Served on behalf of Petitioner COALITION FOR AFFORDABLE DRUGS X LLC
`
`By: Jeffrey D. Blake, Esq.
` MERCHANT & GOULD P.C.
`
`191 Peachtree Street N.E., Suite 3800
` Atlanta, GA 30303
`
`jblake@merchantgould.com
` Main Telephone: (404) 954-5100
` Main Facsimile: (404) 954-5099
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________
`
`
`
`COALITION FOR AFFORDABLE DRUGS X LLC,
`Petitioner,
`
`v.
`
`ANACOR PHARMACEUTICALS, INC.,
`Patent Owner.
`___________________
`
`Case IPR2015-01776 (Patent 7,582,621 B2)
`____________________
`
`PETITIONER’S REPLY TO PATENT OWNER’S RESPONSE
`
`
`
`
`
`

`
`TABLE OF CONTENTS
`
`I. 
`
`II. 
`
`INTRODUCTION ........................................................................................... 1 
`
`BORON-CONTAINING COMPOUNDS WERE NOT CONSIDERED
`TOXIC AS OF FEBRUARY 16, 2005 ........................................................... 3 
`
`A. 
`
`B. 
`
`C. 
`
`The Inventors Of The ’621 Patent And PO’s Founders Did Not
`Believe Boron Was Toxic Before 2005 ................................................ 5 
`
`The Inventors Of The ’621 Patent Confirmed There Was No
`Reason To Suspect Boron Was Toxic In 2005 ..................................... 5 
`
`The Prior Art Is Consistent With PO’s Admissions Concerning
`The Non-Toxicity Of Boron .................................................................. 7 
`
`D. 
`
`Tavaborole Is Administered Topically .................................................. 9 
`
`III.  AUSTIN IS RELEVANT ART ...................................................................... 11 
`
`A. 
`
`B. 
`
`C. 
`
`The Inventors Of The ’621 Patent Rely On Austin As Relevant
`Prior Art In Their Scientific Paper ...................................................... 11 
`
`PO’s Expert Agrees That Cited References Are Relevant .................. 12 
`
`Three Different Patent Examiners Cited Austin As Relevant Art ....... 12 
`
`D.  Allegations Of Boron’s “Promiscuous” Behavior Are Irrelevant ....... 12 
`
`IV.  TAVABOROLE IS THE PREFERRED COMPOUND OF AUSTIN .......... 14 
`
`V. 
`
`THERE IS A REASONABLE EXPECTATION OF SUCCESSFUL
`ACTIVITY AGAINST DERMATOPHYTES .............................................. 16 
`
`VI.  LOW MOLECULAR WEIGHT AND MIC VALUES PROVIDE A
`REASONABLE EXPECTATION OF SUCCESS IN TREATING
`ONYCHOMYCOSIS .................................................................................... 17 
`
`VII.  BREHOVE AND FREEMAN ARE PRIOR ART FOR ALL THEY
`DISCLOSE .................................................................................................... 21 
`
`A. 
`
`Brehove Discloses The Successful Treatment Of
`Onychomycosis ................................................................................... 21 
`
` i
`
`
`

`
`B. 
`
`Freeman Recommends Treating Onychomycosis With Boron-
`Containing Compounds ....................................................................... 22 
`
`VIII.  THERE IS NO CREDIBLE EVIDENCE OF SECONDARY
`CONSIDERATIONS OR THE NECESSARY NEXUS .............................. 23 
`
`IX.  PO’S ATTACKS ON PETITIONER’S EXPERTS ARE BASELESS ........ 28 
`
`X. 
`
`CONCLUSION .............................................................................................. 28 
`
` 
`
`  
`
` ii
`
`
`

`
` 
`
`TABLE OF AUTHORITIES
`
` Page(s)
`
`Cases
`
`Allergan, Inc. v. Sandoz Inc.,
`726 F.3d 1286 (Fed. Cir. 2013) .......................................................................... 25
`
`Alza Corp. v. Mylan Labs., Inc.,
`464 F.3d 1286 (Fed. Cir. 2006) .............................................................. 20, 21, 22
`
`Bone Care Int’l, L.L.C. v. Roxane Labs., Inc.,
`No. 09-cv-285, 2012 U.S. Dist. LEXIS 80450 (D. Del. June 11,
`2012) ..................................................................................................................... 6
`
`In re Brana,
`51 F.3d 1560 (Fed. Cir. 1995) ............................................................................ 25
`
`CFAD v. Anacor,
`IPR2015-01780, Paper 24 (PTAB Feb. 23, 2016) .............................................. 26
`
`Cubist Pharms., Inc. v. Hospira, Inc.,
`805 F.3d 1112 (Fed. Cir. 2015) .......................................................................... 24
`
`Galderma Labs., L.P. v. Tolmar, Inc.,
`737 F.3d 731 (Fed. Cir. 2013) ............................................................................ 24
`
`Janssen Pharmaceutica N.V. v. Teva Pharms. USA, Inc.,
`583 F.3d 1317 (Fed. Cir. 2009) .......................................................................... 27
`
`KSR Int’l Co. v. Teleflex Inc.,
`127 S. Ct. 1727 (2007) ........................................................................................ 28
`
`Medtronic Inc. v. NuVasive Inc.,
`IPR2014-00087, Paper 44 (PTAB April 3, 2015) .............................................. 26
`
`Merck & Cie v. Gnosis S.p.A.,
`808 F.3d 829 (Fed. Cir. 2015) ............................................................................ 23
`
`Merck & Co., Inc. v. Biocraft Labs., Inc.,
`874 F.2d 804 (Fed. Cir. 1989) ...................................................................... 21, 22
` iii
`
`
`

`
`Pfizer, Inc. v. Apotex, Inc.,
`480 F.3d 1348 (Fed. Cir. 2007) .......................................................................... 20
`
`PharmaStem Therapeutics, Inc. v. ViaCell, Inc.,
`491 F.3d 1342 (Fed. Cir. 2007) .................................................................... 21, 22
`
`Syntex (U.S.A.) LLC v. Apotex, Inc.,
`407 F.3d 1371 (Fed. Cir. 2005) ............................................................................ 6
`
`Statutes
`
`35 U.S.C. § 112 ........................................................................................................ 26
`
`Other Authorities
`
`37 C.F.R. § 42.6(e) ................................................................................................... 31
`
`37 C.F.R. § 42.24(a) ................................................................................................. 30
`
`37 C.F.R. § 42.24(a)(1)(i) ........................................................................................ 30
`
`37 C.F.R. § 42.24(d) ................................................................................................ 30
`
`  
`
` iv
`
`
`

`
`IPR2015-01776
`Patent 7,582,621
`Petitioner Reply To PO Response
`
`INTRODUCTION
`
`I.
`
`Claims 1-12 of U.S. Patent No. 7,582,621 (the “’621 patent”) are
`
`unpatentable as obvious. Tavaborole was a known compound with known
`
`antifungal activity against a known cause of onychomycosis (Austin). Other boron-
`
`containing cyclic compounds were effective in vitro against the same or similar
`
`causes of onychomycosis (Brehove or Freeman) and safely administered in vivo to
`
`treat onychomycosis (Brehove). The prior art and Petitioner’s experts furnished
`
`several persuasive reasons to combine Austin with Brehove or Freeman.
`
`Patent Owner’s (“PO”) response does not change these facts, but seeks to
`
`obscure them with four expert declarations and over two-hundred exhibits. PO’s
`
`arguments, however, are directly contradicted by its own scientific papers, patents,
`
`and experts.
`
`Boron is safe for topical administration. While PO alleges that boron was
`
`considered toxic in 2005, its expert concluded in 1998 that a human could safely
`
`bathe in boric acid for 24 hours. PO cites irrelevant and outdated oral and
`
`intravenous boron toxicity studies, but admits that topical administration avoids
`
`systemic toxicity. Additionally, boron has been safely used in eye wash, vaginal
`
`creams, cosmetics, and is present in the human diet. PO asserts that toxicity,
`
`selective toxicity, and tavaborole’s mechanism of action are important, but the
`
`
`
`1
`
`

`
`IPR2015-01776
`Patent 7,582,621
`Petitioner Reply To PO Response
`
`’621 patent discloses none of these.
`
`Austin is relevant or analogous art. While PO disagrees, the inventors of the
`
`’621 patent cited Austin in their scientific paper announcing their alleged
`
`“discovery” of tavaborole. Moreover, three different patent examiners
`
`independently identified Austin as relevant.
`
`Tavaborole is the preferred compound disclosed by Austin for topical
`
`administration because of its low molecular weight and potent antifungal activity.
`
`PO says that tavaborole is merely one compound among thousands disclosed in
`
`Austin, but Austin only tested antifungal activity of three preferred compounds
`
`specifically identified in the abstract, including tavaborole. PO says that the “O-
`
`ester” derivatives were preferred, but tavaborole has the same activity and a lower
`
`molecular weight, the latter being the strongest predictor of nail penetration.
`
`Antifungal activity against C. albicans furnishes a reasonable expectation of
`
`success against dermatophytes. PO says that Austin’s disclosure of antifungal
`
`activity against C. albicans is irrelevant, but admits C. albicans is a known cause
`
`of onychomycosis. PO says that antifungal activity against C. albicans is not
`
`predictive of success against dermatophytes, but the prior art states that
`
`dermatophytes are usually more sensitive to antifungals than yeasts.
`
`Petitioner’s experts opined that there is a reasonable expectation of
`
`
`
`2
`
`

`
`IPR2015-01776
`Patent 7,582,621
`Petitioner Reply To PO Response
`
`successfully treating onychomycosis with Austin’s tavaborole in view of Brehove’s
`
`successful treatment of human volunteers without reported side effects, or in view
`
`of Freeman’s conclusion that its boron-containing compounds “are particularly
`
`useful in treating nail fungal infections.” PO’s attack of Brehove and Freeman is
`
`based on hypothetical arguments and contrary to law because Brehove and
`
`Freeman are prior art for all they disclose.
`
`PO’s secondary considerations are unpersuasive. First, there is no showing
`
`that the ’621 patent claims cover Kerydin®, or that there is a nexus between the
`
`claims and any alleged secondary consideration. Further, the ’621 patent does not
`
`disclose the “unexpected” lack of toxicity or the mechanism of action. Regarding
`
`long-felt need and failure of others, the oral drug terbinafine (approved in 1996)
`
`remains the “gold standard” for treating onychomycosis and the topical drugs
`
`ciclopirox (Penlac®) and efinaconazole (Jublia®) received FDA approval earlier
`
`and have similar or better activity.
`
`Volume does not rebut obviousness. PO took a known, preferred compound
`
`with known activity against a known cause of onychomycosis and suggested
`
`applying it to a nail, which was obvious. Claims 1-12 are unpatentable.
`
`II. BORON-CONTAINING COMPOUNDS WERE NOT CONSIDERED
`TOXIC AS OF FEBRUARY 16, 2005
`
`PO’s response is a retread of the same misleading arguments it made to the
`
`
`
`3
`
`

`
`IPR2015-01776
`Patent 7,582,621
`Petitioner Reply To PO Response
`
`PTO – that there was a “consensus” in 2005 that boron-containing compounds
`
`were toxic. (Ex. 1013 at 5-7.)1 This is inaccurate according to Drs. Kahl and
`
`Groziak, both boron chemistry experts, and PO’s physician expert, Dr. Maibach.
`
`(Ex. 1006 (Kahl) ¶¶28-32 (“generally considered safe”); Ex. 1027 at 322 (“none to
`
`date has been found to be unusually toxic”); Ex. 1049 at 15 (“relatively nontoxic . .
`
`. pose no toxicity threat”); Ex. 1050 at 9 (“low human toxicity”).)
`
`PO builds its misleading argument on outdated and irrelevant reports of
`
`boron toxicity resulting from oral and intravenous administration. (Ex. 2034
`
`(Reider) ¶96; Ex. 1054 at Abstract; Ex. 1043 (Kahl) ¶¶12-24.) But as PO admits,
`
`topical administration often avoids the toxicity associated with oral or intravenous
`
`administration, an important factor that PO’s medicinal chemistry expert, Dr.
`
`Reider, failed to consider. (Paper 32 at 62; Ex. 1048 (Reider) 70:9-71:3 (“you
`
`would need to speak to a toxicologist”), 264:10-266:11, 282:9-285:25 (“I don’t
`
`know anything about . . . [human] expos[ure] to [boron] on a daily basis”), 329:25-
`
`330:23 (“I do not believe I addressed routes of administration”).) Contrary to Dr.
`
`Reider’s opinion, another PO expert, Dr. Maibach, concluded in 1998 that a human
`
`could safely bathe in boric acid for 24 hours. (Ex. 1050 at 8-9.)
`
`
`
`                                                            
`1 Petitioner cites to inserted pagination (footer) where present in CFAD exhibits.
`
`
`
`4
`
`

`
`IPR2015-01776
`Patent 7,582,621
`Petitioner Reply To PO Response
`
`A. The Inventors Of The ’621 Patent And PO’s Founders Did Not
`Believe Boron Was Toxic Before 2005
`
`Dr. Baker (inventor) and Dr. Benkovic (PO co-founder) filed a provisional
`
`patent application in 1999 directed to boron-based pharmaceuticals. (Ex. 1053 at
`
`¶¶[0019], [0212]-[0227].) There is no mention of boron toxicity, which is
`
`consistent with Dr. Benkovic’s 2002 launch of Anacor “on the basis of [his]
`
`research showing that boron containing small molecules had the potential to be
`
`important new antibiotics.” (Ex. 1051.)
`
`
`
`PO filed a second unrelated provisional patent application in 2003 directed
`
`to boron-based therapeutics. (Ex. 1055; see also Ex. 1052.) It advocates for boron-
`
`containing pharmaceuticals: “[b]oron containing compounds have received
`
`increasing attention as therapeutic agents over the past few years.” (Id. at Col.
`
`2:39-43 (citing Groziak (Ex. 1027)).) Contrary to PO’s Response, the application
`
`cites bortezomib (Velcade®) as a “breakthrough” that “demonstrates the feasibility
`
`of using boron containing compounds as pharmaceutical agents.” (Id. at Col. 2:43-
`
`48.)
`
`B.
`
`The Inventors Of The ’621 Patent Confirmed There Was No
`Reason To Suspect Boron Was Toxic In 2005
`
`Dr. Baker also published a 2009 review touting the safety of boron-
`
`containing compounds, citing mostly pre-2005 prior art. (Ex. 1056 at 1; Ex. 1043
`
`(Kahl) ¶¶27-30.) The review concludes that it “has investigated [the claim of boron
`5
`
`
`
`

`
`IPR2015-01776
`Patent 7,582,621
`Petitioner Reply To PO Response
`
`toxicity, and] found it to be largely unfounded,” the “overwhelming data for the
`
`safety of boron [is] to be noted,” and “boron is, quite simply, another useful atom!”
`
`(Ex. 1056 at 1-2.)
`
`The Baker review summarizes a wealth of pre-2005 evidence that directly
`
`rebuts PO’s allegation that boron was considered toxic. Syntex (U.S.A.) LLC v.
`
`Apotex, Inc., 407 F.3d 1371, 1379 (Fed. Cir. 2005) (post-priority date publications
`
`from inventor relevant to obviousness determination); Bone Care Int’l, L.L.C. v.
`
`Roxane Labs., Inc., No. 09-cv-285, 2012 U.S. Dist. LEXIS 80450, at *176, n.90
`
`(D. Del. June 11, 2012) (same). For example, boron is present in toys, eye wash,
`
`vaginal creams, buffers for biological assay solutions, fruits, vegetables, and nuts,
`
`and Boron is consumed by humans in a range of 0.3-4.2 mg daily. (Ex. 1056 at 1
`
`(citing a 1999 publication); Ex. 1043 (Kahl) ¶¶27-30.) With the exception of the
`
`2005 paper discussing bortezomib (approved in 2003) and the 2008 paper
`
`discussing neutron capture therapy for cancer treatment (which is far afield from
`
`topical formulations), the remainder of the evidence the Baker review cites was
`
`available before 2005. (Id.; Ex. 1043 (Kahl) ¶¶14-17, 27-31.)
`
`Notably, the Baker review discredits the 1984 assertion by Grassberger et al.
`
`that boron is inherently toxic, a conclusion that Petitioner’s expert reached
`
`independently after reviewing PO’s Preliminary Response. (Ex. 1056 at 3; Ex.
`
`
`
`6
`
`

`
`IPR2015-01776
`Patent 7,582,621
`Petitioner Reply To PO Response
`
`1043 (Kahl) ¶13.) Seemingly unaware of PO’s admissions, PO’s experts continue
`
`to rely on Grassberger and its progeny. (Ex. 2034 (Reider) ¶96 (citing Exs. 2005,
`
`2008); Ex. 1048 (Reider) 192:10-194:7, 197:17-202:22.)
`
` Moreover, the Baker review cites the 2001 Groziak review of boron
`
`therapeutics (Ex. 1027) as a “valuable review of boronic acids in medicine,”
`
`despite PO’s criticisms in this case. (Ex. 1056 at 9 (reference 9); see also Ex. 1055
`
`at Col. 2:39-43 (pre-2005 reliance on Groziak).) The Groziak article confirms that
`
`boron is ubiquitous and non-toxic. (Paper 1 at 17-18; Ex. 1027 at 322.)
`
`C. The Prior Art Is Consistent With PO’s Admissions Concerning
`The Non-Toxicity Of Boron
`
`A number of relevant publications examined the alleged toxicity of boron
`
`before 2005 and concluded it was safe.2 In 1998, Dr. Maibach recognized that
`
`literature from the first half of the century reported concerns about boric acid, but
`
`concluded based on his human studies that the percutaneous absorption of boron-
`
`containing compounds in human skin “is low and is significantly less than the
`
`                                                            
`2 Dr. Reider also recognized the safety of a boron-containing compound in a
`
`publication omitted from his resume. (Ex. 1057 at 1 (“3-Pyridylboronic acid (3)
`
`was the choice of reagent for this transformation, since it is nontoxic and thermally
`
`and air-stable.”).)
`
`
`
`7
`
`

`
`IPR2015-01776
`Patent 7,582,621
`Petitioner Reply To PO Response
`
`average daily dietary intake.” (Ex. 1050 at 1, 9.) Dr. Maibach even concluded that
`
`a human could bathe in a saturated solution of boric acid for 24 hours without any
`
`toxicity concern. (Id. at Abstract, 8-9.)
`
`A 1998 boron textbook addressed the alleged toxicity of boron-containing
`
`compounds and concluded “borax and boric acid have a relatively low toxicity for
`
`animals,” “[c]hronic toxicity studies over a two-year period gave values of 5.00
`
`and 3.00 g/kg LD50 , respectively, values only 2-3 times that of aspirin (salt is 3.75
`
`g/kg),” and “[s]kin irritation with borate dusts or solutions is usually not a problem,
`
`with the borate cleaners and ointments being less irritating than pure soap.” (Ex.
`
`1058 at 63.) The textbook summarizes the common uses of boron-containing
`
`compounds in medical and cosmetic applications. (Id. at 101-102.)
`
`A 1999 report concluded that “[m]ost of the boronic acids and other low
`
`molecular-weight synthetic boron compounds that have been examined have been
`
`found to be relatively nontoxic” and “[b]oric acid and borates have been studied in
`
`great detail and pose no toxicity threat.” (Ex. 1049 at 15.) A second 1999 article
`
`concluded that “[i]norganic borates, including boric acid . . . generally display low
`
`acute toxicity orally, dermally, and by inhalation.” (Ex. 1054 at 8.)
`
`By 1999, the literature recognized that reports of boron toxicity, like the
`
`articles PO relies on, occur from doses that “are far higher than any levels to which
`
`
`
`8
`
`

`
`IPR2015-01776
`Patent 7,582,621
`Petitioner Reply To PO Response
`
`the human population would be exposed. Humans would need to consume daily
`
`some 3.3 g of boric acid [] to ingest the same dose level as the lowest animal
`
`NOAEL [no observed adverse effect level].” (Id. at 8, 17; Ex. 1043 (Kahl) ¶¶18-
`
`23.) Finally, a 2003 paper reviewing boron-containing compounds as
`
`pharmaceutical agents concluded “[o]ne can expect to see increasing research
`
`activities in this area because of the enormous potential it presents.” (Ex. 1060 at
`
`17.)
`
`D. Tavaborole Is Administered Topically
`PO says that boron is toxic based on publications discussing oral or
`
`intravenous delivery, but inconsistently admits that “[t]opical therapy avoids the
`
`problems associated with . . . systemic drugs.” (Ex. 1043 (Kahl) ¶¶18-23; Paper 32
`
`at 62.)
`
`Several references relied on by Dr. Reider relate to neutron capture therapy
`
`(“NCT”), which is a technique designed to accumulate high concentrations of
`
`boron in brain tumors prior to ionization. (Ex. 2034 (Reider) ¶96 (citing Exs. 2129,
`
`2052, 2130, 2131); Ex. 1048 (Reider) 165:18-180:11.) NCT has little, if any,
`
`bearing on the topical application of boron-containing compounds. (Ex. 1043
`
`(Kahl) ¶¶14-17.)
`
`Another group of references cited by Dr. Reider include Grassberger and its
`
`
`
`9
`
`

`
`IPR2015-01776
`Patent 7,582,621
`Petitioner Reply To PO Response
`
`progeny. (Ex. 2034 (Reider) ¶96 (citing Exs. 2005, 2008).) Both parties agree that
`
`Grassberger is unsubstantiated by data. (Ex. 1056 at 3; Ex. 1048 (Reider) 197:17-
`
`202:22; Ex. 1043 (Kahl) ¶13.)
`
`Many references cited by Dr. Reider relate to oral or intravenous studies
`
`delivering high concentrations of boron-containing compounds that would far
`
`exceed any concentration used for topical therapy. (Ex. 2034 (Reider) ¶96; Ex.
`
`1043 (Kahl) ¶¶18-23; Ex. 1054 at 17.) Notably, Dr. Reider failed to address the
`
`differences between oral or intravenous administration versus topical
`
`administration, (Ex. 1048 (Reider) 70:9-71:3, 329:25-330:23), which further
`
`weakens his opinions on toxicity. (Paper 32 at 62; Ex. 1048 (Reider) 217:5-
`
`221:19.)
`
`Consistent with the prior art, Petitioner’s experts concluded that boron
`
`toxicity would not be a concern in early 2005 when developing a topical
`
`formulation for delivery to the nail. (Ex. 2032 (Murthy) 456:13-460:7; Ex. 1008
`
`(Murthy) ¶135; Ex. 1044 (Murthy) ¶¶46-47; Ex. 1006 (Kahl) ¶¶28-32.) Dr.
`
`Maibach’s 24-hour boric acid bath conclusion is also consistent. (Ex. 1050 at 1, 9;
`
`Ex. 1061 at 8-9; Ex. 1047 (Maibach) 23:11-29:7, 43:20-44:9.)
`
`10
`
`
`
`
`
`
`
`

`
`IPR2015-01776
`Patent 7,582,621
`Petitioner Reply To PO Response
`
`III. AUSTIN IS RELEVANT ART
`The inventors, patent examiners, and PO’s expert all found Austin relevant.
`
`A. The Inventors Of The ’621 Patent Rely On Austin As Relevant
`Prior Art In Their Scientific Paper
`
`The inventors of the ’621 patent published their “discovery” of a “new”
`
`boron-containing compound (tavaborole) for the treatment of onychomycosis in
`
`2006. (Ex. 2157.) The paper also reported on the synthesis of benzoxaborole
`
`derivatives, including the 7-fluoro derivative. (Id. at 3.) The inventors reported
`
`synthesizing the 7-fluoro derivative using “Scheme 3,” citing reference 19, which
`
`is Austin. (Id. at 3, 6; Ex. 1048 (Reider) 293:7-295:3; Ex. 1043 (Kahl) ¶¶6-9.)
`
`
`
`The paper is significant for two reasons. First, it cites Austin as a reference
`
`the inventors relied on as part of their drug discovery process, thus proving that a
`
`POSITA would find Austin directly relevant, and at minimum, analogous art.
`
`Second, the inventors cited Austin in their drug discovery paper in 2006, but
`
`argued to the PTO in 2008 that Austin taught away from pharmaceuticals in order
`
`to overcome an obviousness rejection and obtain approval of the ’621 patent’s
`
`claims. (Ex. 1013 at 5-7; Ex. 1014 at 5.) The inventors also failed to disclose
`
`Austin and their 2006 paper to the PTO, leaving the Examiner to independently
`
`identify Austin. (Ex. 1070 at 171, 174.) The 2006 paper was never made of record.
`
`
`
`11
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`

`
`IPR2015-01776
`Patent 7,582,621
`Petitioner Reply To PO Response
`
`If it did, the inventors never could have made their “teaching away” argument
`
`about Austin.
`
`PO’s Expert Agrees That Cited References Are Relevant
`
`B.
`Dr. Reider testified that he tries to “read and write papers where [he has]
`
`reviewed [the] referenced that [he] cite[s]” and that authors typically cite
`
`references “if it’s been found to be useful to them.” (Ex. 1048 (Reider) 297:13-
`
`298:14 (emphasis added).) Dr. Reider’s testimony establishes that Austin is useful
`
`and relevant given the inventors’ reliance on Austin in their tavaborole drug
`
`discovery paper.
`
`C. Three Different Patent Examiners Cited Austin As Relevant Art
` PO filed two unrelated patent applications (overlapping inventors) directed
`
`to boron-containing therapeutics in 2003 and 2006. (Ex. 1062; Ex. 1063.) The
`
`international search reports for these applications, published in April 2005 and
`
`May 2008, listed Austin as a “document defining the general state of the art”
`
`(different boron compounds) and a “document of particular relevance.” (Ex. 1062
`
`at 2; Ex. 1063 at 3.) The Examiner of the ’621 patent application also
`
`independently identified Austin in 2008 and rejected the pending claims over
`
`Austin. (Ex. 1012 at 10-13.)
`
`D. Allegations Of Boron’s “Promiscuous” Behavior Are Irrelevant
`PO argues that Austin is irrelevant because boron is “promiscuous,” resulting
`12
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`
`
`

`
`IPR2015-01776
`Patent 7,582,621
`Petitioner Reply To PO Response
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`in broad-spectrum activity. PO’s arguments overlook that onychomycosis is caused
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`by a number of different fungi and molds, that the ’621 patent is directed to topical
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`administration, and that the structure of tavaborole reduces boron’s ability to bind
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`non-selectively.
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`The causes of onychomycosis are dermatophytes, Candida species, and
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`molds. (Ex. 1064 at 6 (¶[0002]); Ex. 2050 at 8; Ex. 2070 at 11.) The prior art and
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`the ’621 patent inventors agree that broad-spectrum antifungal activity is preferred
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`for the treatment of onychomycosis due to its multiple causes. (Ex. 1044 (Murthy)
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`¶¶46-47; Ex. 1064 at 10 (¶[0023]); Ex. 2070 at 14 (Griseofulvin was a
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`disappointment because “its spectrum of activity is limited to dermatophytes
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`only”.) The inventors’ statements directly contradict Dr. Reider’s assertion that a
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`POSITA would not choose a compound from Austin because of its potential broad-
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`spectrum activity. (Ex. 1064 at 10 (¶[0023]).)
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`PO’s arguments also fail to address that boron’s location within the
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`heterocycle of tavaborole reduces the ability of tavaborole to interact
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`indiscriminately. (Ex. 1043 (Kahl) ¶¶24-25.) This is beneficial because Austin
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`establishes that tavaborole has significant activity against C. albicans, a cause of
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`onychomycosis. (Ex. 1002 at 37, Table 9; Ex. 1044 (Murthy) ¶¶40-47.) More
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`importantly, any potential concern regarding broad-spectrum activity is lessened
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`by topical delivery, which Dr. Reider failed to address. (Ex. 1048 (Reider) 70:9-
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`71:3, 329:25-330:23; Ex. 1043 (Kahl) ¶26; Ex. 1044 (Murthy) ¶¶46-47; Paper 32
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`at 62.)
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`IV. TAVABOROLE IS THE PREFERRED COMPOUND OF AUSTIN
`PO’s arguments concerning the alleged complexity of Austin’s disclosure
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`fail to account for the plain language of the abstract and that the molecular weight
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`of a compound is directly related to penetration of the nail. (See VI.) The Board
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`should give Dr. Reider’s opinion little weight because he has never developed a
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`drug to treat onychomycosis and does not understand the importance of molecular
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`weight in nail penetration. (Ex. 1048 (Reider) 68:20-69:15, 364:10-365:9.)
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`The parties agree that tavaborole is specifically disclosed by name in the
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`abstract of Austin. (Ex. 1008 (Murthy) ¶61; Ex. 1006 (Kahl) ¶34; Ex. 2034
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`(Reider) ¶148.) Dr. Reider admits that Austin only tested sixteen of the
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`“thousands” of compounds identified in the abstract as “preferred compounds.”
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`(Ex. 1048 (Reider) 304:4-308:11.) Nine of the sixteen compounds were “O-esters”
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`in Table 8 and seven of the sixteen compounds, including tavaborole, were simpler
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`benzoxaboroles listed in Table 9. (Id.) Dr. Reider agrees that the compounds in
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`Table 9, including tavaborole, have a smaller molecular weight than the
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`corresponding “O-esters thereof” in table 8. (Id. at 308:12-309:1; see Ex. 1043
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`(Kahl) ¶¶10-11.) Thus, the compounds of Table 9 are more likely to achieve
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`penetration of the nail.
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`Tavaborole (example 64) had the best anti-fungal activity (MIC=5) of the
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`three compounds specifically disclosed in the Abstract that were tested in Table 9.
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`(Ex. 1044 (Murthy) ¶44-47; Ex. 1043 (Kahl) ¶¶10-11.) No compound in Table 9 or
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`Table 8 had better anti-fungal activity. Tavaborole’s combination of low MIC
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`values and low molecular weight makes it the first compound to choose from
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`Austin for treatment of onychomycosis. (Ex. 1044 (Murthy) ¶¶44-47; Ex. 1043
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`(Kahl) ¶¶10-11.)
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`PO’s argument that “O-esters” are “particularly preferred” ignores the
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`language of the specification by short-citing the only place Austin uses this term.
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`(Ex. 1002 at 5:5-6; Ex. 1048 (Reider) 319:13-320:12.) Austin does not say “O-
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`esters” are particularly preferred compounds of the disclosure. Instead, Austin
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`discloses a “particularly preferred class of oxaborole of formula 3 is that of
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`formula 4.” (Id.) Formula 3 is just one of the two “preferred class[es]” of
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`oxaboroles: “one preferred class [] is a benzoxaborole of formula 1” and “another
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`preferred class of oxaboroles” is of formula 3. (Ex. 1002 at 3:27-29, 3:41-4:10.)
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`Austin discloses a preference for substituents in the “5 and/or 6 position” and
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`“especially fluorine” within formula I. (Id. at 3:30-36.) This includes tavaborole.
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`Austin’s reference to “particularly preferred” is merely a reference to compounds
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`within formula 3, which have a higher molecular weight and are therefore less
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`desirable for topical application. (Ex. 1043 (Kahl) ¶¶10-11; Ex. 1044 (Murthy)
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`¶¶44-47.) PO’s argument that Table 11 in Austin signals a preference for “O-
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`esters” fails for the same reason: every compound in Table 11 has a higher
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`molecular weight than tavaborole and is therefore a less attractive candidate for
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`treating onychomycosis. (Ex. 1043 (Kahl) ¶10; Ex. 1044 (Murthy) ¶¶40-47.)
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`V. THERE IS A REASONABLE EXPECTATION OF SUCCESSFUL
`ACTIVITY AGAINST DERMATOPHYTES
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`It was known in the art before 2005 that antifungal compounds with
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`fungicidal activity against C. albicans (a yeast) almost always had the same or
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`better activity against dermatophytes.3 Mertin reported in 1997 that
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`“[d]ermatophytes are usually more sensitive towards antimycotics than yeasts.”
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`(Ex. 1065 at 6; Ex. 1044 (Murthy) ¶89.) Mertin’s findings of nine fungicidal
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`compounds are in Table 2 (excerpted for clarity) where “MICD” is activity against
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`dermatophytes and “MICY” is activity against yeasts:
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`3 C. albicans is a cause of onychomycosis. (Ex. 2050 at 8; Ex. 2070 at 11; Ex. 1046
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`(Ghannoum) 38:25-39:13.) The inventors agree. (Ex. 1064 at 6 (¶[0002]).) Only
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`claim 6 of the ’621 patent is limited to a fungal infection caused by dermatophytes.
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`(Ex. 1065 at 5; Ex. 1044 (Murthy) ¶89.) Every drug tested had better activity
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`against dermatophytes than yeasts with the exception of nystatin, which had
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`comparable activity. (Id.; Ex. 1044 (Murthy) ¶89.) A number of PO’s own
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`references confirm this expectation. (Ex. 1044 (Murthy) ¶¶82-93.) And the
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`deposition of PO’s mycology expert, Dr. Ghannoum, is consistent. (Ex. 1046
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`(Ghannoum) 22:14-22 (POSITA is not a mycologist), 99:17-107:6, 110:1-111:5,
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`215-221, 222:23-231, 238:22-239:12, 235:5-247:15, 249:6-255:21, 261:21-265:11;
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`Ex. 1044 (Murthy) ¶¶82, 84, 91-93.)
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`VI. LOW MOLECULAR WEIGHT AND MIC VALUES PROVIDE A
`REASONABLE EXPECTATION OF SUCCESS IN TREATING
`ONYCHOMYCOSIS
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`The molecular weight and minimum inhibitory concentration (“MIC”) of a
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`compound are the two most important considerations for predicting successful
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`treatment of onychomycosis via topical application. (Ex. 1044 (Murthy) ¶¶63-81,
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`94-96; Ex. 2032 (Murthy) 497:11-21, 514:13-516:2, 589:3-594:8; Ex. 1045 (Lane)
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`290:11-294:21.) A POSITA only needs to know the molecular weight and MIC
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`values of a compound to have a reasonable expectation of success. (Ex. 1044
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`(Murthy) ¶¶63-73, 94-96; Ex. 2032 (Murthy) 497:11-21, 514:13-516:2, 589:3-
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`594:8.) PO’s argument that additional information is required directly contradicts
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`the prior art and PO’s evidence. (See also Ex. 1045 (Lane) 38:7-70:18 (no relevant
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`experience before 2005).)
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`Mertin established that the ability of a compound to penetrate the nail is
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`directly proportional to its molecular weight. (Ex. 1065 at Abstract (“The
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`relationship between permeability and molecular weight is founded on well-
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`established theories”); Ex. 1044 (Murthy) ¶¶69-70.) Mertin published the
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`following graph and determined that as the molecular weight of a compound
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`decreases, the penetration of the nail by the compound increases. (Id. at 3 (“There
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`was a linear relationship with a negative slope between the permeability coefficient
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`and the molecular weight for both the nail plate [] and the hoof membrane.”).)
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