Cf7C F4
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`
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`4
`
`SERIAL
`(series
`f87)
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`
`PATENT DATE
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`IN
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`PATENT
`M E
`NUMBER
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`1,90:
`45
`
`ISUOCLAS&
`
`GROUPARTUNIT
`
`E
`
`R
`
`'PHTLIP' F.,HUGHES HPEWELL . NJ.
`
`Z..
`
`**CONTINUING :D'ATA***A**************
`VERIFIED
`
`V
`
`,**FOREIGN/PCT'APPLICATIONS**,*** ********
`VERIFIEID
`
`FOREIGN FILING .LICENSE ;GRANTED 11/14190.
`SHEETS
`0 yes 0 no
`claimed
`Foreign priority
`... 0
`DRWGS
`I
`0 yes 0 no
`35 USC 11i9 conditions met
`I
`lIns e
`Examiner'snls Ints
`35,S119onLd'Wt
`0.
`Verlfledand Acknowledged
`; 1- R NALD 'W.' :'ALI.E l .
`
`o~OO,
`OUTR
`.ysrln
`NJ
`NJ
`
`i INADP
`TOTAL
`I
`CLAIMS
`8.1
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`ATORNEYS
`IFILING FEE
`Ii
`DOCKET NO.
`ECEIVED
`RCLAIMS
`p3
`70.00.,1AHP-9695
`''';.
`
`AMERICAN'HCME PRGDUCTS CORP.
`.
`9 685,THIRDAVE...
`NEW'YORK, ;NY 10017
`
`RAPAMYCIN ALKOXYESTERS
`
`.
`
`"
`
`• . ' - ..... ,.,|
`
`,
`
`u.~ n~P1~ ~f COMM.~ Pat. &TM Oftice-PTO-436L(rey, 10.78)
`
`PARTS OF APPLICATION
`FILED SEPARATELY
`
`NOTICE OF'ALLOWANCE MAILED
`
`PREPARED FOR ISSUE
`
`CLAIMS ALLOWED
`Total Claims
`Print Claim
`
`Assistant Examiner
`
`Docket Clark
`
`Amount Due
`
`ISSUE FEE
`Date Paid
`
`Sheets Drwg.
`
`DRAWING
`Figs. Drwg.
`
`Print Fig.
`
`PrImary Examiner
`ISSUE CLASSIFICATION
`Subclass
`
`ISSUE
`NUMBER
`
`Class
`
`WARNING: The Information dlsclpsed herein may be restricted. Unauthorized disclosure may be
`prohibited by the United States Code Title 35, Sections 122, 181 and 368.
`Possession outside the U.S. Patent & Trademark OffIce Is restricted to authorized employees
`and contractors only.
`
`Label
`Area
`
`Form PTO-436
`Rev. 5189
`
`NOVARTIS EXHIBIT 2129
`Par v Novartis, IPR 2016-00084
`Page 1 of 70
`
`

`
`117 598270
`
`Ar
`
`ABAr400NEV
`
`-
`
`"
`
`"-
`
`LTered
`or
`Counted
`
`APPROVED FOR LICENSE
`
`INITIALS
`
`0-"
`
`CONTENTS
`
`Received
`or
`
`______
`
`_____
`
`2.
`
`JA
`
`0
`
`pul 0*
`
`Xi
`
`______
`
`_____
`
`______
`
`_____
`
`6.
`
`7.
`
`____
`
`___
`
`___10.
`
`___________11.
`
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`
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`
`15.
`
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`
`____16.
`
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`
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`
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`
`____18.
`
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`
`21.
`
`22.
`
`23.
`
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`
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`
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`
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`r
`
`NOVARTIS EXHIBIT 2129
`Par v Novartis, IPR 2016-00084
`Page 2 of 70
`
`

`
`-
`
`I.
`
`Staple Isste Slip Here
`
`INDEX OF CLAIMS
`
`Claim
`
`,aS
`
`Date
`
`0 5
`
`1
`52
`53
`54
`55
`56
`57
`58
`59
`60
`61
`62
`63
`64
`65
`66
`67
`68
`69
`70
`71 1 1 1
`72
`73
`74
`75
`76
`77
`78
`79
`8O
`81
`82
`83
`84
`85
`86
`87
`88
`89
`90
`91
`92
`93
`94
`95
`96
`97
`98
`99
`00
`
`[
`
`Date
`
`Claim
`
`0
`
`2 0
`3o
`3 0
`4 o0
`
`4P
`
`o,
`
`SYMBOLS
`........ Rejected
`............ Allowed
`S(TNOrUgh numeral) CUncelad
`. .............. Restdcted
`N ............. Not-elected
`I ..
`Inerference
`A .............Appeal
`0 .............
`Objected
`
`,- I___
`
`.
`
`"
`
`7
`
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`120
`21
`22
`23
`24
`2526
`27
`28
`29
`30
`31
`32
`3334
`35
`36
`37
`38
`39
`40
`41
`42
`43
`44
`45
`46
`47
`48
`49
`50
`
`_
`
`NOVARTIS EXHIBIT 2129
`Par v Novartis, IPR 2016-00084
`Page 3 of 70
`
`

`
`SEARCHED
`
`Class
`
`Sub.
`
`Date
`
`Exmr.
`
`5M- 0
`; (y,
`
`q5s
`/15
`
`C. (L-
`
`'I
`
`(S
`
`INTERFERENCE SEARCHED
`Class
`Sub.
`Date
`Exmr.
`
`.I-
`
`SEARCH NOTES
`
`Date
`
`Exmr.
`
`CAS
`
`J'/&T,,,_4
`
`3/I-;/
`
`('.C-,
`
`CAS
`
`+z.it i-.arqktj,6,,
`
`s7/6 (51(
`
`NOVARTIS EXHIBIT 2129
`Par v Novartis, IPR 2016-00084
`Page 4 of 70
`
`

`
`"PO-154,2-
`
`(4-85)
`
`'r'
`~
`r-w.
`U.S. DEPARTMENT OF COMMERCE
`PATENT AND TRADEMARK OFFICE
`
`--
`
`ONLINE SEARCH REQUEST FORM
`
`USER
`
`SERIAL NUMBER
`
`,
`
`,7Z
`
`ART UNIT
`
`;
`
`PHONE
`
`/
`
`DATE
`
`/C
`
`Please give a detailed statement of requirements. Describe as
`matter to be searched. Define any terms that may have special
`citations, authors, or keywords, if known.
`You may include a copy of the broadest and or relevant claim(s).
`
`specifically as possible the subject
`meaning. Give examples or relevant
`
`0.
`
`Fj.L &9 i/I.(
`
`It'
`
`/,.
`(" /:"
`
`/
`
`//
`
`-
`
`(/I)~ C-i~
`
`A
`
`~2
`//
`
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`
`I.,
`
`**->~.~ c-c.
`
`/ ",.
`
`-7 (,-/,)/s
`
`y
`
`/~ ~
`
`STAFF USE ONLY
`
`TOTAL TIME
`
`6
`
`S.::EMS ONLINE
`DARC/QUESTEL ce
`DIALOG
`,.
`SDC
`'. -OTHER
`
`-
`
`COMPLETED
`SEARCHER
`ONLINE TIME
`(in minutes)
`NO. OF DATABASES
`
`/
`
`NOVARTIS EXHIBIT 2129
`Par v Novartis, IPR 2016-00084
`Page 5 of 70
`
`

`
`-> file reg
`FILE 'REGISTRY' ENTERED AT 14:35:54 ON 29 MAR 91
`USE IS SUBJECT TO THE TERMS OF YOUR CUSTOMER AGREEMENT
`COPYRIGHT (C) 1991 AMERICAN CHEMICAL SOCIETY
`
`STRUCTURE FILE UPDATES: HIGHEST RN 132829-88-0
`DICTIONARY FILE UPDATES: 23 MAR 91 (910323/ED)
`
`HIGHEST RN 132801-80-0
`
`=> d stat que
`Li
`
`STR
`
`C-0
`12
`
`4s 3
`
`4 4 L C 8
`,-'
`
`SC
`0 1.
`391 1011
`
`\C 37
`
`23 CC
`
`51,
`
`9\
`
`C
`Be
`
`C
`-,1-1
`
`-
`
`ow
`
`"wlow
`-0
`CC
`,C,-I--54,
`C
`
`-C4
`
`C C
`'1- 1-1
`C
`
`C
`V-
`C
`C
`
`N
`
`C
`
`25
`
`N
`
`"*, z
`C
`
`33
`
`0 21
`0 2±
`
`C ±6
`
`08s
`
`0I 9
`0 9
`
`- 280
`C-C
`0 2
`
`29
`
`C-0
`28
`
`19
`
`C6
`
`Be 1
`62 7
`'
`C
`
`61
`
`C
`
`64
`
`N7N
`C
`,651
`
`63 o-c
`14 15
`
`0 17
`
`NODE ATTRIBUTES: NONE
`
`GRAPH ATTRIBUTES:
`RING(S) ARE ISOLATED OR EMBEDDED
`NUMBER OF NODES IS 65
`L4
`10 SEA SSS FUL Li
`
`100.0% PROCESSED
`SEARCH TIME: 00.00.17
`
`12 ITERATIONS
`
`10 ANSWERS
`
`=> d sub can 1-10
`
`L4 ANSWER 1 OF i0
`COPYRIGHT (C) 1991 AMERICAN CHEMICAL SOCIETY
`
`RN
`CN
`
`CN
`
`MF
`SR
`
`131704-17-1
`Rapamycin, 42-[4-[[(2-propenyloxy)carbonyl]amino)benzenebutanoate]
`(9CI) (CA INDEX NAME)
`23,27-Epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclohentriacontine,
`rapamycin deriv. (9CI)
`C65 H94 N2 016
`CA
`
`NOVARTIS EXHIBIT 2129
`Par v Novartis, IPR 2016-00084
`Page 6 of 70
`
`

`
`CA, CJACS
`LC
`STE *
`
`R1 -CHH2 -aOC(O)CCH
`
`2 )3
`
`I
`
`IotlE
`
`Me
`
`11.Me
`
`NHC(O)OCH 2 CH:CH 2
`
`I s0
`
`Mu
`
`0
`
`MaO
`
`1 REFERENCES IN FILE CA (1967 TO DATE)
`
`REFERENCE
`
`1:
`
`CA114 (9) :74886n
`
`L4 ANSWER 2 OF 10
`COPYRIGHT (C) 1991 AMERICAN CHEMICAL SOCIETY
`
`110682-08-1
`Rapamycin, 31-ester with N,N-dimethyl-.beta.-alanine,
`monomethanesulfonate (salt) (9CI) (CA INDEX NAME)
`23,27-Epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclohentriacontine,
`rapamycin deriv. (9CI)
`C56 H88 N2 014 . C H4 03 S
`CA
`CA
`
`CM
`
`1
`
`CRN 110682-07-0
`CMF C56 H88 N2 014
`CSTE *
`•** STRUCTURE DIAGRAM IS NOT AVAILABLE ***
`
`CM
`
`2
`
`CRN 75-75-2
`CMF C H4 03 S
`
`NOVARTIS EXHIBIT 2129
`Par v Novartis, IPR 2016-00084
`Page 7 of 70
`
`

`
`0 REFERENCES IN FILE CA (1967 TO DATE)
`
`L4 ANSWER 3 OF 10
`COPYRIGHT (C) 1991 AMERICAN CHEMICAL SOCIETY
`
`CN
`
`RN
`CN
`
`110682-07-0
`Rapamycin, 31-ester with N,N-dimethyl-.beta.-alanine (9CI) (CA
`INDEX NAME)
`23,27-Epoxy-3H-pyrido[2,1-c)[1,4)oxaazacyclohentriacontine,
`rapamycin deriv. (9CI)
`C56 H88 N2 014
`MF
`COM
`CI
`CA
`SR
`STE *
`*** STRUCTURE DIAGRAM IS NOT AVAILABLE ***
`0 REFERENCES IN FILE CA (1967 TO DATE)
`
`L4 ANSWER 4 OF 10
`COPYRIGHT (C) 1991 AMERICAN CHEMICAL SOCIETY
`
`CN
`
`109351-63-5
`RN
`CN Rapamycin, 31,42-diester with N,N-dimethylglycine (9CI) (CA INDEX
`NAME)
`23,27-Epoxy-3H-pyrido[2,,l-c](1,4)oxaazacyclohentriacontine,
`rapamycin deriv. (9CI)
`C59 H93 N3 015
`MF
`CA
`SR
`CA
`LC
`STE *
`*** STRUCTURE DIAGRAM IS NOT AVAILABLE ***
`1 REFERENCES IN FILE CA (1967 TO DATE)
`
`REFERENCE
`
`1: P CA107(8):64867y
`
`L4 ANSWER 5 OF 10
`COPYRIGHT (C) 1991 AMERICAN CHEMICAL SOCIETY
`
`CN
`
`RN
`CN
`
`109351-62-4
`Rapamycin, 31-(1-pyrrolidinebutanoate), monohydrochloride (9CI)
`INDEX NAME)
`23,27-Epoxy-3H-pyrido(2,1-c](1,4]oxaazacyclohentriacontine,
`rapamycin deriv. (9CI)
`C59 H92 N2 014 . C1 H
`MF
`CA
`SR
`CA
`LC
`STE *
`•** STRUCTURE DIAGRAM IS NOT AVAILABLE ***
`1 REFERENCES IN FILE CA (1967 TO DATE)
`
`REFERENCE
`
`1: P CA107(8):64867y
`
`L4 ANSWER 6 OF 10
`COPYRIGHT (C) 1991 AMERICAN CHEMICAL SOCIETY
`
`RN
`CN
`
`109351-61-3
`Rapamycin, 31-ester with N,N-diethyl-.beta.-alanine,
`
`NOVARTIS EXHIBIT 2129
`Par v Novartis, IPR 2016-00084
`Page 8 of 70
`
`

`
`CN
`
`monohydrochloride (9CI) (CA INDEX NAME)
`23,27-Epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclohentriacontine,
`rapamycin deriv. (9CI)
`C58 H92 N2 014 . Cl H
`MF
`CA
`SR
`CA
`LC
`STE *
`•** STRUCTURE DIAGRAM IS NOT AVAILABLE ***
`1 REFERENCES IN FILE CA (1967 TO DATE)
`
`REFERENCE
`
`1: P CA1O7(8):64867y
`
`L4 ANSWER 7 OF 10
`COPYRIGHT (C) 1991 AMERICAN CHEMICAL SOCIETY
`
`109351-60-2
`RN
`CN Rapamycin, 31-ester with N,N-dimethylglycine (9CI) (CA INDEX NAME)
`23,27-Epoxy-3H-pyrido[2, 1-c] [1, 4]oxaazacyclohentriacontine,
`CN
`rapamycin deriv. (9CI)
`C55 H86 N2 014
`MF
`CA
`SR
`CA
`LC
`STE *
`*** STRUCTURE DIAGRAM IS NOT AVAILABLE ***
`1 REFERENCES IN FILE CA (1967 TO DATE)
`
`REFERENCE
`
`1: P CA107(8):64867y
`
`L4 ANSWER 8 OF 10
`COPYRIGHT (C) 1991 AMERICAN CHEMICAL SOCIETY
`
`RN
`CN
`CN
`CN
`
`82165-69-3
`Rapamycin, monoacetate (ester) (9CI) (CA INDEX NAME)
`Rapamycin monoacetate
`23,27-Epoxy-3H-pyrido[2,1-c)[1,4]oxaazacyclohentriacontine,
`rapamycin deriv. (9CI)
`C53 H81 N 014
`MF
`CI
`IDS
`CA
`LC
`STE 8:ID
`
`CM
`
`1
`
`53123-88-9
`C51 H79 N 013
`
`CRN
`CMF
`CSTE
`
`NOVARTIS EXHIBIT 2129
`Par v Novartis, IPR 2016-00084
`Page 9 of 70
`
`

`
`Me
`
`Mao
`
`0
`
`CHM,
`1
`
`0
`
`OMm
`
`CM
`
`2
`
`CRN 64-19-7
`CMF C2 H4 02
`
`HO 2 CMO
`
`1 REFERENCES IN FILE CA (1967 TO DATE)
`
`REFERENCE
`
`1: P CA97(3):23529w
`
`L4 ANSWER 9 OF 10
`COPYRIGHT (C) 1991 AMERICAN CHEMICAL SOCIETY
`
`RN
`CN
`CN
`CN
`
`MF
`CI
`LC
`STE
`
`82111-46-4
`Rapamycin, diacetate (ester) (9CI) (CA INDEX NAME)
`Rapamycin diacetate
`23,27-Epoxy-3H-pyrido[2,1-c](1,4]oxaazacyclohentriacontine,
`rapamycin deriv. (9CI)
`C55 H83 N 015
`IDS
`CA
`8:ID
`
`CM
`
`1
`
`CRN 53123-88-9
`CMF C51 H79 N 013
`CSTE *
`
`-- -
`
`NOVARTIS EXHIBIT 2129
`Par v Novartis, IPR 2016-00084
`Page 10 of 70
`
`

`
`Me
`
`MaO
`
`0
`
`CHM
`
`0
`
`I.
`
`CH 2
`
`OMm
`
`OH
`
`CM
`
`2
`
`CRN 64-19-7
`CMF C2 H4 02
`
`HO 2 CMe
`
`1 REFERENCES IN FILE CA (1967 TO DATE)
`
`REFERENCE
`
`1: P CA97(3):23529w
`
`L4 ANSWER 10 OF 10
`COPYRIGHT (C) 1991 AMERICAN CHEMICAL SOCIETY
`
`RN
`CN
`CN
`CN
`
`CN
`
`CN
`
`53123-88-9
`Rapamycin (9CI) (CA INDEX NAME)
`Antibiotic AY 22989
`23,27-Epoxy-3H-pyrido[2,1-c](1,4]oxaazacyclohentriacontine,
`rapamycin deriv. (9CI)
`
`[3S-[3R*[S*(IR*,3S*,4S*)],6S*,7E,9S*,10S*,12S*,14R*,15E,17E,19E,21R*
`,23R*,26S*,27S*,34aR*]]-9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,
`34a-Hexadecahydro-9,27- dihydroxy-3-[2-(4-hydroxy-3-methoxycyclohexyl
`)-1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-23,27-ep
`oxy-3H-pyrido[2,1-c](1,4]oxaazacyclohentriacontine-1,5,11,28,29(4H,6
`H,31H)-pentone
`
`23,27-Epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclohentriacontine-1,5, 11,28
`,29(4H,6H,31H)-pentone,
`9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-hexadecahydro-9,27-d
`ihydroxy-3-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylethyl]-10,21-d
`imethoxy-6,8,12,14,20,26-hexamethyl-,
`
`NOVARTIS EXHIBIT 2129
`Par v Novartis, IPR 2016-00084
`Page 11 of 70
`
`

`
`[3S-[3R*[S*(IR*,3S*,4S*)],6S*,7E,9S*,10S*,12S*,14R*,15E,17E,19E,21R*
`,23R*,26S*,27S*,34aR*]]-
`C51 H79 N 013
`COM
`BEILSTEIN, BIOSIS, CA, CJACS, IFICDB, IFIPAT, IFIUDB, MEDLINE, PHAR
`
`MF
`CI
`LC
`STE
`
`ICH
`
`2
`
`Me
`
`MaO
`
`37 REFERENCES IN FILE CA (1967 TO DATE)
`
`REFERENCE
`REFERENCE
`REFERENCE
`REFERENCE
`REFERENCE
`REFERENCE
`REFERENCE
`REFERENCE
`REFERENCE
`REFERENCE
`
`1:
`2:
`3:
`4:
`5:
`6:
`7:
`8:
`9:
`10:
`
`CA114 (9) :81347r
`CAl14 (9) :74886n
`CA114 (9) :74881g
`CA114 (7) :55460c
`CA114 (3) :17266m
`CA113 (25) :224286n
`CA113 (25) :224283j
`CA113 (23) :204574b
`CA113 (15) :126030e
`CA113 (11) :93837t
`
`=> file ca
`FILE 'CA' ENTERED AT 14:37:26 ON 29 MAR 91
`USE IS SUBJECT TO THE TERMS OF YOUR CUSTOMER AGREEMENT
`COPYRIGHT (C) 1991 AMERICAN-CHEMICAL SOCIETY
`
`FILE COVERS 1967 - 23 Mar 91 (910323/ED) VOL 114 ISS 12.
`All OFFLINE Prints.or Displays, use the ABS or ALL formats to obtain
`abstract graphic structures. The AB format DOES NOT display structure
`diagrams.
`
`=> s 14/d
`L5
`
`2 L4/D
`
`=> d bib ab hit 1-2
`
`NOVARTIS EXHIBIT 2129
`Par v Novartis, IPR 2016-00084
`Page 12 of 70
`
`

`
`L5 ANSWER 1 OF 2
`COPYRIGHT (C) 1991 AMERICAN CHEMICAL SOCIETY
`
`CS
`LO
`SO
`SC
`DT
`CO
`Is
`PY
`LA
`OS
`AB
`
`AN. CA114(9):74886n
`Rapamycin and FK506 binding proteins (immunophilins)
`TI
`Fretz, Heinz; Albers, Mark W.; Galat, Andrzej; Standaert, Robert F.;
`AU
`Lane, William S.; Burakoff, Steven J.; Bierer, Barbara E.;
`Schreiber, Stuart L.
`Dep. Chem., Harvard Univ.
`Cambridge, MA 02138, USA
`J. Am. Chem. Soc., 113(4), 1409-11
`1-7 (Pharmacology)
`J
`JACSAT
`0002-7863
`1991
`Eng
`CJACS
`The structurally related immunosuppressants FK506 and rapamycin have
`recently been shown to inhibit distinct signaling pathways in T
`lymphocytes. Whereas FK506 and the structurally unrelated
`immunosuppressant cyclosporine A (CsA) potently inhibit a T cell
`receptor-mediate signal transduction pathway, rapamycin appears to
`act at a later stage of T cell activation by interfering with a
`signaling pathway that is mediated by a lymphokine receptor. In
`addn., FK506 and rapamycin, but not CsA, inhibit each other's
`actions in a variety of functional assays, suggesting that FK506 and
`rapamycin have a common biol. receptor 'site. However, concns.
`10-100 times greater than the effective drug concn. of either agent
`(IC50 .apprx.0.5 nM) are required in order to observe this mutual
`antagonism, herein referred to as a buffering action by an
`immunophilin. The synthesis of FK506 and rapamycin affinity
`matrixes and their use in affinity chromatog. expts. with human T
`cells and calf thymus tissue exts. are described. These expts.
`demonstrate that the predominant binding protein to both FK506 and
`rapamycin is the cytosolic receptor, FKBP (FK506-binding proteins).
`The abundance of this protein (ca. 5 nM in JurkatT cells vs. an
`IC50 of 0.5 nM for both drugs) implicates FKBP as the mediator of
`the buffer effect for both FK506's inhibition of the actions of
`rapamycin and rapamyoin's inhibition of the actions of FK506. In
`addn., it is shown that several lower abundance immunophilins are
`retained on both FK506 and rapamycin affinity matrixes. Proteins of
`Mr 60,000 and Mr 80,000 are unique among this set in that they are
`phosphorylated. Lower mol. wt. immunophilins of Mr 15,000 and Mr
`30,000 bind directly to each drug and are related in sequence to
`FKBP.
`IT 53123-88-9DP, Rapamycin, matrix
`matrix
`(prepn. and protein binding of)
`
`104987-11-3DP, FK506,
`
`L5 ANSWER 2 OF 2
`COPYRIGHT (C) 1991 AMERICAN CHEMICAL SOCIETY
`
`AN
`TI
`AU
`CS
`LO
`SO
`PI
`AI
`
`CA107(8):64867y
`Water-soluble rapamycin prodrugs
`Stella, Valentino J.; Kennedy, Paul E.
`University of Kansas
`USA
`U.S., 6 pp.
`US 4650803 A 17 Mar 1987
`US 85-806152 6 Dec 1985
`
`NOVARTIS EXHIBIT 2129
`Par v Novartis, IPR 2016-00084
`Page 13 of 70
`
`

`
`1C
`
`ICM A61K031-395
`ICS C07D491-06
`NCL 514291000
`63-6 (Pharmaceuticals)
`SC
`DT P
`USXXAM
`CO
`1987
`PY
`Eng
`LA
`The title prodrugs are rapamycin derivs. monosubstituted at position
`AB
`28 and disubstituted at position 28 and 43 with the substituents
`CO(CH2)nNR1R2 (n = 1-3; R1,R2 = H, C1-3 alkyl; NRIR2 =
`heterocyclyl). The prodrugs release rapamycin in the presence of
`human plasma and animal tissue homogenates. Rapamycin was
`esterified with 4-pyrrolidinobutyric acid-HCl, in presence of
`dicyclohexylcarbodiimide and 4-N,N-dimethylaminopyridine to give
`rapamycin mono-(28)-4'-(N-pyrrolidino)butyrate ester-HC1. The soly.
`of the product was .apprx.15 mg/mL.
`IT 53123-88-9D, Rapamycin, derivs.
`(water-sol., prodrugs)
`
`=> file caold
`FILE 'CAOLD' ENTERED AT 14:38:38 ON 29 MAR 91
`USE IS SUBJECT TO THE TERMS OF YOUR CUSTOMER AGREEMENT
`COPYRIGHT (C) 1991 AMERICAN CHEMICAL SOCIETY
`
`FILE LAST UPDATED: 16 MAR 91 (910316/ED)
`
`=> s 14
`L6
`
`0 L4
`
`=> file biosis
`FILE 'BIOSIS' ENTERED AT 14:39:01 ON 29 MAR 91
`COPYRIGHT (C) 1991 BIOSIS(R)
`
`FILE COVERS 1969 TO.DATE; CAS REGISTRY NUMBERS ARE PRESENT FROM
`JULY, 1980 TO DATE.
`RECORDS LAST ADDED: 23 MAR 91 (910323/ED) BA9107 BR4007
`CAS REGISTRY NUMBERS (SM) LAST ADDED: 23 MAR 91 (910323/UP)
`
`Changes to SUPERTERM/BC searching --
`
`See HELP STERMS
`
`=> s 14
`L7
`
`30 L4
`
`=> d hist 17-
`
`(FILE 'BIOSIS' ENTERED AT 14:39:01 ON 29 MAR 91)
`30 S L4
`L7
`0 S L7 AND (DERIV? OR ANALOG?)
`L8
`
`NOVARTIS EXHIBIT 2129
`Par v Novartis, IPR 2016-00084
`Page 14 of 70
`
`

`
`07 598270
`
`PATENT APPLICATION SERIAL NO.
`
`U.S. DEPARTMENT OF COMMERCE
`PATENT AND TRADEMARK OFFICE
`FEE RECORD SHEET
`
`P 30256.-10/29/90
`
`0
`
`01I-1425 030, 101
`
`' '.'..,,':#
`" : . •
`
`::
`
`... .,
`
`406.O0CH AHP-9695
`
`DS20042 11/07/90
`
`07598270
`
`01-1425 020
`
`3 6 .O0CR
`
`PTO-1556
`(5/87)
`
`NOVARTIS EXHIBIT 2129
`Par v Novartis, IPR 2016-00084
`Page 15 of 70
`
`

`
`CERTIF4ATE OF MAILING BY "E
`SS MAIL"
`"EXPRESS MAIL" MAILING LABEL NUMBER LB187219461
`October 16, 1990
`DATE OF DEPOSIT
`I HEREBY CERTIFY THAT THIS PAPER OR FEE
`IS BEING
`DEPOSITED WITH THE UNITED STATES POSTAL SERVI
`BY "EXPRCSS-MAIL POST OFFICE TO ADDRESSEE" SERVIA~.
`UNDER 37 CFR 1.10 ON THE DATE INDICATED ABOVE
`D
`IS ADDRESSED TO THE COMMISSIONER OF PATENTS
`TRADEMARKS, WASHINGTON, D.C. 20231
`Roxanne Kelley
`(TYPD O )NAMEOFPERSON AILINGyAEIRF F['
`
`(SIGNATrdRE 0 PERSON MAILING PAPER OR FEO
`
`07 598270
`
`U.S. DEPARTMENT OF COMMERCE
`Patent and Trademark Office
`
`Address Only: COMMISSIONER OF PATENTS
`AND TRADEMARKS
`Washington, D.C. 20231
`
`Docket No.
`
`AHP-9695
`PATENT
`
`THE COMMISSIONER OF PATENTS AND TRADEMARKS
`Washington, D.C. 20231
`
`Sir:
`
`Transmitted herewith for filing is the patent application of
`
`Inventor:
`
`Philip Floyd, Hughes
`
`Rapamycin Alkoxyesters
`
`Enclosed are:
`E]
`sheets of drawing.
`-
`DAn assignment of the invention to
`i A certified copy of a
`EI Associate power of attorney.
`
`application.
`
`'(2)
`
`(1)
`FOR
`
`TOTAL
`CLAIMS
`
`INDEPENDENT
`CLAIMS
`
`MULTIPLE
`DEPENDENT
`CLAIMS
`
`NUMBER FILED
`
`CLAIMS AS FILED
`(3)
`NUMBER EXTRA
`
`-20=
`
`3=
`
`8
`4
`
`0
`
`0
`1
`
`0
`
`(4)
`RATE
`
`x$ 12.00
`
`x $ 36.00
`
`$120.00
`
`TOTAL FILING'
`FEE
`
`(5)
`BASIC FEE
`$370.00
`
`0.00
`
`36.00
`
`0.00
`
`406.00
`4
`
`r
`
`Please charge my Deposit Account No. 01-1425 in the amount of
`$ 406.00
`A duplicate copy of this sheet is enclosed.
`
`V The Commissioner is hereby authorized to charge any fees under 37 CFR 1. 16 and
`1.17 which may be required during the entire pendency of the application to Deposit
`Account No. 01-1425. A duplicate copy of this sheet is enclosed.
`
`A check in the amount of
`
`to cover the filing fee is enclosed.
`
`M-2769-E (3/89)
`
`FORM PO- 1082 (11-69)
`
`Attorney o Record
`Richard K. J ckson
`Reg. No. 24, 48
`(ASM)
`
`USCOMM-DC 60424-P69
`
`NOVARTIS EXHIBIT 2129
`Par v Novartis, IPR 2016-00084
`Page 16 of 70
`
`

`
`10 October 1990
`3ED I:0CO:ASM:mef
`AHP-9695
`
`xtN 07598270
`
`-0
`
`AAMYC-7IN ALKOXYE
`
`'R
`
`BACKGROUND OF THE INVENTION
`This invention relates to novel ethers of rapamycin and a method for using them
`in the treatment of transplantation rejection, host vs. graft disease, autoimmune
`diseases, diseases of inflammation, and fungal infections.
`
`Rapamycin is a macrocyclic triene antibiotic produced by Streptomyces
`hygroscopicus, which was found to have antifungal activity, particularly against
`Candida albicans, both in vitro and in vivo [C. Vezina et al., J. Antibiot. 28, 721
`(1975); S.N. Seghal et al., J. Antibiot. 28, 727 (1975); H. A. Baker et al., J. Antibiot.
`31, 539 (1978); U.S. Patent 3,929,992; and U.S. Patent 3,993,749].
`Rapamycin alone (U.S. Patent 4,885,171) or in combination with picibanil
`(U.S. Patent 4,401,653) has been shown to have antitumor activity. R. Martel et al.
`[Can. J. Physiol. Pharmacol. 55, 48 (1977)) disclosed that rapamycin is effective in
`the experimental allergic encephalomyelitis model, a model for multiple sclerosis; in the
`adjuvant arthritis model, a model for rheumatoid arthritis; and effectively inhibited the
`formation of IgE-like antibodies.
`The immunosuppressive effects of rapamycin have been disclosed in FASEB 3,
`3411 (1989). Cyclosporin A and FK-506, other macrocyclic molecules, also have
`been shown to be effective as immunosuppressive agents, therefore useful in
`preventing transplant rejection [FASEB 3, 3411 (1989); FASEB 3, 5256 (1989); and
`R. Y. Calne et al., Lancet 1183 (1978)].
`Mono- and diacylated derivatives of rapamycin (esterified at the 28 and 43
`positions) have been shown to be useful as antifungal agents (U.S. Patent 4,316,885)
`and used to make water soluble prodrugs of rapamycin (U.S. Patent 4,650,803).
`Recently, the numbering convention for rapamycin has been changed; therefore
`according to Chemical Abstracts nomenclature, the esters described above would be at
`the 31- and 42- positions..
`
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`Page 17 of 70
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`

`
`* 10 October 1990
`3ED1:OCO:ASM:mef
`AHP-9695
`PATENT
`
`-2-
`
`DESCRIPTION OF THE INVENTION
`This invention provides derivatives of rapamycin which are useful as
`-immunosuppressive, anti-inflammatory, and antifungal agents having the structure
`
`5 wherein R1 is
`
`01
`
`I 2
`-CH 2COR
`
`R2 is hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms which is
`optionally unsaturated, aralkyl of 7-10 carbon atoms, or phenyl which is
`optionally mono-, di-, or tri-substituted with a substituent selected from alkyl
`of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, hydroxy, cyano, halo, nitro,
`carbalkoxy of 2-7 carbon atoms, trifluoromethyl, amino, or a carboxylic acid;
`or a pharmaceutically acceptable salt thereof when R2 is hydrogen.
`
`Of the compounds, preferred members are those in which R2 is alkyl of 1-6
`carbon atoms.
`The pharmaceutically acceptable salts may be formed from inorganic cations
`such as sodium, potassium, calcium, magnesium and the like or may be in the form of
`a quaternary ammonium salt..
`
`10
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`Page 18 of 70
`
`

`
`10 October 1990
`3ED 1:OCO:ASM:mef
`AHP-9695
`PATENT
`
`-3-
`
`The compounds of this invention can be prepared by reacting rapamycin with
`the appropriately substituted ester of diazoacetic acid in the presence of a divalent cation
`salt, such as rhodium (II) diacetate dimer or copper (II) triflate, as shown below.
`
`"P(f
`42 ).OH
`
`HN2CCO 2 R2
`11
`
`-
`
`R
`.r'C
`42 )-OCH2CO2R2
`
`10
`
`15
`
`20
`
`25
`
`30
`
`This method of preparing alkoxyesters has been described by B. Ganem et al.,
`J. Am. Chem. Soc. 104, 6787 (1982). The starting mateiials utilized are either
`commercially available or can be prepared by methods disclosed in the literature.
`The compounds of this invention, rapamycin-42-ethers, provide stability
`against hydrolysis of the 42-side chain by virture of the ether moiety connecting the
`side chain to rapamycin at the 42-position.
`Immunosuppressive activity was evaluated in an. in vitro .standard
`pharmacological test procedure to measure lymphocyte proliferation (LAF) and in two
`in vivo standard pharmacological test procedures. The first in vivo procedure was a
`popliteal lymph node (PLN) test procedure which measured the effect of compounds of
`this invention on a mixed lymphocyte reaction and the second in vivo procedure
`evaluated the survival time of a pinch skin graft.
`The comitogen-induced thymocyte proliferation procedure (LAF) was used as
`an in vitro measure of the immunosuppressive effects of representative compounds.
`Briefly, cells from the thymus of normal BALB/c mice are cultured for 72 hours with
`PHA and IL-1 and pulsed with tritiated thymidine during the last six hours. Cells are
`cultured with and without various concentrations of rapamycin, cyclosporin A, or test
`compound. Cells are harvested and incorporated; radioactivity is determined.
`Inhibition of lymphoproliferation is assessed in percent change in counts per minute
`from non-drug treated controls. The results are expressed by the following ratio, or as
`the percent inhibition of lymphoproliferation of 1 gm.
`
`3H-control thymus cells - H3 -rapamycin-treated thymus cells
`3H-control thymus cells - H3-test compound-treated cells
`
`A mixed lymphocyte reaction (MLR) occurs when lymphoid cells from
`genetically distinct animals are cQiabined in tissue culture. Each stimulates the other to
`undergo blast transformation which results in increased DNA synthesis that can be
`
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`Page 19 of 70
`
`

`
`10 October 1990
`3EDI:0CO:ASM:mef
`AHP-9695
`PATENT
`
`-4-
`
`quantified by the incorporation of tritiated thymidine. Since stimulating a MLR is a
`function of disparity at Major Histocompatibility antigens, an in vivo popliteal lymph
`node (PLN) test procedure closely correlates to host vs. graft disease. Briefly,
`irradiated spleen cells from BALB/c donors are injected into the right hind foot pad of
`recipient C3H mice. The drug is given daily, p.o. from Day 0 to Day 4. On Day 3 and
`Day 4, tritiated thymidine is given i.p., b.i.d. On Day 5, the hind popliteal lymph
`nodes are removed and dissolved, and radioactivity counted. The corresponding left
`PLN serves as the control for the PLN from the injected hind foot. Percent
`suppression is calculated using the non-drug treated animals as allogenic control.
`Rapamycin at a dose of 6 mg/kg, p.o. gave 86% suppression, whereas cyclosporin A
`at the same dose gave 43% suppression. Results are expressed by the following ratio:
`
`3H-PLN cells control C3H mouse - 3H-PLN cells rapanycin-treated C3H mouse
`3H-PLN cells control C3H mouse - 3H-PLN cells test compound-treated C3H mouse
`
`The second n vivo test procedure is designed to determine the survival time of
`pinch skin graft from male DBA/2 donors transplanted to male BALB/c recipients. The
`method is adapted from Billingham R.E. and Medawar P.B., J. Exp. Biol. 28:385-
`402, (1951). Briefly, a pinch skin graft from the donor is grafted on the dorsum of the
`recipient as a homograft, and an autograft is used as control in the same region. The
`recipients are treated with either varying concentrations of cyclosporin A as test control
`or the test compound, intraperitoneally. Untreated recipients serve as rejection control.
`The graft is monitored daily and observations are recorded until the graft becomes dry
`and forms a blackened scab. This is considered as the rejection day. The mean graft
`survival time (number of days ± S.D.) of the drug treatment group is compared with
`the control group.
`The following table summarizes the results of representative compounds of this
`invention in these three standard test procedures.
`
`5
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`

`
`10 October 1990
`3ED1:OCO:ASM:mef
`AHP-9695
`PATENT
`
`-5-
`
`TABLE 1
`
`Compound
`
`Example 1
`Example 2
`Rapamycin
`
`LAF*
`(ratio)
`
`0.46
`0.27
`1.0
`
`PLN*
`(raQ)_
`
`0.74**
`+
`1.0
`
`Skin Graft
`(days + SD)
`
`7.5 + 1.2
`+
`12.0 + 1.7
`
`* Calculation of ratios was described spra.
`•* A result of -0.14 also was obtained for Example 1.
`+ Not evaluated
`
`The results of these standard pharmacological test procedures demonstrate
`immunosuppressive activity both in vitro and in vivo for the compounds of this
`test procedures indicate suppression of
`
`invention. Positiv,.i.osin.the1LA._ aPjL.N
`
`5
`
`10
`
`15
`
`20
`
`T cell proliferation. As a transplanted pinch skin grafts are typically rejected within 6-7
`days without the use of an i mmunosuppmssive agent, the increased survival time of the
`skin graft when treated with the compounds of this invention further demonstrates their
`utility as immunosuppressive agents.
`Antifungal activity of the coinpounds of this invention was measured against 5
`strains of Candida albicans using a plate test procedure for measurement of inhibition.
`The following represents the typical procedure used. Compound to be tested was
`placed on sterile dried 1/4" plate disks, and allowed to dry. Agar plates were seeded
`25 with fungi and allowed to solidify. The impregnated disks were placed on the seeded
`Agar surface and incubated for the time required for the particular culture. Results are
`expressed in MIC (g.g/ml) to inhibit growth. The results of this test procedure showed
`that the compounds of this inventionhave antifungal activity.
`
`30
`
`35
`
`Table 2*
`Strain of Candida albicans
`Compound ATCC 10231 "ATCC 38246 ATCC 38247 ATCC 38248
`Example 1
`0.5
`0.1
`0.2
`0.1
`Example 2
`0.05
`0.2
`0.05
`0.1
`Rapamycin
`0.003
`0.025
`0.003
`0.006
`
`3669
`0.05
`0.2
`0.025
`
`* expressed as MIC (jig/ml)
`
`NOVARTIS EXHIBIT 2129
`Par v Novartis, IPR 2016-00084
`Page 21 of 70
`
`

`
`10 October 1990
`3ED1:OCO:ASM:mef
`AHP-9695
`PATENT
`
`-6-
`
`Based on the results of these standard pharmacological test procedures, the
`compounds are useful in the treatment of transplantation rejection such as, heart,
`kidney, liver, bone marrow, and skin transplants; autoimmune diseases such as, lupus,
`rheumatoid arthritis, diabetes mellitus, myasthenia gravis, and multiple sclerosis; and
`diseases of inflammation such as, psoriasis, dermatitis, eczema, seborrhea,
`inflammatory bowel disease; and fungal infections.
`The compounds may be administered neat or with a pharmaceutical carrier to a
`mammal in need thereof. The pharmaceutical carrier may be solid or liquid.
`A solid carrier can include one or more substances which may also act as
`flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants,
`compression aids, binders or tablet-disintegrating agents; it can also be an encapsulating
`material. In powders, the carrier is a finely divided solid which is in admixture with the
`finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier
`having the necessary compression properties in suitable proportions and compacted in
`the shape and size desired. The powders and tablets preferably contain up to 99% of
`the active ingredient. Suitable solid carriers include, for example, calcium phosphate,
`magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl
`cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes
`and ion exchange resins.
`Liquid carriers are used in preparing solutions, suspensions, emulsions,
`syrups, elixirs and pressurized compositions. The active ingredient can be dissolved or
`suspended in a pharmaceutically acceptable liquid carrier such as water, an organic
`solvent, a mixture of both or pharmaceutically acceptable oils or fats. The liquid carrier
`can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers,
`buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening
`agents, colors, viscosity regulators, stabilizers or osmo-regulators. Suitable examples
`of liquid carriers for oral and parenteral administration include water (partially
`containing additives as above, e.g. cellulose derivatives, preferably sodium
`carboxymethyl cellulose solution), alcohols (including monohydric alcohols and
`polyhydric alcohols, e.g. glycols) and their derivatives, and oils (e.g. fractionated
`coconut oil and arachis oil). For parenteral administration, the carrier can also be an
`oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are useful
`in sterile liquid form compositions for parenteral administration. The liquid carrier for
`pressurized compositions can be halogenated hydrocarbon or other pharmaceutically
`acceptable propellent.
`
`5
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`15
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`NOVARTIS EXHIBIT 2129
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`
`

`
`10 October 1990
`3ED 1:0CO:ASM:mef
`AHP-9695
`PATENT
`
`-7-
`
`Liquid pharmaceutical compositions which are sterile solutions or suspensions
`can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous
`injection. Sterile solutions can also be administered intravenously. The compound can
`also be administered orally either in liquid or solid composition form.
`Preferably, the pharmaceutical composition is in unit dosage form, e.g. as
`tablets or capsules.
`In such form, the composition is sub-divided in unit dose
`containing appropriate quantities of the active ingredient; the unit dosage forms can be
`packaged compositions, for example, packeted powders, vials, ampoules, prefilled
`syringes or sachets containing liquids. The unit dosage form can be, for example, a
`capsule or tablet itself, or it can be the appropriate number of any such compositions in
`package form. The dosage to be used in the treatment must be subjectively determined
`by the attending physician.
`In addition, the compounds of this invention may be employed as a solution,
`cream, or lotion by formulation with pharmaceutically acceptable vehicles containing
`0.1-0.5 percent, preferably 2%, of active compound which may be administered to a
`fungally affected area.
`
`The following examples illustrate the preparation of representative compounds
`of this invention.
`
`Example 1.
`
`42-Deoxy-42-(2-ethoxy-2-oxoethoxy)rapamycin
`
`A solution of rapamycin (2.0 g, 2.187 mmol) and rhodium (II) diacetate
`(37 mg, 0.08 mmol) in benzene (50 mL) was heated to reflux and ethyl diazoacetate
`(750 mg, 690 piL, 6.56 mmol) in benzene (10 mL) was added over 10 nin. The
`mixture was concentrated and purified by chromatography (silica gel, ethyl acetate-
`hexane, 1:1) to give 700 mg of product (32%) as a glass. The product was stirred
`
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`

`
`10 October 1990
`3ED 1:OCO:ASM:mef
`AHP-9695
`PATENT
`
`-8-
`
`with hexane with the addition of small amounts of ethyl acetate, ether and methylene
`chloride for 3 d to yield a white powder which was filtered to give 42-deoxy-42-(2-
`ethoxy-2-oxoethoxy)rapamycin (496 mg, 23%). The product was isolated as the
`IR (KBr) 1680, 1730, 2920, 3430 cm.-1 ; 1H-NMR (CDCL 3) 8 1.28
`hemihydrate.
`(3H, t, J = 7.14 Hz), 1.65 ( 3H, s), 1.74 (3H, s), 3.14 (3H, s) 3.34 (3H, s), 3.41
`(3H, s), 4.20 (2H, q, J = 7.14 Hz), 4.30 (2H, dd); Mass Spect (neg. ion FAB) m/z
`999 (94%), 590 (15%), 407 (16%), 379 (4%), 253 (6%), 167 (100%).
`