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 4300
` 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 RESPONSE TO PATENT OWNER’S MOTION FOR
`OBSERVATIONS REGARDING THE CROSS-EXAMINATION
`TESTIMONY OF S. NARASIMHA MURTHY, PH.D.
`
`
`
`
`
`
`
`
`By: Jeffrey D. Blake, Esq.
` MERCHANT & GOULD P.C.
`
`191 Peachtree Street N.E., Suite 4300
` 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 RESPONSE TO PATENT OWNER’S MOTION FOR
`OBSERVATIONS REGARDING THE CROSS-EXAMINATION
`TESTIMONY OF S. NARASIMHA MURTHY, PH.D.
`
`
`
`
`
`
`
`IPR2015-01776
`Patent 7,582,621
`
`I.
`
`INTRODUCTION
`
`Pursuant to the Scheduling Order (Paper No. 25), Petitioner hereby submits
`
`its Response to Patent Owner’s Motion for Observations Regarding the Cross-
`
`Examination Testimony of S. Narasimha Murthy, Ph.D. (Paper No. 56.) In
`
`accordance with the Scheduling Order, Petitioner’s response to each of Patent
`
`Owner’s observations is equally concise and specific.
`
`II.
`
`RESPONSE TO OBSERVATIONS
`
`1.
`
`Petitioner agrees with Dr. Murthy’s testimony that Austin alone
`
`furnishes a reasonable expectation of success in treating onychomycosis in view of
`
`the knowledge of a person of ordinary skill in the art as well as the limited
`
`disclosure of the provisional application (Ex. 1064) to which U.S. Patent No.
`
`7,582,621 claims priority. (See Ex. 2207 at 656:12-657:24.) However, Dr. Murthy
`
`further testified that “the claims were obvious, not only in Austin, it was also when
`
`combined with Brehove and Freeman and other references.” ( Id. at 758:22-759:3.)
`
`This testimony is relevant because Petitioner never argued that claims 1-12 of U.S.
`
`Patent No. 7,582,621 (“the ’621 Patent”) are unpatentable under 35 U.S.C. § 102
`
`over Austin alone. (See Paper No. 1 at 8; Paper No. 24 at 4, 15-16); rather, that the
`
`claims are unpatentable based on a 35 U.S.C. § 103 combination of references
`
`(Paper No. 1 at 8; Paper No. 47 at 1, 28).
`
`
`
`1
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`
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`IPR2015-01776
`Patents 7,582,621
`
`2.
`
`Dr. Murthy testified that “[t]he information that’s . . . provided in
`
`Austin is all [that] a POSITA would need . . . to take the molecule further and
`
`develop a potential medication for the treatment of onychomycosis.” (Ex. 2207
`
`at 657:21-24, emphasis added.) While Dr. Murthy testified that Austin alone
`
`provides a reasonable expectation of success for each limitation of claims 1, 4 and
`
`6 of the ’621 Patent (see id. at 658:20-661:22), Dr. Murthy further testified that
`
`“the claims were obvious, not only in Austin, it was also when combined with
`
`Brehove and Freeman and other references” (id. at 758:22-759:3). This testimony
`
`is relevant because Petitioner never argued that claims 1, 4 and 6 of the ’621 Patent
`
`were unpatentable under 35 U.S.C. § 102 over Austin alone (see Paper No. 1 at 8;
`
`Paper No. 24 at 4, 15-16); rather, that the claims are unpatentable based on a 35
`
`U.S.C. § 103 combination of references (Paper No. 1 at 8; Paper No. 47 at 1, 28).
`
`3.
`
`In contrast to Patent Owner’s allegation that Austin is not relevant or
`
`analogous art, Dr. Murthy testified that “treating industrial fungus and nail fungus
`
`is almost the same field. It’s . . . overlapping fields.” (Ex. 2207 at 717:9-11.) When
`
`asked to elaborate, Dr. Murthy stated: “Well . . . in Austin, he discloses how the
`
`boron-containing compounds can be used for treating fungus. So the fungus that he
`
`discloses is one of the human pathogens, and that human pathogen is . . . one of the
`
`organisms causing onychomycosis. So there’s a lot of relevance between Austin
`
`and ’621 patent.” (Id. at 717:13-19.) Dr. Murthy further testified that “Austin and
`
`
`
`2
`
`
`
`IPR2015-01776
`Patents 7,582,621
`
`the patent owner of ’621 are both trying to develop fungicides, and those fungal
`
`organisms are the most common human pathogens. So the considerations would
`
`not be very different between these two inventions.” (Id. at 724:7-11.) This
`
`testimony is relevant because it rebuts Patent Owner’s allegation that Austin is not
`
`relevant or analogous art. (See Paper No. 32 at 27-33.) Petitioner agrees with Dr.
`
`Murthy that Austin is relevant prior art, or at a minimum analogous prior art, to the
`
`’621 Patent. (See Paper No. 47 at 2, 11-12.)
`
`4.
`
`Dr. Murthy stated that he was not an expert in mycology. (See Ex.
`
`2207 at 651:23-24.) Despite Patent Owner’s assertion, this testimony is irrelevant
`
`because Dr. Murthy’s obviousness analysis does not require expertise in mycology
`
`(see Paper No. 1 at 23), nor does Patent Owner’s proposed definition of a person of
`
`ordinary skill in the art require expertise in mycology (see Paper No. 17 at 16;
`
`Paper No. 32 at 21-22). Rather, when questioned about paragraph 90 of his
`
`declaration (which discusses various antifungal drugs that exhibit better
`
`effectiveness against dermatophytes than against C. albicans), Dr. Murthy replied
`
`that this is “general information [in] my background knowledge, so it doesn’t
`
`require a mycologist to understand.” (Ex. 1044 ¶ 90; Ex. 2207 at 649:18-650:2.)
`
`With respect to understanding and evaluating MIC data, Dr. Murthy stated that this
`
`was also part of his background knowledge. (See Ex. 2207 at 684:21-24.) This
`
`
`
`3
`
`
`
`IPR2015-01776
`Patents 7,582,621
`
`testimony is relevant because it supports Dr. Murthy’s qualifications to conduct an
`
`obviousness analysis of the claims of the ’621 Patent.
`
`5.
`
`Petitioner does not agree with Patent Owner’s characterization of the
`
`record. Dr. Murthy previously opined that tavaborole, within the context of boron-
`
`containing antifungals and in view of shared antifungal activity against Candida
`
`species, would be expected to share other activities with the boron compounds of
`
`Brehove and Freeman, “such as the inhibition of additional fungi responsible for
`
`onychomycosis.” (Ex. 1008 ¶¶ 100-01, 133.) Although Dr. Murthy confirmed
`
`during his first deposition that most antifungals exhibit broad spectrum activity
`
`against different fungi, including dermatophytes and Candida species (see Ex.
`
`2032 at 531:8-535:21), the Patent Owner argued that antifungal activity against C.
`
`albicans was not predictive of activity against dermatophytes, citing a reference
`
`concerning non- boron-based antifungals (see Paper 32 at 11, 44-46; Ex. 2035 ¶¶
`
`63-64, 114, 123, 132). During his second deposition, Dr. Murthy’s testified that,
`
`“because most of . . . the antifungal drugs that are effective against C. albicans are
`
`also effective against dermatophytes . . . the POSA would be motivated to select
`
`tavaborole as a potential therapeutic model for treating onychomycosis.” (Ex. 2207
`
`at 711:2-8, emphasis added; see also id. at 697:11-698:3, 699:12-25, 702:15-21.)
`
`This testimony is relevant because it rebuts Patent Owner’s arguments that
`
`
`
`4
`
`
`
`IPR2015-01776
`Patents 7,582,621
`
`antifungal activity against C. albicans is not predictive of activity against
`
`dermatophytes. (See Paper 32 at 11, 44-46; see also Ex. 1044 ¶¶ 89-93.)
`
`6.
`
`Dr. Murthy stated that “if I know . . . the molecular weight of the
`
`substance and the MIC value, I would be in a position to decide whether to
`
`consider this molecule for product development or not” (Ex. 2207 at 668:7-11),
`
`and further that “as the molecular weight increases, the penetrability decreases. So
`
`if . . . the molecule is able to penetrate at levels about MIC values, then it will be
`
`effective against the fungus” (id. at 668:18-22). This testimony is relevant because,
`
`consistent with his testimony above, Dr. Murthy previously opined that nail
`
`penetration is inversely related to molecular weight, as shown by Murdan (citing
`
`Mertin & Lippold). (See Ex. 1008 ¶¶ 95, 102; Ex. 2032 at 513:11-516:2; Ex. 1028
`
`at 9-10.) In view of the fact that tavaborole has similar or lower molecular weight
`
`than the compounds of Freeman and Brehove, Dr. Murthy stated that tavaborole
`
`would likely penetrate the nail at least as well or better than these compounds. (Ex.
`
`1008 ¶¶ 95, 102, 134.) However, Patent Owner argued that nail penetration was
`
`unpredictable and required test data for numerous other factors in addition to
`
`molecular weight. (Paper 32 at 47-49; Ex. 2036 ¶¶ 22-29.) In rebuttal, Dr. Murthy
`
`cited additional prior art evidence that was summarized by Murdan (Ex. 1028),
`
`including Mertin & Lippold (Ex. 1065) and Kobayashi (Ex. 1076), to establish that
`
`molecular weight and MIC data enable a POSITA to predict whether a compound
`
`
`
`5
`
`
`
`IPR2015-01776
`Patents 7,582,621
`
`could sufficiently penetrate the nail to successfully treat onychomycosis. (See
`
`Paper 47 at 17-21; Ex. 1044 ¶¶ 68-72, 81; Ex. 1065 at 3; Ex. 1076 at 7.)
`
`7. While Dr. Murthy testified that he knew about Mertin & Lippold
`
`since he started working in the field of nail penetration (see Ex. 2207 at 670:1-7)
`
`and Kobayashi since before this proceeding (id. at 746:14-747:1), he stated that
`
`“Mertin and Lippold is cited by Murdan. So probably that’s the reason I did not
`
`cite Mertin and Lippold, why they are not in the first declaration” (id. at 670:19-
`
`21). This testimony is relevant because Dr. Murthy originally cited Murdan (Ex.
`
`1028) to establish that nail penetration is inversely related to molecular weight (see
`
`Ex. 1008 ¶¶ 95, 102 ), but Patent Owner argued that nail penetration was
`
`unpredictable and required test data for numerous other factors in addition to
`
`molecular weight (see Paper 32 at 47-49; Ex. 2036 ¶¶ 22-29). Dr. Murthy cited
`
`Mertin & Lippold (Ex. 1065) and Kobayashi (Ex. 1076) in his reply declaration to
`
`establish that nail penetration was indeed predictable based on molecular weight.
`
`(See Ex. 1044 ¶¶ 68-72, 81; Ex. 1065 at 3; Ex. 1076 at 7.)
`
`8.
`
`Petitioner does not agree with Patent Owner’s characterization that
`
`Dr. Murthy “affirmed that toxicity concerns would play no role in a POSA’s
`
`evaluation of potential molecules to treat onychomycosis.” (Paper No. 56 ¶ 8,
`
`emphasis added.) Rather, in response to Patent Owner’s questions about
`
`formulating a molecule for transungual delivery, Dr. Murthy testified that “I
`
`
`
`6
`
`
`
`IPR2015-01776
`Patents 7,582,621
`
`wouldn’t be much concerned about the toxicity, because . . . when you deliver [a
`
`drug] topically, the amount of drug that penetrates – that gets into systemic
`
`circulation would be negligible. It’s true in my own experience.” (Ex. 2207 at
`
`676:23-677:8, emphasis added.) This testimony is relevant because Petitioner
`
`argued that boron compounds were generally safe and that topical formulations
`
`could avoid the unacceptable risks associated with oral administration. (Paper 1 at
`
`10, 19-20, 48; Ex. 1028 at 2; Ex. 1006 ¶¶ 30, 44; Ex. 1008 ¶ 135.) In response,
`
`Patent Owner argued that boron compounds were considered toxic, citing
`
`numerous references directed to high-dosage, oral and/or intravenous
`
`administration of boron compounds. (Paper 32 at 11-17; Ex. 2034 ¶¶ 40, 67-68, 92,
`
`96.) In rebuttal, Dr. Murthy stated that toxicity is generally not a concern for
`
`topical administration of drugs, as claimed by the ’621 Patent. (Ex. 1044 ¶ 46; Ex.
`
`1028 at 21; Ex. 2050 at 2, 9).
`
`9.
`
`Petitioner agrees with Dr. Murthy’s testimony that keratin binding “is
`
`one of the factors that influence permeation of molecules.” (Ex. 2207 at 673:17-
`
`20.) Dr. Murthy further stated that “[w]hen I say ‘influencing factors’ only, we
`
`have a control over these factors. We can manipulate these factors by the way of –
`
`you know, formulation.” (Id. at 676:2-5.) Dr. Murthy further testified that “[i]f a
`
`molecule has a low MIC value, you’ll be able to deliver effective amounts of drug,
`
`despite the molecule has a high affinity to keratin binding.” (Id. at 673:13-16.)
`
`
`
`7
`
`
`
`IPR2015-01776
`Patents 7,582,621
`
`When asked what one would need to know to have a reasonable expectation of
`
`successfully treating onychomycosis, Dr. Murthy testified that “the primary factor
`
`that would determine the penetrability of a molecule across the nail plate is the
`
`molecular weight.” (Id. at 675:17-19.) This testimony is relevant because, in light
`
`of the MIC and molecular weight of tavaborole disclosed by Austin, Dr. Murthy
`
`testified that “[t]he information that’s . . . provided in Austin is all [that] a POSITA
`
`would need . . . to take the molecule further and develop a potential medication for
`
`the treatment of onychomycosis.” (Ex. 2207 at 657:21-24; see also Ex. 1044 ¶¶ 44,
`
`81, 93.)
`
`10. Petitioner agrees with Dr. Murthy’s testimony that solubility of a
`
`compound is a factor influencing nail penetration. (See Ex. 2207 at 675:11-676:1.)
`
`Dr. Murthy further testified: “We have several approaches to enhance the solubility
`
`of drug molecules: Converting into solvents, using cosolvents, changing pH,
`
`composition, several approaches that are available.” (Id. at 676:12-15.) Although
`
`Dr. Murthy agreed with the equations for the efficacy coefficient and maximum
`
`flux disclosed by Mertin & Lippold (see id. at 736:21-737:8), Dr. Murthy stated:
`
`“[Solubility is] not really a requirement for the molecule to be penetrable across
`
`the nail plate. I know the molecular weight of tavaborole, I would be able to
`
`predict the . . . penetrability of that molecule across the nail plate. If it’s not
`
`soluble, I know how to render it soluble in the formulation.” (Id. at 736:11-17).
`
`
`
`8
`
`
`
`IPR2015-01776
`Patents 7,582,621
`
`This testimony is relevant because Dr. Murthy testified that “[t]he information
`
`that’s . . . provided in Austin is all [that] a POSITA would need to . . . take the
`
`molecule further and develop a potential medication for the treatment of
`
`onychomycosis.” (Ex. 2207 at 657:21-24; see also Ex. 1044 ¶¶ 44, 81, 93.)
`
`11. Dr. Murthy agreed that the highest predicted efficacies against
`
`dermatophytes and yeasts reported by Mertin & Lippold were for antifungal drugs
`
`having high inherent water solubilities. (See Ex. 2207 at 742:2-7.) Dr. Murthy
`
`testified that “inherent water solubility” is the water solubility of a compound that
`
`has not been manipulated by formulation. (See id. at 742:6-12.) However,
`
`Petitioner does not agree with Patent Owner’s statement that the above testimony
`
`“shows that an antifungal compound must be reasonably water soluble in order to
`
`be efficacious.” (Paper No. 56 at ¶ 11, emphasis added.) Rather, as Dr. Murthy
`
`testified: “[Solubility is] not really a requirement for the molecule to be penetrable
`
`across the nail plate. I know the molecular weight of tavaborole, I would be able to
`
`predict the . . . penetrability of that molecule across the nail plate. If it’s not
`
`soluble, I know how to render it soluble in the formulation.” (Ex. 2207 at 736:11-
`
`17.) Dr. Murthy also stated: “as the molecular weight increases, the penetrability
`
`decreases. So if . . . the molecule is able to penetrate at levels about MIC values,
`
`then it will be effective against the fungus.” (Id. at 668:18-22.) This testimony is
`
`relevant because, in light of the MIC and molecular weight of tavaborole disclosed
`
`
`
`9
`
`
`
`IPR2015-01776
`Patents 7,582,621
`
`by Austin, Dr. Murthy testified that “[t]he information . . . that’s provided in Austin
`
`is all [that] a POSITA would need . . . to take the molecule further and develop a
`
`potential medication for the treatment of onychomycosis.” (Ex. 2207 at 657:21-24;
`
`see also Ex. 1044 ¶¶ 44, 81, 93.)
`
`12. Petitioner agrees with Dr. Murthy’s testimony that a POSITA would
`
`be able to determine whether there is a reasonable expectation of successfully
`
`treating onychomycosis based on a compound’s MIC against C. albicans and its
`
`molecular weight. (Ex. 2207 at 657:21-24.) However, Patent Owner asked “if
`
`there’s an increase in molecular weight, how is it possible to predict to what
`
`extent your MIC needs to go lower in order to maintain efficacy through the nail?”
`
`(Id. at 681:12-16.) Dr. Murthy responded that “[a] person of ordinary skill in the
`
`art would . . . have a background knowledge about how much the MIC should be
`
`and, you know, to what extent the molecule would penetrate and would be able to .
`
`. . make a decision on whether to pursue with the molecule or not.” (Id. at 684:6-
`
`12.) Dr. Murthy further stated that “I think there’s no need to go by algorithms to
`
`determine whether a molecule is really a good candidate for product development,
`
`because during product development, we try to work around all the limitations in
`
`the molecule and develop a product that is efficacious.” (Id. at 682:20-25.) This
`
`testimony is relevant because it refutes Patent Owner’s assertion that Dr. Murthy
`
`
`
`10
`
`
`
`IPR2015-01776
`Patents 7,582,621
`
`was “unable” to explain how variations in MIC or molecular weight affect his
`
`analysis. (See Paper No. 56 ¶ 12.)
`
`13. Petitioner agrees with Dr. Murthy’s testimony that Patent Owner’s Ex.
`
`2157, a paper authored by the inventors of the ’621 Patent announcing the alleged
`
`discovery and development of tavaborole for treatment of onychomycosis, was not
`
`available to a POSITA in 2005. (See Ex. 2207 at 719:4-8.) Dr. Murthy testified that
`
`that “I mentioned in my declaration that the patent owners were [aware] of Austin
`
`and the tavaborole molecule disclosed in Austin.” (Id. at 720:21-23.) This
`
`testimony is relevant because Patent Owner argued that Austin was not relevant or
`
`analogous prior art (see Paper No. 32 at 27-33), yet the inventors of the ’621 Patent
`
`relied on Austin to synthesize the 7-fluoro benzoxaborole derivative and cited
`
`Austin in their paper announcing their alleged discovery of 5-fluoro benzoxaborole
`
`(i.e., tavaborole) for use in treatment of onychomycosis (Ex. 2207 at 719:20-
`
`720:3), which supports the relevance of Austin to the development of a
`
`pharmaceutical to treat onychomycosis.
`
`14. Dr. Murthy testified that the MIC value for tavaborole was “middle of
`
`the pack” as compared to MIC values for various commercial antimycotics tested
`
`in Table 2 of Mertin & Lippold (Ex. 1065), including Amorolfine, Bifonazole,
`
`Ciclopirox, Clotrimazole, Econazole, Griseofulvin, Ketoconazole, Naftifine,
`
`Nystatin and Tolnaftate. (See Ex. 2207 at 740:10-25; Ex. 1065 at 5, Table 2.)
`
`
`
`11
`
`
`
`IPR2015-01776
`Patents 7,582,621
`
`Contrary to Patent Owner’s assertion, this testimony is relevant because it shows
`
`that the MIC of tavaborole is comparable to other commercial antimycotics and
`
`supports Petitioner’s Reply Brief that Austin discloses “potent antifungal activity”
`
`for tavaborole. (Paper No. 47 at 2.)
`
`Respectfully submitted,
`
`MERCHANT & GOULD, P.C.
`
`Respectfully submitted,
`
`
`
`
`
`By:
`Jeffrey D. Blake, Esq. Reg. No. 58,884
`Kathleen E. Ott, Esq. Reg. No. 64,038
`Peter A. Gergely, Esq. (Pro Hac Vice)
`Ryan J. Fletcher, Esq., Ph.D. (Pro Hac Vice)
`Brent E. Routman, Esq. (Pro Hac Vice)
`Merchant & Gould P.C.
`191 Peachtree Street N.E., Suite 4300
`Atlanta, GA 30303
`Main Telephone: (404) 954-5100
`Main Facsimile: (404) 954-5099
`
`Counsel for Petitioner
`
`
`
`12
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`
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`
`Date: October 11, 2016
`
`
`
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`IPR2015-01776
`Patents 7,582,621
`
`
`CERTIFICATE OF SERVICE
`
`Pursuant to 37 C.F.R. § 42.6(e), the undersigned certifies that on October 11,
`
`2016, a complete and entire copy of PETITIONER’S RESPONSE TO PATENT
`
`OWNER’S MOTION FOR OBSERVATIONS REGARDING THE CROSS-
`
`EXAMINATION TESTIMONY OF S. NARASIMHA MURTHY, PH.D. was
`
`served by email, by agreement of the parties to:
`
`areister@cov.com; and
`elongton@cov.com.
`
`
`
`Respectfully submitted,
`
`MERCHANT & GOULD P.C.
`
`
`
`
` By:
`
`
`
`
`
` Counsel for Petitioner
`
`
`
`
`
`13
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