UNITED STATES PATENT AND TRADEMARK OFFICE
`__________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________________
`
`FLATWING PHARMACEUTICALS, LLC and
`MYLAN PHARMACEUTICALS INC.,
`Petitioners,
`
`v.
`
`ANACOR PHAMACEUTICALS, INC.,
`Patent Owner.
`__________________
`
`Case No. IPR2018-001681
`U.S. Patent No. 9,549,938
`__________________
`
`PATENT OWNER’S SURREPLY
`
`
`
`
`
`1 Case No. IPR2018-01358 has been joined with this proceeding
`
`

`

`TABLE OF CONTENTS
`
`PATENT OWNER’S SURREPLY ........................................................................... 5
`
`Case No. IPR2018-00168
`U.S. Patent No. 9,549,938
`
`
`ARGUMENT ............................................................................................................. 6
`
`I. What Is Actually Not In Dispute ..................................................................... 6
`
`II.
`
`Petitioners Fail to Rebut Anacor’s Arguments ................................................ 9
`
`A.
`
`Petitioners Fail to Rebut Anacor’s Evidence of Teaching Away ......... 9
`
`1.
`
`2.
`
`3.
`
`Petitioners Do Not Dispute Dr. Lane’s Analysis that
`Samour in Combination with the Cited Art and Evidence
`of Record as a Whole Teaches Away ......................................... 9
`
`The Cited Art Teaches Away from 5% Even Under
`Petitioners’ Incorrect Legal Standard ....................................... 10
`
`Petitioners’ Pivot to Overlapping Ranges in the Cited Art
`Does Not Rebut Anacor’s Evidence of Teaching Away .......... 12
`
`B.
`
`Petitioners Fail to Rebut Anacor’s Evidence That Formulating
`Boron-Containing Compounds Was Not Routine .............................. 14
`
`III.
`
`Petitioners’ Criticisms of Anacor’s Experts Are Irrelevant .......................... 16
`
`A.
`
`B.
`
`Petitioners Mischaracterize Dr. Lane’s Opinions ............................... 17
`
`Dr. Reider is Qualified to Opine on Aspects of Transungual
`Drug Delivery That Require Expertise in Chemistry .......................... 18
`
`IV. Dr. Kahl’s Rebuttal Opinions Regarding Brehove Are Conclusory and
`Not Entitled to Any Weight ........................................................................... 19
`
`V. Dr. Murthy’s Reliance on Anacor’s Post-Priority Dose-Ranging
`Studies Should be Rejected as Pure Hindsight .............................................. 21
`
`CONCLUSION ........................................................................................................ 24
`
`
`
`i
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`

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`Case No. IPR2018-00168
`U.S. Patent No. 9,549,938
`
`
`TABLE OF AUTHORITIES
`
`
`Cases:
`Alcon Research, Ltd. v. Apotex Inc., 687 F.3d 1362 (Fed. Cir.
`2012) ................................................................................................................ 6
`
`Allergan, Inc. v. Sandoz Inc., 796 F.3d 1293 (Fed. Cir. 2015) ........................... 11
`
`Cardiac Pacemakers, Inc. v. St. Jude Med. Inc., 381 F.3d 1371
`(Fed. Cir. 2004) .............................................................................................. 22
`
`Dura Auto. Sys. of Ind., Inc. v. CTS Corp., 285 F.3d 609 (7th Cir.
`2002) .............................................................................................................. 10
`
`Galderma Labs., L.P. v. Tolmar, Inc., 737 F.3d 731 (Fed. Cir.
`2013) .............................................................................................................. 11
`
`Genetics Inst., LLC v. Novartis Vaccines & Diagnostics, Inc., 655
`F.3d 1291 (Fed. Cir. 2011) ............................................................................ 13
`
`Honeywell Int’l Inc. v. Mexichem Amanco Holding S.A., 865 F.3d
`1348 (Fed. Cir. 2017)..................................................................................... 22
`
`In re Cyclobenzaprine Hydrochloride Extended-Release Patent
`Litig., 676 F.3d 1063 (Fed. Cir. 2012) ........................................................... 22
`
`In re Peterson, 315 F.3d 1325 (Fed. Cir. 2003) ................................................. 13
`
`Leo Pharm. Prods., Ltd. v. Rea, 726 F.3d 1346 (Fed. Cir. 2013) ........................ 7
`
`Millennium Pharms., Inc. v. Sandoz, Inc. 862 F.3d 1356 (Fed. Cir.
`2017) .............................................................................................................. 21
`
`PGS Geophysical AS v. Iancu, 891 F.3d 1354 (Fed. Cir. 2018) ........................ 10
`
`Santarus, Inc. v. Par Pharm. Inc., 694 F.3d 1344 (Fed. Cir. 2012) ................... 16
`
`SkinMedica, Inc. v. Histogen Inc., 727 F.3d 1187 (Fed. Cir. 2017) ................... 20
`
`
`
`
`
`ii
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`

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`Rules:
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`Case No. IPR2018-00168
`U.S. Patent No. 9,549,938
`
`
`Fed. R. Evid. 703 ................................................................................................ 10
`
`Fed. R. Evid. 802 ................................................................................................ 20
`
`iii
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`

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`There are two principal reasons why claims 3, 5, and 6 of U.S. Patent No.
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`Case No. IPR2018-00168
`U.S. Patent No. 9,549,938
`
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`9,549,938 (“the ’938 patent,” Ex. 1001) are patentable over the art cited by
`
`FlatWing and Mylan. First, as explained in Anacor’s Patent Owner’s Response, a
`
`person of ordinary skill in the art (“POSA”) in 2005 would have used a
`
`concentration of tavaborole higher than the 5% w/w recited in claims 3, 5, and 6
`
`because the cited art teaches away from 5%. A POSA would have also expected
`
`tavaborole to have high keratin-binding affinity, a fact which would have led a
`
`POSA to a higher concentration in order to overcome the notoriously difficult
`
`challenge of delivering drugs through the human nail plate.
`
`Second, Anacor’s evidence establishes that a POSA in 2005 would not have
`
`arrived at the recited concentration through routine experimentation, including
`
`“routine” dose-ranging studies, because the reactivity of boron-containing
`
`compounds such as a tavaborole would have been expected to render their
`
`formulation highly unpredictable—and thus far from routine. Indeed, the record in
`
`this case contains only two pre-priority formulations of boron-containing active
`
`ingredients—the formulation of a bortezomib prodrug in VELCADE® and
`
`Brehove’s formulation of the dioxaborinanes of Biobor JF®—and a POSA would
`
`have known both to suffer from significant stability problems.
`
`Petitioners’ reply fails to rebut Anacor’s arguments and evidence.
`
`Petitioners first erroneously suggest that the previous Board and Federal Circuit
`
`4
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`decisions in inter partes reviews brought the Coalition for Affordable Drugs
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`Case No. IPR2018-00168
`U.S. Patent No. 9,549,938
`
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`(“CFAD”) on related patents are dispositive of this case. But Petitioners
`
`mischaracterize the scope of these decisions, which plainly did not answer the key
`
`question in this case: whether it would have been obvious to a POSA in 2005 to
`
`formulate a 5% w/w solution of tavaborole to treat onychomycosis. Petitioners and
`
`their experts further offer only piecemeal analysis of Anacor’s arguments and
`
`evidence, and their reply papers further fail to cite any evidence not based on
`
`impermissible hindsight. As Anacor’s evidence remains unrebutted, Petitioners
`
`have failed to establish the obviousness of claims 3, 5, and 6 of the ’938 patent.
`
`PATENT OWNER’S SURREPLY
`
`Patent Owner Anacor Pharmaceuticals, Inc. (“Anacor”) submits this surreply
`
`in response to the reply (“Reply”) filed by FlatWing Pharmaceuticals, LLC
`
`(“FlatWing”) and Mylan Pharmaceuticals, Inc. (“Mylan”) and reply declarations
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`filed by Dr. S. Narasimha Murthy (“Murthy Reply Decl.” Ex. 1048) and Dr.
`
`Stephen B. Kahl (“Kahl Reply Decl.,” Ex. 1047).2
`
`
`2 Transcripts of Dr. Murthy’s and Dr. Kahl’s cross-examinations pursuant to 37
`
`C.F.R. § 42.53 have been filed as Exhibit 2046 (“Murthy Reply Dep.”) and Exhibit
`
`2047 (“Kahl Reply Dep.”).
`
`5
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`Case No. IPR2018-00168
`U.S. Patent No. 9,549,938
`
`
`ARGUMENT
`I. What Is Actually Not In Dispute
`FlatWing and Mylan’s petitions are copycats of previous petitions for inter
`
`partes review filed by CFAD against related U.S. Patent Nos. 7,582,621 and
`
`7,767,657 (“the ’621 patent,” Ex. 1012; and “the ’657 patent,” Ex. 1015). Anacor
`
`has acknowledged that the Board and Federal Circuit’s decisions in the CFAD
`
`IPRs held the ’621 and ’657 patents to be obvious, a holding that Anacor has
`
`further acknowledged extends to certain claim limitations also recited in the claims
`
`of the ’938 patent. But claims 3, 5, and 6 of the ’938 patent recite an additional
`
`new limitation—the 5% w/w limitation—that neither the Board nor the Federal
`
`Circuit had the opportunity to consider. These prior decisions do not render the
`
`additional 5% limitation obvious a fortiori.
`
`Petitioners are thus wrong to contend the Board to have determined the
`
`“entire range” of therapeutically effective amounts to be obvious—including the
`
`specific 5% w/w concentration recited in claims 3, 5, and 6—by holding claims of
`
`the ’621 patent reciting a “therapeutically effective amount” of tavaborole to be
`
`obvious. See Reply at 2. Indeed, that would have been an elementary mistake of
`
`patent law as the patentability of a narrow claim reciting a specific concentration is
`
`separable from that of a broader claim generically reciting a “therapeutically
`
`effective amount.” See, e.g., Alcon Research, Ltd. v. Apotex Inc., 687 F.3d 1362,
`
`6
`
`

`

`1370 (Fed. Cir. 2012) (dependent claim to “0.1 w/v concentration” not obvious
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`Case No. IPR2018-00168
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`despite determination of obviousness with respect to independent claim reciting
`
`“therapeutically effective amount”).
`
`Petitioners are also wrong to the extent they suggest the Board to have
`
`determined that a POSA would have arrived at the 5% w/w concentration through
`
`routine experimentation. See Reply at 4. Although the Board did credit Dr.
`
`Murthy’s previous testimony that “[f]ormulating compositions involves nothing
`
`more than routine experimentation based on well-known protocols,” id., the Board
`
`did so in the context of rejecting Anacor’s argument that a POSA would not have
`
`combined certain references—an argument Anacor is not raising in this
`
`proceeding. See Ex. 1017 at 39–41; Ex. 1018 at 37–39. Inasmuch as Petitioners
`
`have interpreted the Board’s prior statement to have established a rule of law
`
`holding all pharmaceutical formulations to be obtainable through “well-known
`
`protocols” and “routine experimentation,” Petitioners’ interpretation is inconsistent
`
`with the large body of case law holding claims to pharmaceutical formulations to
`
`be nonobvious and finding their development far from routine. See, e.g., Leo
`
`Pharm. Prods., Ltd. v. Rea, 726 F.3d 1346, 1357 (Fed. Cir. 2013) (“Without a
`
`reasonable expectation of success or clues pointing to the most promising
`
`combinations, an artisan could have spent years experimenting without success.”).
`
`7
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`

`

`Finally, Petitioners err in characterizing Anacor’s experts as offering a
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`“rehash . . . of previously considered and rejected arguments concerning keratin
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`binding in the nail, the ‘promiscuous’ nature of boron, the difficulty of transungual
`
`penetration and the supposed importance [of] factors other than molecular weight
`
`as affecting nail penetration.” Reply at 7. Petitioners’ arguments are rife with
`
`overstatement. With respect to Dr. Reider, the Board hardly rejected his
`
`explanation of boron’s “promiscuous” nature—the Board in fact accepted Dr.
`
`Reider’s testimony that “boron binds non-selectively with oxygen, nitrogen, and
`
`sulfur atoms found widely in other biomolecules,” but was ultimately not
`
`persuaded that this would create toxicities that would have discourage a POSA.
`
`See, e.g., Ex. 1014 at 27. With respect to Dr. Lane, the Board did not hold keratin-
`
`binding to be an irrelevant factor in transungual drug delivery. The Board simply
`
`agreed with Dr. Murthy that a POSA would have considered molecular weight to
`
`be more important. See, e.g., id. at 23–24. The Board also made no findings with
`
`respect to whether a POSA in 2005 would have understood transungual drug
`
`delivery to be challenging, as Dr. Lane has opined. Critically, these basic
`
`“fundamental” points offered by Anacor’s experts are not disputed by either Dr.
`
`Murthy or Dr. Kahl. See, e.g., Kahl Dep. (Ex. 2017) at 73:20–74:3, 89:9–21,
`
`75:20–76:1, 42:21–43:9; Murthy Dep. (Ex. 2018) at 75:6–9 (“Penetrability of
`
`8
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`

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`drugs across a nail plate is a challenge. . . . It’s definitely a challenge.”); Murthy
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`2016 Dep. (Ex. 2002) at 88:12–89:16.
`
`II.
`
`Petitioners Fail to Rebut Anacor’s Arguments
`A.
`
`Petitioners Fail to Rebut Anacor’s Evidence of Teaching Away
`1.
`
`Petitioners Do Not Dispute Dr. Lane’s Analysis that Samour
`in Combination with the Cited Art and Evidence of Record
`as a Whole Teaches Away
`
`As Anacor’s expert Dr. Majella Lane has explained, Samour’s Example 9
`
`demonstrates that antifungal concentrations higher than 5% w/w achieve better nail
`
`penetration, a result consistent with what a POSA in 2005 would have expected in
`
`accordance with Fick’s law. See Lane Decl. (Ex. 2014) ¶¶ 67–75. Samour’s
`
`example is highly relevant because the remainder of the cited art discloses broad
`
`ranges, all of which encompass concentrations higher than 5% w/w. Id. ¶¶ 68–69.
`
`Moreover, the state of the art of transungual drug delivery in 2005 would have
`
`further spurred a POSA to use higher concentrations, given that it was universally
`
`recognized—including by Dr. Murthy as a “fundamental proposition”—that the
`
`“[d]evelopment of topical formulations to deliver effective amounts of drugs into
`
`the nail apparatus is highly challenging.” Murthy Dep. (Ex. 2002) at 88:12–89:16
`
`(quoting Ex. 2030 at vii); see also Lane Decl. (Ex. 2014) ¶ 55.3
`
`3 Dr. Lane’s opinions on the cited art with respect to the 5% limitation renders
`
`Petitioners’ observation that Dr. Reider did not render the same opinions, e.g.,
`
`9
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`

`

`Samour’s Example 9 is precisely the kind of dose-ranging study that
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`Case No. IPR2018-00168
`U.S. Patent No. 9,549,938
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`Petitioners assert a POSA would have “routinely” undertaken, yet Petitioners
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`continue to ignore the salience of Example 9. In fact, Petitioners and their
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`declarants in reply do not address any aspect of Dr. Lane’s analysis of Samour’s
`
`Example 9 in the context of the cited art and evidence as a whole. Petitioners’
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`cherry-picked view of the record is legally unsound, and fails to rebut Anacor’s
`
`evidence that the art “as a whole” teaches away from the claimed invention. PGS
`
`Geophysical AS v. Iancu, 891 F.3d 1354, 1366 (Fed. Cir. 2018).
`
`2.
`
`The Cited Art Teaches Away from 5% Even Under
`Petitioners’ Incorrect Legal Standard
`
`Instead of offering countervailing factual analysis or opinions from their
`
`declarants, Petitioners rely on the purely legal argument that Anacor’s teaching-
`
`away evidence is insufficient as a matter of law. As an initial matter, Petitioners’
`
`insistence that a teaching away “require[s] a suggestion that the 5% combination
`
`was inoperative” vastly inflates the applicable legal standard, which Petitioners
`
`
`Reply at 9, inapposite piecemeal analysis. Dr. Lane’s opinions in fact permissibly
`
`rely on Dr. Reider’s opinions with respect to boron chemistry and keratin-binding,
`
`see Lane Decl. (Ex. 2014) ¶ 76; Petitioners’ conclusion that Dr. Reider’s
`
`declaration “is of no weight,” Reply at 9, is a non sequitur. See Fed. R. Evid. 703;
`
`Dura Auto. Sys. of Ind., Inc. v. CTS Corp., 285 F.3d 609, 612–13 (7th Cir. 2002).
`
`10
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`have selectively quoted. Reply at 23–24 (quoting DePuy Spine, Inc. v. Medtronic
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`Case No. IPR2018-00168
`U.S. Patent No. 9,549,938
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`Sofamor Danek, Inc., 567 F.3d 1314, 1327 (Fed. Cir. 2009)). As stated by the
`
`Federal Circuit in DePuy Spine:
`
`“A reference may be said to teach away when a person of
`
`ordinary skill, upon reading the reference, would be
`
`discouraged from following the path set out in the
`
`reference, or would be led in a direction divergent from
`
`the path that was taken by the applicant.” A reference
`
`does not teach away, however, if it merely expresses a
`
`general preference for an alternative invention but does
`
`not “criticize, discredit, or otherwise discourage”
`
`investigation into the invention claimed.
`
`567 F.3d at 1327 (emphasis added) (quoting Ricoh Co. v. Quanta Computer Inc.,
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`550 F.3d 1325, 1332 (Fed. Cir. 2008), and In re Fulton, 391 F.3d 1195, 1201 (Fed.
`
`Cir. 2004)); see also Allergan, Inc. v. Sandoz Inc., 796 F.3d 1293, 1305 (Fed. Cir.
`
`2015); Galderma Labs., L.P. v. Tolmar, Inc., 737 F.3d 731, 738 (Fed. Cir. 2013).
`
`There is simply no legal requirement that Anacor prove that a 5% w/w
`
`concentration of tavaborole would have been expected to be inoperable.
`
`Even so, Anacor’s evidence satisfies even Petitioners’ inflated standard. As
`
`Dr. Lane has explained, transungual drug delivery in 2005 was understood to be a
`
`11
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`

`challenging and still-elusive goal: “[I]t was well-established in the art both before
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`Case No. IPR2018-00168
`U.S. Patent No. 9,549,938
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`and after Brehove (as well as Freeman and Samour) that topical treatments for
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`onychomycosis have yet to achieve adequate nail penetration.” Lane Decl. (Ex.
`
`2014) ¶ 55. The record is littered with failed formulations, see id. ¶ 44 (discussing
`
`amorolfine and terbinafine). And as Dr. Reider has explained, these failures
`
`include Brehove’s formulation of Biobor JF—although Brehove reports curing
`
`onychomycosis through topical treatment with Biobor JF, a POSA would have
`
`understood Brehove’s formulation to be unstable. See Reider Decl. (Ex. 2013)
`
`¶ 67 (“Instead of penetrating the nail plate, Brehove’s mixture of dioxaborinanes
`
`would have hydrolyzed at the surface of the nail or shortly thereafter.”). Against
`
`this backdrop of the state of the art—and in light of Samour’s dose-ranging study
`
`in Example 9—a POSA in 2005 “would have been discouraged from pursuing a
`
`5% w/w formulation.” Lane Decl. (Ex. 2014) ¶ 75.
`
`3.
`
`Petitioners’ Pivot to Overlapping Ranges in the Cited Art
`Does Not Rebut Anacor’s Evidence of Teaching Away
`
`Having been confronted with the fact that the cited art teaches away,
`
`Petitioners and Dr. Murthy’s reply papers emphasize the presence of overlapping
`
`ranges in Austin, Brehove, and Freeman that encompass an antifungal
`
`concentration of 5% w/w. See, e.g., Murthy Reply Decl. (Ex. 1048) ¶¶ 2–13.
`
`Petitioners’ emphasis gets the applicable legal standard exactly backwards—
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`12
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`evidence of a teaching away “in any material respect” rebuts obviousness based on
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`Case No. IPR2018-00168
`U.S. Patent No. 9,549,938
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`overlapping ranges, not the other way around. In re Peterson, 315 F.3d 1325, 1331
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`(Fed. Cir. 2003) (citing In re Geisler, 116 F.3d 1465, 1469 (Fed. Cir. 1997)).
`
`Petitioners’ reliance on overlapping ranges is also misplaced given that the
`
`cited art teaches ranges “so broad as to encompass a very large number of possible
`
`distinct compositions.” Genetics Inst., LLC v. Novartis Vaccines & Diagnostics,
`
`Inc., 655 F.3d 1291, 1306 (Fed. Cir. 2011) (quoting Peterson, 315 F.3d at 1330).
`
`The broadest range in the prior art—“0.1% to about 100% by weight” in Freeman
`
`(Ex. 1009) ¶ [0064]—covers virtually any dose, while the narrowest range
`
`encompassing 5% w/w is in Samour, which includes a dose-ranging study
`
`(Example 9) that teaches away. Moreover, as Dr. Murthy has testified, the POSA
`
`would have been aware that many concentrations within these broad ranges would
`
`be too unstable, unsafe, or expensive to formulate, and that the POSA accordingly
`
`would “not go forward” with these concentrations. Murthy Reply Dep. (Ex. 2046)
`
`at 43:23–44:19; see also Murthy Reply Decl. (Ex. 1047) ¶ 16. The overlapping
`
`ranges in the cited art therefore encompass a broad continuum of “distinct”
`
`concentrations that precludes a prima facie case of obviousness. It is perhaps for
`
`this reason that FlatWing and Mylan did not rest their petitions for inter partes
`
`review against claims 3, 5, and 6 of the ’938 patent solely on the overlapping
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`13
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`ranges in Austin, Brehove, and Freeman, but additionally cited Samour, which
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`specifically teaches antifungal lacquer formulations using a 5% w/w concentration.
`
`B.
`
`Petitioners Fail to Rebut Anacor’s Evidence That Formulating
`Boron-Containing Compounds Was Not Routine
`
`Based on his experience and expertise in boron chemistry, including his
`
`experience in developing FDA-approved drugs, Dr. Reider has opined that a POSA
`
`in 2005 would not have found “experimentation” with boron-containing active
`
`compounds to be “routine” because “all available evidence would have
`
`demonstrated to a POSA that formulation of boron-containing compounds was
`
`unpredictable due to the propensity of boron to interact with known pharmaceutical
`
`excipients.” Reider Decl. (Ex. 2013) ¶ 68. Dr. Reider therefore disputes Dr.
`
`Murthy’s opinion (and Petitioners’ argument) that a POSA would have arrived at
`
`5% w/w of tavaborole, a boron-containing compound, through routine
`
`experimentation. In support of his opinion, Dr. Reider relies on the lack of data
`
`and limited experience in developing boron-containing compounds as drug
`
`candidates, including the pharmaceutical industry’s experience with VELCADE®,
`
`a formulation of a boron-containing compound that succeeded only by formulating
`
`a prodrug of bortezomib produced from the reaction of bortezomib with mannitol,
`
`a pharmaceutical excipient that was widely (and still) understood to be inert. See
`
`id. ¶¶ 38–40, 68–71. Dr. Reider also opined that a POSA would have known that
`
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`Case No. IPR2018-00168
`U.S. Patent No. 9,549,938
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`Brehove’s formulation of the boron-containing active compounds in Biobor JF was
`
`not successful from a formulation standpoint due to the hydrolysis of Biobor’s
`
`active compounds to boric acid. See id. Accordingly, the only record evidence
`
`regarding actual formulations of boron-containing compounds as active
`
`pharmaceutical ingredients are two failed direct formulations.
`
`Petitioners offer no response to Dr. Reider’s overall conclusion that
`
`experimentation with boron-containing compounds was not routine. Dr. Kahl’s
`
`reply declaration is completely silent on this issue and offers only a conclusory
`
`opinion on tavaborole’s hydrolytic stability that is irrelevant to both Dr. Reider’s
`
`analysis of Brehove, as well the understanding of a POSA in 2005.4 Dr. Murthy is
`
`not qualified to offer an opinion on boron chemistry, see Murthy Dep. (Ex. 2018)
`
`
`4 At various points, Petitioners’ and their declarants confuse which compounds are
`
`at issue or disclosed in the cited references. With respect to Dr. Kahl’s reply
`
`declaration, to the extent that Dr. Kahl intended to opine on the hydrolysis of
`
`Brehove’s active compounds (instead of tavaborole), his opinion is unsupported by
`
`any evidence or scientific analysis, and ignores contrary evidence in the record—
`
`his opinions therefore deserve no weight. See Part IV, infra.
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`15
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`at 20:15–21:11, and further agreed that the POSA would have been concerned with
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`drug-excipient interactions, see Murthy Reply Dep. (Ex. 2046) at 62:4–12.5
`
`III. Petitioners’ Criticisms of Anacor’s Experts Are Irrelevant
`Petitioners’ charge that Anacor’s experts do not offer “any ultimate opinion”
`
`on obviousness. See Reply at 7. Petitioners’ point is irrelevant. Instead of
`
`offering conclusory opinions concerning ultimate legal questions reserved for the
`
`Board, Anacor’s experts have confined their opinions to their respective areas of
`
`expertise, including (for Dr. Reider), whether the POSA would have understood
`
`Brehove’s formulation of Biobor JF to be susceptible to hydrolysis, and (for Dr.
`
`Lane) whether the cited art teaches away. See Santarus, Inc. v. Par Pharm. Inc.,
`
`694 F.3d 1344, 1354 (Fed. Cir. 2012) (“Whether a prior art reference teaches away
`
`. . . is a question of fact.”) These factual determinations are relevant and are
`
`properly offered to assist the Board as the trier of fact.
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`5 To the extent that Dr. Murthy is understood to opine that potential drug-excipient
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`interactions would not have discouraged a POSA from performing dose-ranging
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`studies, his opinion does not speak to whether those studies would have been
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`routine in light of boron’s “unique chemistry and reactivity,” Reider Decl. (Ex.
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`2013) ¶ 57, a topic on which Dr. Murthy concedes he is not qualified to opine.
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`16
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`Petitioners Mischaracterize Dr. Lane’s Opinions
`
`A.
`Dr. Lane’s declaration describes in detail the factors that a POSA in the field
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`of transungual drug delivery would have considered in arriving at an opinion on
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`nail penetration, including both molecular weight and keratin-binding affinity. Her
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`principal critique of Dr. Murthy’s declaration is that he failed to consider these
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`factors in favor of a singular focus on molecular weight—despite his repeated
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`emphasis on the other factors in his own research and peer-reviewed
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`publications—and that consideration of the factors as a whole would have led a
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`POSA to a different conclusion. See Lane Decl. (Ex. 2014) ¶¶ 77–83.
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`Petitioners characterize Dr. Lane as insisting on “absolute predictability.”
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`Reply at 15. This is a straw-man argument that mischaracterizes her opinions.
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`The central dispute between Dr. Lane and Dr. Murthy is methodological and not
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`about the desired quantum of scientific certainty. Indeed, Petitioners and their
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`declarants continue in their reply papers to ignore the role of keratin-binding
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`affinity in transungual drug penetration, despite Dr. Murthy’s previous recognition
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`of its importance. See Murthy et al. 2007 (Ex. 2008) at 305–06 (identifying
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`“binding of the drug to keratin” as one of “at least two factors” that “decreases the
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`amount of drug penetrating into the deeper nail layers”); see also Murthy Dep. (Ex.
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`2018) at 59:9–12; Lane Decl. (Ex. 2014) ¶ 81.
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`17
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`B. Dr. Reider is Qualified to Opine on Aspects of Transungual Drug
`Delivery That Require Expertise in Chemistry
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`Dr. Murthy has conceded that the degree to which a compound binds to
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`keratin turns on its chemical structure and whether “there are any such
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`substitutions on the molecule that favors the binding.” Murthy Dep. (Ex. 2018) at
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`60:18–61:3. The question of to what degree a boron-containing substituent binds
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`to keratin therefore implicates Dr. Reider’s expertise in chemistry, including his
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`decades-long experience working with boron compounds. See also Lane Decl. (Ex.
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`2014) ¶ 44 (“Whether a compound possesses high keratin-binding affinity is
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`largely a function of its chemical structure”). Notably, Petitioners and their
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`declarants offer no response on the merits to Dr. Reider’s opinion that a POSA in
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`2005 would have expected tavaborole to have high-keratin binding affinity due its
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`boron substituent’s propensity to bond with electron-rich functional groups present
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`in keratin. See Reider Decl. (Ex. 2013) ¶ 58.
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`Petitioners’ observation that Dr. Reider “is not an expert on the human nail,”
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`Reply at 8, is beside the point because his opinions are limited to the areas of
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`transungual drug delivery that implicate his chemistry expertise. Indeed,
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`Petitioners’ expert, Dr. Kahl, lacks the same exact qualifications that Petitioners
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`insist upon. Compare Reply at 8–9, with Kahl Reply Dep. (Ex. 2047) at 14:11–
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`15:14. Petitioners suggestion that Dr. Reider’s absence at specialty conferences on
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`18
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`boron chemistry somehow detracts from his opinions, see Reply at 8, likewise does
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`not render Dr. Reider unqualified. Tellingly, Petitioners’ own declarant agrees
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`with Dr. Reider’s basic analysis of boron’s unique properties. See Kahl Dep. (Ex.
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`2017) at 73:20–74:3, 89:9–21, 75:20–76:1, 42:21–43:9.
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`IV. Dr. Kahl’s Rebuttal Opinions Regarding Brehove Are Conclusory and
`Not Entitled to Any Weight
`
`Dr. Reider’s opinion that Brehove’s formulation of Biobor JF—a mixture of
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`dioxaborinane compounds—undergoes hydrolysis to boric acid is supported by his
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`own experience with boron compounds, technical materials authored by Biobor
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`JF’s manufacturer, and publicly available scientific literature on Biobor JF. See
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`Reider Decl. (Ex. 2013) ¶ 67 (citing Exs. 1022, 2002, 2022, 2038, and 2040).
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`In reply, Dr. Kahl offers the bare conclusion that the hydrolysis kinetics of
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`“the tavaborole in Brehove” are “extremely slow.” Kahl Reply Decl. (Ex. 1047)
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`¶ 4 (emphasis added). This would appear to be a mistake as Brehove does not
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`disclose tavaborole, and Dr. Reider’s opinions with respect to hydrolysis were
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`directed to the dioxaborinane compounds that Brehove actually used. See Kahl
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`Reply Dep. (Ex. 2047) at 16:18–19. But even if Dr. Kahl’s reply declaration were
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`rewritten to reflect the correct compounds, Dr. Kahl fails to identify any scientific
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`principles underlying his opinions and cites no evidence. His opinions therefore
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`cannot “assist the trier of fact to understand evidence or to determine a fact in
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`19
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`issue,” and deserve zero weight from the Board. Fed. R. Evid. 802; see also, e.g.,
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`SkinMedica, Inc. v. Histogen Inc., 727 F.3d 1187, 1210 (Fed. Cir. 2017).
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`Dr. Kahl also fails to consider record evidence that contradicts his opinions.
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`Anacor’s evidence demonstrates that a POSA in 2005 reading Brehove would have
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`been concerned with hydrolytic stability given the extremely high concentration of
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`Brehove’s dioxaborinanes and the water-rich environment of the human nail. The
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`rate of a hydrolysis reaction is proportional to the concentration of water and the
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`concentration of the pre-hydrolyzed compound, a principle in kinetics commonly
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`referred to as the law of mass action. See Kahl Reply Dep. (Ex. 2047) at 24:18–23;
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`see also id. at 47:10–11 (“Reaction rate usually increases as concentration
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`increases.”). In a technical manual Biobor JF’s manufacturer underscored limits to
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`both concentrations to avoid hydrolysis of Biobor to boric acid during blending:
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`1000 PPM for the dioxaborinanes and 30 PPM for water. See Ex. 2038 at 12. Dr.
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`Kahl agrees, however, that the concentration of Biobor JF used by Brehove and the
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`concentration of water in the human nail are “orders of magnitude greater.” See
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`Kahl Reply Dep. (Ex. 2047) at 37:9–18, 38:13–18. Dr. Kahl fails consider these
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`contrary facts, and further fails to identify any evidence to support his rebuttal
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`opinions regarding Brehove. His opinions should be disregarded.
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`20
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`V. Dr. Murthy’s Reliance on Anacor’s Post-Priority Dose-Ranging Studies
`Should be Rejected as Pure Hindsight
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`Petitioners and Dr. Murthy reprise their argument that a POSA would have
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`arrived at tavaborole concentration of 5% w/w through routine experimentation by
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`asserting that “dose-ranging is routine” and that “materials filed with the FDA” by
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`Anacor to obtain regulatory approval “show that here the 5% solution was reached
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`through just such routine experimentation with standard dose ranging studies.”
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`Reply at 18 (citing Murthy Reply Decl. (Ex. 2014) ¶ 19).
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`As an initial matter, Petitioners are incorrect that “[t]here has been no
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`showing that the experimentation that would have been required to arrive at the
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`[specific] dose was anything other than routine.” Id. (quoting Tyco Healthcare
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`Grp. LP v. Mutual Pharm. Co., 2010 WL 1799457, at *8 (D.N.J. May 5, 2010)).
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`Petitioners overlook Dr. Reider’s opinion that such experimentation would not
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`have been routine as a consequence of, inter alia, boron’s relatively novel
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`application in active pharmaceutical ingredients and its propensity “to interact with
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`known pharmac