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`I
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`M15
`
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`
`
`
`-
`
`NCE-lncontince Meeting
`Monheim, May 28, 1999
`
`Participants:
`
`C- Nth
`. B
`k
`H
`°e 5“
`C. van Dorp
`_
`H. Fnehe
`C. M
`eese
`P. Ney
`A. Schuetz
`e. Span‘
`
`
`
`SYNTHESELABOFI
`.
`at .m.n.I my
`
`'
`
`5
`
`Preclinical Development
`- 7 Jun :2:
`signature:
`
`'"""‘""'""““”"“—
`\
`‘ti-s‘ en es-as
`
`_
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`‘ W M ‘MW
`.
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`0
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`\._I--
`G1 *7 ‘wry
`_
`H
`r£.‘;wf/7
`E. SPM saw " ,9 ‘
`,3; Mn .‘ote_
`.
`3 “’f,"";am;_‘fi h:u':c:[P£_‘
`’ Ztwcfyfizr §”“‘'‘'P:,‘‘‘
`6'
`0 The selected candidate is: HOiOiBut
`1...$.....:‘it:. Pt.5c.2.,..;t.:.u.:ta¢
`PRIVILEGED
`rwfut H;
`F
`‘Ct/a""‘r'~§
`2. Chemistry (C. Meese)
`C. Meese explained the present route of synthesis (attachment 1). The aim is to get about
`80 ~ 70 g of H0,’OiBut in the lab—scale and about 0,5 kg of H0/0iBut in the kilo-lab-scale by
`the mid of July. A stable and crystalline salt is requested: Reference standards for HO/OH
`and HO,/Di But with certificates of analysis are requested.
`
`/
`
`/1
`
`.
`
`I W '
`
`L
`
`_
`
`2 H
`
`..............................................................................................................................
`
`W
`
`""'
`
`‘
`
`‘V-5
`
`::
`
`3. Biological (H. Boekens)
`The PK—results of the second bioavailable study in dogs are complete. They demonstrate
`that the half—life of tollerodine is shorter and the bioavailability of the metabolite is less than
`alter application of H0!0iBut (attachment 2). Method development for tox study has been
`started and method validation for rats and dogs is ongoing.
`
`4. Development Plan (P. Ney)
`In order to put a development plan together. timelines and Concepts for all necessary
`chemical, pharmaceutical and preclinical activities have been discussed. Cost estimations
`of the departments have to be given to P. Ney. H0;’0iBut is called SPM 8228 for the
`moment. This number will be changed due to the internal system as soon as a salt is
`known.
`
`5. Milestone decision
`Ol-t;’0iBut has been selected as drug candidate for the NCE-incontinence project.
`
`6. Actions until board presentation
`- Development Plan (P. Ney)
`. Cost estimations of the departments have to be given to F’. Nay asap.
`
`A. Schulz
`
`May 31, ‘I999
`
`O:‘\PK__l'U<‘.!|.\SC1IUET'Z\NCElN(UN\T‘RD_2W!5.\IIVc
`
`_ RESTRICTED CONFIDENTIAL — SUBJECT TO PROTECTIVE ORDER
`
`..u'.r:_-'.:-.- .,_ _,
`
`,-.,1.-,;...‘.'_-..;.t.-
`
`.:
`
`-
`
`
`uceoosersss L
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2099 - 0001
`
`

`
`
`
`RESTR]CTED CONFIDEEIZAL — SUBJECT TO PROTECTIVE ORDER
`
`WUCBOOBBTSQVT
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2099 - 0002
`
`

`
`
`
`ISP Modification of the P 8. U Route
`
`Present Process, May 28, ‘I999
`
`B
`
`- o
`
`00
`
`Br
`
`I
`
`Br
`
`Br
`
`0 ° 5
`
`1
`
`2
`
`res ciuffon
`
`(1S,2R)-{'+)-
`ephedrin
`
`I R-(-)
`
`chiref acid
`
`3
`
`R-(+) hydroxy metabolite base
`
`§If1"§§i§'§3“’
`'§'55.’.5. Phnrml
`
`I
`
`H:
`
`H02
`
`H’
`
`R—(-) HCI salt
`R-(+) mandelate salt
`
`R«(+)-Toilerodin base
`
`confidentral
`
`RESTRICTED CONFIDENTIAL — SUBJECT TO PROTECTIVE ORDER
`
`UCB00B3739—3I
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`Patent Owner, UCB Pharma GmbH — Exhibit 2099 - 0003
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`Patent Owner, UCB Pharma GmbH — Exhibit 2099 - 0004
`
`

`
`
`
`LPT Protocol No. 11997Ilf99, BA 304-02
`DRAFT PK-Results glgterim Regort)
`
`BrIay 27, 1999
`
`1
`
`Study Summary
`
`
`
`
`
`SCHWARZ PHARMA AG, Mcmhelrn (Germany)
`Sponsor:
`Study Responsible:
`Dr. P. Ney, Dept. NPTA
`
`
`
`Testing Facilities
`Administration and plasma sampling:
`
`
`
`LPT, Hamburg (Germany)
`Study Director:
`Dr. phil. J. Leuschner
`Protocol ‘No;
`LPT 1199711/99
`SCHWARZ PHARMA AG, Mfonheim (Germany)
`‘ Study Director:
`Dr. W. Hammes, Dept. BA
`Analytical Report:
`BA 3040;
`
`
`
`SPIVI 3427, SPM 6723, SPIVI 6725, SPl\rI 8223, SPJM 8229,
`SPM 8230 and SPM 9073
`
`Bioanalytics:
`
`
`
`
`
`
`Test Substances:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Dose Level:
`Animals:
`
`0.3 tunolfkg b.w.
`5 Beagle dogs (male I age: to be amended! b.w. 10 - 15 kg)
`
`
`Design:
`
`
`
`
`
`
`0
`.
`
`8~way cross-over design.
`Single doses of the ‘test substances were administered according to the
`following scheme. All administrations were separated by a wash-out phase
`of at least two days.
`Substance
`
`Batch Nu. Route
`
`Dose Level
`[pmollkg b.w.}
`
`test day
`
`dogs
`
`SPM 542'? [{+)-I-to-I-0H*Hc1]
`
`SPM 6723 [(*)-B30-r‘-Ol3z‘I-1C1]
`SPM 6725 [{-)-AC0-«'-DB2‘!-[Cl]
`SPM 8223 [(4-)-H0-I-OiEut.‘HCl]
`SPM 3229 [(+)=.a.co4-ouau:-ztct]
`SPM S230 {(=~}.Ho-.'-on;-act}
`SPM 9078 [(-t}-(R)-H~'-0l+I*Ta::.]
`
`AB-5430
`:
`
`Bu-{.5723
`RK-572$
`AQ3223
`AC-8229
`AC-3230
`FP-9092
`
`i.v.
`13.0.
`
`p.o.
`12.0.
`p,u.
`13.0.
`p.o.
`13.0.
`
`0.3
`0.3
`
`0.3
`0.3
`0.3
`0.3
`0.3
`0.3
`
`1
`5
`
`9
`12
`15
`20
`B
`26
`
`l - 5
`1 . 5
`
`I - 5
`1 - 5
`1 - 5
`1 - 5
`1 - 5
`1 « 5
`
`
`
`
`
`
`
`
`Study Dates:
`
`date of final protocol
`start of administration:
`
`
`
`EDTA plasma samples containing sodium fluoride
`i.v.:
`-I0 (predose), 5, 10, 20, 40, 60 min and 2, 3, 4, 6 and 3 h
`51.0.:
`-10 (predose}, 20, 40, 60 min and 2, 3, 4, 6 and S h
`
`determination of SPM 5427 plasma levels and of SPM 90T5 plasma levels (test day
`Bioannlytics:
`26 only) by GC-E1-MSIMS, bql: 0.040 ng/ml
`
`March 1st, 1999
`March 13th, 1999
`
`U. Schm-Ienecker/P'I“'l'
`C‘K K'Wfit6C
`
`page 1 of 3
`
`—
`—-4
`'REsfifc‘rEocoNI=IDENTIAL—suB.JEcTTo'l=RoTEcTIvE ORDER
`
`'
`
`* '—' '-_-‘~«~—- -.
`..—-._—-- -7-—~ --.-.... .4...
`__-.....-.._.._n...‘;.x..:|_‘.,*.,.'_‘,'.,
`
`
`
`------.-."'fT'-'fi"1 ' - - A
`
`ucaooasmoo
`'
`'
`‘
`'
`‘
`‘
`" ‘
`"
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2099 - 0005
`
`

`
`RESTRICTED CONEIDENTIAL — SUBJECT TO PROTECTIVE ORDER
`
`UCBOOBEFMO1 7
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2099 - 0006
`
`

`
`
`
`LPT Protocol Nu. 1199101/99, BA 304-02
`DRAFT PK-—Results glnterim Regort!
`
`2 -
`
`Pharmncokinetic Evaluation
`
`May 27, 1999
`
`Plasma concentrations below the limit of quantification (tower than 0.04 nytnl) were treated as
`zero.
`
`the software Topfit 2.0 was used. The following
`calculations
`For pharmacokinetic
`pharmacokinetic pararneters were estimated by noncompartmental analysis:
`cm.
`maximum observed concentration
`
`tm
`
`time of maximum observed concentration
`
`AUC(0-t)
`
`BA
`
`area under the plasma eoricentratiomtime data Erorn time 0 to the last
`sampling time using the linear trapezoidal rule
`Dose {SPM 5-4271.1) ' AUC(p.o. {annotation}
`Dose (p.o. formulation} ' AUC (SPM 5427 iv.)
`
`absolute bioavailability: ea abs =
`
`relative bioavailability: BA rel =
`
`Dose (SFM 5422-‘ p.o.) * AUG {p.o. formulation)
`Dose (p.o. formulation) ‘ AUG SPM 5-127 p.o.)
`
`3
`
`Results
`
`AUC 0-Sh) min*n-zfml (detection of SPM 5427]
`#5
`#4
`Substance
`Route
`#1
`#3
`#3
`
`
`1386
`
`
`
`
`SPM5427{(+)-Ho-J-0H'HCl]
`1663
`1790
`128‘?
`1386
`77.06 50.13 202.82 93.44 59.83
`
`p.o.
`75.39 77.06 50.13 202.32 86.30
`
`med min max mean
`
`SD
`
`1275
`
`790
`
`1430 233.3
`
`1275
`
`6.73
`
`-1.22 27.16
`
`13.23
`
`10.71
`
`25.36
`
`11.02 52.68 30.82 20.39
`
`74.09 -14.82 147.14 32.41 39.39
`
`
`
`6.78
`
`11.02
`
`12.38
`
`5.60
`
`4.22 27.16
`
`37.63 25.36 17.42 62.68
`
`56.93
`
`39.09 -14.321411-1 “£4.09
`
`SPM5-t27[€+)~Ho«'~ou-net]
`
`SP}~«I6'f23[(~)-13:04-osrttczi
`
`SP;\[6725[(—)—.x;o-'~oez°1—:cI1
`
`SPi\[3223[q«)-Ho-'—oaBut-Hr::]
`
`SPMS229[(+y.tco..'.oaBu;-sci]
`
`54.02 61.13 19.14 53.73 50.79
`
`p.o.
`
`p.o.
`
`p.o.
`
`p.o.
`
`p.o.
`
`
`
`
`
`
`
`Substance
`
`AUC 0-31:1 min*n9./ml {detection ol'SPM 9015}
`
`#3
`#2
`#1
`Route
`#4
`
`52.49 253.90 52.49 353.80 200.68 131.37
`
`SP1‘-I 9078 [(4-)—(R)-HJ-OH'T;ltt]
`p.o.
`70.66 353.30 73.53 233.90
`
`
`#5 med min max mean
`
`SD
`
`
`
`Absolute Biozwaiiabiii
`
`(comared with SPM S42?/i.v.)
`
`Substance
`
`#1
`
`#2
`
`#3
`
`SPM 6725 [(*)-Aco-a’-«DBz'11Cl] SPM 3223 [(+;.ao-I-oiisuvncii
`
`SPM 5427 [(+}-H0-I-t3H“HCl]
`SPM 54-27 [(+}Ho-.'.on-H-:21]
`
`‘
`
`SPM 6723 [(+H3zo4-oBz*Hc11
`
`SPM 3229 [(+)-Ac:o-I-0iBu:'1{c11
`
`SPM 3230 [(+)-HO-I-OBz’1ICl]
`SPM 9073 [(+)-(R)~H~ivOi-1"I':ut.1
`
` U. Scharfcnccker/P'I'1'
`G‘!!!
`HEJOGBIDQC
`
`page 2 of 3
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`CONFIDENTIAL
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`
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`
`‘
`
`.‘
`
`.. ......-.:l;___,.._
`
`.
`
`.
`
`ucBooa374o2
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2099 - 0007
`
`
`
`
`
`
`
`SPM 8230[(—)—z-:o.r.o13z-Hot]
`
`SPM 9073[{«‘-)-{R}-$1-«'-OEI'Ta.n.]
`
`47.03
`
`44.97 33.04 62.94 37.75
`
`52.04 62.71
`
`
`
`19.14 63 .73 49.77
`54.02
`44.97 37.75 62.94 -16.15
`
`17.91
`10.25
`
`
`52.04 23.16 130.02 60.69 41.61
`23.16 130.02 35.53
`
`
`H6411 0c [-01
`
`(0.M{{t\I1[¢{C.
`
`722Iem6‘~.e
`
`

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`
`7
`
`7
`
`7
`
`UCBO0BB7403
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2099 - 0008
`
`

`
`
` - LPT Protocol No. 11997/1/99, BA 304-oz
`
`DRAFT PK-Results §§r_|terim Regort)
`
`Nfay 27, 1999
`
`Relative Bionvniiabili
`
`comnared with SPM 5427! _ .
`
`Substance
`
`#1
`
`#3
`
`#4
`
`#5 mad min max mean
`
`SD
`
`.
`
`100
`
`8.4
`32.9
`
`85.9
`
`53.9
`
`58.4
`
`64.1
`
`100
`
`7.3
`12.8
`
`72.5
`
`31.4
`
`31.0
`
`41.2
`
`100
`
`19.5
`49.6
`
`11.5.6
`
`79.4
`
`75,9
`
`31.4
`
`100
`
`13.3
`32.2
`
`87.’!
`
`55.8
`
`54.2
`
`60.3
`
`0
`
`9.4
`L3,].
`
`17.1
`
`20.7
`
`17.3
`
`‘
`3
`
`SPI\'I5427[(+)—HO-I-OH'HC1]
`
`SPM6723 [(«»).Bz0-I-o13z*11'c1]
`SPM 6725 [(+)-Ace-I-0Bz'1-1C1]
`
`SPM 8228 [(+)—Ho4.oi13u:-uca]
`
`_
`
`SPM 8229 [(4-)-AcO~f-0iBut'IiCI]
`
`SPM8230 [(«)-I-IO-J-OBz‘HCl]
`
`5P1VI9073{(+)-(R)-E-I-I-OH"1';u1.}
`
`.
`
`.
`.
`
`.
`
`.
`
`_
`
`.
`
`.
`.
`
`.
`
`.
`
`.
`
`.
`
`L65
`
`L":l1A.'lzf|rl-raldowtm-vmoanoc
`U. Scharfencck<:r,fP"I‘T
`
`page 3 of 3
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`UCB00687404
`
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