clinical cure’ (s10% nail involvement and mycological
`cure) may be more practical and most patients and physicians
`find this degree of resolution satisfactory.
`
`Physical Modalities
`Laser treatments and photodynamic therapy (PDT) are only
`FDA-approved for temporarily improving the appearance of
`affected nails and there is limited published peer-reviewed
`clinical data on which to base their use.” Consequently, most
`experts feel it is premature to recommend it.
`
`In combination with topical therapy, debridement may reduce
`Symptoms, improve appearance, and lead to better patient sat-
`isfaction39"‘°; however, debridement alone has not been shown
`to impact mycological cure.“
`
`Systemic Treatments
`Currently available systemic treatments that are widely used
`include terbinafine,
`itraconazole, and fluconazole, although
`
`Tricyc|icAntidepressants Antihypertensives Antihistamines
`
`Selective Serotonin
`Reuptake Inhibitors
`(SSRIs)
`
`Monoamine Oxidase
`Inhibitors (MAO|s)
`
`Benzodiazepines
`Opioids
`
`Antipsychotics
`Vasoconstrictors
`(ie, migraine
`treatments)
`
`Following recent regulatory actions related to liver and ad-
`renal
`toxicity,“ ketoconazole should not be used to treat
`
`superficial fungal infections, including onychomycosis, under
`any circumstances.
`
`Topical Therapies
`With the recent approval of two new agents, available FDA-
`approved topical treatment options now include ciclopirox 8%
`nail
`lacquer, efinaconazole 10% solution, and tavaborole 5%
`solution.The rates of mycological cure, clinical cure, and com-
`
`plete cure observed in pivotal Phase 3 studies with these topical
`agents are summarized in Table 3.‘”'‘‘9 Note that these products
`were studied in different trials and conclusions regarding com-
`parative differences is not possible.
`
`Considerations for Treatment Choice
`
`Treatment choice may be based on causative agent, particular-
`ly differentiating between dermatophytes, yeasts, and molds,
`though in practice some patients begin treatment without my-
`cologic disease confirmation.
`In vitro antifungal activities, as
`measured by minimally inhibitory concentration (M|C),5°'53 are
`predictive (but not definitive) of clinical success (low MIC val-
`ues) or failure (higher MIC values). (Figure 1)
`
`This rnaterial was copied
`at the N LM a m:I may be
`Su bjeezt US {ie:»;:ry‘right Laws
`
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`

`226
`
` JOURNAL OF DRUGS IN DERMATOLOGY
`T. Rosen, S. F. Friedlander, L. Kircik, et :11.
`MARCH 2015 - VOLUME 14 -
`Issue 3
`
`
`
`FIGURE 1. MIC Values for Fluconazole,“ Tavaborole,5"52 Ciclopirox,5’v53 ltraconazo|e,53 Terbinafine,“ and Efinaconazole.53
`
`Dermatophytes“
`
`Nondermatophyte Molds”
`
`Yeasts/Ctmdida°
`
`.
`0
`I
`
`0
`
`100 ‘I
`
`0
`3
`
`10 J .
`
`E
`\
`$2;
`E
`
`1 1
`
`01
`
`0.01 -'
`
`0001 J
`
`8
`9
`
`.
`i
`o
`
`0
`0
`u
`o
`0
`
`0
`
`o
`0
`O
`0
`
`100 -l 0
`
`10 "
`
`1 "I
`
`0.1 ‘I
`
`0.01
`
`-|
`0.001 '
`
`0
`
`0
`3
`Q
`
`0
`.
`
`0
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`\%
`o"?\@ 0’°¢°\ -0'50 0°’?
`0'99 ~<>°‘°
`0°69 6°06, g°Q\‘ 0°69 '\°%Q 0°01?
`o
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`vs‘
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`c,
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`<.
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`/3} 6&0“
`<<\\>
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`/\° <30”
`<35
`3 T. rubrum, 7." mentagrophytes, E. floccosum, I tonsurans, M. gypseum, M. canis
`” A. fumigatus, /-T so/an/', A. potron/i, A. so/erot/genum, A. sydow//', S. brev/cau/is
`0 C. a/b/cans, C. neoformans, C. paraps//osis, C. rrop/ca//s, C. /<ruse/, C. g/abrata
`
`100 1
`
`J
`
`10
`
`1
`
`o
`
`.
`9
`.
`
`0.1 ‘I
`
`001 J
`
`0,001 J
`
`°
`0
`0
`
`0
`.
`.
`0
`
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`0
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`
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`
`3
`
`e
`0
`o
`Q
`Q
`
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`\o°\‘o 0'99 -0""§ 0&0
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`4%
`0 <60“
`«cf é\¢2>°
`Q0“
`
`
`
`Mycological Cure
`
`(negative microscopy [KOH] and negative culture)
`Clinical Cure
`
`29.35% VS 9.11%
`
`31_35 vs 742%
`
`55% V5 17%
`
`(some nail involvement and mycological cure, not defined consistently)
`Complete Cure
`
`7-12% vs 1%l=
`
`25.23% V5 9.15%b
`
`23% vs 8%c
`
`6.9% VS 04%
`(0% nail involvement and mycological cure)
`‘’ due to differences in study design, direct comparison between agents is not possible
`" ’almost complete cure‘ (s10% nail involvement and mycologic cure)
`" ‘almost complete cure’ (<5% nail involvement and mycologic cure)
`
`7_9% Vs 1_2%
`
`19% VS 5%
`
`Overall, the evidence to date supports the use of topical treatment
`for patients with mild—to-moderate onychomycosis.There is inter-
`est in considering topical therapy for maintenance/preventative“
`or booster therapy,“ though this has yet to be formally studied.
`
`ticular challenge. Little clinical data are available about the
`prevalence or treatment of these infections, but both terbi~
`
`nafine“ and itraconazo|e63 have proven effective in treating
`mixed nondermatophyte-dermatophyte infections.
`
`ln pediatric patients, topical therapy may be particularly effective
`due to faster nail growth and thinner nails,“ and parents certainly
`
`Whether the newer topical agents can treat severe onychomy~
`cosis as monotherapy has not been determined.
`
`may appreciate that topical therapy does not require laboratory
`monitoring. In addition, early topical treatment, instituted when
`the disease is still mild, may alleviate the necessity for systemic
`
`therapy, and may also prevent permanent nail plate alterations.
`
`For patients with severe onychomycosis and/or poor prognosis
`factors,7 oral treatment or combination oral-topical treatment
`
`may be most approprlate.57"" Mixed infections present a par-
`
`fcoNc~:LUsIoN§
`
`Our understanding of the epidemiology and optimal treat-
`ment ofonychomycosis continues to evolve. As the population
`ages and other high-risk groups expand (diabetes, PVD), the
`prevalence of onychomycosis is expected to increase. Current
`research suggests that prevalence may also be increasing
`among pediatric patients and confirms that psoriasis is a
`
`This material was to-pied
`at the NLM and may be
`Su.l:ljes:t.‘ UE {lo-pzyrigrht Laws
`
`CFAD V. Anacor, |PR2015-01776
`ANACOR EX. 2161 - 5/7
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`.
`
`CFAD v. Anacor, IPR2015-01776
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`

`

` JOURNAL or DRUGS IN DERMATOLOGY
` T. Rosen, S. F. Friedlander, L. Kircik, ct al.
`MARCH 2015 - VOLUME 14 -
`ISSUE 3
`
`227
`
`In the past, treat-
`significant risk factor for onychomycosis.
`ment options have been limited by safety concerns (systemic
`treatments) and/or lack of proven efficacy (ciclopirox,
`laser
`therapy, PDT). Recent FDA approvals of two new topical treat-
`ments with higher cure rates, tavaborole and efinaconazole,
`have expanded available therapeutic options for those with
`mild-to-moderate disease, and those who cannot use or prefer
`not to use systemic therapy.
`
`
`
`-*A'cKNoWLED'GMEN:1“i1
`The content of this article is based on the proceedings of a
`roundtable meeting attended by each of the authors, held
`January 27, 2014 in Maui, HI, and sponsored byValeant Pharma-
`ceuticals North America LLC (Bridgewater, NJ). All manuscript
`content was developed independent of funding source. Prescott
`Medical Communications Group (Chicago,
`IL) assisted with
`preparation of the manuscript at the direction of the authors
`with financial support from Valeant.
`
`=DISGL'OSURESE
`
`Theodore Rosen has received financial compensation for
`his work as a consultant and Advisory Board member for
`Valeant Pharmaceuticals North America LLC and Anacor
`Pharmaceuticals, Inc.
`
`Sheila Fallon Friedlander has received financial compensation
`for her work as a consultant and Advisory Board member for
`Valeant Pharmaceuticals North America LLC.
`
`Leon Kircik has served as an investigator for Valeant Pharma-
`ceuticals International, Medicis Pharmaceutical Corporation
`(now part of Valeant), Coria Laboratories, Ltd. (now part of
`Valeant), Obagi Medical Products, Inc. (now part of Valeant),
`Dow Pharmaceutical Sciences,
`Inc (now part of Valeant),
`Anacor Pharmaceuticals, Inc. and Novum Pharmaceutical Re-
`search Services. He has also received financial compensation
`for his work as a consultant, Advisory Board member, and/or
`Speakers Bureau member for Valeant Pharmaceuticals North
`America LLC, Valeant Pharmaceuticals International, Dermik
`Laboratories, Inc (now part ofVa|eant),Anacor, and Merz Phar-
`ma. He also holds stock in Johnson & Johnson.
`
`Linda Stein Gold has served as an investigator for Leo Pharma
`Inc., Galderma Laboratories, L.R, and Novartis Corporation. She
`has received financial compensation for her work as a consul-
`tant, Advisory Board member, and/or Speakers Bureau member
`from Valeant Pharmaceuticals North America LLC, Leo, Galder-
`ma, Novartis, Eli Lilly and Company, Pfizer Inc., GlaxoSmithKline
`plc,Taro Pharmaceutical Industries Ltd., and Allergan, Inc.
`
`Matthew Zirwas has received financial compensation for his
`work as consultant and Advisory Board member for Valeant
`Pharmaceuticals North America LLC.
`
`Neal Bhatia has received financial compensation for his work as
`a consultant and Advisory Board member for Valeant Pharma-
`ceuticals North America LLC and Anacor Pharmaceuticals, Inc.
`
`Aditya Gupta has been a clinical trials investigator for Valeant
`Canada, Bristol Meyers Squibb, Eli Lilly and Company, Merck &
`Co., Inc., Novartis Pharmaceuticals Canada Inc., Janssen Phar-
`maceuticals, lnc., and Allergan, Inc. He has received financial
`compensation for his work as Speakers’ Bureau member for
`Valeant Canada and Bayer Inc.
`
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`survey of 15,000 patients. J Am Acad Dermatol. 2000;43:244-248.
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`This material was copied
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`CFAD v. Anacor, |PR2015-O1776
`ANACOR EX. 2161 - 6/7
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`CFAD v. Anacor, IPR2015-01776
`ANACOR EX. 2161 - 6/7
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`

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`JOURNAL OI‘ DRUGS IN DERMATOLOGY
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