2_,'
`
`_
`
`.
`
`‘\ _
`
`
`
`,..L.' I
`
`-’.~‘
`
`SCIWARZ
`PIIARIIA
`
`Chemical Development Plan
`Incontinence Project
`
`Aim:
`
`Synthesis of prodrugol
`
`Update (5)
`
`Feb. 10 - Feb. 20,
`
`;9_93
`
`:
`
`‘
`
`-
`
`-
`-
`
`Pure hydroxy metabolite is now nvnilnbie (>”10g), another lot of ca. 60g is
`expected CW 9, first 4 scnleup steps (kg-scale) are outsourced
`Chemical and enzymatic synthesi_s'ol' totally 22 potential prodrugs
`The in-vitro assay ‘wil_l_|-luun‘:1n liver homogennte (hepatic S9 supernatant) ‘shows
`the following l'BSIIl(5,'(-K/Y for NSCH,-[p:1ra-Pl1enyI]—Y):
`Effieient liberation of liyd:-ow‘ inetnbolite:
`'
`AeO/OAe, i-!3ut0/Oi-But, I-I0/Oi-But
`Moderate liberation nl‘I1ydroxy metabolite:
`Piv0IOI’iv, MeO/Ol-l
`Malrginal liberation nfl1yclI'm:y metabolite:
`I-IOf0Bn, AeOlOBn_. i-BuO/Olin,
`ll7.0!OBn, I-IOIOTBDMS, TBDMSOIOH
`Non-enzymatic _hydrnl_y5is:
`-
`'
`ACOIOH, n-BIIOIOH, i-BIIOIOI-l,Pi\'O;’OI-I, BZOIOH
`No liydroxy metabolite l"o1‘m.'uion:
`IICJ/O-Et-enrbnni, TIlDMSO,’OTBD:‘vlS, Et-em-l1nmO/OTBDMS, Et-e:u'hamOfOH, Et-
`czufbnmO10-Et-enrbnm, Et-tnrlnon0,'O-{:arbon-Et
`
`Next challenge:
`.
`O -
`Preparation of l‘n:‘tI1er protlrngs of the hydroxy metabolite (5. patent drnft)
`(.7
`-
`Assessment of the elieniical stability, enzymatic lability and salt formation
`-
`Scnleup of drug candidate
`
`.
`
`Patent apfllicntiou
`
`.
`
`\
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`'
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`
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`Patent Owner, UCB Pharma GmbH — Exhibit 2094 - 0001
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`UCBUO7191B0
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`Patent Owner, UCB Pharma GmbH — Exhibit 2094 - 0002
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`Patent Owner, UCB Pharma GmbH — Exhibit 2094 - 0003
`
`',
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`T
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`

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`RESTRICTED CONFIDENTIAL — SUBJECT TO PROTECTIVE ORDER
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2094 - 0004
`
`UC5007191E3; ‘
`
`

`
`if
`sp. 253-02 ‘
`
`‘I-
`-4%M-—‘> maxim "r—:o-cfcwr
`3*'°{—:”"*‘45“l 5;? -1115‘-
`
`
`
`Method Report BA 263-02
`
`ivicnheirn, 23 March 1998
`
`Authors: Mr. Dr. H. Btikens
`
`Mrs. K. Becker
`
`Mrs. S. Giersbach
`
`lncubations of prodrugs of SPM 7500 with human liver 5'3-fraction to investigate
`the in~vi_trc metabolism with regard to the effect "of different protective moieties.
`
`_
`
`-Copy No.: 3
`Number of copies:
`Distribution list:
`
`Sponsor.
`'
`
`Testing Facility:
`
`_
`
`7
`Mr. Dr. H. Békens, BA
`Mr. Dr. P. Ney, BD
`Mr. Dr. C. 0. Meese, SIL ‘
`Mrs. K. Becker. MOB!
`Mrs. S. Giersbach, BA
`Mr. Dr. H. Rackur. Pi-{ASYS
`Filing omce, EA
`
`Schwarz Pharma AG
`Aifred~Nobel-Sirafle 10
`D-40789 Monheim
`
`Schwarz Pharma AG
`- Department of Bieanalytics
`
`Aifred—Nob_ei—StrarLe 10
`
`D-40789 Monheim
`
`.,,}
`
`§
`='5_
`‘Z.
`‘E M
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`03
`
`Copy:
`1/?
`2!?
`an
`417
`5/?
`an
`717
`
`
`
`RESTRICTED CONFIDENTIAL - SUBJECT TO‘ PROTECTIVE ORDER
`
`UCBOO7191B4
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2094 - 0005
`
`

`
`RESTRICTED CONFIDENTIAL - SUBJECT TO PROTECTIVE ORDER
`
`UC500719165
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2094 - 0006
`
`

`
`
`
`Signature list of scienfists and further protessionals involved in this study:
`
`Head of Department
`
`of Bioanalyticsz
`
`T
`
`I.
`3 -L’t-
`----——~—————----—--~~~~
`Date
`
`L
`
`~
`Xx’) [/\_/7
`-
`—--—-4-------~--------—---~~--—
`Dr. H. Béikens
`
`Research Assistant:
`
`, :—
`£‘-’Z’-—€?-Z‘--’5-°-{--—-
`Date
`0
`a
`
`'7
`.-
`--~Z5-£;--—-{ -------
`Mrs. K. Becker
`
`g
`‘:_
`2
`
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`
`5:3
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`
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`
`Research Assistant:
`
`(‘\
`
`0 -
`
`-';}—'-S'3:E-'-1—¥3-——---
`Date
`
`'
`
`‘
`
`--~~-~-§—=~$-!mE;-9-3)-------—----
`Mrs. S. Giersbach
`
`‘
`
`,.
`We, the undersigned, hereby declare that the work was performed under our
`supervision according to the procedures herein described and that this report provides a
`correct and faithful record of the results obtained.
`
`<3
`
`- a
`EC.
`:2.
`O <
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`A
`}
`3;;
`
`4 3I 0g
`
`r)
`
`RESTRICTED CONFIDENTIAL — SUBJECT TO PROTECTIVE ORDER
`
`UCBUO-H9136
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2094 - 0007
`
`

`
`
`RESTRICTED CONFIDENTIAL - SUBJECT TO PROTECTIVE ORDER
`
`___4
`UC5007191B7
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2094 - 0008
`
`

`
`BA 253-02
`
`,
`
`- 3!'1 6 -
`
`
`Tables of Contents
`
`‘
`
`‘ 1.
`2.
`3.
`3.1
`3.2
`3.3
`3,4
`3.5
`3,6
`3.7
`3.8
`3.9
`4.
`4.1
`42
`4.3
`5.
`6.
`7.
`'
`B
`
`v
`
`'
`
`Summary A
`Introduction
`Experimental
`Equipment
`Materials and Supplies
`Chemicals and Reagents
`Cleaning of the Glassware
`Preparation of Solution
`Solutions of Chemicals
`.|n-zubations
`Chromatography and Detection
`Calculation of Results
`Results
`Chromatography
`Incubation results
`Documentation of the Raw Data
`Discussion
`Rafarences
`Table
`-
`G
`1'-‘lgur..s
`0
`
`P593
`4
`-4
`4
`4-5
`5
`6
`7
`7
`7
`'7
`8-9
`9
`9 _
`‘
`~
`9
`9
`10
`‘to
`10
`11
`‘l2
`
`‘
`
`§
`"E
`E
`3
`‘"1
`r::
`*3
`E 3
`E
`§
`‘:3
`5::
`L; 3
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`.-2
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`1:
`.<
`
`'
`
`_
`
`3I 1
`
`'.)
`U:
`
`RESTRICTED CONFIDENTIAL — SUBJECT TO PROTECTIVE ORDER
`
`.
`
`UcBUo719165
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2094 - 0009
`
`

`
`
`
`RESTRICTED CONFIDENTIAL — SUBJECT TO PROTECTIVE ORDER
`
`UC8U0719169m
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2094 - 0010
`
`

`
`
`
`1 .
`
`Summary
`A pooled human liver S9-preparation was used to investigate the in-vitro
`metabolism of different prodrugs of SPM 7500 both to prove in principal its
`
`generation by enzymatic processes and to ciassify the ability of different
`
`protection moieties to regulate its formation.
`The analysis was performed by a routine HPLC-method with UV-detection.
`Depending on the prodrug chosen the formation of SPM7500 ranged from
`nearly 100% to zero. Based on these data it should be possible to regulate
`the in-vivo formation of SPM 7500 by adequate choice of prodrugs using
`
`reasonable combinations of protective groups.
`
`2.
`
`Introduction
`
`‘
`
`SS-incubations were perforrned to investigate the in-vitro metabolism of different
`prodrugs of SEM 7500 both to study in principal the generation of the active
`metabolite by enzymatic processesand to classify the ability of different
`protection groups to regulate the formation of the active.
`The formation of the active (SPM 7500) was measured using a routine HPLC-
`method with.LlV-detection.
`The experimental work was performed from February to March 1998.
`
`3.
`
`3.1
`
`Experimental
`
`_
`Equipment
`
`.
`
`in the foiiowing list. the equipment and its suppliers are given. ‘
`Laboratory Equipment
`Balance, AT 250
`Balance, PM 2000
`Mixer (Vortex)
`Centrifuge S402
`pH-Meter 605
`a Magnetic stirrer
`Water bath
`-Nanopure system for
`water purification
`Laboratory giass washer
`Therrnomixer 5437
`
`r
`
`T
`
`Mettler, Giessen, Germany
`Mettler. Giessen. Germany
`Retsch, I-iaan, Germany
`Eppendorf, Hamburg, Germany
`Metrohm, Germany
`IKA. Staufen, Germany
`-
`Juiabo. Seelbach. Germany
`Barnsteaci. Dubuque,
`"Iowa, USA
`Miele, Koln, Germany
`Eppendorf, Hamburg. Germany
`
`‘
`
`'
`
`-
`
`
`
`:'1If1'crl-Nuke!-'Slr.NJ,D-lU789PvImIhci|1| =3,
`
`E
`
`Q; E
`<1 E
`<2:
`15-
`*5 3
`
`'
`
`_ I
`
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`‘J :
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`3
`E2)
`‘-0
`
`RESTRICTED CONFIDENTIAL — SUBJECT TO PROTECTIVE ORDER
`
`UCBUO-H9190
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2094 - 0011
`
`

`
`RESTRICTED CONFIDENTIAL — SUBJECT TO PROTECTIVE ORDER
`
`UCBUO719191
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2094 - 0012
`
`

`
`BA 253.02
`
`'
`
`- 5:16 -
`
`
`Pipel-washer
`M
`Hfilzel, Dcrfen, Germany
`Glass drier
`Heraeus, Osterode, Germany
`
`.
`
`HPLC-equipment
`HPLC-pump M596
`Degasser ERG-33f‘: 5
`Aulosampler Wisp‘?17 plus
`UV-Detector SPD-10A
`
`-
`
`Waters, Milfbrd, MA, USA
`ERG. Alteglofsheim. Germany
`Waters. Milford, MA, USA
`Shlmadzu, Kyoto, Japan -
`
`Guard column: Symmetry Shield RP8, 5 pm
`L = 2 cm. ID = 3.9'mm
`
`Waters, Milford, MA, USA
`
`-‘
`
`‘g
`
`‘I’ §
`E“
`:
`:3 .
`E an
`
`Analytical column:
`Symmetry Shield RP8, 5 urn
`L =1s.o cm, [D = 3.9 mm ‘
`Hardware:
`Micro-Vax—31{lCJ
`Software:
`Access Chrom 1.9
`
`Waters, Milford. MA. USA
`
`Digital, Mflnchen, Germany
`_
`n
`'
`'
`‘
`Perkin Elmer, Uberlingen, Germany
`
`3.2
`
`-g
`
`'}._~"5_'
`5
`(5 3
`2:
`_'::
`. E 5
`'
`J
`
`N
`g
`E
`E
`U}
`
`‘ Materials and Supplies
`Glass tubes with teflon lined screw caps 16 x 100 mm
`(ID :4 L), GL3
`Scholt, Mainz, Germany
`Volumetric flasks
`Brand. Wertheim, Germany.
`Beakers
`Schott, Mainz, Germany
`Erlenmeyer conical flasks
`Schult, Mainz, Germany
`l\aleasuring cylinders‘
`'
`Brand, Wertheim, Germany
`Pipets, Giison pipetman
`Gilson, Villiers-le—Bel, France
`?- Pipet tips
`-
`Abimed, Langenfeld, Germany
`Autosampler vials with micro-
`insert 200 pl, tefion lined
`\
`
`.
`
`.
`
`Waters, l’vlilfcrci_ MA, Germany
`
`‘
`
`-
`
`_
`
`RESTRICTED CONFIDENTIAL — SUBJECT TO PROTECTIVE ORDER
`
`UCBUCi71(E‘lM1m-éuémmm
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2094 - 0013
`
`

`
`RESTRICTED CONFIDENTIAL — SUBJECT TO PROTECTIVE ORDER
`
`UCBDO719193
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2094 - 0014
`
`

`
`BA 253-e2
`
`‘
`
`- ans —
`
`
`
`3.3
`
`Chemicals and Reagents
`
`Predrugs introduced in the essay
`
`
`
`‘SCHWARZPHARMAAGAlfred-Nnlacl-S11‘.1o,_n4I:7s9rI4.,..1..,;....
`
`1 J
`
`
`
`
`
`'
`
`DcpnrlnicrltofBlunrinlytics
`
`weight
`
`structure x—l—y
`ACO-/-OAC
`HO-/-OBut
`HO-I-Oiaut
`IE-3utO-I-Oi But
`HO-I‘-OPIV
`EtO-I-OHxMesyIat
`MeO-I-OH
`iEutO—I'—O8n
`H0-!OBn
`ACO-I-OBn
`E10-CO-O-I-O-CG-OEt
`TB DMSiO-f~OH
`Pivo-I-OPiv
`E3zO-/-OBn
`HO-f—OC ON1-IE1
`EtN HCO-O—!-O-
`OONI-IEI
`- (complete Iist_orI table 1)
`
`RK-6638ia
`RD-‘K512
`FP~90r50
`FF’-9061
`RD-7496
`RK—6651l1
`RK-6645
`_RD-7472
`745811
`AC-8135
`FP-SD59
`FF’-9053
`AC-8156
`RD-7471
`RK-664?
`FP-9058
`
`R
`
`Nanopure Water
`KH2PO.-, M
`K2HP0_,
`~
`Mgclz
`EDTA (Titriplex lll)
`Acetonilfile, Lichrosolv
`.Phosphor‘Ic acid, 85 3’;
`Nag}-IP04
`NaI—I2F>_Ca.* H2O_
`Neodisher A8, N, LM3
`
`‘
`
`_
`
`,
`
`'
`
`. Water purified by a Nanopure system '
`.
`Merck, Darmstadt, Germany
`Merck, Dermstadt, Germany
`Merck, Darmstadt, Germany
`Merck, Darmstadt, Germany
`Merck, Darmstadt, Germany
`Merck, Darmstadt, Germany
`Merck, Darmstadt, Germany
`Merck, Darmstadt, Germany
`Chem. Fabrik Dr._Weiger'f.
`Hamburg, Germany
`
`Pooled Human liver S9-fraction, H961
`
`Gentest. Woburn, MA, USA
`
`RESTRICTED CONFIDENTIAL — SUBJECT TO PROTECTIVE ORDER
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`
`Patent Owner, UCB Pharma GmbH — Exhibit 2094 - 0015
`
`

`
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`
`UCEUO719195
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2094 - 0016
`
`

`
`EA 263-02
`
`- TI16 -
`
` '
`
`3.4
`
`Cleaning of the Glassware
`All laboratory glassware is cleaned in a laboratory glass washer using
`neodisher AB and neodisher N as detergents. The glasspipets are cleaned
`
`with neodisher Li-:13 in a pipet washer.
`
`3.5
`
`Preparation of Solutions
`Volumetric flasks and Gilson pipets are used for the preparation of all
`
`solutions.
`
`Solutions of Prodrugs
`
`Stock solution
`
`(c = 10 mg!mi):
`
`Diluted solutions of prodrugs
`(0 == 1 mg/ml):
`
`10 mg prodrug are dissolved
`in ‘t ml EtOH
`
`_
`0.1 ml of the stock solution is diluted
`with nanopure water to 1.0 ml..
`-0
`
`3.6
`
`Solutions of Chemicals
`
`Mobile phase buffer 0.05 M Nal-l3PO4: 6.9 g Na}-l2F'O4 are dissolved in
`1000 ml water, adjusted with phosphoric acid, as % to pH 3.0.
`
`3.7
`
`Incubations
`
`197.5 pl 100 mM Kl-t2PO». (pH 7.4) containing 3.3 mllzl Mgclz are mixed with
`25 ].II -10 rnM NADPH. 2.5 pl of the prodrug solution ('1 mglml) and after mixing
`25 pt 39 (o = 20 mg proteinfml) or buffer (controls) areaddeci.
`The mixture is kept in a thermomixer for 1 h at 37’ “C and further centrifuged‘
`
`'
`
`i
`at 12000g (5“c) for so min.
`Most of the resulting supernatant is removed‘ and placed in autosampler vials.
`
`50‘pI are injected for HPLC analysis.
`Controls were prepared by the same procedure with addition of buffer.
`
`E
`
`Alfrul-Nzilicl-Slr.MuniiuimIt},D-10189
`
`
`
`
`SCHWARZPHARMAno
`
`
`
`
`
`Dcpnrlinciilii!’Itioanniytics
`
`RESTRICTED CONFIDENTIAL - SUBJECT TO PROTECTIVE ORDER
`
`UCBUO’-H9196
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2094 - 0017
`
`

`
`RESTRICTED CONFIDENTIAL — SUBJECT TO PROTECTIVE ORDER
`
`4
`
`UCBU0719197
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2094 - 0018
`
`

`
`
`
`3.8
`
`Chromatography and Detection
`
`injection volume:
`Eluent:
`
`80 pi.
`- 780 mt NaH2PO4 (0.05 M. pH 3.0) and 220 ml
`acetonitrile are mixed. (stable for 2 weeks, RT)
`
`'
`
`The etuent is degassed by an "in-line" degasser.
`
`Eiuent flow:
`
`-
`
`1.0 mlirnin
`
`UV detection:
`
`220 nm, response 5
`
`Parameters for the Access Chrom Chromatography Software (Perkin Elmer)
`
`3.00’
`30.0
`
`.so.o
`
`1.0
`
`2.0
`
`1000
`
`O
`
`5 N
`
`1.00
`
`ngimi
`
`Peak height
`
`one i
`
`_ 30.0
`
`A 0
`
`100000
`
`'Ucparlmculoflliazmnlytics
`
`Acquisition Parameters
`
`Delay time (min)
`
`Run time (min)
`
`Starting peak width (sec)
`
`Sampling rate tptslsec)
`
`Noise threshoid (microvolts)
`
`Area threshold (counts)
`
`AID range (volts)
`
`Analysis Parameters
`
`Type of analysts
`
`Area reject (counts)
`Absolute search window (sec)
`
`' Relative search window (%)
`
`Events track reference peeks?
`
`Default volume ‘
`
`Report units
`
`Area or height quantitation
`
`Plot Parameters
`
`Start time (min)
`End time (min)
`
`Y—axis scaling (RIA)
`
`Min. counts
`
`M Max.‘ counts
`
`
`
`
`
`";\Il‘:'cd-Ntihr.-3-Sir.Ill,D-40789Munmm
`
`RESTRICTED CONFIDENTIAL - SUBJECT TO PROTECTIVE ORDER
`
`UCBUO719195
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2094 - 0019
`
`

`
`RESTRICTED CONFIDENTIAL — SUBJECT TO PROTECTIVE ORDER
`
`UCEUO719199
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2094 - 0020
`
`

`
`ea 263-02
`
`‘
`
`. 9/16 -
`
`Time axis length (cm)
`
`'
`
`.
`
`Response axis length (cm)
`include headerlmargin (B.H,M,l\l)
`Baseline option (YIN)
`
`'
`
`Timed events option (YIN)
`
`Named peaks option (YIN)
`
`include ret. times (YIN)
`
`Time to display the peak names (F,M,A)
`
`Rotate plot (YIN)
`Mark peak startlend option (YIN)
`Label plot units
`Counts to units conversion
`
`-
`
`'
`
`.
`
`15.00
`
`11.00
`B
`Y
`
`N
`
`Y
`
`Y
`
`M
`
`N‘
`N
`Counts
`M
`'1.l'.i0{)E+D{)
`
`Calculation of Results
`
`The peak area of the blank was subtracted from SPM 7500 peak area found
`after injection of the incubation sample. The areas" were normalized by their -
`
`molecular weight. Amounts [:19] were calculated referring to standard solution
`
`injections. The amounts found were divided by the theoretical amount
`assuming a 100 [Va] formation at 8PM 7500. Thus, the results are given in %
`of the theoretically possible turn-over to 8PM 7500.
`’
`7
`
`Results
`
`Chromatography
`
`Typical chromatograms of blank incubation samples are given in fig. 2 - 5.
`
`‘ incubation results
`The results expressed in [‘/o] of theoretical turn~ove_r
`
`They ranged from 96 to 0.1 ‘fa.
`There is a large variety in the behaviour of the diffel:
`from ne.-arty completely hydrolizect compounds like
`compounds that are almost completely stahte like
`Somekof the produgs show a decrease in Oi-t~l-Ol-l—i
`plausible in cases where the produgs already conta
`and additionally, the respective prodrug being not attacked by respective
`S9~activities.
`
`
`
`A|l'n::I-Nuhcl-Sir.IU,D-407fl9J\-"I{;:1!gci|11
`
`8
`'-;—'_,
`:5:
`‘-3
`G
`
`E
`_.__e
`
`‘:3
`
`RESTRICTED CONFIDENTIAL - SUBJECT TO PROTECTIVE ORDER
`
`UCBUO719200
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2094 - 0021
`
`

`
`
`RESTRICTED CONFIDENTIAL — SUBJECT TO PROTECTIVE ORDER
`
`UCBUO719201
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2094 - 0022
`
`

`
`BA 263-02
`
`'
`
`- ions -
`
`
`
`SPM 7500 itself shows only a loss of 13% in concentration after ‘lh~treatment.
`with S9.“ This shows that SPM 7500 is not a good substrate for the S9-
`
`enzymes at the conditions applied.
`
`'
`
`_
`
`Compounds only ecylated in the benzylic position are in genera! too instai:-la
`
`at pi-t‘7 to provide reasonabte data on the enzymatic formation of SPM 7500
`
`by S9.
`
`A reasonable collection of_tum-over data is given in fig. E1.
`
`4.3
`
`Documentation of the Raw Data
`
`All raw data of this study are kept in the project files of B/5263. After
`
`compietition of the study, they will be stored in the archives of the department
`
`{including protocol and fine! report).
`
`5.
`
`Discussion
`
`The formation of the active metabolite is dependent on the sustituents both at
`
`.
`the benzylic and phenolic side of the resp. prodrugs.
`Both esters and cliesters are rapidly hyclroiysed by esterases. in case of steric
`
`hindrance {PivO—a'-OF’iv)_ only little turn-over occurs.
`Ethers and carbonates show only little conversation to the aktive rnetabolite.
`
`Carbarnates remain stable at the conditions applied.
`
`it should be‘ possible to regulate the in-vivo formation of the active by
`
`reasonable choice of protection groups in adequate positions of the molecule.
`
`D£II=!I'lI=wIItnfltinaiialytiu
`
`6.
`
`References
`
`
`
`
`
`SCHWARZPHARMAAGAlfrcil-Nobel-Sir.Ii],13.411739Mrmianim
`
`RESTRICTED CONFIDENTIAL - SUBJECT TO PROTECTIVE ORDER
`
`ucBoo7192o2
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2094 - 0023
`
`

`
`
`RESTRICTED CONFIDENTIAL - SUBJECT TO PROTECTIVE ORDER
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2094 - 0024
`
`UC500719203
`
`

`
`Tables
`
`Table ‘I:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
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`amusing
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`
`
`
`
`
`
`
`RESTRICTED CONFIDENTIAL - SUBJECT TO PROTECTIVE ORDER
`
`UCBUO7_192_04
`Patent Owner, UCB Pharma GmbH — Exhl
`It 2094 - 0025
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`

`
`RESTRICTED CONFIDENTIAL — SUBJECT TO PROTECTIVE ORDER
`
`UCBU0719205
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2094 - 0026
`
`

`
`BA 263-02
`
`-
`
`- 12/‘I6 -
`
`-_j
`8.
`Figures
`
`Figure '1:
`
`—
`
`ACO-I-OAc
`
`E
`
`T 1
`
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`%
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`
`RESTRICTED CONFIDENTIAL - SUBJECT TO PROTECTIVE ORDER
`
`ucBo57192o6
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2094 - 0027
`
`

`
`n-..:j
`
`RESTRICTED CONFIDENTIAL - SUBJECT TO PROTECTIVE ORDER
`
`UC500719207— ‘
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2094 - 0028
`
`

`
`A 253-02
`
`— 13:16 -
`
`
`
`Figure
`
`SPM 7501 control
`
`
`
`MI'1'I.'d-Nulu:I-SlI'.ll],I)-5i}7S‘Jf\’IIIII11.1-'I11
`
`
`nrtmuntofBitmnnlylics.__
`
`
`SCHWARZPHfikRIViAAG 2.~'I’
`
`Dan: Bile:
`Repwt:
`Acquired:
`‘nae :'ange:
`
`u;:.a.mo= [DO0DU|1.H?LC3|HUFELIJN-351.S.AU';2
`5;1vm- 1993 15 "5 1:.
`A
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`
`!l.._..._____zI..Z._,____,'r:
`
`RESTRICTED CONFIDENTIAL - SUBJECT TO PROTECTIVE ORDER
`
`UcBoo7192oé T
`
`Exhibit 2094 - 0029
`
`

`
`n—_?_.
`RESTRICTED CONFIDENTIAL — SUBJECT TO PROTECTIVE ORDER
`
`0..
`UCEUO719209
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2094 - 0030
`
`

`
`BA 253-02
`
`-14116 —
`
`
`
`Figure 3: SPM 7501 S9-incubation
`
`Data file:
`Report:
`icquitad:
`4.1:-.2 :-angn:
`
`DICMOO: §OUOCl0G. H?LC3] HUFFLON-363 .R..W3J.
`515.18
`.
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`0.00-10.00
`
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`33
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`
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`
`
`
`8CHWARZ-PHARMAAGA1I"rc<l-Nrnbcl-Sit‘.10,mmvsuMun]:
`
`RESTRICTED CONFIDENTIAL - SUBJECT TO PROTECTIVE ORDER
`
`ucBdo71921o
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2094 - 0031
`
`

`
`RESTRICTED CONFIDENTIAL - SUBJECT TO PROTECTIVE ORDER
`
`UC5007192‘l1
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2094 - 0032
`
`

`
`BA 263-U2
`
`- 15316 —
`
`
`
`Figure 4: SF-‘M 5645 contro!
`
`Dana file:
`Report:
`Acquired:
`Time range:
`
`DKA109: (B00000. HE‘LC3|HUEE'I.0N-375..FU.U';1
`51232
`3-FEB-1998. 19:56:56
`mo-an-.ao
`
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`
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`
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`
`SCHWARZPHQRMAAGAtrrcd-Nc:l;L-1.3”‘“L13.40739M.,,.|,ui..,
`
`RESTRICTED CONFIDENTIAL - SUBJECT TO PROTECTIVE ORDER
`
`UCBUO719212
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2094 - 0033
`
`

`
`-—.L—_.
`
`—-
`
`—
`
`-
`
`-
`
`.
`
`._
`
`.
`
`RESTRICTED CONF|bENT|AL — S—UBJECT TC;
`
`OIQDEFEY
`
`-
`
`UCfi007192‘l3
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2094 - 0034
`
`

`
`8:; 253.02
`
`- 16/16 -
`
`
`
`Figure 5: SPM 6545 S9-incubation
`
`DaI:1_ file:
`Report:
`Acqu1:ed:
`Time range:
`
`DECAIOO: (GUDDQD. H_PLC3]HUFfL01f{-375..RA‘3;l
`5123‘
`J-FEE-1993 10:27:58
`0.DU—:0.00
`
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`
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`
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`
`
`
`
`
`Dr.-p:u'lrm:ntr;l'liiesmazllyllcs
`
`RESTRICTED CONFIDENTIAL - SUBJECT TO PROTECTIVE ORDER
`
`UCBUO71‘92'“‘l;1A‘ A
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2094 - 0035
`
`

`
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`
`UCBU0719215
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`Patent Owner, UCB Pharma GmbH — Exhibit 2094 - 0036
`
`

`
`Minutes - Team Meeting -
`NOE Incontinence 25.06.98
`
`RESTRICTED CONFIDENTIAL — SUBJECT TO PROTECTIVE ORDER
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`UCEUO719216
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`Patent Owner, UCB Pharma GmbH — Exhibit 2094 - 0037
`
`

`
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`UCEU0719217
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2094 - 0038
`
`

`
`srnicrw CONTFIDENTIAL
`
`MlNUTES
`
`'
`
`Team Meeting ,,NCE Incontinence.‘
`
`June 25,1 998)
`
`Participants: Hilmar Boekens
`Peter Ney
`
`_
`
`Claus lvieese '
`Bengt Sparf
`
`‘Distribution: Participants. Lars Ekrnan, Ulrike Kluge, Dietrich Schacht
`
`Agenda:
`
`_
`
`Boekens)
`
`_._-‘
`.
`.,§r;_:.;'.~
`
`1) Chemistry
`‘
`2) Biological
`
`- upscale
`- status of synthetic routes
`- caco cell studies
`- bioavailability dog
`
`(C. Meese)
`
`-
`
`(H.
`
`3) Pharmacology
`4) Miscellaneous
`
`,
`
`- definition of Panlabs screen
`-' board presentation
`~involvementofotherdepartmentslcolleagues -
`
`.
`
`(P. Nay)
`
`(P. Ney)
`
`Ad 1) For details see handout of 0.0. Meese .,Chemical Development Plan - Update 6“
`(attachment 1). it is obvious that the availability of pure enantiomers of the prodrugs is
`critical. Issues are currently addressed with the intellectual and technical help of external
`experts.
`Ad 2) H. Eloaltens explained the results of the caco cell experiments and of the bioavailability
`study (attachments 2. 3). It was decided to extend the study once more to include ‘lurnollkg _
`SPM 8163 (metabolite) in order to confirm its low bioavailability in the clinical dose range.
`The experimental part of the study will now belinalized at LPT on July 14, 1998. Final
`bioavailability data will be available no later than July 31,1998.
`
`Ad 3) A reasonable outline of selected tests as well as budget outline will be prepared- The
`decision, which substances have to be included will be taken at the next meeting.
`
`~
`._
`
`‘-
`
`Ad 4) P. Nay presented the updated development plan, which he intends to present at the Project
`Review during the Board Meeting. The team agreed to. the timelines and noted that a 2nd
`bioavallability study using the pure enantiomers has to be included (attachment 4).
`
`Since the patent has been tiled and the risk of negligent communication is now lower, the
`strict confidentiality that was posed on the project up to date appears no longer reasonable.
`it was decided that other departments and colleagues may be involved in the project on a
`case by case basis as needed.
`A
`-
`.
`-
`‘
`Actions:
`Amendment bioavailability study (low dose)
`(LPTIP. Nay, asap)
`Enatiomer synthesis andlor racemate separation
`(c.o. Meese, 10.08.98)
`Data of bioavallability study in dogs
`(H. Boekens, _10.08.98)
`Follow up preclinical program e.g. receptor screen
`(P. Ney, 10.08.93)
`-
`
`-
`
`M
`
`Next meeting: August 10, 1998; 9:30 a.m.
`
`Peter Ney
`Monheim, July ‘l0,‘l_9Q8
`q:\npta\ncy\aktno\mctapro4.dcc
`
`3
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`7
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`UCBOO719213 I
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`Patent Owner, UCB Pharma GmbH — Exhibit 2094 - 0039
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`RESTRICTED CONFIDENTIAL — SUBJECT TO PROTECTIVE ORDER
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`UCBU0719219
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`Patent Owner, UCB Pharma GmbH — Exhibit 2094 - 0040
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`Chemical Development Plan
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`Update
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`‘Feb. 2] - .]uno.25, 1998
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`Patent
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`l'1lin_:_v_ dnic May 12 I998
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`Patent Owner, UCB Pharma GmbH — Exhibit 2094 - 0041
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`RESTRICTED CONFIDENTIAL — SUBJECT TO PROTECTIVE ORDER
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`UCBUO719221
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`Patent Owner, UCB Pharma GmbH — Exhibit 2094 - 0042
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`UCBUO719222
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`Patent Owner, UCB Pharma GmbH — Exhi
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`it 2094 - 0043
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`RESTRICTED -CONFIDENTIAL - SUBJECT TO PROTECTIVE ORDER
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`Patent Owner, UCB Pharma GmbH — Exhibit 2094 - 0044
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`UCEOO?19223
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`REsTRIT:‘FEB CONFIDENTIAL — SUBJECT TO PROTECTIVE ORDER"
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`’ ucBdo719224
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`Patent Owner, UCB Pharma GmbH — Exhibit 2094 - 0045
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`

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`RESTRICTED CONFIDENTIAL — SUBJECT TO PROTECTIVE ORDER
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`UCEUO719225
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`Patent Owner, UCB Pharma GmbH — Exhibit 2094 - 0046
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`

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`Minutes ~ Team Meeting -
`NCE Incontinence 10.08.98
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`RESTRICTED CONFIDENTIAL - SUBJECT TO PROTECTIVE ORDER
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`UCBUO71922B
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`Patent Owner, UCB Pharma GmbH — Exhibit 2094 - 0047