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 Nos. IPR2018-00168, -00169, -00170, and -001711
`
`U.S. Patent Nos. 9,549,938, 9,566,289, 9,566,290, and 9,572,823
`______________________
`
`DECLARATION OF NARASIMHA MURTHY, PH.D
`IN SUPPORT OF PETITIONER’S REPLY TO PATENT OWNER’S
`RESPONSE
`
`1 Case Nos. IPR2018-01358, -01359, -01360, and -01361 have been joined with
`these proceedings.
`
`FlatWing Ex. 1048, p. 1
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`FLATWING PHARMACEUTICALS, LLC and
`MYLAN PHARMACEUTICALS, INC.,
`Petitioners,
`
`v.
`
`ANACOR PHARMACEUTICALS, INC.,
`Patent Owner.
`
`Case Nos. IPR2018-00168, -00169, -00170, and -001711
`
`U.S. Patent Nos. 9,549,938, 9,566,289, 9,566,290, and 9,572,823
`______________________
`
`DECLARATION OF NARASIMHA MURTHY, PH.D
`IN SUPPORT OF PETITIONER’S REPLY TO PATENT OWNER’S
`RESPONSE
`
`1 Case Nos. IPR2018-01358, -01359, -01360, and -01361 have been joined with
`these proceedings.
`
`FlatWing Ex. 1048, p. 1
`
`
`
`1.
`
`I, S. Narsimha Murthy, Ph.D., hereby declare that the following is true
`
`and correct. I previously provided a Declaration filed as Ex. 1005 in support of
`
`Paper #1, Petition for Inter Partes Review (“Petition”), and my testimony from that
`
`first Declaration remains the same. I am competent to make this Declaration based
`
`upon my personal knowledge and technical expertise, which I addressed in my first
`
`declaration.
`
`2.
`
`A person of ordinary skill in the art (“POSA”) would not have been
`
`surprised to learn that 5% by weight of tavaborole is an appropriate concentration
`
`in a topically applied composition for the treatment of onychomycosis. An active
`
`ingredient concentration of 5% by weight is well within the range of values that a
`
`person of ordinary skill in the art would have considered to be typical in view of
`
`the prior art.
`
`3.
`
`Austin discloses ranges of tavaborole encompassing 5% as an
`
`effective biocide (Ex. 1007, Austin 9:5–9), as noted in my initial testimony, and as
`
`Dr. Lane agrees. 2 The ranges Austin discloses specifically include a 5% solution as
`
`2 See previous declaration testimony in IPR2018-00168 (Ex. 1005, ¶ 191; Ex.
`
`2014, ¶ 58, 68 (“within a certain weight percent range encompassing the 5%
`
`w/w”)), in IPR2018-00169 (Ex. 1005, ¶ 278; Ex. 2014, ¶ 61, 71), in IPR2018-
`
`1
`
`FlatWing Ex. 1048, p. 2
`
`
`
`the endpoint of a preferred range of an effective anti-fungal. (Ex. 1007, Austin 9:5–
`
`9.)
`
`4.
`
`The fact that Austin discloses a “preferably” broader range that
`
`encompasses 5%, and “especially” an intermediate range that specifically and
`
`explicitly recites 5% as an endpoint, and “more especially” a narrower range would
`
`not have discouraged a POSA from trying a 5% solution or in any manner taught
`
`away from a 5% solution.
`
`5.
`
`Instead, the overlapping ranges in Austin that encompass and even
`
`expressly recite a 5% solution as an effective biocide would have encouraged a
`
`POSA to include that percentage solution in routine dose ranging studies. In light
`
`of Austin in combination with other references as explained in my initial testimony
`
`and the Petition, it would have been obvious to a POSA at the time of the alleged
`
`invention to try a 5% solution in routine dose ranging studies.
`
`6.
`
`Dr. Lane testifies that Austin “is not directed to topical (or even
`
`pharmaceutical) compositions,” but Austin includes disclosures (including those set
`
`forth in ¶¶ 7–9 infra) that, in combination with the other references cited, would
`
`suggest a topical pharmaceutical formulation to a POSA.
`
`00170 (Ex. 1005, ¶ 143; Ex. 2014, ¶ 62, 72), and in IPR2018-00171 (Ex. 1005, ¶
`
`138; Ex. 2014, ¶ 56, 66).
`
`2
`
`FlatWing Ex. 1048, p. 3
`
`
`
`7.
`
`Austin discloses that while tavaborole “may be used in undiluted
`
`form” it is “preferably formulated in a composition included a carrier” which “is
`
`generally selected so that the biocide composition is compatible with the medium
`
`to be selected.” (Ex. 1007, Austin at 8:11–12, 24–25.) A POSA would understand
`
`from reading Austin, in combination with other references cited including Brehove,
`
`that a topical pharmaceutical formulation is an example such a “carrier” applied to
`
`the selected “medium” of the nail.
`
`8.
`
`Austin further discloses:
`
`If the medium to be protected is an aqueous medium, the carrier is
`preferably water or a water-miscible organic solvent or mixture
`thereof. Examples of suitable water-miscible organic solvents are
`acetic acid, N,N-dimethylformamide, dimethylsulphoxide, N-methyl-
`2-pyrrolidine, alcohols such as ethanol or glycols such as ethylene
`glycol, propylene glycol and dipropylene glycol and lower C1-4-alkyl
`carbitols such as methyl carbitol.
`
`(Ex. 1007, Austin at 8:32–38.) Dr. Lane agrees that the nail is such an “aqueous
`
`environment” testifying that the “nail plate has been described as a hydrophilic gel
`
`membrane, or a hydrogel” and that “water content of the nail is an important factor
`
`in ensuring appropriate integrity and function of this tissue.”3 Dr. Reider agrees,
`
`3 See declaration testimony in IPR2018-00168 (Ex. 2014, ¶¶ 24 (“The water
`
`content of the nail is an important factor in ensuring appropriate integrity and
`
`3
`
`FlatWing Ex. 1048, p. 4
`
`
`
`testifying that “[n]ail also contains a relatively high level of water content.”4 A
`
`POSA at the time of the alleged invention would have read these passages from
`
`Austin, in combination with the other references cites, as suggesting application to
`
`the nail with a reasonable expectation of success in the ranges disclosed, or at a
`
`minimum as providing a reasonable expectation of success in including the 5%
`
`solution disclosed in a routine dose ranging study.
`
`9.
`
`I am informed that the Board has previously determined that “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); that 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, 21, 23; see also, Ex. 1014 at 28 (same finding for
`
`Freeman)) and “would have had a reasonable expectation that administering
`
`function of this tissue.”), 48 (“the aqueous environment of the nail”)), in IPR2018-
`
`00169 (Ex. 2014, ¶ 27, 51), in IPR2018-00170 (Ex. 2014, ¶ 28, 52), and in
`
`IPR2018-00171 (Ex. 2014, ¶ 22, 46).
`
`4 See declaration testimony in IPR2018-00168 (Ex. 2013, ¶ 41), in IPR2018-00169
`
`(Ex. 2013, ¶ 44), in IPR2018-00170 (Ex. 2013, ¶ 45), and in IPR2018-00171 (Ex.
`
`2013, ¶ 39).
`
`4
`
`FlatWing Ex. 1048, p. 5
`
`
`
`tavaborole topically would penetrate the nail,” (Ex. 1014 at 24). I agree with these
`
`previous findings by the Board, and which are fully consistent with my opinion
`
`that a POSA at the time of the alleged invention would have read these passages
`
`from Austin, in combination with the other references cites, as suggesting
`
`application to the nail with a reasonable expectation of success in the ranges
`
`disclosed, including at a 5% solution, or at a minimum as providing a reasonable
`
`expectation of success in including the 5% solution in a routine dose ranging study.
`
`10.
`
`Brehove (Ex. 1008) teaches the effectiveness of its organo-boron
`
`compounds against Candida albicans at concentrations of 0.1%, 1%, 10%, 25%,
`
`50%, and 75%, and in combinations at 25% of the combined active ingredients.
`
`(Ex. 1008 at ¶ [0032], Table 1) It discloses and claims “concentration of the active
`
`ingredient is at least about 0.1 wt%” (Ex. 1008 at 5, Claim 11) and in ranges of
`
`“between 0.1 wt % and 75 wt %” (Ex. 1008 at 5, Claim 12), “between 0.1 wt %
`
`and 50 wt %” (Ex. 1008 at 5, Claim 13), and “between 0.1 wt% and 25 wt%”
`
`(Ex. 1008 at 5, Claim 14). An active ingredient concentration of 5% by weight falls
`
`within the range taught by Brehove, and a POSA reading Brehove, in combination
`
`with theother references cited, would have a reasonable expectation of success in
`
`topical application of tavaborole to the nail to treat nail fungus in the ranges
`
`disclosed, including at a 5% solution, or at a minimum as providing a reasonable
`
`expectation of success in including the 5% solution in a routine dose ranging study.
`
`5
`
`FlatWing Ex. 1048, p. 6
`
`
`
`11. Dr. Lane testifies that Brehove (Ex. 1008) “purports to obtain
`
`cosmetic or superficial cure without identifying the pretreatment state of the nail,
`
`the severity of infection or whether the infection is superficially localized,”5 that
`
`“would not have reasonably demonstrated to a POSA in 2005 that Brehove’s
`
`compounds effectively penetrate the nail,” and “it would be an elementary mistake
`
`to conflate cosmetic or superficial cure with actual nail penetration,”6; and that its
`
`“observations regarding cosmetic cure of onychomycosis in humans are based on
`
`only superficial examination, with no clinical reports or testing,”7 apparently
`
`disputing the sufficiency of visual inspection to confirm treatment and also the
`
`expectation of success in penetrating the nail. It is my understanding that the Board
`
`5 See declaration testimony in IPR2018-00168 (Ex. 2014, ¶¶ 54), in IPR2018-
`
`00169 (Ex. 2014, ¶ 57), in IPR2018-00170 (Ex. 2014, ¶ 58), and in IPR2018-
`
`00171 (Ex. 2014, ¶ 52).
`
`6 See declaration testimony in IPR2018-00168 (Ex. 2014, ¶ 54), in IPR2018-00169
`
`(Ex. 2014, ¶ 57), in IPR2018-00170 (Ex. 2014, ¶ 58), and in IPR2018-00171 (Ex.
`
`2014, ¶ 52).
`
`7 See declaration testimony in IPR2018-00168 (Ex. 2014, ¶ 60), in IPR2018-00169
`
`(Ex. 2014, ¶ 63), in IPR2018-00170 (Ex. 2014, ¶ 64), and in IPR2018-00171 (Ex.
`
`2014, ¶ 58).
`
`6
`
`FlatWing Ex. 1048, p. 7
`
`
`
`has previously determined that upon reading Brehove, in combination with the
`
`other references cited, a POSA “would have had a reasonable expectation that
`
`administering tavaborole topically would penetrate the nail” (Ex. 1014 at 24). It is
`
`my understanding that the Board has also previously determined:
`
`Having reviewed the complete record, we find that
`Brehove reasonably suggests administering Biobor to
`treat onychomycosis. We are persuaded by Dr. Murthy’s
`testimony that it is reasonable to assume that where
`Brehove states a volunteer “has onychomycosis,” that the
`volunteer was diagnosed before treatment. Ex. 1044 ¶ 51
`(citing Ex. 1003 ¶¶ 34–38). Dr. Murthy explains why this
`belief is reasonable, stating Brehove describes symptoms
`in the patients that are associated with onychomycosis,
`such as detachment of the nail from the nail bed. Id.
`Similarly, we credit Dr. Murthy’s testimony that where
`Brehove states the compositions “are effective in curing
`the onychomycosis without skin irritation and evidence
`side effects,” he takes those statements to be true. Id. ¶
`52. Dr. Murthy’s belief is reasonable in light of
`Brehove’s description of the “clear zone in the treated
`nail,” which is similar to observations made by others,
`including the inventors. Id. (citing Ex. 1003 ¶¶ 34–38;
`Ex. 1066, 2; Ex. 2001, 5; Ex. 2065, 943). As such, we are
`not persuaded that the alleged inaccuracies, unexplained
`data, and prophetic examples identified by Patent Owner
`
`7
`
`FlatWing Ex. 1048, p. 8
`
`
`
`(PO Resp. 37–39) detract from these teachings of
`Brehove.
`
`(Ex. 1014 at 20.) I agree with the Board’s previous determination, contrary to Dr.
`
`Lane’s current testimony, that Brehove reasonably discloses to a POSA (i) the
`
`existence of a nail infection before treatment, (ii) treatment penetrating the nail,
`
`and (iii) treatment efficacy confirmed by a visual inspection observing a clear zone
`
`in the treated nail, which is fully consistent with my opinion that a POSA reading
`
`Brehove, in combination with other references cited, would have a reasonable
`
`expectation of success in topical application of tavaborole to the nail to treat nail
`
`fungus in the ranges disclosed, including at a 5% solution, or at a minimum as
`
`providing a reasonable expectation of success in including the 5% solution in a
`
`routine dose ranging study.
`
`12.
`
`Freeman discloses ranges of tavaborole encompassing 5% as an
`
`effective biocide (Ex. 1009, Freeman ¶ [0064]), as noted in my initial testimony,
`
`and as Dr. Lane agrees. 8 Although Dr. Lane further opines that the range in
`
`8 See previous declaration testimony in IPR2018-00168 (Ex. 1005, ¶ 147; Ex.
`
`2014, ¶ 62, 68), in IPR2018-00169 (Ex. 1005, ¶ 220; Ex. 2014, ¶ 61, 71), in
`
`IPR2018-00170 (Ex. 1005, ¶ 175; Ex. 2014, ¶ 62, 72), and in IPR2018-00171 (Ex.
`
`1005, ¶ 151; Ex. 2014, ¶ 56, 66).
`
`8
`
`FlatWing Ex. 1048, p. 9
`
`
`
`Freeman is “exceptionally broad” and “would not have led a POSA to any
`
`particular percent composition, much less 5%,”9 such a broad range would have
`
`indicated to a POSA a reasonable likelihood of success across a broad range for
`
`any given value through a routine dose ranging study.
`
`13. Neither Dr. Lane nor Dr. Reider disputes that a POSA would have had
`
`a reasonable expectation of combining Austin in view of Brehove (or Austin in
`
`view of Freeman) with Samour’s disclosure of topical antifungal preparations at
`
`dosages including 5%. It is undisputed that Samour discloses a nail lacquer usable
`
`as a vehicle for antifungal agents like tavaborole, with “no particular limitation on
`
`the antifungal agents used in the compositions of this invention; any of the agents
`
`known to be effective for this purpose may be used . . . .” (Ex. 1010, Samour
`
`col. 11:39–41.) Dr. Lane agrees that Samour indicates “amounts of active
`
`antifungal agent in the range of from about 0.5 to 20 percent by weight, preferably
`
`from about 1 to 10 percent, by weight of the total composition (including solvents,
`
`9 See previous declaration testimony in IPR2018-00168 (Ex. 2014, ¶ 68), in
`
`IPR2018-00169 (Ex. 2014, ¶ 61), in IPR2018-00170 (Ex. 2014, ¶ 72), and in
`
`IPR2018-00171 (Ex. 2014, ¶ 66).
`
`9
`
`FlatWing Ex. 1048, p. 10
`
`
`
`film forming polymer, enhancer, etc.) will suffice.”10 Samour goes on to indicate
`
`that “the amount of active agent is generally about 1 to 50%, preferably about 2 to
`
`35%, more preferably, from about 2 to 30%, especially preferably from about 5
`
`to 20% . . . .” (Ex. 1010, col.12:23–26.) Thus, Samour includes 5% as one of the
`
`endpoints in the range “especially preferably” disclosed. It discloses lacquers with
`
`5% active ingredient in columns 3–21 of Table I (Ex. 1010, cols. 14–16.) It
`
`specifically discloses 5% active ingredient in Example 4 (Ex. 1010, col. 20:30–36),
`
`Example 5 (Ex. 1010, col. 21:1–13), Example 6 (Ex. 1010, col. 21:50–65),
`
`Example 8 (Ex. 1010, col. 21:60–24:10), Example 9 (Ex. 1010, col. 24:30–40),
`
`Example 10 (Ex. 1010, col. 25:30–35), and Example 11 (Ex. 1010, col. 21:63–67).
`
`Samour therefore specifically discloses an active ingredient of 5%.
`
`14. Although Dr. Lane opines that higher concentration solutions deliver
`
`more active ingredient through the nail, she does not testify that a 5% solution
`
`would deliver insufficient active ingredient to be effective. On the contrary, based
`
`on the teachings of Samour, read together with the other references relied upon, a
`
`POSA would have had a reasonable expectation of success that a 5% solution of
`
`10 Ex. 1010 col. 10:9–13; See Dr. Lane’s testimony in IPR2018-00168 (Ex. 2014,
`
`¶ 66), in IPR2018-00169 (Ex. 2014, ¶ 59), in IPR2018-00170 (Ex. 2014, ¶ 70), and
`
`in IPR2018-00171 (Ex. 2014, ¶ 64)
`
`10
`
`FlatWing Ex. 1048, p. 11
`
`
`
`tavaborole would be effective to treat a nail fungus, and at a minimum would have
`
`been motivated to include a 5% solution in a routine dose ranging study.
`
`15. Contrary to the testimony offered by Dr. Lane, a POSA would not
`
`have sought to prepare a formulation having the highest possible concentration of
`
`the active ingredient. As a POSA would have understood, there are a number of
`
`important factors that weigh in favor of using the lowest concentration that is
`
`effective to achieve the desired result (e.g., treating onychomycosis). See Ex. 1049
`
`at 1 (“Dosage forms for topical application are intended to produce the required
`
`therapeutic action at specific targets in the skin with the least probable adverse
`
`effects.”).
`
`16.
`
`For example, increasing the concentration of the active ingredient will
`
`typically decrease the overall stability of the formulation, and particularly the long-
`
`term storage stability of the formulation. A lower concentration of the active
`
`ingredient will also provide a greater safety margin relative to the safe upper limit
`
`of administration for that active ingredient. Maintaining an appropriate safety
`
`margin is particularly important for obtaining regulatory approval (e.g., approval
`
`by the Food and Drug Administration). And increasing the concentration of the
`
`active ingredient beyond the level required to achieve the desired result will result
`
`in an increased cost of manufacturing the formulation, potentially without
`
`11
`
`FlatWing Ex. 1048, p. 12
`
`
`
`providing any additional benefit to the consumer. These factors are well-
`
`understood by POSA.
`
`17. A POSA therefore would have, at a minimum, tested an active
`
`ingredient concentration of 5% by weight as part of a routine dose ranging study. I
`
`am not aware of any surprising or unexpected benefits that are obtained by using a
`
`tavaborole concentration of 5% by weight, as compared to other reasonable
`
`concentrations that would have been considered by a POSA.
`
`18. Dose ranging studies are a routine part of the drug development
`
`process, and are well understood by those skilled in the art. In particular, the data
`
`collected as part of dose ranging studies are typically submitted to the Food and
`
`Drug Administration as part of the process for obtaining regulatory approval for
`
`new pharmaceuticals. As an example, the standardized “Clinical Filing Checklist
`
`For NDA” indicates that the results of “appropriately designed dose-ranging
`
`studies” should typically be included as part of the submission for obtaining
`
`regulatory approval. Ex. 1040 at 102 (“13. If needed, has the applicant made an
`
`appropriate attempt to determine the correct dosage and schedule for this product
`
`(i.e., appropriately designed dose-ranging studies)?”).
`
`19.
`
`The dose ranging studies that were conducted on tavaborole as part of
`
`the approval process for Kerydin were of a routine and ordinary nature, and are
`
`representative of the dose ranging studies typically conducted by those skilled in
`
`12
`
`FlatWing Ex. 1048, p. 13
`
`
`
`the art. (Ex. 1040 at 67 (“During development, 1500 subjects were exposed to
`
`tavaborole solution in various concentrations and dosing regimens”); id. (“The
`
`applicant conducted three dose ranging phase 2 studies that explored tavaborole
`
`solutions of 1%, 2.5%, 5%, and 7.5% applied topically once daily or three times
`
`per week for total of 180 to 360 days.”)). The description of the first study
`
`conducted by the applicants for Kerydin, AN2690-ONYC-201, is typical of dose
`
`ranging studies that are frequently conducted as part of the regulatory approval
`
`process:
`
`Study AN2690-ONYC-201
`This was an open-label, dose-rising, multicenter study of subjects with
`distal, subungual onychomycosis of one great toenail. Total of 89
`subjects were treated as follows:
`Cohort 1……tavaborole solution 5% daily for 180 days
`Cohort 2……tavaborole solution 7.5% daily for 180 days
`Cohort 3……tavaborole solution 5% daily for 360 days
`(Ex. 1040 at 68.) The description of the second study conducted by the applicants
`
`for Kerydin, AN2690-ONYC-203, is also typical of dose ranging studies that are
`
`frequently conducted as part of the regulatory approval process:
`
`This was an open-label, multi-center study of subjects with distal
`subungual onychomycosis of at least one great toenail. Total of 60
`subjects were treated as follows:
`Cohort 1……tavaborole solution 1.0%, daily for 180 days
`
`13
`
`FlatWing Ex. 1048, p. 14
`
`
`
`Cohort 2……tavaborole solution 5.0%, daily for 30 days followed by
`3× weekly for 150 days.
`At the end of the 180-day treatment period, subjects classified as
`complete or partial responders were followed until Day 360 (off
`treatment).
`(Ex. 1040 at 69.) And the description of the third study conducted by the applicants
`
`for Kerydin, AN2690-ONYC-200/200A, is likewise typical of dose ranging studies
`
`that are frequently conducted as part of the regulatory approval process:
`
`This was a multi-center, randomized, double-blind, parallel-group,
`vehicle-controlled study utilizing tavaborole solutions 2.5%, 5.0%,
`and 7.5% and vehicle in adults with onychomycosis of the great
`toenail. Subjects applied study drug once daily for 90 days followed
`by 3× weekly for an additional 90 days for a total of 180 days. At the
`end of the 180-day treatment period, subjects who were classified as
`complete or partial responders were followed for an additional 180
`days off treatment.
`(Ex. 1040 at 70.) Taken together, these dose ranging studies are of a routine and
`
`ordinary nature, and are the type of study that would routinely be carried out by
`
`those skilled in the art as part of the standardized process for obtaining regulatory
`
`approval for new drugs.
`
`20.
`
`In her testimony, Dr. Lane identified other factors that may affect a
`
`compound’s ability to penetrate the nail plate and successfully treat
`
`onychomycosis, such as the compound’s log P, water solubility, and keratin
`
`14
`
`FlatWing Ex. 1048, p. 15
`
`
`
`binding affinity. I am informed that the Board previously considered this position,
`
`and determined as follows:
`
`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. . . . Dr. Murthy cites various
`references explaining that, “As expected, molecular size has an
`inverse relationship with penetration into the nail plate.”
`. . .
`Dr. Murthy’s testimony is consistent with the specification of the
`provisional application to which the ’621 patent claims priority, where
`the inventors state that “[c]ompounds with a molecular weight of less
`than 200 Da penetrate the nail plate in a manner superior to the
`commercially
`available
`treatment
`for onychomycosis.”
`. . .
`Accordingly, we determine 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 23–24.) I agree with the Board, that these factors identified by
`
`Dr. Lane are of less importance than a compound’s molecular weight, because the
`
`other factors they can be managed using routine techniques for formulating
`
`pharmaceuticals. For example, many compounds having low water solubility have
`
`15
`
`FlatWing Ex. 1048, p. 16
`
`
`
`been successfully incorporated into pharmaceutical formulations using routine
`techniques known to those ofordinary skill in the art (e.g., through the use of an
`
`appropriate solvent system). Conversely, if a molecule is too large (i.e., has a high
`
`molecular weight), it simply will not fit through the keratin matrix, no matter how
`
`it is formulated. Accordingly, as l have previously stated, a person of ordinary skill
`
`in the art will understand that molecular weight is the most important factor when
`
`evaluating a compound for the treatment of onychomycosis.
`
`:1:
`
`:1:
`
`=1:
`
`As provided in 28 U.S.C. § 1746, I declare under penalty of perjury under
`
`the laws of the United States of America that the foregoing is true and correct.
`
`
`
` Executed on: December 0 l , 2018 By: I 7 \_.~ W’LAQ
`
`
`
`
`
`16
`
`FlatWing Ex. 1048, p. 17
`FIatWing Ex. 1048, p. 17
`
`
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