IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`COALITION FOR AFFORDABLE DRUGS X LLC,
`Petitioner,
`
`ANACOR PHARMACEUTICALS, INC.,
`Patent Owner.
`
`Case No. IPR201 5-01776
`Patent No. 7,582,621
`
`DECLARATION OF HOWARD I. MAIBACH, M.D., PH.D., IN SUPPORT
`OF PATENT OWNER RESPONSE PURSUANT TO 37 C.F.R. § 42.120
`
`CFAD v. Anacor, |PR201 5-01776 ANACOR EX. 2037 - ‘I/33
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`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2037 - 1/33
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`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`COALITION FOR AFFORDABLE DRUGS X LLC,
`Petitioner,
`
`ANACOR PHARMACEUTICALS, INC.,
`Patent Owner.
`
`Case No. IPR201 5-01776
`Patent No. 7,582,621
`
`DECLARATION OF HOWARD I. MAIBACH, M.D., PH.D., IN SUPPORT
`OF PATENT OWNER RESPONSE PURSUANT TO 37 C.F.R. § 42.120
`
`CFAD v. Anacor, |PR201 5-01776 ANACOR EX. 2037 - ‘I/33
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`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2037 - 1/33
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`IPR2015—01776
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`I.
`
`Background ................................................................................................... .. 5
`
`A.
`
`B.
`
`Onychomycosis and Its Treatment ..........................................
`
`......... .. 5
`
`The Anacor Patents ............................................................................. .. 8
`
`1.
`
`The ’621 Patent................................. .. ...................................... .. 8
`
`II.
`
`Discussion ..................................................................................................... .. 9
`
`Long—Felt Need ................................................................................. .. 10
`
`I 1.
`
`Oral Treatments ........................................................................ 10
`
`2.
`
`3.
`
`4.
`
`Laser Treatments, Surgery, Nail Avulsion, and
`Debridement Are Not Solutions for Onychomycosis
`Treatment ...... .. ........................................................................ .. 15
`
`_
`Topical Treatments Available Prior to the Patented
`Inventions ............................................................................... .. 17
`
`The Need for an Effective Topical Treatment with High
`Patient Acceptance ......................... .. ...................................... .. 21
`
`B.
`
`C.
`
`Failure of Others ...... ..; ....................................................... ., ............. .. 24
`
`Tavaborole Met the Long—Felt Need for a Safe and Effective I
`Topical Treatment with High Patient Acceptance and Received
`Praise for its Success in Doing So .................................
`................. .. 27
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`
`I, Howard I. Maibach, hereby declare as follows:
`
`1.
`
`I received B.A. and M.D. degrees at Tulane University, and honorary
`
`Ph.D. and MD. degrees from L’Université de Paris-Sud in Paris, Université
`
`Claude Bernard in Lyon, Université de Franche—Comté in Besangon, and the
`
`University of Southern Denmark.
`
`2.
`
`I completed my internship at the William Beaumont Army Hospital in
`
`El Paso and on—the—j ob training in neurology and psychiatry at the Walter Reed
`
`Army Hospital in Washington, DC.
`
`I then practiced neurology_and psychiatry in
`
`the U.S. Army. My military service was followed by a residency in dermatology
`
`and a National Institutes of Health research fellowship at the University of
`
`Pennsylvania Hospital. I joined the faculty at the University of Pennsylvania
`following my residency and fellowship, and in 1961 moved to the University of
`
`California Medical School—San Francisco (“UCSF”), where I am currently a
`
`professor.
`
`3.
`
`On arriving at UCSF, I initiated laboratory and clinical investigation
`
`into skin physiology, pharmacology, and toxicology. Our laboratory focuses on
`
`penetration of chemicals through skin and, more recently, through nails——in both
`
`humans, experimental animals, and in test-tube surrogates of the former (in vitro
`
`penetration).
`
`1
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`4.
`
`I have been treating patients with dermatological conditions, including
`
`onychornycosis, since 1961. One of my first research endeavors involved the use
`
`of griseofulvin (the first oral antifungal indicated for treatment of onychomycosis).
`
`I have founded several clinics, including a psoriasis clinic in which some patients
`
`had fungal disease of the nail.
`
`.
`
`5.
`
`From approximately 1962 to 1995, I was the volunteer dermatologist
`
`for male prisoners in northern California state prisons. Once a vveek, I traveled to
`
`the California Medical Facility and examined inmate patients. Many of these
`
`patients had onychomycosis. During the course of my career, I have treated many
`
`hundreds of patients with onychomycosis. In addition to treating patients, I have
`
`led and participated in many clinical trials of onychomycosis therapies.
`
`I still see
`
`patients regularly at UCSF.
`
`6.
`
`The psoriasis clinic I founded treats patients with psoriasis with and
`
`without nail involvement. The clinic offered outpatient treatment of skin diseases,
`
`and included a large in-patient service at UCSF.
`
`I also founded and acted as chief
`
`of the UCSF Patch Test Clinic and an occupational dermatology clinic.
`
`I
`
`encountered (and continue to encounter) patients with onychomycosis at these
`
`clinics.
`
`2
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`7.
`
`Today, I work as a tertiary care consultant.
`
`I see onychomycosis
`
`patients in that work, too. I also direct laboratory work, including some of the
`
`work referred to in this Declaration.
`
`8.
`
`I have authored and co-authored over one thousand published chapters
`
`and articles. Ialso have authored, co-authored, and edited approximately eighty-
`
`five published books, including Topical Nail Products and Ungual Delivery with
`
`Dr. Narasimha Murthy and the Handbook ofSystemic Drug Treatment in
`
`Dermatology with Dr. Sarah Wakelin and Dr. Clive Archer.
`
`9.
`
`I have consulted with and performed studies for many pharmaceutical
`
`companies in connection with potential treatments for onychomycosis, including
`
`the following.
`
`10.
`
`I performed pre—clinical studies for Novartis~—over several years-
`
`while that company attempted to develop a topical onychomycosis treatment using
`
`a formulation with terbinafine, an oral onychomycosis medication.
`
`1 1.
`
`I performed pre—clinical studies for Power Paper Limited, and was a
`
`consultant in Power Paper’s attempted development of an iontophoretic-based
`
`topical antifimgal treatment.
`
`12.
`
`I performed pre—clinical studies and acted as a consultant for Topica in
`
`their development of a topical onychomycosis therapy.
`
`3
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`13.
`
`I performed pre-clinical studies and acted as a consultant for Meiji
`
`Seika Pharma in their development of a topical onychomycosis therapy.
`
`14.
`
`I was involved in the pre-clinical studies and consulting work relating
`
`to Anacor’s development of tavaborole.
`
`15. A current Curriculum Vitae and bibliography that summarizes the
`
`current state of my experience are attached as Exhibit 2031.
`
`16.
`
`I have reviewed the Petitions for Inter Partes Review of U.S. Patent
`
`Nos. 7,767,657 and 7,582,621 filed by Coalition for Affordable Drugs X LLC,
`
`including.Dr. Murthy’s Declaration and Dr. Kahl’s Declaration, as well as the
`
`exhibits and articles cited in those documents. I have also reviewed the articles
`
`and documents cited in this Declaration.
`
`17.
`
`For my work on thiscase, I am compensated at my usual and
`
`customary hourly rate for expert services. My compensation is not dependent on
`
`the opinions I give or on the outcome of this case.
`
`4
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`IPR2015-01776
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`I.
`
`Background
`
`A.
`
`Onychomycosis and Its Treatment
`
`18. Onychomycosisl is a fungal infection of the nail plate and sometimes
`
`the nail bed. (Murdan, Ex. 2041 at 20; Roberts, Ex. 2158 at 1.) Onychomycosis
`
`affects approximately 10% of the population or more. (Murdan, Ex. 2041 at 20;
`
`Roberts, Ex. 2158 at 1; Jinna & Finch, Ex. 2060 at 6185; Vlahovic eta1., Ex. 2159
`
`at 2.) Millions of Americans suffer from onychomycosis. (Gupchup & Zatz, Ex.
`
`2054 at 363.)
`
`19. Onychomycosis is caused by fungi. In 90-95% of cases, those fiingi
`
`are dermatophytes, most commonly Trichophyron rubrum. i(Murdan, Ex. 2041 at
`
`20.) In less than 5% of onychomycosis patients, Candida albicans, a yeast-like
`
`fungus, is the cause of the onychomycosis.2 (Freedberg eta1., Ex. 2160 at 2001.)
`
`I The word “onychomycosis” comes from the Greek words onyx (nail) and mykes
`
`(fungus).
`
`2 Even this low number of onychomycosis cases caused by Candida may be
`
`exaggerated. (Summerbell, Ex. 2186 at 33.) Candida occurs naturally in the
`
`environment, and it exists in the gastrointestinal tract. In many instances, Candida,
`
`a common fllngus, may have been present as a contaminant and not the pathogen
`
`causing the onychomycosis. (Baran et al., Ex. 2053 at 33, 68)
`
`5
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`Candida is especially rare as the cause of toenailonychomycosis. (Del Rosso, Ex.
`
`2164 at 11.).
`
`20.
`
`The incidence of onychomycosis may be increasing, perhaps spurred
`
`by a growing elderly population and the role of HIV and AIDS, among other
`
`things. (Murdan, EX. 2041 at 20; Tom & Kane, Ex. 2162 at 865; Jinna & Finch,
`
`Ex. 2060 at 6185.)
`
`21. Dnychomycosis can have a serious impact on patients—physically
`
`and psychologically. The dystrophic nails the disease causes can be unsightly,
`
`painful, and lead to serious complications if left untreated, including toe and finger
`
`deformities. The risk is greater in diabetic patients, where onychomycosis can lead
`
`to diabetic foot and necessitate amputations. (Rosen et al., Ex. 2161 at .223-—224.)
`
`Onychomycosis can cause anxiety, depression, and an overall decrease in quality
`
`of life. (Stier et al., Ex. 2163 at 521; Del Rosso, Ex. 2164 at 10.) As Dr. Wang
`
`and Dr. Sun state, the psychological toll onychomycosis takes can be “profound.”
`
`(Wang & Sun, Ex. 2165 at 72.)
`
`22. Dermatologists, podiatrists, general-practice physicians, and other
`
`healthcare workers, such as nurse practitioners, treat onychomycosis. The best
`
`practice when onychomycosis is suspected is for the treating physician to take a
`
`sample of the nail for laboratory confirmation. (Ameen et al., Ex. 2166 at 942;
`
`Baran et al., Ex. 2053 at 28.) Though the sample can be examined under a
`
`6
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`IPR2015—01776
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`microscope immediately, lab cultures are used to confirm the diagnosis, even when
`
`microscopy is negative, and identify the specific organism. (Baran et a1., Ex. 2053
`
`at 31.) These lab cultures can take three to six weeks to complete. (Baran et a1.,_
`
`Ex. 2053 at 31.) Because some patients seek immediate treatment and some
`
`physicians are confident in their ability to diagnosis onychomycosis without
`
`confirmatory testing, many healthcare workers forgo testing samples from affected
`
`nails in the lab before initiating treatment. (Vlahovic et al., Ex. 2167 at 155-156.)
`
`23.
`
`In those instances, the healthcare worker will perforce be treating the
`
`dystrophic nail empirically, i.e., without knowing with the relative certainty of
`
`laboratory testing that the patient has onychomycosis or the precise fungal species
`
`responsible for the probable infection.
`
`24. Additionally, it is my experience that healthcare workers prefer
`
`treatments that will be effective against the major pathogens causing a particular
`
`disease rather than
`
`agent that will only be effective against a particular
`
`pathogen. That is especially the case if the particular pathogen is one that is
`
`seldom encountered. This preference stems from the fact that it is easier to obtain
`
`comfort and familiarity with the profile of an agent that will be prescribed" on a
`
`regular basis than one that is prescribed only rarely.
`
`25. A treating healthcare worker in 2005 would have had little interest in
`
`an agent that would only be effective against, for example, Candida albicans,
`
`7
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`IPR20 15-01776
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`which is responsible for less than 5% of onychomycosis cases. (Freedberg et al.,
`
`_ Ex. 2160 at 2001.) Similarly, in my experience, pharmaceutical companies
`
`seeking to develop antifungals for treating onychomycosis are interested in
`
`antifungals that are useful in treating most cases of onychomycosis, not just those
`
`caused by pathogens responsible for only a minute percentage of cases.
`
`26. Onychomycosis remains persistent in part because it is a difficult
`
`disease to clear completely. Before 2005, topical treatments were largely
`
`ineffective due to their inability to reach and kill the fungal organisms in and
`
`through the nail plate. (Gupchup & Zatz, Ex. 2054 at 364.) Even when treatment
`
`is successful, relapse is common. (Elkeeb et al., Ex. 2055 at 2; Gupta & Paquet,
`
`Ex. 2168 at 555.)
`
`27.
`
`Tavaborole is an oxaborole antifungal with the chemical name 5-
`
`fluoro—l ,3—dihydro-1-hydroxy—2,1-benzoxaborole. The chemical formula is
`
`C-,H6BFO2. (Ex. 2001 at 4.)
`
`B.
`
`The Anacor Patents
`
`28.
`
`I understand that Anacor’s U.S. Patent No. 7,582,621 (“the ’62l
`
`patent”) is involved in this proceeding.
`
`1.
`
`The ’621 Patent
`
`29.
`
`The ’621 patent has 12 claims. I understand that all 12 claims are at
`
`issue.
`
`8
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`IPR201 5—0l776
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`30.
`
`In general, the claims of the ’62l patent recite methods of treating an
`
`infection, including onychomycosis, using 1,3-dihydro-5—fluoro-1-hydroxy-2,1-
`
`benzoxaborole (i.e., tavaborole), at different sites on the body, including at the nail. _
`
`31.
`
`Claim 1 of the ’621 patent recites:
`
`1. A method of treating an infection in an animal, said method
`
`comprising administering to the animal a therapeutically effective
`
`amount of 1,3 —dihydro~5—fluoro~l—hydroxy—2,l—benzoxaborole, or a
`
`pharmaceutically acceptable salt thereof, sufficient to treat said
`
`infection.
`
`32.
`
`The dependent claims of the ’621 patent add further limitations on the
`
`method of treatment. Claim 8, for example, recites that the administration site is
`
`the nail, among other places.
`
`II.
`
`Discussion
`
`33.
`
`I understand that the Petitioner contends that the inventions claimed in
`
`the ’62l patent would have been obvious.
`
`I disagree, and believe that the non-
`
`obviousness of the claims is demonstrated by objective evidence, including a long-
`
`felt need for the inventions, praise for the inventions, and failures of others to make
`
`the claimed inventions.
`
`34. As discussed further below, there was a long-felt need for a safe and
`
`effective topical onychomycosis treatment in the decades before 2005. Anacor
`
`filled that need with the inventions of its tavaborole treatment, known
`
`9
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`IPR201'5-01776
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`commercially as KERYDIN®. Moreover, at least seven other companies have tried
`
`and failed to develop safe and effective topical onychomycosis treatments. Finally,
`
`since Anacor launched its tavaborole product, it has been the subject of well-
`
`deserved praise within the field.
`
`35.
`
`I understand that, for this objective evidence to be relevant to non-
`
`obviousness, the evidence must have a “nexus” to the claimed inventions. In my
`
`opinion there is such a nexus, as discussed below.
`
`A.
`
`Long-Felt Need
`
`36. Before tavaborole, there was a need for a safe and effective topical
`
`treatment for onychomycosis because of problems with the available oral
`
`treatments and with the available topical treatments.
`
`1.
`
`Oral Treatments
`
`37.
`
`Oral treatments for onychomycosis had serious flaws at the time of
`
`the inventions in 2005. Chief among those problems were contraindications,
`
`adverse reactions, drug-drug interactions, and patient aversion to taking oral
`
`medications.
`
`38.
`
`The problems discussed here were exacerbated by the fact that the
`
`typical course of treatment using oral onychomycosis drugs is long; for example,
`
`terbinafine, the leading systemic onychomycosis treatment, is taken once daily for
`
`twelve weeks to treat toenail onychomycosis. (Ex. 2075 at 8-9.)
`
`is
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`39.
`Oral onychomycosis treatments available at the time of the inventions
`had contraindications that limited their use. As described below, oral
`I
`
`onychomycosis medications are contraindicated for patients taking certain
`
`commonly prescribed drugs. Additionally, terbinafine was (and remains)
`
`contraindicated for patients with a history of hypersensitivity (Torn & Kane, Ex.
`
`2162 at 868.) And terbinafine was not recommended for nursing mothers.
`
`(Freedberg et al., Ex. 2160 at 2443; Daly et al., Ex. 2169 at 70.) Terbinaflne was
`
`also contraindicated for patients with decreased renal filnction or with pre-existing
`
`liver impairment. (Daly et al., Ex. 2169 at 69.)
`
`40.
`
`That patients were contraindicated for onychomycosis treatment in
`
`conjunction with certain other medications was especially troubling because
`
`onychomycosis is particularly prevalent among the elderly, who are more likely to
`
`take multiple prescription medications. A Centers for Disease Control study found
`that 39.1% ofpeople 65 or older had taken five or more different prescription
`
`medications in the previous thirty days, and that 89.8% of people 65 or older had
`
`taken at least one. (Ex. 2170 at 272.)
`
`41.
`
`Terbinafine and itraconazole—in 2005 the most commonly prescribed
`
`systemic medications indicated for treating nail infections—can cause serious and
`
`11
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`sometimes fatal liver failure.3 Though rare, patients taking oral onychomycosis
`
`medications have died from liver failure. (Song & Deresinski, Ex. 2179 at 174-
`
`175.) Given the grave hepatotoxicity concerns, physicians prescribing terbinafine
`
`are recommended to order a baseline liver-function test (LFT) and follow up LFTs
`
`every 4-6 weeks during treatment (Daly et al., Ex. 2169 at 68.) Similar
`
`recommendations exist for patients on a course of treatment of itraconazole lasting
`
`over a month. (Daly et al., Ex. 2169 at 60). Dr. Effendy described liver-function
`
`monitoring as a “necessity” for patients undertaking a course of oral
`
`onychomycosis treatment. (Effendy, Bx. 2171 at S7.)
`
`3 Griseofulvin, the first oral onychomycosis treatment to reach the market, was
`
`rarely prescribed after terbinafme reached the market in 1996. As Fitzpatrick’s
`
`Dermatology in General Medicine put it in 2003, “[g]riseofulvin is no longer
`
`considered standard treatment for onychomycosis because of its adverse effects,
`
`drug interactions, prolonged treatment course, and low cure rates.” (Freedberg et
`al., Ex. 2160 at 2603.) Griseofulvin still has the complications of other systemic
`
`antifiingals, including liver impairment necessitating liver—function tests, other
`
`adverse effects including gastrointestinal problems and blood disorders, and many
`
`contraindications. (Daly et al., Ex. 2169 at 68-74.)
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`12
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`42.
`
`Less serious side effects are more common. Ten percent of patients
`
`taking terbinafine reported adverse events, compared to 5% for placebo. (Effendy,
`
`-
`
`Ex. 2171 at S7.) The most common side effects were mild to moderate
`
`gastrointestinal discomfort and skin reactions such as rashes and urticaria (hives).
`
`(Effendy, Ex. 2171 at S7; Daly et al., Ex. 2169 at 69.) A loss oftaste is “not
`
`uncommon” in patients taking terbinafine; in some cases, it appears the loss of
`
`taste may be permanent. (Daly et al., Ex. 2169 at 69.)
`
`43.
`
`Drug—drug interactions also would have been of concern in
`
`onychomycosis treatment with oral medications. As Dr. Hay et al. described the
`
`problem, “potent systemic therapy is undesirable [for some patients] because of
`
`toxic effects or drug interactions.” (Hay et al-., Ex. 2047 at 147.) These risks
`
`necessitated close monitoring of patients taking oral onychomycosis medications
`
`and other drugs. (Daly et a1., Ex. 2169 at 59—75.)
`
`44.
`
`For example, terbinafine is contraindicated for patients taking some
`
`commonly prescribed medications, including cimetidine, rifampicin,
`
`phenobarbital, warfarin, nortopyline, and nicotinamide. (Hay et al., Ex. 2047 at
`
`150; Ex. 2075 at 6-7; Daly et al., Ex. 2169 at 66-70.)
`
`45.
`
`Itraconazole includes a blackybox safety warning on its label and is
`
`contraindicated for patients taking some commonly prescribed medications,
`
`including rifampicin, isoniazid, phenytoin, phenobarbital, carbamazepine, H2 '
`
`13
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`antagonists, antacids,'didanosine, anticholinergic drugs, warfarin, H1 antagonist
`
`terfenadine and astemizole, digoxin, alprazolam, triazolarn, midazolam, felodipine,
`fluoxetine, nifedipine, corticosteroids, methylprednisolone, cyclosporin A,‘
`
`cisapride, zidovudine, protease inhibitors, busulfan, vincristine, oral antidiabetic
`
`drugs, lovastatin, simavastain, quinidine, tacrolimus, antipryine, and potentially
`
`oral contraceptives. (Hay, Ex. 2047 at 150; Ex. 2074 at letter 1, 3-4, label 1, 10-
`
`21.)
`
`46. Another problem with oral onychomycosis treatments is that many
`
`people do not want to take tablets or capsules. In this case, the issue is exacerbated
`
`by the long treatment courses. Many people do not like the sensory aspects of
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`tablets and capsules, some have difficulty swallowing tablets and capsules, and
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`some are uncomfortable with a systemic treatment for a localized problem. For
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`oral onychomycosis medications in particular, there is the added inconvenience of
`
`needing to take liver-function tests throughout the course of treatment. (Effendy,
`
`Ex. 2171 at SS.) With that in mind, Dr. Effendy described the low acceptance by
`
`patients as a disadvantage of oral antifiangal therapy. (Effendy, Ex. 2171 at SS).
`
`Dr. Roberts also noted problems with patient compliance in taking oral
`
`onychomycosis medications. (Roberts, Ex. 2158 at 141.) As Dr. Gupchup and Dr.
`
`Zatz put it in 1999,
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`adverse effects combined with treatment times that extend to several
`
`months, and frequent incidences of relapses observed with oral
`
`antifungals, often lead to patient noncompliance and interruption of
`
`therapy. Thus, topical therapy is the most desirable, but it has met
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`with limited success to date.
`
`(Gupchup & Zatz, Ex. 2054 at 364.)
`
`47. Given the serious risk factors associated with oral onychomycosis
`
`medications, I do not recommend them for toenail onychomycosis. It is often not
`
`worth the risk of serious liver injury to treat a mild case of onychomycosis,
`
`particularly now that there are effective topical treatments on the market——-
`
`tavaborole, marketed as KERYDIN® and efmaconazole, marketed as JUBLIA®.
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`Before prescribing terbinafme or other systemic onychomycosis medications, I
`
`have a detailed conversation with my patients to ascertain that they understand the
`
`risks.
`
`2.
`
`Laser Treatments, Surgery, Nail Avulsion, and
`Debridement Are Not Solutions for Onychomycosis
`Treatment
`
`48. Onychomycosis treatments outside of topical and oral medications are
`
`problematic and are not widely used to treat onychomycosis. These problematic
`
`treatments include laser therapy, surgery, nail avulsion, and debridement. Because
`
`ofthe problems discussed below, these treatments did not obviate the need by 2005
`
`for a safe and effective topical onychomycosis medication.
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`49.
`
`Laser treatments and photodynamic therapies are FDA-approved to
`
`“temporarily improve the appearance of the nail,” with no claims regarding
`
`mycological cure. (Vlahovic, EX. 2180 at 6; Rosen et a1., Ex. 2161 at 225.) Thus,
`
`While some physicians now use laser treatments for aesthetic improvements, they
`
`are not recommended as a cure for onychomycosis. There is limited peer-reviewed
`
`clinical data supporting their use. (Rosen et al.. Ex. 2161 at 225; Vlahovic et al.,
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`Ex. 2167 at 158.)
`
`50.
`
`Removal of an afflicted nail by surgery or chemical avulsion (non-
`
`surgical removal) is also disfavored. (Vlahovic, Ex. 2180 at 7.) Surgery is painful
`
`and entails potential complications. (Tom & Kane, Ex. 2162 at 866.) It is
`
`generally not worth it. Dr. Baran et al. stated,
`
`Total surgical removal has to be discouraged: the distal nail bed may
`
`shrink and become dislocated dorsally. In addition, the loss of
`
`counter-pressure produced by the removal of the nail plate allows
`
`expansion of the distal soft tissue and the distal edge of the regrowing
`
`nail then embeds itself.
`
`"(Baran et al., Ex. 2053 at 49.) Even after the nail is removed (surgically or '
`otherwise), the area must be cleared and kept clean to make sure that the fllngi do
`
`not reappear. Dr. Vlahovic et al. wrote, “removal of the nail itself will not result in
`
`clearance of the infection, even when followed by topical antifungal therapy.”
`
`(Vlahovic, Ex. 2180 at 6.)
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`51. Debridement is the filing or trimming of the nail, which in theory
`
`allows the topical agent to reach the offending fungal elements. Debridement on
`
`its own, however, does nothing to cure onychomycosis because it does not actually
`
`treat the underlying cause of the diseasee—-the presence of fungi. (Vlahovic, Ex.
`
`2180 at 6.) Debridement can be a useful adjunct to oral or topical antifungals, but
`
`it is of little or no use alone. (Baran et al., Ex. 2053 at 47; Rosen et al., Ex. 2161 at
`
`225.)
`
`1
`
`3.
`
`Topical Treatments Available Prior to the Patented
`Inventions
`
`52. Given the problems with systemic and other treatments described
`
`above, at the time of the inventions there was a need for a safe and effective topical
`treatment for onychomycosis. PEN1.AC® (ciclopirox) was at that time the only
`
`topical onychomycosis treatment marketed in the U.S.4 (Bodman et al., Ex. 2172
`
`at 140.) Though safer than oral onychomycosis medications, ciclopirox did not
`
`meet this need because it is only marginally effective, as it appears that ciclopirox
`
`is, at best, only slightly better than placebo. (Effendy, Ex. 2171 at S8; Bennett &
`
`Plum, Ex. 2046 at 2214; Ex. 2077 at label 6-7.) Another medication, LOCERYL®
`
`(amorolfine), was available abroad, but there were similar doubts as to its efficacy,
`
`4 Ciclopirox remained the only approved topical onychomycosis treatment in the
`
`U.S. until the FDA approved tavaborole and efinaconazole in 2014.
`
`177
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`and it was not approved in the U.S. (Childs-Kean & Jourjy, Ex. 2061 at 26;
`
`Elewski et al., Ex._2045 at 290-291.)
`
`I 53.
`
`The FDA approved ciclopirox, but only after its advisory board
`
`questioned the drug’s efficacy. In particular, during the FDA’s application
`
`proceedings, members of the FDA’s Dermatologic and Ophthalmic Drugs
`
`Advisory Committee voiced concerns about ciclopirox’s low clinical efficacy. At
`
`a proceeding on November 4, 1999, committee member Dr.|O. Fred Miller, III
`
`stated,
`
`the efficacy [of ciclopirox] is limited to a very small subset [of
`
`patients]. .
`
`.
`
`. So we had six out of 186 patients who were clinically
`
`cure[d] at 12 and 24 weeks after the study was completed‘. That’s a
`
`very small subset.
`
`_(Ex. 2173 at 163-164.) Dr. Lynn A. Drake, the acting chairwoman of the
`
`committee, noted that f‘everybody” on the committee “understands it’s a small
`
`subset” of patients that might respond to ciclopirox. (Ex. 2173 at 161.) In the
`
`context of proceedings specifically for ciclopirox’s approval, a Special
`
`Government Employee Consultant from the National Institutes of Health noted “a
`
`great need” for safe and effective topical treatments in the field:
`
`We do not have any demonstrated effective topical therapy. So I
`
`think there will be a great need for this, for one that would be
`
`effective in a large percentage of patients.
`
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`I believe that the studies here demonstrate efficacy, but again only in a
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`small percentage of patients.
`
`(Ex. 2173 at 166.)
`
`54.
`Though many in the field hoped that ciclopirox would prove an
`effective topical treatment for onychomycosis, it quickly became apparent that
`
`ciclopirox was only marginally effective. As early as l995—based on its use in
`
`other countries and trials in the U.S.—physicians thought that ciclopirox would not
`
`come close to meeting their obj ectives for a topical onychomycosis treatment. Dr.
`
`Effendy wrote that ciclopirox “should only be chosen for treatment of superficial
`
`and minor subungual onychomycosis.” (Effendy, Ex. 2171 at S8.) The 1996
`
`edition of Cecil’s Textbook of Medicine concluded that “[t]opical antifungal
`
`therapy is ineffective [for onychomycosis].” (Bennett & Plum, Ex. 2046 at 2214.)
`
`Petitioner’s 2003 Freeman reference states that ciclopirox and other topical
`
`antifungals “proved to be generally ineffective against fungal infections of the nails
`
`because of their inability to penetrate the entire nail unit and eradicate the
`
`infection.” (Freeman, Ex. 1004 at 1] 0010.)
`
`55. Another drawback of ciclopirox is that its complicated application
`
`impedes patient compliance. Ciclopirox is a lacquer, like a nail polish. A patient
`
`using ciclopirox must apply the lacquer daily, at least eight hours before bathing or
`
`showering. (Ex. 2077 at label 11, 15.) In addition, every seven clays the patient
`
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`must also file away any loose nail material with an emery board. (Ex. 2077 at
`
`label 11, 15.) Patients must also remove the lacquer from their nails with alcohol
`
`I weekly. (Ex. 2077 at label 15.) It should also be noted that onychomycosis is
`
`more common in older patients, some of whom have difficulty debriding their
`
`onycholytic nails and applying a lacquer. Further, the patient’s healthcare worker
`
`must, as frequently as monthly, trim the onycholytic nail and file any excess horny
`
`material. (Ex. 2077 at label 11.) Hence, ciclopirox is difficult to use, is indicated
`
`only as a component of a comprehensive nail treatment program and, as a
`
`consequence, patient compliance suffers. (Vlahovic et al., Ex. 2167 at 157.)5
`
`56.
`
`Researchers later attempted to improve the efficacy of available
`
`topical agents with permeation enhancers such as urea ointment. (Bodman, Ex.
`
`2172 at 137.) These attempts yielded little in the way of practical results.
`
`5 7. Given these problems with ciclopirox, the need for a safe and
`
`effective topical treatment for onychomycosis remained.
`
`5 As discussed below, tavaborole is much simpler and easier to use. It is a liquid.
`
`The patient simply uses an eye dropper to drop tavaborole on affected nails once
`
`daily. (Ex. 2001 at 8-10.) There are no other restrictions or requirements for use,
`
`other than letting the nail dry for “a couple of minutes.” (Ex. 2001 at 10.)
`
`20
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`58. Amorolfine, a topical onychomycosis treatment, was available in _
`
`other countries, but did not meet the need for a safe and effective topical treatment.
`
`Itis only marginally effective: a 2011 study using 5% arnorolfine formulation
`
`reported a complete cure rate of under 1%. (Elewski et al., Ex. 2045 at 290-291.)
`
`The 5% amorolfine formulation is the only strength currently available. (Childs-
`
`Kean & Jourjy, Ex. 2061 at 25.) Dr. Childs-Kean and Dr. Jourjy described the
`
`efficacy rate of amorolfine monotherapy as “not optimal.” (Childs-Kean & Jourjy,
`
`Ex. 2061 at 26.) Amorolfine was never approved in the U.S.
`
`59.
`
`Finally, there are numerous topical over-the-counter and home -
`
`remedies that patients try, including foot soaks with bleach, vinegar, or hydrogen
`
`peroxide; salicylic acid; mentholated vapor rub; and tea tree oil. Given the
`
`difficulties in delivering medication through the nail plate and curing
`
`onychomycosis, it would not have been s
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