Paper # 19
`Dec. 7, 2018
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`______________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`______________________
`
`FLATWING PHARMACEUTICALS, LLC and
`MYLAN PHARMACEUTICALS, INC.,
`Petitioners,
`
`v.
`
`ANACOR PHARMACEUTICALS, INC.,
`Patent Owner.
`______________________
`
`Case No. IPR2018-001681
`U.S. Patent No. 9,549,938
`______________________
`
`PETITIONERS’ REPLY TO PATENT OWNER’S RESPONSE
`
`1 Case No. IPR2018-01358 has been joined with this proceeding.
`
`
`Dec. 7, 2018
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`______________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`______________________
`
`FLATWING PHARMACEUTICALS, LLC and
`MYLAN PHARMACEUTICALS, INC.,
`Petitioners,
`
`v.
`
`ANACOR PHARMACEUTICALS, INC.,
`Patent Owner.
`______________________
`
`Case No. IPR2018-001681
`U.S. Patent No. 9,549,938
`______________________
`
`PETITIONERS’ REPLY TO PATENT OWNER’S RESPONSE
`
`1 Case No. IPR2018-01358 has been joined with this proceeding.
`
`
`
`Case No. IPR2018-00168
`U.S. Patent No. 9,549,938
`
`TABLE OF CONTENTS
`
`TABLE OF CONTENTS............................................................................................i
`
`TABLE OF AUTHORITIES ................................................................................... iii
`
`TABLE OF EXHIBITS..............................................................................................v
`
`REPLY .......................................................................................................................1
`
`I. What Is NOT In Dispute..................................................................................1
`
`II.
`
`Patent Owner’s Experts Do Not Rebut Petitioner’s Case. ..............................7
`
`A. Dr. Reider’s Testimony Does Not Undercut Petitioner’s Proof that
`the Remaining Claims Are Invalid........................................................8
`
`1.
`
`2.
`
`3.
`
`Dr. Reider’s Testimony Does Not Address the Proper
`Standard, of Whether a POSA Would Have Had A
`Reasonable Expectation of Success with 5%. ............................9
`
`Dr. Reider Testified that Boron-Containing Compounds
`Ultimately Break Down In Water, But Fails To Consider
`Reaction Kinetics Showing How Long the Supposed Break
`Down Would Take....................................................................10
`
`Dr. Reider Also Repeats Previously Rejected Arguments
`About Boron’s “Promiscuity” and “Keratin-Binding
`Affinity.”...................................................................................11
`
`B.
`
`Dr. Lane’s Testimony Does Not Undercut Petitioner’s Proof that
`the Remaining Claims Are Invalid......................................................12
`
`1.
`
`2.
`
`Dr. Lane Did Not Consider that Dose Ranging Studies Are
`A Routine Part Of Drug Development Which Would Lead
`A POSA To The 5% Solution Claimed. ...................................13
`
`Dr. Lane Continues To Rely on Theories the Board Has
`Already Rejected.......................................................................14
`
`– i –
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`Case No. IPR2018-00168
`U.S. Patent No. 9,549,938
`
`III.
`
`Petitioner has proven by at least a preponderance of the evidence that a
`POSA would have a reasonable expectation of success at 5%. ....................17
`
`A. A POSA Would Seek a Formulation with the Minimum Effective
`Amount, Not Just Assume More Is Better. .........................................17
`
`B.
`
`C.
`
`Dose Ranging Studies Are Routine, and Here Lead to a 5%
`Solution. ..............................................................................................18
`
`Patent Owner Does Not Even Argue that the 5% Solution
`Produces an Unexpected Result, and Its “Teaching Away”
`Argument Is Legally Insufficient........................................................21
`
`CONCLUSION........................................................................................................24
`
`CERTIFICATE OF WORD COUNT......................................................................26
`
`CERTIFICATE OF SERVICE ................................................................................27
`
`– ii –
`
`
`
`Case No. IPR2018-00168
`U.S. Patent No. 9,549,938
`
`TABLE OF AUTHORITIES
`
`CASES
`
`Anacor Pharm., Inc. v. Iancu,
`889 F.3d 1372 (Fed. Cir. 2018)......................................................................2, 6
`
`Baxter Int’l, Inc. v. McGaw, Inc.,
`149 F.3d 1321 (Fed. Cir. 1998)........................................................................24
`
`Coalition for Affordable Drugs X LLC v. Anacor Pharm., Inc.,
`IPR2015-01776 (P.T.A.B. Feb. 23, 2017),
`Paper #70....................................................... 1, 2, 3, 4, 6, 11, 12, 14, 16, 21, 24
`
`Coalition for Affordable Drugs X LLC v. Anacor Pharm., Inc.,
`IPR2015-01780 (P.T.A.B. Feb. 23, 2017),
`Paper No. 70........................................................................................ 2, 4, 5, 24
`
`Coalition for Affordable Drugs X LLC v. Anacor Pharm., Inc.,
`IPR2015-01785 (P.T.A.B. Feb. 23, 2017),
`Paper No. 70........................................................................................ 2, 4, 5, 24
`
`DePuy Spine, Inc. v. Medtronic Sofamor Danek, Inc.,
`567 F.3d 1314 (Fed. Cir. 2009)........................................................................23
`
`EI DuPont De Nemours & Co. v. Synvina C.V.,
`904 F.3d 996 (Fed. Cir. 2018)..........................................................................22
`
`Galderma Labs., L.P. v. Tolmar, Inc.,
`737 F.3d 731 (Fed. Cir. 2013)..........................................................................23
`
`Hoffmann-La Roche Inc. v. Apotex Inc.,
`No. 07-4417,
`2012 WL 869572 (D.N.J. Mar. 14, 2012),
`aff'd, 496 F. App’x 46 (Fed. Cir. 2012)..................................................... 12, 18
`
`In re Aller,
`220 F.2d 454 (CCPA 1955) ..............................................................................19
`
`In re Antonie,
`559 F.2d 618 (CCPA 1977) ..............................................................................21
`
`– iii –
`
`
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`Case No. IPR2018-00168
`U.S. Patent No. 9,549,938
`
`In re Boesch,
`617 F.2d 272 (CCPA 1980) ..............................................................................19
`
`In re Dow Chemical Co.,
`837 F.2d 469 (Fed. Cir. 1988)..........................................................................20
`
`In re Geisler,
`116 F.3d 1465 (Fed. Cir. 1997) ..................................................... 19, 21, 22, 23
`
`In re O’Farrell,
`853 F.2d 894 (Fed. Cir. 1988)................................................................... 12, 15
`
`In re Peterson,
`315 F.3d 1325 (Fed. Cir. 2003)........................................................... 19, 21, 22
`
`Merck & Co. v. Biocraft Labs., Inc.,
`874 F.2d 804 (Fed. Cir. 1989)........................................... 12, 17, 18, 20, 22, 23
`
`Pfizer, Inc. v. Apotex, Inc.,
`480 F.3d 1348 (Fed. Cir. 2007)........................................................................19
`
`Tyco Healthcare Grp. LP v. Mut. Pharm. Co.,
`No. 07-1299 (SRC),
`2010 WL 1799457 (D.N.J. May 5, 2010),
`aff'd, 642 F.3d 1370 (Fed. Cir. 2011)........................................................ 17, 18
`
`United States v. Telectronics, Inc.,
`857 F.2d 778 (Fed. Cir. 1988)..........................................................................20
`
`– iv –
`
`
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`Case No. IPR2018-00168
`U.S. Patent No. 9,549,938
`
`TABLE OF EXHIBITS
`
`Ex. 1014
`
`DESCRIPTION
`EXHIBIT
`Ex. 1001 U.S. Patent No. 9,549,938
`Ex. 1002
`Prosecution History of the ’938 Patent
`Ex. 1003 Declaration of Stephen Kahl, Ph.D.
`Ex. 1004 Curriculum Vitae of Stephen Kahl, Ph.D.
`Ex. 1005 Declaration of S. Narasimha Murthy, Ph.D.
`Ex. 1006 Curriculum Vitae of S. Narasimha Murthy, Ph.D.
`Ex. 1007 Austin et al., PCT Pub. No. WO 1995/033754
`Ex. 1008 Brehove, U.S. Patent Pub. No. 2002/0165121
`Ex. 1009
`Freeman et al., PCT Pub. No. WO 2003/009689
`Ex. 1010
`Samour et al., U.S. Patent No. 6,224,887
`Ex. 1011
`Intentionally omitted – Exhibit number not used
`Ex. 1012 U.S. Patent No. 7,582,621
`Ex. 1013
`Prosecution History of the ’621 Patent
`Final Written Decision, Coalition for Affordable
`Drugs X LLC v. Anacor Pharmaceuticals, Inc.,
`IPR2015-01776 (P.T.A.B. Feb. 23, 2017), Paper 70
`Ex. 1015 U.S. Patent No. 7,767,657
`Ex. 1016
`Prosecution History of the ’657 Patent
`Final Written Decision, Coalition for Affordable
`Drugs X LLC v. Anacor Pharmaceuticals, Inc.,
`IPR2015-01780 (P.T.A.B. Feb. 23, 2017), Paper 70
`Final Written Decision, Coalition for Affordable
`Drugs X LLC v. Anacor Pharmaceuticals, Inc.,
`IPR2015-01785 (P.T.A.B. Feb. 23, 2017), Paper 70
`Ex. 1019 U.S. Patent No. 4,202,894
`
`Ex. 1017
`
`Ex. 1018
`
`SHORT FORM
`
`’938 Patent
`
`Kahl Decl.
`
`Murthy Decl.
`
`Austin
`Brehove
`Freeman
`Samour
`
`’621 Patent
`
`IPR ’776, FWD
`
`’657 Patent
`
`IPR ’780, FWD
`
`IPR ’785, FWD
`
`’894 Patent
`
`– v –
`
`
`
`SHORT FORM
`
`Murdan 2002
`
`Case No. IPR2018-00168
`U.S. Patent No. 9,549,938
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`EXHIBIT
`
`Ex. 1020
`
`Ex. 1025
`
`DESCRIPTION
`Murdan, Sudaxshina. “Drug delivery to the nail
`following topical application.” International journal
`of pharmaceutics 236, no. 1 (2002): 1-26.
`Ex. 1021 BioborJF® Specification Sheet (2015)
`Ex. 1022 BioborJF® Material Safety Data Sheet (2004)
`Ex. 1023
`Intentionally omitted – Exhibit number not used
`Ex. 1024
`Intentionally omitted – Exhibit number not used
`National Center for Biotechnology Information
`(NCBI), PubChem Compound Database,
`CID=6440876, available at
`https://pubchem.ncbi.nlm.nih.gov/compound/64408
`76 (retrieved on May 26, 2017)
`National Center for Biotechnology Information
`(NCBI), PubChem Compound Database,
`CID=3198, available at
`https://pubchem.ncbi.nlm.nih.gov/compound/3198
`(retrieved on May 26, 2017)
`National Center for Biotechnology Information
`(NCBI), PubChem Compound Database,
`CID=11499245, available at
`https://pubchem.ncbi.nlm.nih.gov/compound/11499
`245 (retrieved on May 26, 2017)
`Meds. & Healthcare Prods. Regulatory Agency,
`Curanail 5% Nail Lacquer (Amorolfine
`Hydrochloride) PL 10590/0049, UK Public
`Assessment Report (approved July 4, 2006)
`National Center for Biotechnology Information
`(NCBI), PubChem Compound Database,
`CID=22497760, available at
`https://pubchem.ncbi.nlm.nih.gov/compound/22497
`760 (retrieved on May 26, 2017)
`
`Ex. 1026
`
`Ex. 1027
`
`Ex. 1028
`
`Ex. 1029
`
`– vi –
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`
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`Case No. IPR2018-00168
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`EXHIBIT
`
`Ex. 1030
`
`Ex. 1031
`
`Ex. 1032
`
`Ex. 1033
`
`Ex. 1034
`
`DESCRIPTION
`National Center for Biotechnology Information
`(NCBI), PubChem Compound Database,
`CID=61764, available at
`https://pubchem.ncbi.nlm.nih.gov/compound/61764
`(retrieved on May 26, 2017)
`Mertin, Dirk, and Lippold, Bernhard C. “In-vitro
`permeability of the human nail and of a keratin
`membrane from bovine hooves: Prediction of the
`penetration rate of antimycotics through the nail
`plate and their efficacy.” Journal of pharmacy and
`pharmacology 49, no. 9 (1997): 866–872
`Groziak, Michael P. “Boron therapeutics on the
`horizon,” American journal of therapeutics 8, no. 5
`(2001): 321–328
`National Center for Biotechnology Information
`(NCBI), PubChem Compound Database,
`CID=66827, available at
`https://pubchem.ncbi.nlm.nih.gov/compound/66827
`(retrieved on May 26, 2017)
`National Center for Biotechnology Information
`(NCBI), PubChem Compound Database,
`CID=2775922, available at
`https://pubchem.ncbi.nlm.nih.gov/compound/27759
`22 (retrieved on May 26, 2017)
`
`Exs.
`1035-1039 Intentionally omitted – Exhibit numbers not used
`Ex. 1040
`FDA Medical Review of NDA 240-427
`Exs.
`1041-1042 Intentionally omitted – Exhibit numbers not used
`Brief of Appellant-Patent Owner, Anacor
`Pharmaceuticals, Inc. v. Joseph Matal, No. 17-1947
`(Fed. Cir. Aug. 4, 2017)
`Ex. 1044 Transcript of Nov. 7, 2018 Deposition of Majella E.
`Lane, Ph.D.
`
`Ex. 1043
`
`SHORT FORM
`
`Mertin 1997
`
`Groziak 2001
`
`Lane Dep.
`
`– vii –
`
`
`
`Case No. IPR2018-00168
`U.S. Patent No. 9,549,938
`
`DESCRIPTION
`EXHIBIT
`Ex. 1045 Transcript of Nov. 9, 2018 Deposition of Paul J.
`Reider, Ph.D.
`Ex. 1046 Handwritten calculations marked at the Nov. 7,
`2018 Deposition of Dr. Lane
`Ex. 1047 Rebuttal Declaration of Stephen Kahl, Ph.D.
`Ex. 1048 Rebuttal Declaration of S. Narasimha Murthy, Ph.D.
`Simões, Ana, Francisco Veiga, Carla Vitorino, and
`Ana Figueiras. “A Tutorial for Developing a
`Topical Cream Formulation Based on the Quality by
`Design Approach.” Journal of pharmaceutical
`sciences 107, no. 10 (2018): 2653-2662.
`
`Ex. 1049
`
`SHORT FORM
`
`Reider Dep.
`
`– viii –
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`
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`Case No. IPR2018-00168
`U.S. Patent No. 9,549,938
`
`REPLY
`
`Petitioner FlatWing Pharmaceuticals, LLC (“Flatwing”) respectfully submits
`
`this Reply to Paper #13, Patent Owner’s Response (filed Sept. 7, 2018) (hereinafter
`
`“Response”) and in further support of Paper #1, Petition For Inter Partes Review
`
`Of U.S. Patent No. 9,549,938 under 35 U.S.C. §§(cid:2271)311–319 and 37 C.F.R.
`
`§(cid:134)(cid:2271)42.100 et. seq. (filed Nov. 21, 2017) (hereinafter “Petition”).
`
`I. WHAT IS NOT IN DISPUTE
`
`Patent Owner Anacor Pharmaceuticals, Inc. (“Anacor”) does not dispute that
`
`Claims 1, 2, and 4 of the U.S. Patent No. 9,549,938 (“the ’938 patent”) are invalid,
`
`arguing instead only for Claims 3, 5, and 6 based solely on a claim limitation of
`
`about “5%” of tavaborole. Response at 6. Patent Owner’s witnesses Drs. Lane and
`
`Reider testified concerning the validity of only those claims. (Ex. 2013 (cid:136)(cid:3031)1; Ex.
`
`2014 ¶(cid:3031)1; Ex. 1044 at 29:19–30:4; Ex. 1045 at 49:9–50:6.)
`
`Patent Owner further agrees that the findings in the Board’s previous Final
`
`Written Decisions in Inter Partes Reviews (“IPRs”) invalidating related patents2
`
`are binding on it, and does not collaterally challenge them in this proceeding:
`
`2 Coalition for Affordable Drugs X LLC v. Anacor Pharm., Inc., IPR2015-01776
`
`(P.T.A.B. Feb. 23, 2017), Paper #70, Final Written Decision (hereinafter “FWD”)
`
`(herein Ex. 1014); Coalition for Affordable Drugs X LLC v. Anacor Pharm., Inc.,
`
`– 1 –
`
`
`
`Case No. IPR2018-00168
`U.S. Patent No. 9,549,938
`
`Anacor acknowledges the Board’s rulings in these prior cases, as well
`the affirmance of the Board’s final written decision in IPR2015-
`01776, see Anacor Pharm. Inc. v. Iancu, 889 F.3d 1372 (Fed. Cir.
`2018), and does not challenge here limitations that were found to
`have been obvious in those proceedings.
`
`Response at 6 (emphasis added). The “limitations that were found to have been
`
`obvious in those proceedings” includes “therapeutically effective amount.”
`
`(Ex. 1014 at 4; 7–8, 15, 18, 38.) A “therapeutically effective amount” is “the
`
`amount of drug needed to effect the desired therapeutic result.” (Ex. 1014 at 8.)
`
`Thus, that limitation “found to have been obvious” encompasses the entire range
`
`of all
`
`therapeutically effective amounts. Patent Owner’s witnesses also
`
`acknowledged that the Board’s previous determinations are binding here and not
`
`subject to collateral attack in these proceedings. (Ex. 1044 at 18:14–50:12 (“I was
`
`aware of the Board's decision. But in this current matter, I don't think it's my role
`
`to challenge the Board. So . . . I accept that this is a given. . . . I'm not here to
`
`challenge their decision.”); Ex. 1045 at 16:15–17:8 (“I have accepted the Board's
`
`ruling.”).)
`
`IPR2015-01780 (P.T.A.B. Feb. 23, 2017), Paper No. 70 (herein Ex. 1017);
`
`Coalition for Affordable Drugs X LLC v. Anacor Pharm., Inc., IPR2015-01785
`
`(P.T.A.B. Feb. 23, 2017), Paper No. 70 (herein Ex. 1018).
`
`– 2 –
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`
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`Case No. IPR2018-00168
`U.S. Patent No. 9,549,938
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`The following facts are therefore undisputed:
`
`•
`
`“Austin discloses tavaborole as Example 64, as well as the results of a
`
`study showing tavaborole has effective antifungal activity against five
`
`different fungi,” which includes fungi that cause onychomycosis.
`
`(Ex. 1014 at 11.)
`
`•
`
`“Austin is reasonably pertinent to the particular problem the inventors
`
`sought to solve” and “logically would have commended itself to the
`
`problem facing the inventors . . . .” (Ex. 1014 at 13, 14.)
`
`• A person of ordinary skill in the art (“POSA”) “would have chosen
`
`tavaborole as a potential candidate for treating onychomycosis.”
`
`(Ex. 1014 at 18.)
`
`• A POSA would have been drawn preferably to the list of compounds on a
`
`table including tavaborole because those compounds “have a lower
`
`molecular weight that is more likely to penetrate the nail.” (Id. at 16)
`
`•
`
`“Austin and Brehove together suggest administering to a human a
`
`therapeutically effective amount of tavaborole.” (Ex. 1014 at 18.)
`
`• A POSA “would have had a reason to combine Austin and Brehove to
`
`reach the claimed invention with a reasonable expectation of success.”
`
`(Ex. 1014 at 18, 23; see Ex. 1014 at 21, 28; see also, Ex. 1014 at 39, 41–
`
`42 (same finding for Freeman).)
`
`– 3 –
`
`
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`Case No. IPR2018-00168
`U.S. Patent No. 9,549,938
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`•
`
`“Brehove
`
`reasonably
`
`suggests
`
`administering Biobor
`
`to
`
`treat
`
`onychomycosis.” (Ex. 1014 at 20.)
`
`• A POSA “would have had a reasonable expectation that administering
`
`tavaborole topically would penetrate the nail.” (Ex. 1014 at 24
`
`(emphasis added).)
`
`•
`
`“Samour exemplifies a number of lacquer formulations including a
`
`formulation having 71% ethanol, 24% film-forming polymer and 5%
`
`antifungal.” (Ex. 1017 at 16; Ex. 1018 at 16.)
`
`• As Dr. Murthy previously testified, and the Board agreed, the patent-in-
`
`suit recognizes that “formulating pharmaceutical compositions was well
`
`known in the art of cosmetics and topical pharmaceuticals.” (Ex. 1017 at
`
`40, 50; Ex. 1018 at 39, 48–49.)
`
`• As Dr. Murthy testified previously, and the Board agreed, “[f]ormulating
`
`pharmaceutical compositions
`
`involves nothing more
`
`than routine
`
`experimentation based on well-known protocols,” (Ex. 1017 at 41, 43,
`
`50; Ex. 1018 at 39, 42, 48–49.)
`
`• As Dr. Murthy previously testified, and the Board agreed, a topical
`
`formulation comprising “about 10% tavaborole” by weight is obvious in
`
`view of the prior art, including Austin and Samour. (Ex. 1017 at 43, 50;
`
`Ex. 1018 at 42, 48–49.)
`
`– 4 –
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`• As before, the patent specification “does not describe any new or
`
`unexpected results attributable to the claimed pharmaceutical formulation
`
`. . ., nor was the claim formulation added to avoid prior art during
`
`prosecution.” (Ex. 1017 at 41, 43, 50; Ex. 1018 at 39, 42, 48–49.)
`
`•
`
`“We also credit Dr. Murthy’s testimony . . . that ‘lower molecular weight
`
`compounds are more effective at crossing the nail plate following topical
`
`administration’ and, therefore, because the topical formulations described
`
`in Samour ‘effectively delivered compounds of higher molecular weight’
`
`than tavaborole through the nail barrier, a person of ordinary skill in the
`
`art would be motivated to substitute tavaborole for the higher molecular
`
`weight compound in Samour to arrive at the pharmaceutical formulation
`
`recited . . ., and would have a reasonable expectation of success in doing
`
`so.” (Ex. 1017 at 43–44; Ex. 1018 at 42.)
`
`•
`
`“We also credit Dr. Murthy’s testimony that a person of ordinary skill in
`
`the art would have had a high expectation of success that substituting
`
`low-molecular-weight tavaborole into topical formulations that deliver
`
`higher-molecular-weight molecules
`
`would
`
`effectively
`
`treat
`
`onychomycosis . . . .” (Ex. 1017 at 50; Ex. 1018 at 48.)
`
`For the only claim appealed, the Federal Circuit affirmed that substantial
`
`evidence supported the Board’s finding of obviousness:
`
`– 5 –
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`U.S. Patent No. 9,549,938
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`As to that issue, the Board found that a person of skill in the art
`would have been motivated to combine Austin and Brehove and
`would have had a reasonable expectation of success in doing so. . . .
`Tavaborole, in particular, was identified as being especially potent
`against the various species of fungi that Austin tested. Austin also
`disclosed that tavaborole was a low molecular weight compound,
`which would enable the compound to penetrate the nail plate
`covering the locus of the infection.
`. . .
`. . . In light of the full record before the Board, we conclude that
`substantial evidence supports the Board’s findings that a person of
`ordinary skill in the art would have been motivated to combine the
`pertinent teachings of Austin and Brehove and would have had a
`reasonable expectation of success in doing so.
`Anacor, 889 F.3d at 1382–83 (emphasis added).
`
`Patent Owner does not assert or even identify any special, unexpected result
`
`for the 5% amount in particular within the broader range of therapeutically
`
`effective amounts generally. In the previous IPRs the Board rejected Patent
`
`Owner’s argument that secondary considerations including unexpected results
`
`(Ex. 1014 at 31–33), long-felt need (Id. at 33–35), and industry praise (Id. at 35–
`
`36) supported patentability. Here, Patent Owner does not even try to argue that any
`
`secondary considerations support the validity of the claims limited to a 5%
`
`solution.
`
`– 6 –
`
`
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`Case No. IPR2018-00168
`U.S. Patent No. 9,549,938
`
`II.
`
`PATENT OWNER’S EXPERTS DO NOT REBUT PETITIONER’S
`CASE
`
`As a preliminary matter, neither Dr. Lane nor Dr. Reider offers any ultimate
`
`opinion on obviousness. (Ex. 1044, Lane Dep. at 11:2–10 (“I’ve not given any
`
`opinion on obviousness.”); Ex. 1045, Reider Dep. at 10:14–17 (“Q: . . . Does this
`
`declaration contain an opinion on obviousness? A: I don't believe it does.”).)
`
`Neither testified that a POSA would not have expected a 5% solution to work, or
`
`would have expected a 5% solution not to work. Neither testified that a POSA
`
`would not have reached a 5% solution in ordinary dose ranging studies. Neither
`
`testified that a 5% solution produces any unexpected results within the broader
`
`range of therapeutically effective amounts generally, which limitation the Board
`
`has already determined did not impart patentability.
`
`Also, while both acknowledged this proceeding is bound by the Board’s
`
`findings and determinations in the previous IPRs (see supra p.2), much of their
`
`declarations are simply a rehash of previous arguments. As discussed next below in
`
`II.A and II.B, infra, the Board previously considered and rejected arguments
`
`concerning keratin binding in the nail, the “promiscuous” nature of boron, the
`
`difficulty of transungual penetration, and the supposed importance factors other
`
`than molecular weight as affecting nail penetration.
`
`– 7 –
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`Case No. IPR2018-00168
`U.S. Patent No. 9,549,938
`
`A.
`
`Dr. Reider’s Testimony Does Not Undercut Petitioner’s Proof that
`the Remaining Claims Are Invalid.
`
`While Petitioner’s witness Dr. Kahl is one of the leading experts on boron
`
`chemistry, that is not Dr. Reider’s particular area of expertise. Dr. Reider agreed
`
`with Dr. Kahl’s definition of the level of ordinary skill in the art, which is also in
`
`the Board’s
`
`institution decisions.
`
`(Ex. 1045 at 18:21–19:2; 21:11–22:4.)
`
`Dr. Reider indicated that he is being offered as an expert on, inter alia, organic
`
`boron compounds (organoboranes) (Ex. 1045 at 27:5–20). However, Dr. Reider
`
`acknowledges that he has never been involved in developing any boron-containing
`
`compounds for use as drug candidates. (Ex. 2013, (cid:136)(cid:3031)11; Ex. 1045 at 29:1–12.) He
`
`has never attended any of the various conferences devoted to boron chemistry,
`
`such as the Boron Chemistry Meeting in the Americas (“BORAM”), the European
`
`Conference on Boron Chemistry (“Euroboron”), the International Conference on
`
`Boron Chemistry and Applications (“ICBCA”), the International Meeting on
`
`Boron Chemistry (“IMEBORON”); the only conference he could name attending
`
`that could relate in any way to boron chemistry is the generalist biannual American
`
`Chemical Society meeting. (Ex. 1045 at 29:15–40:10.)
`
`He also is not an expert on the human nail or transungual delivery systems.
`
`No parts of his education or training have focused on the human nail or
`
`transungual drug delivery. (Ex. 1045, Reider Dep. at 40:12–7.) He has never
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`– 8 –
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`U.S. Patent No. 9,549,938
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`developed any drug products for transungual delivery, and none of his publications
`
`or patents concerns transungual drug delivery (id.) or the keratin composition of
`
`the human nail or the water composition of the human nail (id. at 42:21–43:4).
`
`1.
`
`Dr. Reider’s Testimony Does Not Address the Proper
`Standard, of Whether a POSA Would Have Had A
`Reasonable Expectation of Success with 5%.
`Even though the entire theme of Patent Owner’s response is that the specific
`
`5% solution limitation makes the remaining claims as a whole non-obvious,
`
`nowhere in his direct testimony does Dr. Reider address this specific percentage.
`
`(Ex. 1045 at 50:17–57:19.) His only mention of amount at all is an oblique
`
`reference to the “Claimed Amount” in a heading—none of the numbered
`
`paragraphs stating his various opinions address it at all. (Ex. 2014, (cid:136)(cid:3031)29.) His same
`
`testimony could apply just as broadly to any claimed specific percentage within the
`
`broader range of “therapeutically effective amounts” generally that the Board has
`
`already found insufficient to avoid obviousness. Because his declaration does not
`
`even address the specific the limitation on which Patent Owner relies, it is of no
`
`weight in overcoming Petitioner’s prima facie showing of obviousness.
`
`– 9 –
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`Case No. IPR2018-00168
`U.S. Patent No. 9,549,938
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`2.
`
`Dr. Reider Testified that Boron-Containing Compounds
`Ultimately Break Down In Water, But Fails To Consider
`Reaction Kinetics Showing How Long the Supposed Break
`Down Would Take.
`A central theme of Dr. Reider’s testimony is that the “ultimate” fate of boron
`
`compounds is to decay into boronic acid. (E.g., Ex. 2013 ¶(cid:136)(cid:3031)37, 52; Ex. 1047, (cid:136)(cid:3031)3.)
`
`However, he admitted he had given no thought to the kinetics of the action and the
`
`rate at which such compounds might decay. (Ex. 1045 at 84:7–5; Ex. 1047, (cid:136)(cid:3031)3.) In
`
`fact, such decay is usually an extremely slow process, and can take years or
`
`decades. (Ex. 1047, (cid:136)(cid:3031)4). For tavaborole, the rate is extremely slow, orders of
`
`magnitude longer than the treatment period in which tavaborole penetrates the nail,
`
`and sufficiently slow to permit formulation of a product having a useful shelf life.
`
`(Ex. 1047, (cid:136)(cid:3031)5.) As such, it would have no bearing on the use of tavaborole as a
`
`pharmaceutical generally, on
`
`the percentage
`
`tavaborole
`
`in solution in a
`
`pharmaceutical formulation, or on whether a POSA would have a reasonable
`
`expectation of success in formulating a solution ending up at 5%. (Ex. 1047, (cid:136)(cid:3031)5.)
`
`Dr. Reider opines that tavaborole in Brehove would not penetrate the nail
`
`plate but would instead undergo hydrolysis to boric acid before doing so.
`
`(IPR2018-00168, Ex. 2013 ¶(cid:136)(cid:3031)66–67, 69; IPR2018-00169, Ex. 2013 ¶(cid:136)(cid:3031)69–70, 72;
`
`IPR2018-00170, Ex. 2013 ¶(cid:136)(cid:3031)70–71, 73; IPR2018-00171, Ex. 2013 ¶(cid:136)(cid:3031)64–65, 67.)
`
`However, the Board has already determined that “administering tavaborole
`
`– 10 –
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`U.S. Patent No. 9,549,938
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`topically would penetrate the nail.” (Ex. 1014 at 24; Ex. 1047, (cid:136)(cid:3031)6.) Moreover,
`
`Austin expressly discloses tavaborole as an effective antifungal in an aqueous
`
`medium, which is how Dr. Reider describes the nail. (Ex. 1047, (cid:136)(cid:3031)7; Ex. 1007 at
`
`8:32–38.)
`
`3.
`
`Dr. Reider Also Repeats Previously Rejected Arguments
`About Boron’s “Promiscuity” and “Keratin-Binding
`Affinity.”
`Dr. Reider continues to offer his previously-rejected testimony about “the
`
`tendency of boron-containing compounds to ‘interact promiscuously’ with other
`
`compounds.” (Ex. 2013 (cid:136)(cid:3031)25; Ex. 1047, (cid:136)(cid:3031)2.) The Board previously considered and
`
`rejected this argument, finding that “boron’s allegedly ‘promiscuous’ behavior
`
`does not dissuade a person of ordinary skill in the art from considering boron-
`
`containing compounds generally, or tavaborole in particular.” (Ex. 1014 at 27;
`
`Ex. 1047, (cid:136)(cid:3031)2.)
`
`Similarly, Dr. Reider also continues to rely on his theory that concern about
`
`boron’s “keratin-binding” affinity would turn a POSA away. (Ex. 2013 ¶(cid:136)(cid:3031)58–65.)
`
`Keratin and keratin-binding affinity are not within Dr. Reider’s area of expertise,
`
`as seen by the fact that none of Dr. Reider’s publications or patents concern keratin
`
`as being part of the composition of the human nail. (Ex. 1045 at 42:21–43:4.)
`
`Moreover, the Board has already rejected Patent Owner’s argument about the
`
`importance of keratin binding affinity, finding instead that a POSA would have had
`
`– 11 –
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`Case No. IPR2018-00168
`U.S. Patent No. 9,549,938
`
`a reasonable expectation of success in combining Austin (Ex. 1007) with Brehove
`
`(Ex. 1008) or Freeman (Ex. 1009). (Ex. 1014 at 23, 27–28, 39–41.)
`
`B.
`
`Dr. Lane’s Testimony Does Not Undercut Petitioner’s Proof that
`the Remaining Claims Are Invalid.
`
`Much of Dr. Lane’s testimony centers on whether the performance of
`
`tavaborole would not have been absolutely predictable to a POSA, perhaps because
`
`her own research focus included “prediction of percutaneous drug penetration.”
`
`(Ex. 2014 (cid:136)(cid:3031)6.) She maintains that a POSA in 2005 could not necessarily have
`
`predicted which compounds would penetrate the nail (Ex. 2014 (cid:136)(cid:3031)29), but the
`
`Board has already determined that “that a person of ordinary skill in the art would
`
`have had a reasonable expectation that administering tavaborole topically would
`
`penetrate the nail,” (Ex. 1014 at 24). As the Board also explained before:
`
`We note that conclusive proof of efficacy is not required to
`show obviousness. See Hoffmann-La Roche Inc. v. Apotex Inc., 748
`F.3d 1326, 1331 (Fed. Cir. 2014) (“Conclusive proof of efficacy is not
`necessary to show obviousness. All that is required is a reasonable
`expectation of success.”).
`
`(Id. at 3.) Merck & Co. v. Biocraft Labs., Inc., 874 F.2d 804, 809 (Fed. Cir. 1989)
`
`(“But, ‘absolute predictability of success’ is not the criterion; ‘[f]or obviousness
`
`under (cid:134)(cid:3031)103, all that is required is a reasonable expectation of success.’”) (quoting
`
`In re O’Farrell, 853 F.2d 894, 903 (Fed. Cir. 1988)).
`
`– 12 –
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`Case No. IPR2018-00168
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`1.
`
`Dr. Lane Did Not Consider that Dose Ranging Studies Are A
`Routine Part Of Drug Development Which Would Lead A
`POSA To The 5% Solution Claimed.
`Dr. Lane’s background includes developmental work with mathematical
`
`models to identify candidate compounds for formulations, but does not include
`
`conducting preclinical or clinical trials for those products, which were never
`
`brought to market. (Ex. 1044 at 22:6–25:2.) If a product were going to be marketed
`
`commercially it would have to go through such clinical trials. (Ex. 1044 at 25:3–
`
`11; Ex. 1048, (cid:136)(cid:3031)18–19.) Dr. Lane has never been involved in conducting clinical
`
`trials, although her consultancy has occasionally helped to analyze data from them.
`
`(Ex. 1044 at 25:12–26:6.)
`
`Dr. Lane did not consider the dose ranging studies for tavaborole included in
`
`the public FDA submission for Kerydin. (Ex. 1044 at 72:14–73:8, 73:20–74:4;
`
`Ex. 1040 at 66–71.) Asked whether dose ranging studies are an ordinary part of
`
`clinical trials to obtain regulatory approval for a product, Dr. Lane agreed they “are
`
`often a part of regulatory practice.” (Ex. 1044 at 74:6–12.) And in such a trial,
`
`“different doses can be studied.” (Ex. 1044 at 74:14–75:7.) Dr. Lane did not
`
`disagree that a POSA would know how to conduct a dose ranging study, but
`
`admitted she would not have been the person to have designed one. (Ex. 1044 at
`
`75:9–76:8.) It is outside the scope of her area of expertise. In fact, dose ranging
`
`– 13 –
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`Case No. IPR2018-00168
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`
`studies are routine, ordinary development work in any drug trial, including
`
`products for transungual treatment of onychomycosis. (Ex. 1048, (cid:136)(cid:3031)18–19.)
`
`2.
`
`Dr. Lane Continues To Rely on Theories the Board Has
`Already Rejected.
`Dr. Lane testifies extensively about keratin and other “factors affecting nail
`
`permeability” (Ex. 2014 ¶¶(cid:3031)26–49) including keratin-binding affinity (¶(cid:136)(cid:3031)43–46),
`
`water solubility ((cid:136)(cid:3031)47), and hydrophilicity/lipophilicity ((cid:136)(cid:3031)48). The Board has heard
`
`(and rejected) all of this before:
`
`Although other factors such as lipophilicity, keratin binding, and
`potency of the compound may influence transungual drug delivery,
`we are persuaded by the well-supported testimony of Dr. Murthy that
`low molecular weight is the most important factor in predicting
`whether a molecule will penetrate the nail plate, and that the
`remaining factors described by Patent Owner’s declarant, Dr. Lane,
`are of less importance, particularly with a low molecular weight and
`low MIC molecule such as tavaborole.”
`
`(Ex. 1014 at 23–24 (emphasis added); see Ex. 1048, (cid:136)(cid:3031)20.)
`
`Dr. Lane also identifies the “vehicle” as a factor affecting permeability
`
`(Ex. 2014 (cid:136)(cid:3031)49), but that vehicle is some
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