I lllll llllllll Ill lllll lllll lllll lllll lllll 111111111111111111111111111111111
`US007767657B2
`
`c12) United States Patent
`Baker et al.
`
`(IO) Patent No.:
`(45) Date of Patent:
`
`US 7,767,657 B2
`Aug. 3, 2010
`
`(54) BORON-CONTAINING SMALL MOLECULES
`
`(75)
`
`Inventors: Stephen J. Baker, Mountain View, CA
`(US); Tsutomu Akama, Sunnyvale, CA
`(US); Vincent S. Hernandez,
`Watsonville, CA (US); Karin M. Hold,
`Belmont, CA (US); Kirk R. Maples,
`San Jose, CA (US); Jacob J. Plattner,
`Berkeley, CA (US); Virginia Sanders,
`San Francisco, CA (US); Yong-Kang
`Zhang, San Jose, CA (US); Gregory
`Fieldson, Morgantown, WV (US)
`
`(73) Assignee: Anacor Pharmaceuticals, Inc., Palo
`Alto, CA (US)
`
`( *) Notice:
`
`Subject to any disclaimer, the term ofthis
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 348 days.
`
`(21) Appl. No.: 11/505,591
`
`(22) Filed:
`
`Aug.16, 2006
`
`(65)
`
`Prior Publication Data
`
`US 2007/0155699 Al
`
`Jul. 5, 2007
`
`Related U.S. Application Data
`
`(63) Continuation-in-part of application No. 11/357,687,
`filed on Feb. 16, 2006.
`
`(60) Provisional application No. 60/654,060, filed on Feb.
`16, 2005, provisional application No. 60/755,227,
`filed on Dec. 30, 2005, provisional application No.
`60/746,361, filed on May 3, 2006.
`
`(30)
`
`Foreign Application Priority Data
`
`Feb. 16,2006
`
`(WO)
`
`............... PCT/US2006/005542
`
`(51)
`
`Int. Cl.
`A61K 31169
`
`(2006.01)
`
`(52) U.S. Cl. ......................................... 514/64; 558/288
`(58) Field of Classification Search ................. 558/288;
`514/64
`See application file for complete search history.
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`5,880,188 A *
`
`3/1999 Austin et al. ................ 524/109
`
`FOREIGN PATENT DOCUMENTS
`
`WO
`
`WO 2005/013892 A3
`
`212005
`
`OTHER PUBLICATIONS
`
`Austin et al., CAS: 124:234024.*
`Sudaxshina Murdan, "Drug Delivery to the Nail Following Topical
`Application," International Journal of Pharmaceutics, 236:1-26
`(2002).
`S. J. Baker, et al., "Progress on New Therapeutics for Fungal Nail
`Infections," Annual Reports in Medicinal Chemistry, 40:323-335
`(2005).
`* cited by examiner
`Primary Examiner-Rei-tsang Shiao
`(74) Attorney, Agent, or Firm-Morgan, Lewis & Bockius
`LLP
`
`(57)
`
`ABSTRACT
`
`This invention relates to compounds useful for treating fungal
`infections, more specifically topical treatment of onychomy(cid:173)
`cosis and/or cutaneous fungal infections. This invention is
`directed to compounds that are active against fungi and have
`properties that allow the compound, when placed in contact
`with a patient, to reach the particular part of the skin, nail,
`hair, claw or hoof infected by the fungus. In particular the
`present compounds have physiochemical properties that
`facilitate penetration of the nail plate.
`
`24 Claims, 63 Drawing Sheets
`
`MYLAN - Ex. 1015, p. 1
`
`

`

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`32
`
`32
`
`U.S. Patent
`
`Aug. 3, 2010
`
`Sheet 1of63
`
`US 7,767,657 B2
`
`FIGURE 1A
`
`MIC ug/ml)
`
`C1
`
`C2
`
`C3
`
`C4
`
`cs
`
`C6
`
`Cl
`
`CB
`
`C9
`
`16
`
`32
`
`32
`
`16
`
`16
`
`64
`
`64
`
`> 64
`
`32
`
`32
`
`4
`
`8
`
`8
`
`16
`
`2
`
`8
`
`2
`
`4
`
`0.25
`
`4
`
`16
`
`16
`
`64
`
`16
`
`> 64
`
`> 64
`
`> 64
`
`> 64
`
`32
`
`2
`
`2
`
`8
`
`2
`
`4
`
`4
`
`2
`
`64
`
`8
`
`> 64
`
`> 64
`
`> 64
`
`> 64
`
`64
`
`>64
`
`64
`
`MYLAN - Ex. 1015, p. 2
`
`

`

`U.S. Patent
`
`Aug. 3, 2010
`
`Sheet 2 of 63
`
`US 7,767,657 B2
`
`FIGURE 18
`
`C10
`
`0.5
`
`0.5
`
`0.25
`
`0.25
`
`~0.5
`
`<0.06
`
`1
`
`2
`
`C11
`
`32
`
`32
`
`32
`
`32
`
`2
`
`2
`
`4
`
`C12
`
`256
`
`C13
`
`C16
`
`16
`
`32
`
`>64
`
`2
`
`8
`
`16
`
`16
`
`C17
`
`64
`
`64
`
`64
`
`16
`
`4
`
`16
`
`8
`
`C18
`
`C19
`
`C20
`
`C21
`
`C22
`
`C23
`
`2
`
`0.5
`
`8
`
`8
`
`4
`
`>64
`
`>64
`
`MYLAN - Ex. 1015, p. 3
`
`

`

`U.S. Patent
`
`Aug. 3, 2010
`
`Sheet 3 of 63
`
`US 7,767,657 B2
`
`FIGURE 1C
`
`16
`
`>64
`
`>64
`
`>64
`
`<0.06
`
`4
`
`8
`
`C24
`
`C25
`
`C26
`
`C27
`
`C28
`
`C31
`
`MYLAN - Ex. 1015, p. 4
`
`

`

`U.S. Patent
`
`Aug. 3, 2010
`
`Sheet 4 of 63
`
`US 7,767,657 B2
`
`FIGURE 2A
`
`EXAMPLE2A
`
`MIC u2/mL
`
`Fungus
`A. fumigatus ATCC 13073
`C. a!bicans A TCC 90028
`C. a!bicans F56
`C J!fabrata A TCC 90030
`C. krusei ATCC 44507
`C neoformans F285
`C. parapsi/osis A TCC 22019
`C. trooicalis A TCC 13803
`E. f!occosum A TCC 52066
`F. solani A TCC 36031
`M furfur ATCC 44344
`M pachydermalis ATCC 96746
`M svmpodialis A TCC 44031
`M audouinii ATCC 42558
`M canis A TCC 10214
`M. !!VDSeum A TCC 24103
`T. menfa>!rophytes FJ 11
`T rubrum F296
`
`T. rubrum F296
`T. tonsurans A TCC 28942
`nt = not tested
`
`Broth used
`RPMI
`RPMf
`RPMI
`RPM! +MOPs
`RPMl+MOPs
`RPM!
`RPMf+MOPs
`RPMI+MOPs
`RPMI+MOPs
`RPM! +MOPs
`Urea
`Urea
`Urea
`RPMI + MOPs
`RPMI +MOPs
`RPMI +MOPs
`RPMI + MOPs
`RPMI + MOPs
`RPMI +MOPS+
`5% keratin powder
`RPMI + MOPs
`
`~
`
`~
`
`-
`- u
`=
`-
`u
`0.25
`I
`0.5
`S0.5
`I
`0.25
`s 0.5
`s 0.5
`s 0.5
`:S 0.5
`l
`I
`I
`2
`2
`2
`I
`I
`
`Cl.I
`
`Cl.I
`
`Cl.I -
`=
`-;
`~
`~
`= =
`= =
`-
`u
`u
`f
`:s
`....
`~
`""""
`0.25
`so.12
`0.25
`so.5
`so.5
`:s 0.12
`s 0.5
`l
`so.5
`>256
`s 0.5
`so.5
`so.s
`< 0.5
`so.5
`so.s
`<0.12
`:S 0.12
`
`>64
`0.25
`>64
`nt
`nt
`2
`nt
`nt
`nt
`nt
`nt
`nt
`nt
`nt
`nt
`nt
`32
`1
`
`=
`e =
`....
`Cll
`.9
`.s
`...
`....
`,Q
`Cl.I
`fo-
`nt
`nt
`nt
`64
`64
`nt
`:S 0.5
`256
`so.5
`64
`2
`s 0.5
`so.5
`<0.5
`so.5
`so.s
`< 0.5
`so.s
`
`\,.)
`
`nt
`0.5
`nt
`so.5
`so.5
`nt
`s 0.5
`s 0.5
`so.5
`4
`s 0.5
`S0.5
`:S 0.5
`I
`so.5
`S0.5
`0.5
`1
`
`2
`2
`
`I
`:S 0.5
`
`nt
`:so.5
`
`I
`nt
`
`nt
`'.S 0.5
`
`MYLAN - Ex. 1015, p. 5
`
`

`

`U.S. Patent
`
`Aug. 3, 2010
`
`Sheet 5 of 63
`
`US 7,767,657 B2
`
`FIGURE 28
`
`EXAMPLE2B
`
`MFC (Lll!lmL)
`
`Fungus
`T mentaKrophytes f 3 l l
`T. rubrum F296
`
`Broth used*
`RPMI + MOPs
`RPMl+MOPs
`
`~
`
`0
`
`e
`·-
`- c.
`- u
`-
`-
`=
`·-
`u
`u
`l
`2
`
`16
`8
`
`~
`
`r=
`-== ~
`.s
`..
`
`~
`
`~
`E-
`so.5
`S0.5
`
`~
`
`=
`..
`Cl
`-
`0
`•
`u
`...
`
`4
`4
`
`MYLAN - Ex. 1015, p. 6
`
`

`

`U.S. Patent
`
`Aug. 3, 2010
`
`Sheet 6 of 63
`
`US 7,767,657 B2
`
`FIGURE 3
`
`Nail Samples
`
`Radioactivity as mg Eguivalent/g Nail SamQles
`
`Group A
`(ClO)
`
`Group C
`(Ciclopirox)
`
`Dorsal/intermediate center
`
`25.65 ± 8.80
`
`7.40 ± 3.47
`
`Ventral/intermediate center
`
`20.46 ± 4.72
`
`3.09 ± 2.07
`
`Remainder nail
`
`26.06 ± 12.41
`
`4.38 ± 2.73
`
`* The data represents the mean± S.D. of each group (n = 6).
`
`P value
`(t-test)
`
`0.0008
`
`0.0001
`
`0.0022
`
`MYLAN - Ex. 1015, p. 7
`
`

`

`U.S. Patent
`
`Aug. 3, 2010
`
`Sheet 7 of 63
`
`US 7,767,657 B2
`
`FIGURE 4
`
`Sampling day
`
`Radioactivit~ as mg Eguivalent/Samgles•
`
`Group A (CIO)
`
`Group C (Ciclopirox)
`
`P-value (t-test)
`
`Day3
`
`Day6
`
`Day9
`
`Day 12
`
`Day 15
`
`Total
`
`0.0609 ± 0.0605
`
`0.0011 ± 0.0020
`
`0.1551 ±0.1314
`
`0.0013 ± 0.0027
`
`0.3892 ± 0.3714
`
`0.0018 ± 0.0030
`
`0.6775 ± 0.6663
`
`0.0014 ± 0.0019
`
`0.9578 ± 0.6106
`
`0.0033 ± 0.0041
`
`2.2405 ± l.7325
`
`0.0089±0.0131
`
`* The data represents the mean± S.D. of each group (n = 6).
`
`0.0043
`
`0.0022
`
`0.0022
`
`0.0022
`
`0.0022
`
`0.0022
`
`MYLAN - Ex. 1015, p. 8
`
`

`

`

`

`U.S. Patent
`
`Aug. 3, 2010
`
`Sheet 9 of 63
`
`US 7,767,657 B2
`
`FIGURE 6
`
`Full thickness Human Nail
`5x 2 µI over 5 days application of
`C10
`
`MYLAN - Ex. 1015, p. 10
`
`

`

`

`

`

`

`

`

`U.S. Patent
`
`Aug. 3, 2010
`
`Sheet 13 of 63
`
`US 7,767,657 B2
`
`Figure 1 O(A)
`
`SUMMARY:
`SEQ ID NO: 1-15
`
`SEQ ID NO: 1
`
`ammo acid sequences of leucyl-tRNA synthetase editing domain
`
`amino acid sequences of leucyl-tRNA synthetase editing domain from
`S. cerivisiae.
`
`SEQ ID NO: 2
`
`amino acid sequences of leucyl-tRNA synthetase editing domain from
`S. cerivisiae - overexpressed version
`
`SEQ ID NO: 16-17 genomic sequences for tRNA-leu and tRNA-ile from S. cerivisiae.
`
`SEQ ID NO: 18-68
`
`tRNA sequences fortRNA-leu
`
`A.
`SEQ ID NO: 1
`TPQEYIGVKIEALEF ADDAAKIIDSSSDLDKSKKFYFV AATLRPETMYGQTCCFVSPTI
`EYGIFDAGDSYFITTERAFKNMSYQKLTPKRGFYKPIVTVPGKAFIGTKIHAPQSVYPE
`LRILPMETVIA TKGTGVVTCVPSNSPDDYITTKDLLHKPEYYGIKPEWIDHEIVPIMHT
`EKYGDL TAKAIVEEKKIQSPKDKNLLAEAKKIA YKEDYYTGTMIYGPYKGEKVEQA
`KNKVKADMIAAGEAFVYNEPESQDP
`
`SEQ ID NO: 2
`MTPQEYIGVKIEALEF ADDAAKIIDSSSDLDKSKKFYFV AATLRPETMYGQTCCFVSP
`TI
`EYGIFDAGDSYFITTERAFKNMSYQKLTPKRGFYKPIVTVPGKAFIGTKIHAPQSVYPE
`LRILPMETVIA TKGTGVVTCVPSNSPDDYITTKDLLHKPEYYGIKPEWIDHEIVPIMHT
`EKYGDLTAKAIVEEKKIQSPKDKNLLAEAKKIA YKEDYYTGTMIYGPYKGEKVEQA
`KNKVKADMIAAGEAFVYNEPESQDPQDPNSSSVDKLAAALEHHHHH
`
`B.
`SEQ ID NO: 3 G- E.coli crystal structure (185 amino acids) - tRNA synthetase editing
`domain
`EGVEITFNVNDYDNTL TVYTTRPDTFMGCTYLA V AAGHPLAQKAAENNPELAAFID
`ECRNTKV AEAEMATMEKKGVDTGFKA VHPLTGEEIPVW AANFVLMEYGTGA VMA
`VPGHDQRDYEF ASKYGLNIKPVILAADGSEPDLSQQAL TEKGVLFNSGEFNGLDHEA
`AFNAIADKLT AMGVGERK
`
`SEQ ID NO: 4 G+ Propionibacter acnes (185 aa) - tRNA synthetase editing domain
`EGA YVDFTIDGHKEPVRVFTTRPDTL YGA TFMVVAPDSALAQEIVSDEARP AFETYL
`DEVKKKSEIERQATDHEKTGVPLGVEA TNPVNGAKVPVW AGDYVLADYGTGA VM
`A VPAHDQRDLDF ARTYGIDVIPVIDTGEADPRESGV A TTGDGVYQNSGFLNGIA TKA
`EAIAKMCEFLDEKGIGE
`
`MYLAN - Ex. 1015, p. 14
`
`

`

`U.S. Patent
`
`Aug. 3, 2010
`
`Sheet 14 of 63
`
`US 7,767,657 B2
`
`Figure lO(B)
`
`SEQ ID NO: 5 from G- Pseudomonas aeruginosa (194 aa) - tRNA synthetase editing
`domain
`
`GMEIGFPYDQASIGHAGQLKVFTTRPDTLMGATYV AV AAEHPLA TQAAQNDPQLQA
`FIDECKRGGV AEADIA TQEKKGMA TSLFVEHPL TGDKLPVWV ANYVLMNYGEGA V
`MA VPGHDERDFEFANKYGLPIRQVIAKVEGDDDFESSVWKEWYGAKDESVLTVNS
`GKYDNLGYQAAFDAIGADLEAKGLGQAR
`
`SEQ ID NO: 6 G+ Bacillus anthracis (183 aa)- tRNA synthetase editing domain
`EGAEVHFNIDGTDEKFTVFTTRPDTLFGASYCVLAPEHAL V ADITT ADQKEA VEA YI
`NSVKMKSDLERTELAKEKTGVFTGA YA VNPVNGEKLPIWIADYVLATYGTGA VMA
`VPAHDERDYEF ASTFNLPMKEVVKGGDITKEA YTGDGAHVNSAFLDGLNKEEAIAK
`MIEWLEVTSAGNQKV
`
`SEQ ID NO: 7 from G+ Staphylococcus aureus (183 aa)- tRNA synthetase editing domain
`EGAKVTFKIEQSDQNIEVFTTRPDTIYGTSFL VLSPEHPL VNEITTSDKEQEVKL YQNE
`ASKKSDLERTDLAKEKTGVFTGTFAINPLSGDKLPIWIADYVLSTYGTGA VMA VPGH
`DERDHEF A TKFNLPIIEVIEGGEVQKY A YTGEGKHINSGELDGLENEAAISKAIELLES
`KGAGEKKV
`
`SEQ ID NO: 8 G+ Streptococcus pyogens (182 aa) - tRNA synthetase editing domain
`GANVTFKVKDTDKNFTVFTTRPDTLFGATYAVLAPEHALVDAITTADQAEAYADYK
`RQASLKSDLARTDLAKEKTGVWTGSY AINPVNGKEIPVWIADYVLASYGTGAIMA V
`PAHDERDWEF AKQFNLDIIPVLEGGNVEEAAFTEDGLHINSGFLDGLDKASAIAKMY
`EWLEAEGVGNEKV
`
`SEQ ID NO: 9 G+ Thermus thermophilus (187 aa) - tRNA synthetase editing domain
`EGAEILFPVEGKEVRIPVFTTRPDTLFGA TFL VLAPEHPL TLELAAPEKREEVLA YVEA
`AKRKTEIERQAEGREKTGVFLGA Y ALNPA TGERIPIWT ADYVLFGYGTGAIMA VPAH
`DQRDYEF ARKFGLPIKKVIERPGEPLPEPLERA YEEPGIMVNSGPFDGTESEEGKRKVI
`A WLEEKGLGKGR
`
`SEQ ID NO: 10 Mycobacterium tuberculosis (186 aa) - tRNA synthetase editing domain
`FEVDIEVFTTRPDTLFGATYLVLAPEHDL VDEL V AAS WP AGVNPL WTYGGGTPGEAI
`AA YRRAMAAKSDLERQESREKTGVFVGSY AINP ANGEPVPIFIADYVLAGYGTGAIM
`A VPGHDQRDWDF ARAFGLPIVEVIAGGNISESA YTGDGIL VNSDYLNGMSVPAAKR
`AIVDRLESAGRGRARI
`
`SEQ ID NO: 11 Candida albicans (251 aa) - tRNA synthetase editing domain
`YVGIKIRLTDV APQAQELFKKESLDVKENKVYLVAATLRPETMYGQTCCFVSPKIDY
`GVFDAGNGDYFITTERAFKNMSFQNLTPKRGYYKPLFTINGKTLIGSRIDAPY A VNK
`NLRVLPMETVLATKGTGVVTCVPSDSPDDFVTTRDLANKPEYYGIEKDWVQTDIVPI
`VHTEKYGDKCAEFL VNDLKIQSPKDSVQLANAKELA YKEGFYNGTMLIGKYKGDK
`VEDAKPKVKQDLIDEGLAFVYNEPE
`
`MYLAN - Ex. 1015, p. 15
`
`

`

`U.S. Patent
`
`Aug. 3, 2010
`
`Sheet 15 of 63
`
`US 7,767,657 B2
`
`Figure I O(C)
`
`SEQ ID NO: 12 Aspergillus fumigatus (256 aa) - tRNA synthetase editing domain
`YTAMKLQVKEW APEIAEL VKGKIEDDAKVYFVPATLRPETMYGQTCCFLGPKIKYGI
`FRVKEKEYYIVTKRAA WNMAFQGIFFDSEHFPKTQDELPL VLEAPGSAFVGTLVNAP
`LSFHTEGVRILPMEGVSATKGTGVVTSVPSDSPDDY ATL VDLAKKPEYYGIKKEW AE
`LEIFPLIETPTYGNLT APTL VKKLKINSPKDVNQLAQAKELA YGEA YYKGTML VGEF
`KGEPVSAAKEKIRKSL YESGDAFPF ADP
`
`SEQ ID NO: 13 Trichophyton rubrum CPI (256 aa)- tRNA synthetase editing domain
`YTAMKLKVKEWSPKAKEIIQGKIEKDANVYFVPATLRPETMYGQTCCFVGPAISYGI
`FKVKEKEYYVVTKRAA WNMAFQGIFFDVNNLPKSQDELPPVVEAPGSALIGTL VNA
`PLSFHKEGVRILPMETVSANKGTGVVSCVPSDSPDDFATISDLAKKADYYGIQKEWA
`ELEIHPLIETPTYGNLTAPALVKQLKINSPKDTVQLAQAKDLA YTEGFYKGKML VGE
`FKGEPVQT AKEKVRNSLIKSGDAFPF ADP
`
`SEQ ID NO: 14 Homo sapiens (253 aa) - tRNA synthetase editing domain
`VGPQEYTLLKLKVLEPYPSKLSGLKGKNIFL V AATLRPETMFGQTNCWVRPDMKYIG
`FETVNGDIFICTQKAARNMSYQGFTKDNGVVPVVKELMGEEILGASLSAPLTSYKVI
`YVLPML TIKEDKGTGVVTSVPSDSPDDIAALRDLKKKQALRAKYGIRDDMVLPFEPV
`PVIEIPGFGNLSA VTICDELKIQSQNDREKLAEAKEKIYLKGFYEGIMLVDGFKGQKV
`QDVKKTIQKKMIDAGDALIYMEPE
`
`SEQ ID NO: 15 Trypanosoma brucei (259 aa) - tRNA synthetase editing domain
`YTVVKLKVKNPLEQPALAPFSEIIGNRSVILPGA TLRPETVIGQTNCWVSPNFSYMA Y
`SILNGTGEEEIYIMTSRAARNLA YQNFTVNGKTGVDPSPLFEVDGAKLIGLPLSAPLCP
`YDTIYTLPMQSIIETKGTGVVMSVPADSPDDYINYVQL VNKPDYRAKLGLKDEWV A
`NKIVSLIEVPGEMGRESAKYMCEKLKINGPNATDLLEEAKKVIYQAGFYQGVMIAGP
`FAGEKVSAAKVKTVKLLEEQNAAIRYYEP
`c.
`
`SEQ ID NO: 16 Saccharomyces cerevisiae tRNA-Leu (genomic)
`gggagtttgg ccgagtggtt taaggcgtca gatttaggct ctgatatctt cggatgcaag ggttcgaatc ccttagctct caeca
`
`SEQ ID NO: 17 Saccharomyces cerevisiae tRNA-Ile (genomic)
`gaaactataa ttcaattggt tagaatagta ttttgataag gtacaaatat aggttcaatccctgttagtt teat
`
`D.
`
`SEQ ID NO: 18 Saccharomyces cerevisiae tRNA-Leu
`G GU U GU U U G m2G C ac 4C GAG C Gm GD CD A AG G C m2
`2G C CU GA 'I' U
`m5C A Am 1G C 'I' C AG G U AU C GU A A GA U G m5C A A GA G T 'I' C G A A U C
`UCUUAGCAACCACCA
`
`MYLAN - Ex. 1015, p. 16
`
`

`

`U.S. Patent
`
`Aug. 3, 2010
`
`Sheet 16 of 63
`
`US 7,767,657 B2
`
`Figure 1 O(D)
`
`SEQ ID NO: 19 Haloferax volcanii tRNA-Leu
`GCGAGGGUAGCUAA~~GUCAGGAAAAAGCm}GGCGGACU
`CA A m1G A qt CC G CUC CC GU AG G G GU Cm5C GU G G G m 1qt qt Cm m 1I A
`AUCCCUCCCCUCGCACCA
`
`SEQ ID NO: 20 Phage T4 tRNA-Leu
`G CG AG A A s4U G GU CA A ADU m2G GD A A AG G CA CA G CA CU unkU
`A A ms2i6A A 'I' G CU G CG GA A UGA U U UC CU U GU G G GT 'I' CG AG UC
`CCACUUCUCGCACCA
`
`SEQ ID NO: 21 Phage TS tRNA-Leu
`GGGGCUAUGCUGGAACDGmGDAGACAAUACGGCCUUA
`Gm~U'l'CCGUAGCUUAAAUGCGUGGGAGT'l'CGAGUCUCCC
`UAGCCCCACCA
`
`SEQ ID NO: 22 Bacillus subtilis tRNA-Leu
`GCGGG U GU G C G G GA AUD G GD A GA C C G G C U AG A U U C A Gm 1G A
`qt CU AG G GU CU U U AUG GA CCU GAGG GT qt CA m1A GU CCC U UC
`ACCCGCACCA
`
`SEQ ID NO: 23 Escherichia coli tRNA-Leu
`G C C C G GA s4U G GU G GA A DC Gm GD A GA CAC A AGGGA 'I' U unkA A A
`ms2i6 A A qt C C C U C G G C G U U C G C G C U G U G C G G G T qt C A A G U C C C
`GCUCCGGGUACCA
`
`SEQ ID NO: 24 Salmonella typhi tRNA-Leu
`GCGAAGGUGGCGGAADDGmGDAGACGCGCUAGCUUCAGu~G
`'l'G'l'UAGUGUCCUUACGGACGUGGGGGT'l'CAAGUCCCCCC
`CCUCGCACCA
`
`SEQ ID NO: 25 Rhodospirillum rubrum tRNA-Leu
`GCCUU U G U A G C G G A A D G G D A A C G C G G C A G A C U C A A unkA A 'I'
`CUGCUUUGGUAACCCAGGUGGUAGT'l'CGACUCUCCCCAA
`AGGCACCA
`
`SEQ ID NO: 26 Anacystis nidulans tRNA-Leu
`GGGCA A GU G G C G GA AUD G GD AG A C G C AG C A GA CUC A A u~A
`A'l'CUGCCGCUAGCGAUAGUGUGUGGGT'l'CGAGUCCCACC
`UUGCCCACCA
`
`SEQ ID NO: 27 Anacystis nidulans tRNA-Leu2
`GCGGAA CU G GC GGAA UD G GD A GAC G CG CU A GA UUCAGm 1G'I'
`'l'CUAGUGGUUUCACGACUGUCCGGGTqtCAAGUCCCGGGU
`UCCGCACCA
`
`MYLAN - Ex. 1015, p. 17
`
`

`

`U.S. Patent
`
`Aug. 3, 2010
`
`Sheet 17 of 63
`
`US 7,767,657 B2
`
`Figure I O(E)
`
`SEQ ID NO: 28 Bacillus stearothermophilus tRNA-Leu
`G C C G A U G s4U G G C G GA A UD G GC A Gm 1 A C G C G C A C GA C U Cm A A
`m~hA~CGUGUGGGCUUUGCCCGUGUGGGT~CGACUCCCA
`CCAUCGGCACCA
`
`SEQ ID NO: 29 Glycine max tRNA-Leu
`GCCUU G GU G GU GA A AU Gm GD A G C C A C G C G A GA C U Cm A A unkA
`A~CUCGUGCUACAGAGCGUGGAGGT~CGAGUCCUCUUCA
`AGGCACCA
`
`SEQ ID NO: 30 Glycine max tRNA-Leu2
`GGGGAUAUGGCGAAAUUGmGDAGACGC~ACGGACUUmAA
`unkAA~CCGUCGACUUAAGAAAUCAUGAGGGT~CAAGUCCC
`UCUAUCCCCACCA
`
`SEQ ID NO: 31 Glycine max tRNA-Leu3
`GCCGC U AU G GU G A A AU U Gm GD A G A C A C G C U G C U C U U Am 7 G
`m 1G AAGC AGUGC U AGAGC AU CUC G GT~ C GAGU CC GAG U AG
`CGGCACCA
`
`SEQ ID NO: 32 Phaseolus vulgaris tRNA-Leu2
`GGCUU G A U G GU G A A AU U Gm GD A GA C A C G C GA GA C U Cm A A
`unUAUCUCGUGCUAAAGAGCGUGGAGGT~CGAGUCCUCU
`UCAAGUCACCA
`
`SEQ ID NO: 33 Phaseolus vulgaris tRNA-Leu!
`GGGG AU AU GGC GAAA UU GmGDAGAC GC ~AC G GA CU unkU AA
`unkAA~CCGUCGACUUAAUAAAUCAUGAGGGT~CAAGUCCC
`UCUAUCCCCACCA
`
`SEQ ID NO: 34 Phaseolus vulgaris tRNA-Leu3
`GCCGC U AU G G U G A A AU U Gm GD A G A C A C G C U G C U C U U Am 7 G
`m 1G AAGC A GU GC U AG AG CA UC UC GGT~C GAG UC CG A GU AG
`CGGCACCA
`
`SEQ ID NO: 35 Spinacia oleracea tRNA-Leu
`GCCGC U A U G GU G A A AU U Gm GD A G A C A C G C U G C U C U U Am 7 G
`m 1G A AGC AG U G CG AG AG CA UC UC GGT~ C GA GU CC GAG U AG
`CGGCACCA
`
`SEQ ID NO: 36 Neurospora crassa tRNA-Leul
`AUCCG A G U G A U G GA AD G GD A GA C AU A A C AU G C U unkU A A A A
`CAUGUGGGCUUCAAGCUGUGAAGGT~CAAGUCCUUCUUC
`GGAUACCA
`
`MYLAN - Ex. 1015, p. 18
`
`

`

`U.S. Patent
`
`Aug. 3, 2010
`
`Sheet 18 of 63
`
`US 7, 767,657 B2
`
`Figure 1 O(F)
`
`SEQ ID NO: 37 Neurospora crassa tRNA-Leu2
`AUAGG U GU G CU G GA ADU G GD AG AC AG GU UC CG'¥ U U A Gm 1G C
`CGGAAUGGUUUAAAAACUGUACAAGT'PCAAGUCUUGUCA
`UCUAUACCA
`
`SEQ ID NO: 38 Saccharomyces cerevisiae tRNA-Leu
`GCUAU U U U G GU G GA ADU G GD A GA C A CmlG AU A C '¥ C U cmnm 5U A
`A m 1G A'¥ GU AU U AC U U U AC AGUA U GA AG GT'¥ CA AG UC CU U U
`AAAUAGCACCA
`
`SEQ ID NO: 39 Solanum tuberosum tRNA-Leu
`GU C AG GAU G G C ac4C GA GD Gm GD C acp3U A A G G C m/G C C A G A C U
`unk A A m 1G U '¥ C U G G Um CU U C GU A AG AG G G m5C GU G G GT'¥ CA
`m 1AA UCC CAC UUCUGA CA CC A
`
`SEQ ID NO: 40 Phaseolus vul§aris tRNA-Leul
`GU CA G GAU G m2G C ac CG AG D Gm GD C acp 3U A AG G C m2
`2G CC AG A
`CU unk A A m 1G '¥'¥CU G G Um CU UC GAG AG AG G G m5C GU G G GT'¥ C
`AmlAA UC CCA C UUC U GACACCA
`
`SEQ ID NO: 41 Phaseolus vul§aris tRNA-Leu2
`GU C A G GA U G m2G C ac C GA GD Gm G D C acp3U A A G G C m/G C C AG A
`CU unk A A m 1G '¥'¥CU G G Um CU UC GA A AG AG G G m5C GU G G GT'¥ C
`Am 1AA UC CC AC UU CU GA CA CC A
`
`SEQ ID NO: 42 Phaseolus vulgaris tRNA-Leu3
`GAU AG U U U G m2G C ac4C GAG D Gm GD C acp3U A A G G C m12G C CA GA
`'¥ U unk AG m 1G C '¥CU G G Um CC GA A A unk G G G m5C GU G G GT'¥ CA
`m 1AA UC C CAC AGC UGU CA C CA
`
`SEQ ID NO: 43 Phaseolus vulgaris tRNA-Leu4
`2G GA AG AC U unk A
`G CU GG U U U G G C ac4C GAG A Gm GD DA AG G C m2
`A m 1G A'¥ CU UC Um G CA GU CA AC U G CG m5C AUG G GT'¥ CG m1A AC
`CCCAUAGCCAGCACCA
`
`SEQ ID NO: 44 Rat Liver A tRNA-Leu I
`CU U U U AU m 1A m2GG AU AG A AG DA AU CC A'¥ U G GU CU U A Gm 1G A
`A C CAA A A AC m5C U U G GU G C A AC U C C A A AU A A A AG U AC C A
`
`SEQ ID NO: 45 Candida albicans tRNA-Leu
`GAU AC GAU G G C ac4C GA GD Gm GD D A A G G C m/G A A G GAU G C A
`Gm 1G '¥'¥CCU U U G G G C AUU G CCC G m5C G CA G GT'¥ CG m 1A AC CCU
`GCUCGUGUCGCCA
`
`MYLAN - Ex. 1015, p. 19
`
`

`

`U.S. Patent
`
`Aug. 3, 2010
`
`Sheet 19 of 63
`
`US 7,767,657 B2
`
`Figure 1 O(G)
`
`SEQ ID NO: 46 Saccharomyces cerevisiae tRNA-Leul
`G GU U GU U U G m2G C ac4C GAG C Gm GD CD A AG G C m/G CCU GA 'PU
`m5C A A m 1G C 'PC AG GU AU CG U A AG AUG m5C A AG AG T 'PC GA AU C
`UCUUAGCAACCACCA
`
`SEQ ID NO: 47 Saccharomyces cerevisiae tRNA-Leu2
`GG GA G U U U G m2G C ac4C GA GD Gm GD DD A A G G C m/G 'P C A G A 'I1 U
`U A Gm 1G C 'I1 CU GAU AU CU UC G GAU G m5C A AG G GT 'I1 CG m 1A AU C
`CCUUAGCUCUCACCA
`
`SEQ ID NO: 48 Candida cylindracea tRNA-Leu3
`GGCUC UC U G G C ac4C GAG D G GD CD A AG G C m2
`2G CU AG G GU I A
`Gm 1G 'I1 CCU AG UC UC U UC G GAGG m5C G CG AG T 'I1 CG m 1A AC CUC
`GCGGGAGUCACCA
`
`SEQ ID NO: 49 Phaseolus vulgaris tRNA-Leul
`GU CA G GAU G m2G C ac4C GAG D G GD C acpJu A AG G C m!G CC AG AC U
`unk A A mIG 'I1 'I1 C U G G Um C U U C G A GA GA G G G m5C G U G G GT 'I1 C A
`m 1AA UC CC AC U UC UGA C AC CA
`
`SEQ ID NO: 50 Phaseolus vulgaris tRNA-Leu2
`GU CA G GAU G m2G C ac4C GAG D G GD C acp3U A A G G C m/G CC AG AC
`U unk A A m 1G 'I1 'I1 CU G G Um CU UC GA A AG AG G G m5C GU G G GT 'I1 CA
`m 1AA UC C CAC UU CU GA C AC CA
`
`SEQ ID NO: 51 Phaseolus vulgaris tRNA-Leu3
`2G CC AG A 'I1
`GAU AG U U U G m2G C ac4C GAG D G GD C acp3U A AG G C m2
`U unk A G m 1 G C 'I1 C U G G Um C C G A A A unk G G G m5C G U G G G U 'I1 C A m 1 A
`AUCCCACAGCUGUCACCA
`
`SEQ ID NO: 52 Phaseolus vulgaris tRNA-Leu4
`G C U GG U U U G G C ac4C GA GA G GD D A A G G C m2 2G GA A GA C U unk A
`A m 1G A 'I1 CU UC Um G CA GU CA AC U G CG m5C AUG G GT 'I1 CG m 1A AC
`CCCAUAGCCAGCACCA
`
`SEQ ID NO: 53 Solanum tuberosum tRNA-Leu
`GUCAGGAUGGC~CGAGDGGDC~~UAAGGCm!GCCAGACU
`unk A A m 1G U 'I1 CU G G Um CU UC GU A AG AG G G m5C GU G G GT 'I1 CA
`m 1AA UC CCAC UUCUG ACAC CA
`
`SEQ ID NO: 54 Cucumis sativus tRNA-Leu
`GU CA G GAU G m2G C m 5C GAG D G GD C acp3U A AG G C m/G CC A GA C
`U unkU A A mlG 'I1 'I1 CU G G Um CCU CU A AG GAGG G m5C GU G G GT 'I1 C
`Am 1AA UC C CA C UU CU GACAC CA
`
`MYLAN - Ex. 1015, p. 20
`
`

`

`U.S. Patent
`
`Aug. 3, 2010
`
`Sheet 20 of 63
`
`US 7, 767,657 B2
`
`Figure lO(H)
`
`SEQ ID NO: 55 Caenorhabditis elegans tRNA-Leu
`GGAGAGAUGGC~CGAGCGGDCUAAGGCGCUGGUUUlAGG
`CACCAGUCCCUUCGGGGGCGUGGGTUCGAAUCCCACUCU
`CUUCACCA
`
`SEQ ID NO: 56 Mycoplasma capricolum tRNA- Leu2
`CCC CAAGunkU GGC GGAA U AGGDAGm 1AC GC A UU GGA CU
`cmnm5Um A A m6A A'¥ CC A AC G G G CU U A AU AU CCU GU G CC G GU'¥
`CAAGUCCGGCCUUGGGGACCA
`
`SEQ ID NO: 57 Mycoplasma capricolum tRNA- Leul
`GCCUU U U U G G C G GA AUD G G CA GmlA C G CA U U AG AC U Cm A A
`m6AA '¥CU AAC GAAGAAA UUC GU AU C GGU'¥ CGAA U CC GAU A
`AAGGGCACCA
`
`SEQ ID NO: 58 Haloferax volcanii YX tRNA- Leu4
`G C G C G G GU AG CC A A fa7d7GU G GC CA A A GGCm22G CA G C G CU mo5U
`AG m 1G AC G CU GU G GU GU AG AC CU U m5C G CA G G m 1'¥ 'I' Cm GA AC
`CCUGUCCCGCGCACCA
`
`SEQ ID NO: 59 Haloferax volcanii YX tRNA- LeuS
`GCGGG G GU G G CU GA fa7d7G CC AG G CC A A A AG C m2G G CG GA CU U
`A Am 10 A '¥ C C G C U C C C G U A G G G G U U C G C G A Gm 1 '¥ '¥ Cm G A A U C
`UCGUCCCCCGCACCA
`
`SEQ ID NO: 60 Haloferax volcanii tRNA- Leu3
`G CG U G G GU AG CC A A fa7d7G CC AG G CC A AC G G C m/G CA G CG U U
`GA Gm 1G G m5CG CU GU CCU GU AG AG GU Cm5C G CC G G m 1'1' 'I' Cm m 1l A
`AUCCGGUCCCACGCACCA
`
`SEQ ID NO: 61 Haloferax volcanii tRNA- Leu2
`GCAGGG AU AGC CAAfa7d7GU CU GG CC AA C GGCm/GC A GC GUU C
`A Gm 1G G CG CU GU CUC AU AG GAG UC m5C G CA G G m 1'1' 'I' Cm m 1l A A
`UCCUGCUCCCUGCACCA
`
`SEQ ID NO: 62 Haloferax volcanii tRNA- Leul
`G CG AG G GU AG CU A A fa7d7G UC AG GA A A A AG C m12G G CG GA CU
`CA Am 1G A 'I' CC G CUC CC GU AG G G GU Cm5C GU G G G m 1'1' 'I' Cm m 1l A
`AUCCCUCCCCUCGCACCA
`
`MYLAN - Ex. 1015, p. 21
`
`

`

`U.S. Patent
`
`Aug. 3, 2010
`
`Sheet 21 of 63
`
`US 7,767,657 B2
`
`Figure 1 O(I)
`
`SEQ ID NO: 63 Escherichia coli tRNA-Leu2
`GCGAAG GU GGC GGAADD Gm GDAG AC GC GC U A GC UU CA GunkG
`'l'G'l'UAGUGUCCUUACGGACGUGGGGGT'l'CAAGUCCCCCC
`CCUCGCACCA
`
`SEQ ID NO: 64 Escherichia coli tRNA-Leu3
`GCCGA G GU G GU G GA AD D Gm GD AG A C A C G C U A C C U U GA G unkG
`'l'GGUAGUGCCCAAUAGGGCUUACGGGT'l'CAAGUCCCGUC
`CUCGGUACCA
`
`SEQ ID NO: 65 Saccharomyces cerevisiae tRNA-Leu3
`G GA GG G U U G m2G C ac4C GAG D Gm GD C D A A G G C m2
`2G G C A GA Cm U
`U A Am 1G A 'I' C U GU U G G A C GG U U G U C C Gm 5C G C G A G T 'I' C Gm 1 A A
`CCUCGCAUCCUUCACCA
`
`SEQ ID NO: 66 Torulopsis utilis tRNA-Leu
`GGAUC U U U G m2G C ac4C GA G C Gm GD DU A AG G C m/G C U C GA Cm U
`Cm A A m 1G A 'I' CG AGUA UC GU A AG AUG m5C AUG AG T 'I' CG m1A AU
`CUCAUAGGAUCCACCA
`
`SEQ ID NO: 67 Candida cylindracea tRNA-Leu
`G G C C G U U U G m2G C ac4C GA GD Gm GD C D A A G G C m/G U C U GA Cm
`U Cm A A m 1G A 'I' CA GA Um CUC GU A AG AG G m5C GU GU GT 'I' CG m 1A
`ACCACACAGCGGUCACCA
`
`SEQ ID NO: 68 Candida cylindracea tRNA-Leu2
`GGUUC UC U G G C ac4C GAG D G GD CD A AG G C m/G CA U G Go/ U I A
`Gm 1G 'I' CC AUG UC UC U UC G GAGG m5C G CG AG T 'I' CG m 1A AC CUC
`GCGGGAAUCACCA
`
`MYLAN - Ex. 1015, p. 22
`
`

`

`U.S. Patent
`
`Aug. 3, 2010
`
`Sheet 22 of 63
`
`US 7,767,657 B2
`
`FIGURE 11A
`
`a't
`i(Y'B;'"N,-H
`~oMe
`F
`
`NCH3 mO'-N,-H
`mO'-N,-H
`
`, H
`o
`
`a
`
`~3
`
`oH
`
`Cl
`
`~3
`
`' H
`0
`
`mO'-N,-H
`
`Cl
`
`of)
`~a;-N,-H
`Cl~QH
`
`MYLAN - Ex. 1015, p. 23
`
`

`

`U.S. Patent
`
`Aug. 3, 2010
`
`Sheet 23 of 63
`
`US 7,767,657 B2
`
`FIGURE 118
`
`OH
`
`pH
`
`OH
`
`I
`
`OH
`
`I
`
`h
`
`0
`
`h
`
`j)H
`
`h
`
`pH
`
`0
`
`h
`
`f3C
`
`Br
`
`OH
`
`I
`
`0
`
`j)j
`F
`
`OH
`
`'o
`
`I "°'
`
`h
`
`OH
`I
`
`0
`
`F
`
`OH
`
`I
`
`0
`
`Cl
`
`;/
`
`°t
`cq
`Fm
`
`OH
`
`I
`
`0
`
`CN
`
`F
`I
`
`h
`
`pH
`,
`
`pH
`
`pH
`,
`
`I
`
`H3C-0
`
`CH3
`
`F
`
`OH
`
`OH
`I
`
`j)j
`
`0
`
`~
`
`0
`
`'o
`
`h
`
`~
`
`cCN
`f -
`0
`
`&° OX,0
`pH
`C lw QJ)::0
`I ~'o
`I
`,
`pH m
`m
`F'Cd
`QC
`m
`F~O Fm
`F »
`ED
`m
`F
`cc
`
`CCH ~"
`ED
`cGo
`
`0
`
`'
`0
`
`F
`
`,B-oH
`HO
`
`fl
`mo_ ~N.-H
`
`' H
`0
`
`Cl
`
`PH
`F
`~d,
`~o
`
`MYLAN - Ex. 1015, p. 24
`
`

`

`

`

`

`

`U.S. Patent
`
`Aug. 3, 2010
`
`Sheet 26 of 63
`
`US 7,767,657 B2
`
`FIGURE 11E
`
`I
`
`OH 019H
`CGa
`
`CN •
`'
`
`O
`
`OH •
`'
`
`PH
`
`PH
`8
`
`pH
`8
`
`CC{ CC{ CC{
`
`N02 •
`'
`
`COOH •
`'
`
`Br •
`'
`
`OH
`NB~
`~a.m.
`
`OH
`
`'
`
`'
`
`OH
`OH
`0
`OH
`I
`I
`/ ~~ B,
`/ ~B~
`OH
`7-'
`o ~ I
`~o ~~ s0
`h-
`Br
`/
`;
`;
`o
`
`O
`
`.4-
`
`Et
`
`HO'B,
`o;
`OH
`I
`
`OH
`
`0
`OH
`I
`
`;
`
`Q
`CF
`3 •
`'
`
`F3C
`
`Q:I~ B,
`
`.4-
`HJC
`
`Q
`CH3
`
`'CCJB,
`~ B,
`OH
`Bu
`OH
`I ~
`I
`I
`0
`0
`• /0
`.
`.4-
`•
`'
`'
`
`.4-
`
`0
`
`(
`• Ph
`'
`
`MYLAN - Ex. 1015, p. 27
`
`

`

`U.S. Patent
`
`Aug. 3, 2010
`
`Sheet 27 of 63
`
`US 7,767,657 B2
`
`FIGURE 11F
`
`' N
`
`I
`
`-N
`\
`
`MYLAN - Ex. 1015, p. 28
`
`

`

`U.S. Patent
`
`Aug. 3, 2010
`
`Sheet 28 of 63
`
`US 7,767,657 B2
`
`FIGURE 12A
`
`~\_ (Y\~
`Cl~""""-; VJ' Cl
`
`I
`
`~
`\ ; F
`
`; NC
`
`F
`
`F
`
`F
`
`MYLAN - Ex. 1015, p. 29
`
`

`

`

`

`U.S. Patent
`
`Aug. 3, 2010
`
`Sheet 30 of 63
`
`US 7,767,657 B2
`
`FIGURE 12C
`
`f:f
`
`NC
`
`MYLAN - Ex. 1015, p. 31
`
`

`

`U.S. Patent
`
`Aug. 3, 2010
`
`Sheet 31of63
`
`US 7,767,657 B2
`
`FIGURE 120
`
`; F
`
`0
`
`s
`
`0
`
`H
`N
`
`0
`
`MYLAN - Ex. 1015, p. 32
`
`

`

`

`

`

`

`U.S. Patent
`
`Aug. 3, 2010
`
`Sheet 34 of 63
`
`US 7,767,657 B2
`
`FIGURE 12G
`
`~N
`s
`
`Cl
`
`n
`
`~N
`
`Cl
`
`MYLAN - Ex. 1015, p. 35
`
`

`

`

`

`U.S. Patent
`
`Aug. 3, 2010
`
`Sheet 36 of 63
`
`US 7,767,657 B2
`
`FIGURE 121
`
`NC~O
`;and V
`
`MYLAN - Ex. 1015, p. 37
`
`

`

`Percent cdc60 Bound with C10 at Equilibrium
`0/o cdc60
`Occupied
`
`Free [C1 O], IJM
`
`Additive
`
`20 mM ATP
`
`5 mM ATP
`2.5 mM ATP
`0.5 mM ATP
`0.1 mM ATP
`
`20 mM AMP
`Nothing
`
`27.5
`
`30.1
`39.1
`34.8
`36.8
`
`33.3
`42.6
`
`44.0
`
`29.9
`7.7
`7.4
`-2.9
`
`59.0
`-6.6
`
`Assay conditions: 31 uM cdc60, 1 mM OTT, 0 mM Leucine, 0 mM tRNA,
`initial [C10] are 72 - 79 uM, pre-equilibrium. 1x AARS buffer
`
`~
`00
`•
`~
`~
`~
`
`~ = ~
`
`(.H
`
`~
`
`N
`
`> = ~
`0 ....
`
`0
`
`'Tl
`(j)
`c
`::0 m
`...a. w
`
`('D
`
`1J1 =-('D
`.....
`(.H
`-....J
`0 .....
`O'I
`(.H
`
`d
`rJl
`-....l
`~
`0--,
`
`-....l °" tit
`-....l = N
`
`MYLAN - Ex. 1015, p. 38
`
`

`

`

`

`

`

`

`

`Cl 0 inhibits post transfer editing (PTE) of
`S. cerevisiae CDC60
`
`1.1
`1~1
`~ o.~a
`~ 0.8
`rx: 0.7
`
`; 0.6 = 0.5'
`:c 0.4'
`0 0.3
`8_0.2
`0.1
`0.0 I
`0
`
`PTE with C10=1, 1 OµM/ml
`
`I
`
`•
`
`•
`
`I
`
`•
`
`•
`
`•
`
`• CDC60 only
`A CDC60+1µg/ml C10
`• CDC60+10µg/ml C10
`• no CDC60, no C10
`
`I
`
`I
`
`I
`5
`
`I
`
`I
`I
`10
`15
`Time (min)
`
`w
`
`I
`20
`
`u
`
`I
`25
`
`~
`00
`•
`~
`~
`~
`
`~ = ~
`
`(.H
`
`> = ~
`0 ....
`
`~
`
`N
`
`0
`
`.i;...
`
`1J1 =(cid:173)
`('D a
`....
`0 .....
`O'I
`(.H
`
`"TI -G')
`c:
`;o
`m
`.....
`-..a
`
`d
`rJl
`-....l
`~
`0--,
`
`-....l °" tit
`-....l = N
`
`MYLAN - Ex. 1015, p. 42
`
`

`

`U.S. Patent
`
`Aug. 3, 2010
`
`Sheet 42 of 63
`
`US 7,767,657 B2
`
`FIGURE 18A
`
`5-chlorobenzo[ c ][I ,2]oxaborol- l (3H)-ol, benzo( c] [ l ,2]oxaborol- I (3H)-ol, 5-chloro-3-
`
`methylbenzo[ c] [ 1,2]oxaborol-1 (3H)-ol, 6-fluoro-3,4-dihydrobenzo[ c ][ l ,2]oxaborinin-
`
`1-ol, 5 ,6-difluoro benzo[ c] [ 1,2]oxaborol-1 (3H)-ol, 1-hydroxy-1,3-
`
`dihydrobenzo [ c ][ l ,2]oxaborole-5-carbonitrile, 5-methoxybenzo[ c ][ 1,2]oxaborol(cid:173)
`
`l (3H)-ol, 5-methylbenzo[ c ][ 1,2]oxaborol- I (3H)-ol, 5-
`
`(hydroxymethyl)benzo[ c] [ 1,2]oxaborol- l (3H)-ol, 5-fluorobenzo[ c] [ 1,2]oxaborol(cid:173)
`
`l (3H)-ol, naphtho[l,2-c][l,2]oxaborol-1(3H)-ol, 6-fluorobenzo[c][l,2]oxaborol-
`
`1 (3H)-ol, 3-benzyl-3-methylbenzo[ c ][ l ,2]oxaborol-1 (3H)-o1, 3-
`
`benzylbenzo[ c](l,2]oxaborol-1 (3H)-ol, 4-fluorobenzo( c ][l,2]oxaborol-1(3H)-ol, 4-(l(cid:173)
`
`hydroxy-1,3-dihydrobenzo[ c ][ l ,2]oxaborol-5-yloxy)benzonitril, 4-(1-hydroxy- l ,3-
`
`dihydrobenzo[ c ][1,2]oxaborol-6-yloxy)benzonitrile, 3-(1-hydroxy- l ,3-
`
`dihydrobenzo[ c ][ l ,2]oxaborol-6-yloxy)benzonitrile, 6-(4-
`
`chlorophenoxy)benzo[ c ][ l ,2]oxaborol-1 (3H)-ol, 6-phenoxybenzo( c ][ 1,2]oxaborol-
`
`1 (3H)-ol, 4-((1-hydroxy-1,3-dihydrobenzo[ c][l,2]oxaborol-5-
`
`yloxy)methyl)benzonitrile, 2-( 1-hydroxy-1,3-dihydrobenzo[ c ][ 1,2]oxaborol-5-
`
`yloxy)benzonitrile, 5-phenoxybenzo[ c ][ 1,2]oxaborol-1 (3H)-ol, N,N-diethyl-4-(1-
`
`hydroxy-1,3-dihydrobenzo( c] [ l ,2]oxaborol-5-yloxy)benzamide, (4-( 1-hydroxy-1,3-
`
`dihydrobenzo[ c ][ 1,2]oxaborol-5-yloxy)phenyl)(rnorpholino )rnethanone, 4-(1-
`
`hydroxy- l ,3-dihydrobenzo[ c ][ l ,2]oxaborol-5-yloxy)phthalonitrile, 6-
`
`(phenylthio )benzo[ c ][ l ,2Joxaborol-1 (3H)-ol, 6-( 4-
`
`(trifluoromethoxy)phenoxy)benzo[ c ][ l ,2]oxaborol- l (3H)-ol, N-(1-hydroxy- l ,3-
`
`dihydrobenzo[ c ][ l ,2]oxaborol-5-yl)-N-methylbenzenesulfonamide, 6-(4-
`
`rnethoxyphenoxy)benzo[ c ][ l ,2]oxaborol- l (3H)-ol, 6-( 4-
`
`methoxyphenylthio )benzo[ c ][ 1,2]oxaborol-1 (3H)-ol, 6-( 4-
`
`methoxyphenylsulfonyl)benzo[ c ][ 1,2]oxaborol-1 (3H)-ol, 6-( 4-
`
`rnethoxyphenylsulfinyl)benzo[ c ][ l ,2]oxaborol- l (3H)-ol, 5-
`
`(trifluoromethyl)benzo[ c ][ l ,2]oxaborol- l (3H)-ol, 4-( 1-hydroxy-1,3-
`
`dihydrobenzo[ c ][ 1,2]oxaborol-4-yloxy)benzonitrile, 3-(1-hydroxy-1,3-
`
`dihydrobenzo[ c] [ 1,2 ]oxaborol-5-yloxy)benzonitrile, 4-( l -hydroxy-1,3-
`
`dihydrobenzo [ c] [ l ,2 ]oxaborol-5-yloxy)benzoic acid, 5-(4-(lH-tetrazol-5-
`
`yl)phenoxy)benzo[ c ][ 1,2]oxaborol-1 (3H)-ol, 7-Hydroxy-2, 1-oxaborolano[ 5,4-
`
`c ]pyridine [[1,2]oxaborolo[3,4-c]pyridin-1(3H)-ol], Ethyl 2-(1-hydroxy-l,3-
`
`MYLAN - Ex. 1015, p. 43
`
`

`

`U.S. Patent
`
`Aug. 3, 2010
`
`Sheet 43 of 63
`
`US 7,767,657 B2
`
`FIGURE 188
`
`dihydrobenzo[ c ][ 1,2]oxaborol-5-yloxy)acetate, 2-(1-hydroxy-1,3-
`
`dihydrobenzo[ c ][l ,2]oxaborol-5-yloxy)acetic acid, 6-(thiophen-2-
`
`ylthio )benzo [ c] [ 1,2]oxaborol-1 (3H)-ol, 6-( 4-fluorophenylthio )benzo[ c] [ l ,2]oxaborol-
`
`1 (3H)-ol, 1-(3-(( l-hydroxy-1,3-dihydrobenzo[ c ][l,2]oxaborol-5-
`
`yloxy)methyl)phenyl)pentan-l-one, 2-(l-hydroxy-1,3-dihydrobenzo[ c] [1,2Joxaborol-
`
`5-yloxy)- l-(piperidin-l-yl)ethanone, 2-( l-hydroxy-1,3-dihydrobenzo[ c ][ 1,2]oxaborol-
`
`5-yloxy)-l-( 4-(pyrimidin-2-yl)piperazin-l-yl)ethanone, 6-( 4-(pyridin-2-yl)piperazin-
`
`1-yl)benzo[ c ][1,2]oxaborol-1(3H)-ol, 6-nitrobenzo[ c ][l ,2]oxaborol-1(3H)-ol, 6-
`
`aminobenzo[ c ][ 1,2]oxaborol-1 (3H)-ol, 6-( dimethylamino )benzo[ c] [ 1,2]oxaborol-
`
`1 (3H)-ol, N-(1-hydroxy-1,3-dihydrobenzo[ c ][ 1,2]oxaborol-6-yl)benzamide, 6-( 4-
`
`phenylpiperazin-1-yl)benzo[ c][l ,2]oxaborol-1 (3H)-ol, 6-(lH-indol-1-
`
`yl)benzo[ c ][1,2]oxaborol-1 (3H)-ol, 6-morpholinobenzo[ c ][ l,2]oxaborol- l (3H)-ol, 6-
`
`( 1-hydroxy-'l ,3-dihydrobenzo[ c] [ l ,2]oxaborol-5-yloxy)nicotinonitrile, 5-fluoro-6-
`
`nitrobenzo[ c ][ l ,2]oxaborol-1(3H)-ol,5-bromo-6-
`
`(hydroxymethyl)benzo[ c ][1,2]oxaborol-l (3H)-ol, 3, 7-dihydro-1,5-dihydroxy-1H,3H(cid:173)
`
`benzo[ 1,2-c:4,5-c']bis[l ,2]oxaborole, 1-(1-hydroxy-l,3-
`
`dihydrobenzo[ c ]( 1,2]oxaborol-6-yl)-3-phenylurea, N-(l-hydroxy-1,3-
`
`dihydrobenzo[ c][l,2]0xaborol-6-yl)benzenesulfonamide, N-(1-hydroxy-1,3-
`
`dihydrobenzo[ c ][ 1,2]oxaborol-6-yl)acetamide, 7-
`
`(hydroxymethyl)benzo[ c ][ l ,2]oxaborol-1(3H)-ol, 7-methylbenzo[ c ][1,2]oxaborol-
`
`1 (3H)-ol, 6-(3-(phenylthio)-1 H-indol-1-yl)benzo[ c][l ,2]oxaborol-1 (3H)-ol, 3-(1-(1-
`
`hydroxy-l,3-dihydrobenzo[ c ][ l ,2]oxaborol-6-yl)-1 H-indol-3-ylthio )propanenitrile, 6-
`
`(5-methoxy-1 H-indol-l-yl)benzo[ c ][l ,2]oxaborol-l (3H)-ol, 6-amino-5-
`
`fluorobenzo[ c ][ l ,2]oxaborol-1(3H)-ol, 6-(benzylamino)-5-
`
`fluorobenzo[ c ][ l ,2]oxaborol-1(3H)-ol, 6-(5-methoxy-3-(phenylthio )-lH-indol-1-
`
`yl)benzo[ c][ l ,2]oxaborol-1(3H)-ol, 3-(1-(1-hydroxy-l ,3-
`
`dihydrobenzo[ c ]( l ,2]oxaborol-6-yl)-5-methoxy-1H-indol-3-ylthio )propanenitrile, 4-
`
`(1-hydroxy-1,3-dihydrobenzo[ c ][ 1,2]oxaborol-7-yloxy)benzonitrile, 6-(5-chloro- lH(cid:173)
`
`indol-1-yl)benzo( c ][ l,2]0xaborol-l(3H)-ol, 3-(5-chloro-1-(1-hydroxy-1,3-
`
`dihydrobenzo[ c ][ 1,2 ]oxaborol-6-yl)- lH-indol-3-ylthio )propanenitri le, 6-
`
`(benzylamino )benzo[ c ][ l ,2]oxaborol-1(3H)-ol, 6-
`
`( dibenzylamino )benzo[ c J[ l ,2]oxaborol-1 (3H)-ol, 7-( 4-(1 H-tetrazol-5-
`
`MYLAN - Ex. 1015, p. 44
`
`

`

`U.S. Patent
`
`Aug. 3, 2010
`
`Sheet 44 of 63
`
`US 7,767,657 B2
`
`FIGURE 18C
`
`yl)phenoxy)benzo[ c] [ l ,2]oxaborol-1 (3H)-ol, 6-(5-chloro-3-(phenylthio )-lH-indol-1-
`
`yl)benzo[ c ][ 1,2]oxaborol-1 (3H)-ol, 3,4-dihydro-1H-thieno[3,2-c] [1,2]oxaborinin-1-
`
`ol, 6-( 4-(pyrimidin-2-yl)piperazin-l-yl)benzo[ c ][ l ,2]oxaborol-1 (3H)-ol, 7-
`
`(benzyloxy)benzo[ c ][1,2]oxaborol-1(3H)-ol, 4-(1-hydroxy-1,3-
`
`dihydrobenzo[ c] [ l ,2]oxaborol-6-ylthio )pyridinium chloride, 6-(pyridin-2-
`
`ylthio )benzo[ c ][ l ,2]oxaborol-1 (3H)-ol, 6-(pyridin-2-ylthio )benzo[ c ][1,2]oxaboro