a)
`
`Europaisches
`
`Patentamt
`
`European
`Patent Office
`
`Office européen
`des brevets
`
`Bescheinigung
`
`Certificate
`
`Attestation
`
`Die angehefteten Unterla-
`gen stimmen mit der
`ursprflnglich eingereichten
`Fassung der auf dem nach-
`sten Blatt bezeichneten
`europaischen Patentanmel-
`dung fiberein.
`
`The attached documents
`are exact copies of the
`European patent application
`described on the following
`page, as originally filed.
`
`Les documents fixes a
`cette attestation sont
`conformes a la version
`initialement deposee de
`la demande de brevet
`européen specifiee a la
`page suivante.
`
`Patentanmeldung Nr.
`
`Patent application No.
`
`Demande de brevet n°
`
`040165 19 . 3
`
`Der Prasident des Europaischen Patentamts;
`Im Auftrag
`
`For the President of the European Patent Office
`
`Le President de I’Office européen des brevets
`p.o.
`
`R C van Dijk
`
`EPA/EPO/OEB Form 1014.1 - 02.2000
`
`7001014
`
`Apotex, Inc. (IPR2019—00400), EX. 1016, p. 001
`
`Apotex, Inc. (IPR2019-00400), Ex. 1016, p. 001
`
`

`

`p)
`
`Européhches
`Patentamt
`
`European
`Patent Office
`
`Office européen
`des brevets
`
`Anme1dung Nr:
`App1ication no.:
`Demande no:
`
`04016519.3
`
`Anme1detag:
`Date of fi1ing:
`Date de depot:
`
`14.07.04
`
`Anme1der/App1icant(s)/Demandeur(s):
`
`UCB Farchim S.A.
`
`Z.I. Planchy
`Chemin de Croix Blanche, 10
`C.P. 411
`CH-1630 Bulle
`SUISSE
`
`Bezeichnung der Erfindung/TitIe of the invention/Titre de 1'invention:
`(FaIIs die Bezeichnung der Erfindung nicht angegeben ist, siehe Beschreibung.
`If no tit1e is shown p1ease refer to the description.
`Si aucun titre n'est indique se referer a 13 description.)
`
`Pharmaceutical composition of piperazine derivatives
`
`In Anspruch genommene Prioriat(en) / Priority(ies) c1aimed /Priorité(s)
`revendiquee(s)
`Staat/Tag/Aktenzeichen/State/Date/Fi1e no./Pays/Date/Numero de depot:
`
`Internationaie Patentkiassifikation/InternationaI Patent C1assification/
`Ciassification internationa1e des brevets:
`
`A61K31/00
`
`Am Anme1detag benannte Vertragstaaten/Contracting states designated at date of
`fi1ing/Etats contractants designees Iors du depot:
`
`AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL
`PL PT RO SE SI SK TR LI
`
`04016519.3
`
`2
`
`EPA/EPO/OEB Form 1014-2 - 01-2000
`
`700%0tex, Inc. (IPR2019—00400), EX. 1016, p. 002
`
`Apotex, Inc. (IPR2019-00400), Ex. 1016, p. 002
`
`

`

`14. JUL.2004 11:57
`
`UCB [PD 32 2 5599409
`
`N9644
`
`P.
`
`10
`
`Pharmaceutical composition of pi - razine derivatives
`
`17.80.EP
`
`The present invention relates to a liquid
`
`- harmaceutical composition
`
`containing an active substance belonging to the
`
`
`.‘ u' y of substituted benzhydryl
`
`piperazines.
`A number of substances belonging to the
`
`‘
`
`u y of substituted benzhydryl
`
`
`piperazines are known to be substances with us
`
`Patent GB 817231, for example, filed in
`
`phannacological properties.
`
`substituted benzhydryi piperazmes having the g eral formula
`
`
`in which R and R1 independently of one anoth-u iv epresent a hydrogen or halogen
`or R and R1 to be in the ortho. meta
`
`
`atom, an alkyl or alkoxy group. it being possibl- ;I
`or 2, as well as their pharmaceutically
`
`Or para position, and n stands for the number
`acceptable salts.
`I
`‘
`In particular, these compounds include -[2-[4—[[4-chloropheny])pheny1mefl1y1]—
`own under the name of
`1—piperazmylleth0xy1ethanol. in particular, also >
`
`: j-vell known for their antihistaminic
`hydroxyzine, and its dichlorohydrate. which .
`
`
`Patent EP 58146. filed in the name of U
`
`and tranquilljsing properties-
`
`benzhydryl piperazines having the general fo --
`
`
`
`Empf.zeit:14/O7/2004 11:59
`
`
`Apotex, 199,34,
`'13;%fii$+5@@600), BX. 1016, p. 003
`
`R
`
`R l
`
`N
`
`N—— (C 2CHZO )n—CHZCHon
`
`
`
`5
`
`10
`
`1 5
`
`20
`
`25
`
`Apotex, Inc. (IPR2019-00400), Ex. 1016, p. 003
`
`

`

`14. JUL.2004 11:57
`
`UCB IPD 32 2 5599409
`
`N-“fi44
`
`P. H
`
`2
`
`X
`
`X,
`
`/
`
`\
`
`N
`N
`U
`
`o
`//
`(CH2)n-O]E-H2C—C\
`L
`
`10
`
`15
`
`20
`
`25
`
`- henyllphenylmethyll- 1-
`
`—[ [4—cmorophenprhenyhnefl1yll— 1-
`
`
`;
`
`[bist4-fluorophenynn1ethyll—1-
`orophenyllphenyhnethyl]44(3-
`
`mefltylphmyllmethyllpiperazme (meclizine) or 1 ‘
`
`In the pharmaceutical filed, solutions -
`. - drops are generally produced as
`
`germ-free compositions dun'ng their producfio '
`
`the containers is broken, and the pharmaceufi
`
`‘
`
`
`in which L stands for an —OH or -NI'12 gOup, X .
`
`hydrogen atom. a halogen atom, a linear or b .
`hifluoromethyl radical. m equals 1 or 2, n eq .
`
`phan-naceutically acceptable salts.
`
`Of these compounds, 2-[2—[4—[t4—ch10rop nyl)phenylmethy1]—1—
`piperazinyllethoxy] acetic acid, also known und ‘ the name of cetirizine, and its
`
`‘c properties.
`dichlorohydrate are well known for their antihis ‘—
`The active substances belonging to the f - ‘ u ‘ y of substituted benzhydryl
`
`
`
`
`
`closed.
`
`
`It has now surprisingly been found tha-
`e active substances belonging to the
`sess a preservative efi'ect in aqueous
`
`family of substituted benzhydryl piperazines p -
`solutions.
`
`Empf .zeit:]4/U7/20C|4 11:53
`
`Apotex, IsfiprlRRsflifimtOO), Ex. 1016, p. 004
`
`Apotex, Inc. (IPR2019-00400), Ex. 1016, p. 004
`
`

`

`14. JUL. 2004 11:57
`
`UCB IPD 32 2 5599409
`
`N'-’ 644
`
`P.
`
`12
`
`The purpose of the invention concerns a I. quid pharmaceutical composition
`
`containing an active substance belonging to the ie .. ‘ y of substituted benzhydryl
`
`
`
`
`
`piperazines and a reduced amount of preservati ‘-
`.
`’llie present-invention is based on the
`*cpected recognition that a I
`pharmacwfical composition comprising an acti
`Substance belonging to the family of
`substituted benzhydryl piperazines and a reduc in amount of preservatives is stable
`during a long period of time. Stability means
`capacity to resists to microbial
`4
`contamination.
`- eutical composition comprising
`The present invention encompasses a p 7
`an active substance belonging to the family of s s-tituted benzhydryl piperazines and
`an amount of parahydroxybenzoate esters used ‘ preservatives less than 3 mg/ml of
`the composition. a normal concentration to pre rve aqueOus solutions.
`The present invention encompasses a p
`n . ceutical composition comprising
`an active substance belonging to the family of s -stituted benzhydryl piperazines and
`at least One preservative, wherein the amount olpreservative is in the case of
`parahydroxy’oenzoate-esters more than 0 and l- 1: than 1.5 mg/ml of the composition,
`and in the case ofother preservatives correspo {s to the bactericidal effect ofa
`
`parahydroxybenzoate esters concentration of mm: c than 0 and less than 1.5 rug/m1.
`Generally. the pharmaceutical composi- nn of the invention is liquid and
`
`:
`preferably aqueous.
`By active substances belonging to the f. '4' ‘ y of substituted benzhydryl
`piperazines, we understand also their Dpficale :
`tive isomers and their
`
`pharmaceutically acceptable salts.
`
`In the pharmaceutical composition of th invention. the active substance is
`generally selected from the group of cefirizine, lr‘ ocetjn'zine, hydroxyzine. efletirizine,
`
`active substance is selected from the group of can
`
`' e. levocetirizine. and their
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`-
`
`E acceptable salts. Preferably, the
`meclizine. buclizjne . and theirphannaceuh'
`I
`.
`pharmaceutically acceptable salts.
`The term "cetirizine" refers to the racem. e of [2-[4—[t4
`chlomphenyllphenylmethyl] -1-piperaainyl]etho E. ]—acetic acid and its dihydrochlonde
`salt which is well known as cetirizine dihydro - luride; its levorotatory and
`dextrorotatory enantiomers are known as levoc ‘-
`‘
`' e and dextrocetirizine; Processes
`for preparing cefin‘zine. an individual optical is m yuer thereof or a pharmaceutically
`acceptable salt thereof have been described in : ; opean Patent 0 058 146. Great
`Britain Patent 2.225.320. Great Britain Patent ', 225.321. United States Patent
`
`5,478,941, European Patent application 0 601 4% 8. European PatentApplication 0 301
`064 and International Patent Application WO 9 ‘- 37982.
`
`
`
`EmPf .291 t: 14/07/2004 12:00
`
`
`Apotex, IBM. 'rRfiilfitQfitOO), EX- 1016, p. 005
`
`Apotex, Inc. (IPR2019-00400), Ex. 1016, p. 005
`
`

`

`14. JUL. 2004 11:58
`
`UCB IPD 32 2 5599409
`
`N9644
`
`P.
`
`13
`
`
`
`
`cetin'zine. More precisely, it means that the acti :
`by weight. preferably at least 95% by weight, of o '
`
`cefinzine and at most 10% by weight. preferably -.
`
`.
`individual optical isomer of cetin'zine. Each indi
`by conventional means, i.e.. resolufion from the . L-rresponding racernic mixture or by
`
`prepared fiom the racemic mixture by enzymafi -iocatalyh‘c resolution. Such as
`
`and phosphoric acids and the like, but also its wftal salts (for example sodium or
`
`a product incubated with a large number‘of ba
`
`period.
`
`
`
`Empf.zeit:14/D7/2EIDA 12:00
`
`ApoteX, IgfipflWR;%@1$Lm§r00),EX. 1016, p. 006
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`
`best results have been obtained with dihydrochl- 'de salts.
`
`International patent application 94/064
`describes a method utilising
`
`Generally. the pharmaceutical composi -' n of the invention contains an
`
`amount of preservatives selected in the range 0 ‘I .01 and 1.4 mg/ml of the
`preservatives selected in the range of
`
`‘ an amount of preservatives selected
`
`in the range of 0.3 and 1 mg/ml. The best resu
`
`of 0.375 to 0.75 mg/ml of the composition.
`
`have been obtained with an amount
`- amount of the selected preservative is
`
`defined by comparison with the amount of p
`
`
`
`0.2 and 1.125 rug/ml of the pharmaceutical co wposition.
`ally substance that inhibits the
`
`- ce. kills them: so antimicrobial
`
`By preservatives we understand a che u
`development of microorganisms or. in an ideal
`
`
`
`Apotex, Inc. (IPR2019-00400), Ex. 1016, p. 006
`
`

`

`14.JUL.2004 11:58
`
`UCB [PD 32 2 5599409
`
`‘N9 644
`
`P.
`
`14
`
`Examples of preservatives are p—hydroxy ‘
`
`parahydroxybenzoate, ethyl parahydroxybenzoa ,-
`
`
`
`
`
`acn'nol. methyl rosaniline chloride, benzalkoni
`cetylpyridinium chloride, cetylpyrodium bromid
`
`alcohoL chlomhutanol, isopropanol. ethanol.
`
`
`
`‘
`
`benzoate, sodium benzoate, caICium acetate, c
`
`
`ethylenediaminetet-aacetate, calcium propionat-.
`
`pyroaarbonate, sulphur dioxide. sodium sulphit-
`
`
`oate, ethyl parahydroxybenzoate ,
`
`. Ienzoate . Cl—CZO alkyl
`nyI the preservative is selected from
`
`parahydroaybenzoate or a mixture thereof. Pref .
`the group of sodium benzoate. methyl parahydr
`
`tetraborate. propionic add, sodium and calci u a
`
`or a mixture therefore. Generally. the preserve: ‘
`
`hydroxybenzoate esters (methyl parahydroxyb -..
`
`propyl parahydroxybcmzoate , butyl parahydro
`
`and a mixture of methyl parahydroxybenzoate .
`
`results have been obtained with a mixture of am
`
`parahydroxybenzoate.
`
`
`
`
`By patient, we understand children, ado -
`years old. The targeted patients are usually old Ii -m 2 years and more.
`
`A preferred daily dosage provides from a-‘
`levocetirizine or a pharmaceutically acceptable + t thereof. per kg of body weight per
`
`
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`
`
`kg of body weight per patient. The best results
`from about 0.005 to 1 mg per kg of body weight ‘
`
`
`pafient. A particularly preferred daily dosage is
`
`administered once per day of h-eairuent. or diViI- -
`
`1 to 4 times a day. and preferably 1 to 3 fimes .
`
`24 hours time period to reach a total given dos ;I_
`with an administrafion of a composition of the ‘urvention twice a day for infants: and 5
`
`mg once a day for children and adults. The - v:i
`
` of use, the mode of use. the
`
`are administrated can vary according to the typ
`
`t dosages in which the compositions
`
`Empf.zeit:14/U7/200412:DD
`
`_
`
`APOteX? 112%
`
`Apotex, Inc. (IPR2019-00400), Ex. 1016, p. 007
`
`

`

`14.JUL. 2004 11:58
`
`UCB IPD 32 2 5599409
`
`N9644
`
`P.
`
`15
`
`1
`
`1
`1
`
`6
`
`1
`.
`The pharmaceutical forms according to n‘e present invention may be prepared
`according to conventional methods used by ph n 11- — cists. The forms can be
`
`administered together with other components 0 -iologicaly active agents.
`
`pharmaceutically acceptable surfactants, excipi-1 ts. carriers. diluents and vehicles.
`The pharmaceutical compositions of the ‘ vention include any conventional
`1
`therapeutical inert carrier. The pharmaceutical c ompositions can contain inert as well
`as pharmacodynamically active additives. Liqui- compositions can for example take
`the form of a sterile solution which is miscible "-1 water. FurthermOre, substances
`conventionally used as preserving, stabilizing,
`..1.isture—retaining. and emulsifying
`agents as well as substances such as salts for I g the osmotic pressure.
`substances for varying pH such as buffers, and -ther additives can also be present. If
`desired an antioxidant can be included in the p 11L u aceutical compositions.
`Pharmaceutical acceptable excipients or canier- for compositions include saline.
`buffered saline. dextrose or water. Composition may also comprise specific stabilizing
`agents such as sugars, including mannose and :1: -
`‘tol. Carrier substances and
`diluents can be Organic or inorganic substance 1 far example water. gelatine. lactose.
`starch. gum arable. polyalkylene glycol and the I
`' - .A prerequisite is that all
`adjuvants and substances used in the manufac
`- of the pharmaceutical
`compositions are nontoxic.
`‘- 'stered byspray inhalation. Any
`Pharmaceutical compositions can be a-
`conventional pharmaceutical composition for s - 1y inhalation administration may be
`used. Another preferred mode of administratio . is by aerosol.
`
`1
`
`The pharmaceutical compositions acco - g to the present invention may also
`be administered orally. They may also be a-n-u'11istered by nasal instillation, aerosols.
`The pharmaceutical compositions which can beused for oral administration is liquid.
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`
`
`for example, in the form of solutions. syrups. drups and the like.
`
`'
`
`nasal drops, are prepared by
`The pharmaceutical forms, such as dro -
`conventional pharmaceutical methods. The co --11-0uncls of the present invention are
`minced with a solid or liquid, non—toxic and ph 11- . ceutically acceptable carrier and
`possibly also mixed with a dispersing agent. a s1: nilizing agent and the like. If
`appropriate. it is also possible to add preservati .1 - s. sweeteners. coloring agents and
`the like.
`1
`Preferably. the pharmaceuticalcomposii'fn of the invention is administered in
`traditional fOrm for oral‘administration, as oral 1quid preparation such as syrup
`Best results have been obtained with an 1-ral dosage form. in particular liquid
`formulations such as, syrup for children.
`1
`An advantage of the invention is that re- cing the concentration of the
`preservative leads to a reduction of the risk of 11 allergic reaction in sensitive patients-
`11
`
`EmpfzeitIIA/DWZUDA 12:01
`
`Apotex, IEEIPK.
`
`Ragisqggom EX. 1016 p. 008
`
`1
`
`Apotex, Inc. (IPR2019-00400), Ex. 1016, p. 008
`
`

`

`J
`
`119644
`
`P.
`
`11
`
`him}: to make easier the
`
`14. JUL.2004 11:59
`
`UCB IPD 32 2 5599409
`
`
`
`5
`
`Example 1. Preservafive éfi'ect of cetirizine.
`
`An oral solufion and drops containing cetjn‘zine
`
`,
`
`given in table 1-
`
`10
`
`Cetirizine hydrochloride (mg)
`
`Sorbitol 501. At 70% (mg)
`Glycerine (mg)
`Propyleneglycol (mg)
`Sodium saccharinate (mg)
`
`15
`
`Banana flavour (mg
`Sodium acetate (mg
`Acetic acid
`Purified water (ml)
`
`0
`
`754-
`
`pH 5
`1
`
`250
`350
`10
`
`-
`10
`ad pH 5
`ad 1
`
`20
`
`The anmnicrobial preservative effectiveness tes ‘
`
`25 microorganisms per ml of preparations under t a
`
`given in tables 2 and 3.
`
`
`
`EmPf.Zei 1: 14/07/2004 12:01
`
`Apotex, ImpfimRfiDllegOO), EX. 1016, p. 009
`
`Apotex, Inc. (IPR2019-00400), Ex. 1016, p. 009
`
`

`

`14.JUL. 2004 11:59
`
`UCB IPD 32 2 5599409
`
`N9644
`
`P.
`
`17
`
`Time
`(clays)
`Inoculum
`o
`7
`'14
`21
`28
`
`Time
`
`(days)
`Inoculum
`O _
`7
`14
`21
`
`28
`
`5
`
`10
`
`15
`
`20
`
`25
`
`Table 2. — Micro-1211 come t in inoc
`.tr
`sam- - of the o . solutio
`Pseudomonas
`Escherichia
`Sta-[ylococcus Candida Aspergillus
`aeruginosa
`coli
`— ureus
`albicans
`niger
`5.5 x 105
`4.6 x 105
`"I1. 2; 105
`3.7 x 105
`2.3 x 10‘5
`4.9 x 105
`4.7 x 105
`£1.11: 105
`2.6 x 105
`1.7 x 106
`< 100
`< 100
`< 100
`< 100
`4.8 x 105
`<1
`<1
`1 <1
`2
`8.22:103
`<1
`<1
`1 <1
`<1
`5.5x103
`<11
`<1
`1 <1
`<1
`5.0x103
`1
`
`'
`
`
`
`‘
`
`Table 3. -Microbial contnt in inoc_1l ated sam-le of the dro -s
`Pseudomonas
`Escherichia Statiylococcus Candida
`Aspergillus '
`
`aeruginosa
`4.0 x 105
`3.5 x 105
`< 100
`< 1
`< 1
`
`< 1
`
`co
`3.4 x 105
`3.8 x 105
`< 100
`< 1
`< 1
`
`< 1
`
`albicans
`3.5 x 105
`2.6 x 105
`< 100
`< 1
`< 1
`
`< 1‘
`
`niger
`1.8 x 10‘3
`1.6 x 10‘5
`< 104
`<100
`< 1
`
`< 1
`
`'516 1:105
`!12 x 105
`< 100
`1
`< 1
`1:
`
`1
`1
`
`In both cases a rapid disappearance of Pseudo "1onas aeruginosa Escherichia C011.
`
`Staphylococcus aureus and Candida albicans idobserved in the inoculated samples.
`For Asperglllus niger. the number of viable spo s is significantly reduced in the oral
`solution while a rapid disappearance is observe 1 in the drops
`
`
`
`1
`.1 e were prepared. 'me compositions
`
`Emma 2. Preservativ'e eflect of levocefiriziiw.
`An oral solution and drops containing 1evoce-'
`
`are given in table 4.
`
`
`
`
`E031 .zeit: 14/07/2004 12:01
`
`
`Apotexa 1001'£%101%§111§00),EX. 1016, p. 010
`
`Apotex, Inc. (IPR2019-00400), Ex. 1016, p. 010
`
`

`

`N9644
`
`P.
`
`18
`
`1
`
`1 11 i
`
`1 1
`
`9
`
`14.JUL.2004 11:59
`
`UCB IPD 32 2 5599409
`
`Tab e 4. - Levocetirizin com-nosi ans
`
`Drops
`5
`—
`294.1
`
`350
`
`10
`
`-
`5.7
`
`0.53
`
`ad 1
`
`0 II} solution
`l 0.5
`1400
`1235.2
`
`—
`
`0.5
`
`1 0.15
`1 3.4
`
`1 0.5
`
`ad 1
`
` 1
`
`Levocetirizine hydrochloride (mg)
`MaltitoI—Lycasin 8055 (mg)
`Glycerine 85 wing)
`
`Propyleneglycol (mg)
`
`Sodium saccharinate (mg)
`
`Tutti frutti flavour (mg)
`Sodium acetate (mg)
`
`10
`
`Acetic acid (mg)
`
`Puflfied water (r111)
`
`The antimicrobial preservative effectiveness tes- ‘ were realized according to the
`
`15
`
`European Pharmacopoeia (Chap. 5. 1.3.]. Samplp of the oral solution and the drops
`
`were inoculated with bacterial and yeast suspe ions of Pseudomonas aeruginosa
`
`ATCC 9027, Escherichia Coli ATCC 8739, Stap -lococcus aureus ATC 06538. Candida
`1
`
`albicans ATCC10231 and Aspergillus niger ATC 16404. The number of viable
`
`microorganisms per m1 of preparations under t- 3 t were determined. The reSults are
`1
`
`20
`
`given in tables 5 and 6.
`
`1
`
`Table 5. - MiCrobial content in inoculai- - sam-le of the o . solution
`
`Time
`
`Pseudomonas
`
`Escherichia
`
`S 4hy10coccus Candida
`
`Asperg‘llus
`
`(days)
`
`aeruginosa
`
`coli
`
`-ureus
`
`albicans
`
`Inoculum
`
`3.6 x 105
`
`1.7 x 105
`
`.7 x -105
`
`3.4 x105
`
`0
`
`7
`
`14
`
`21
`
`28
`
`3.2): 105
`
`1.8:; 105
`
`'.5x 105
`
`3.9::105
`
`150'
`
`< 1
`
`< 1
`
`< 1
`
`< 100
`
`< 1
`
`'
`
`< 1
`
`< 1
`
`. < 100
`
`< 1
`
`< 1
`
`< 1
`
`2.8 x 104
`
`1.4 x 104
`
`2.6 x 102
`
`6.2 x 103
`
`25
`
`30
`
`niger
`
`1.7 x 10‘5
`
`1.6 x 105
`
`1.0 x 108
`
`4.8 x 105
`
`2.2 x 105
`
`5.3 x 105
`
`
`
`Empf .zeit:14/07/2004 12:02
`
`APOteXa IEffim‘.
`
`3.210%991100), EX-
`
`1016,p.011
`
`Apotex, Inc. (IPR2019-00400), Ex. 1016, p. 011
`
`

`

`14.JUL. 2004 11:59
`
`UCB [PD 32 2 5599409
`
`N[3 644
`
`P;
`
`19
`
`10
`
`
`Pseudomonas
`Escherichia
`Sta
`
`
`aemginosa
`
`Inoculum
`3.6x105
`1.7:: 105
`7x 105
`3.4:: 105
`1.7:: 105
`1.5:: 10511 1:105
`0
`3-224105
`1.81; 105
`1.72; 105
`
`< 100
`
`
`<1
`<1
`<1
`<1
`
`28
`'
`
`
`
`- onas aeruginosa. Escherichia C011.
`
`
`Staphylococcus aureus is observed in the inoc
`ted samples.
`
`
`A disappearance of Candida alhicans and Asper
`
`vllus niger is also observed in the
`
`drops.
`
`Exam-1e 3. Effica
`
`
`of antimicrobial IIESEIVatiOn of cetirizine a-ueous solufions bv
`
`g— ‘ygroxzbgnzgate esters-
`
`I
`
`Oral solutions and drops containing cetirizine a- ording to example 1 but also
`
`containing mixtures of p-hydroxybenzoate ester (methyl p-hydroxybenzoate/propyl p—
`hydroxybenzoate in a ratio of 9/ 1 expressed in [eight). The total amounts of p-
`hydroxybenzoate esters were 0.15 mg/ml. 0.45 J. — ml, 0.75 rug/ml and 1.05 mg/ml.
`
`The efficacy of antlmlcrobialpresewafion of the- ~ solufions and drops was determined
`according to the European Pharmacopoeia [C1115]; 5.1.3.). The results of the tests is
`given in tables 7 to 14.
`
`11 1
`
`Table 7. — Microbial centent in inoculaid sam-le of the oral solution
`1
`containin- 0.15 m_ m1 of --hI-rovaenzoate esters
`
`Time
`
`Pseudomonas
`
`Escherichia St uhylococcus Candida
`
`Aspergillus
`
`albicans
`3.7 x 105
`
`niger
`2.3 x 108
`
`4-0 x 105
`
`4.1 x 105
`
`<1
`<1
`
`9.1x103
`750
`
`aureus
`‘
`colt
`4.6 1: 1051.0 3; 105
`
`1
`
`1 <1
`
`4.5 x 105
`
`<1
`
`<1
`
`-.0 x 105
`
`1 <
`
`(days)
`Inoculum
`
`aeruginosa
`5.5 x 105
`
`0
`
`14
`
`28
`
`'
`
`5.1 x 105
`
`'
`
`<1
`
`<1
`
`10
`
`15
`
`20
`
`25
`
`30
`
`1
`
`1 1
`
`Empf .ze11:14/07/2004 12:02
`
`Apotexa 1%{1'112111119P00149001EX- 1016a p- 012
`
`Time
`
`
`
`(days)
`
`7
`
`14
`
`21
`
`< 100
`
`< 1
`
`<1
`
`< 100
`
`< 1
`
`< 100
`
`9.0 x 104
`
`< 1
`
`< 1
`
`<1000
`
`Apotex, Inc. (IPR2019-00400), Ex. 1016, p. 012
`
`

`

`14. JUL. 2004 12:00
`
`UCB IPD 32 2 5599409
`
`NE 644
`
`P.
`
`20
`
`Table 8. -
`crobial content in inOCulat ‘. sam -1e If the oral solution
`1
`con '
`- 0.45 m- m] of -—h 1E1" benzoate -
`ters
`Pseudomonas
`Escherichia
`Stai ylococcus Candida Aspergfllus
`aeruginosa
`c011
`‘
`aureus
`albicans
`niger
`5.5 x 105
`4.5 x 10510 x 105
`3.7 x 105
`2.3 x 106
`
`5.2 x 105
`< 1 9
`< 1
`
`4.9 x 105
`< 1
`< 1
`
`i .3 x 105
`‘
`i
`
`< 1
`
`2.9 x 105
`< 1
`< 1
`
`1.2 x 10‘5
`<100
`2
`
`Time
`(days)
`hmculum
`
`O
`14
`28
`
`1
`Table 9- - Mi obial cont -t in inoculan-d sam- - of the oral solution
`cont.'
`'
`; 0.75 n; m1 of --h .
`'j’ o b-nzoate esters
`Pseudomonas
`Escherichia
`Sta 5' ‘. YIOCOCCuS Candida
`
`Aspergfllus
`
`aerug‘nosa
`
`5.5 x 105
`3-9x105
`< 1
`< 1
`
`c011
`
`4.6 x 105
`4.4:: 105
`< 1
`< 1
`
`aureus
`
`albicans
`
`niger
`
`-'$0 In: 105
`1.02: 105
`‘<
`
`3.7 x 105
`1.9:: 105
`< 1
`< 1
`
`2.3 x 105
`1.9}: 10‘3
`<100
`< 1
`
`Time
`
`[days]
`
`Inoculum
`0
`14
`28
`
`Table 10. - Mi obial content in mood!' d sam-le o the oral soution
`
`Time
`(days)
`InOCulum
`0
`14
`
`28
`
`Time
`(days)
`Inoculum
`0
`
`< l
`
`< 1
`
`5
`
`< 1
`
`< 1
`
`< 1
`
`contain'. 1 1.05 m_ ml of --h uro
`nenzoate esters
`Pseudonionas
`Escherichia
`Stalhylmaoccus Candida Aspergillus
`aeruginosa
`0011
`I
`aureus
`albicans
`niger
`5.5 x 105
`4.6 x 105
`i1o x 105
`3.7 x 105
`2.3 x 106
`3.3 x 105
`4.1 x 105
`C1.1 x 105
`1.4}; 105
`1.2 x 10"5
`< 1
`< 1
`I
`< 1
`< 1
`<100
`I
`Tabie 11. — Micmbial untent in in- ._ ated sarn n1e 0f the dro -s
`containin 0.15 m_ m] of uJ-hd .
`uenzoate esters
`Pseudomonas
`Escherichia
`S r: u;hylococcus Candida
`aeruginosa
`c011
`m
`aureus
`albicans
`4.0 x 105
`3.4 x 105
`.6- 105
`3.5 x 105
`4.3 x 105
`4.0 x 105
`i 0 x 105
`2.5 x 105
`
`Asperg'dlus
`Inger
`1.8 x 106
`1.5 x 103
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`
`
`14
`28
`
`. < 1
`< 1
`
`< 1
`< 1
`
`< 1
`< 1
`
`< 1
`< 1
`
`<100
`< 1
`
`EmPf .2121 1: 14/07/2004 12:02
`
`Apotex, 11131591113140.2500), EX. 1016, p. 013
`
`Apotex, Inc. (IPR2019-00400), Ex. 1016, p. 013
`
`

`

`14. JUL. 2004 12:00
`
`UCB IPD 32 2 5599409
`
`9
`
`N9644
`
`P.
`
`21
`
`12
`
`Table 12. - Microbial content in ino t- ated sa I1e of the Iro Is '
`contai in_ 0.45
`- mi of --h “El: 0.
`Ienzoate esters
`Pseudomonas
`Escherichia
`Sta-[ylococcus Candida
`
`Aspergillus
`
`aeruginosa
`
`coll
`
`5 aureus
`
`albicans
`
`niger
`
`’Dme
`
`(days)
`
`Inoculum
`
`4.0 x 105
`
`O
`
`14
`28
`
`3.6 x 105
`
`< 1
`< 1
`
`3.4 x 105
`
`3.6 x 105
`
`< 1
`< 1
`
`'
`
`-.*- x 105
`
`3.5 x 105
`
`1.3 x 106
`
`l x 105
`
`. 2.1 x 105
`
`1.4 x 105
`
`< 1
`< 1
`
`1
`
`< 1
`< 1
`
`<100
`< 1
`
`Table 13. —— Microbial ontent in ino Iu ate- 5am Ile of the dro Is
`
`r—
`
`containin_ 0.75
`
`; m1 of I- h 1. o. berm-ate esters
`
`Time
`
`Pseudomonas
`
`Escherichia
`
`Sta g- Iylococcus Candida Aspergillus
`
`albicans
`3-5 2:105
`2.5:: 105
`<1
`< 1
`
`niger
`1.8 x 106
`1.6x 1o6
`<100
`< 1
`
`‘ aureus
`coli
`3.4 x 10516 x 105
`3.612105
`'62: 105
`<1
`1 <1
`< 1
`< 1
`
`1 11
`
`(days)
`Inoculum
`o
`14
`28
`
`aeruginosa
`4.0 x 105
`4.1:: 105
`<1
`< 1
`
`Table 14. - Min obial co t t in inom ated 5 dc ofthe dro-s
`con .
`'
`; 1.05 m ml of I-h 91- oz. Ienzoate esters
`Pseudomonas
`Escherichia
`Stall ylococcus Candida
`aeruginosa
`coli
`1 aureus
`albicans
`4.0 x 105
`3.4 x 105
`[.6 x 105
`3.5 x 105
`3.9 x 105
`3.7 x 105
`[.8 x 105
`2.2 x 105
`< 1
`< 1
`1
`< 1
`< 1
`
`Aspergfllus
`niger
`1.8 x 108
`1.3 x 106
`<100
`
`< 1
`
`< 1
`
`1
`
`< 1
`
`< 1
`
`< 1
`
`Time
`(days)
`Inoculum
`0
`14
`
`28
`
`In all cases. the disappearance of Pseudomon - ‘: eruginosa. Escherichia C011.
`
`' observed in the inoculated samples.
`1
`For Aspergjllus niger, the number of viable spo . Is is significantly reduced in. the oral
`.1 in the drops.
`
`Solution while a rapid disappearance is observe
`
`Inall cases the recommended efficacy criteria -[a e achieved.
`Exam- 7 4. Effica
`of antimicrob'al IreservafiI 1 of levoc-tirizine a-ueous solutions b
`
`
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`E-hxdrdgbenzoate esters.
`
`Oral solutions and drops containing levoce-
`
`m e according to example 2 but also
`
`containing mixtures of p-hydroxybenzoate este (methyl p-hydroxybmzoate/propy1 p—
`
`hydroxybenzoate in a ratio of 9/1 expressed in 1
`
`Empf .zeimzvmxzam 12:02
`
`Apotexa Isfipffi"l?s%fi1$tfi§ftoo)a EX- 1016, p- 014
`
`Apotex, Inc. (IPR2019-00400), Ex. 1016, p. 014
`
`

`

`14.JUL.2004 12:00
`
`UCB [PD 32 2 5599409
`
`N9644
`
`P.
`
`22
`
`13
`
`hydroxy’oenzoate esters were 0.375 mg/ml, 0.75
`'ons and drops was determined
`efficacy of antimicrobial preservation of these sol
`according to the European Pharmacopoeia (Chap 5.1.3.). The results of the tests is
`
`mland 1.125 rug/nu- The
`
`given in tables 15 to 20.
`
`sam-le of the oral soluti-n >
`Table 15. —- Mia obial .ontent in inocula
`~
`9
`ontainin_ 0.375 m_ ml of -— 1E r0 benzoate esters
`Pseudomonas
`Escherichia
`Staplylococms Candida
`aemgmosa
`coli
`ureus
`albicans
`3-6 x 105
`1.7 x 105
`97 x 105
`3.4 x 105
`3.7::105
`1.3:: 105
`,8x105
`3.8:: 105
`< 1
`< 1
`9 < 1
`1.7 x 104
`< 1
`< 1
`< 1
`< 1
`
`99 999 999
`
`-
`
`Time
`(days)
`Inoculum
`o
`14
`28
`
`ASPergillus
`
`niger
`
`1.7 x 10,6
`
`1.6 x 10‘5
`
`1.6 x 105
`
`<100
`
`Time
`(days)
`Inoculum
`o
`'14
`28
`
`Tlme
`(days)
`Inoculum
`
`O
`
`14.-
`
`28
`
`Table 16. — Microbial content in me ula -d --amle o the oral solution
`can '
`; 0.75 n; ml of —h 1E 02. benzoate esters
`Pseudomonas
`Escherichia Sta'2 ylococcus Candida
`aeruginosa
`coli
`ureus
`albicans
`3.6 x 105
`1.7 x 105
`[.7 x 105
`3.4 x 105
`3.5 x .105
`1.6 x 105
`.4 x 105
`3.4 x 105
`<1
`<1
`.<1
`5.52:102
`< l
`< 1
`< l
`< 1
`
`Asperglllus
`
`niger
`
`1.7 x 105
`
`1.6 x 106
`
`1.4 x 10‘
`
`<1
`
`9
`
`Table 17. —Microbial contentinmeml: ated sam-le ofthe oral solution
`
`containin_1.125m ml of -- idrox nenzoate sters
`Pseudornonas
`Escherichia Stall ylococcus Candida
`aenzginosa
`coli
`9 aureus
`albicans
`3.6 x 105
`1.7 x 105
`3 4 x 105
`
`Aspergillus
`
`niger
`
`3.9 x 105
`
`1.2 x 105
`
`< 1
`
`< 1
`
`< 1
`
`< 1
`
`3 5 x 105
`
`<10
`
`< 1
`
`10
`
`15
`
`20
`
`25
`
`30
`
`EmPf.zeit:14/D7/2L104 12:00
`
`Apotexa 1%K.'r13%fil%9@§00), Ex. 1016, p. 015
`
`Apotex, Inc. (IPR2019-00400), Ex. 1016, p. 015
`
`

`

`14. JUL. 2004 12:00
`
`UCB [PD 32 2 5599409
`
`.
`
`N9 644
`
`P.
`
`23
`
`14
`
`Table 18. - Microbial content in in-
`
`ated sam-le 0f the dro. -
`
`containin_ 0.375 m- m1 of -—h -
`
`-
`
`nenzoate este
`
`Time
`
`Pseudomunas
`
`Escherichia
`
`Stap ',| lococcus Candida
`
`Aspergillus
`
`5
`
`(days)
`
`aeruginosa
`
`coli
`
`1'
`
`eus
`
`albicans
`
`niger
`
`Inoculum
`
`3.5 x 105
`
`1.7 x 105
`
`J x 105
`
`3.4 x105
`
`1.7 x 108
`
`0
`
`14
`
`28
`
`Time
`[days]
`
`Inocuium
`0
`14-
`28
`
`10
`
`15
`
`20
`
`3.1 x 105
`
`1.2 x 105
`
`4 - 1:105
`
`1.7 x 105
`
`' 1.8 x 10‘5
`
`< 1
`
`< 1
`
`a 1
`
`< 1
`
`< 1
`
`‘ < 1
`
`‘
`
`< 1
`
`< 1
`
`< 1000
`
`< 1
`
`Ta- 3 19. — Microbial content in inoc ated sam-le of the dro us
`containin- 0.75 n; ml If —h -!o ‘benzoate esters
`Pseudomonas
`Escherichia
`Stat» .9. lacoccus Candida
`aerugjnosa
`coli
`I aureus
`albicans
`
`Aspergilius
`niger
`
`3.6 x 105
`3.1 x 105
`< 1
`< 1
`
`1.7:: 105
`1.0 x 105
`< 1
`< 1
`
`A x 105
`'10 x 105
`1 < 1
`1 < 1
`l
`
`3.4. x 105
`1.8 x 105
`< 1
`< 1
`
`1.7 x 106
`1.4:; 103
`< 1000
`< 1
`
`Table 20. — Microbial contentin inoc lated sam-le ofthe dro-s
`
`Time
`(days)
`
`co_;_tai
`'
`Pseudomonas
`aeruginosa
`
`- l. 25 11;
`n_-__ -f —h 111;- u ---nzat
`-
`ers
`Escherichia
`Stap 1!} lococcus Candida
`coli
`.5 reus
`A
`' albicans
`
`Aspergjllus
`niger
`
`Inoculum
`o
`
`3.6 x 105
`2.9 x 105
`
`25
`
`1.7 x 105
`6.9 x 104
`
`l x 105
`1‘ x 105
`
`3.4 x 105
`5.0 x 104
`
`1.7 x 106
`1.5 x 108
`
`14
`
`28
`
`< 1
`
`< 1
`
`'
`
`< 1
`
`< 1
`
`< 1
`l
`
`i < 1
`1
`
`< 1
`
`< 1
`
`< 1000
`
`< 1
`
`In all cases, the disappearance of Pseudomonas . -ruginosa, Escherichia Coli.
`Staphylococws aureus and Candida albicans is . 1‘“ served in the inoculated samples.
`For Aspergillus niger. the number of viable spo - -. is significantly reduced in the oral
`solution while a rapid disappearance is observed
`the drops.
`
`In all cases the recommended efficacy criteria we r achieved.
`
`30
`
`35
`
`
`
`Empf .Zeit: 14/07/2004 12:03
`
`Apotexa IEHPK.13:'%@1$*9@§00)’ EX- 1016’ P. 016
`
`Apotex, Inc. (IPR2019-00400), Ex. 1016, p. 016
`
`

`

`14. JUL. 2004 12:01
`
`UCB IPD 32 2 5599409
`
`CLAIMS
`
`15
`
`N9644
`
`P.
`
`24
`
`
`
`1.
`
`5
`
`10 '
`
`2.
`
`,
`
`3.
`
`15
`
`4.
`
`20
`
`5.
`
`25
`
`30
`
`6.
`
`7.
`
`8.
`
`9.
`
`10-
`
`35
`
`A liquid pharmaceutical composition com - 1 'sing an active substance belonging
`
`to the family of substituted benzhydryl pi-
`
`razines and at least one preservative.
`
`
`
`wherein the amount of preservaiive is in
`
`more than 0 and less than 1.5 rug/ml of
`
`‘ ‘- case of parahydroxybenzoate esters
`
`composition, and in the case of
`‘cidal effect of a
`
`other preservatives corresponds to the ba- -
`fmore than 0 and less than 1.5
`
`
`parahydroxybenzoate esters concentration
`rug/m1.
`‘
`
`A liquid pharmaceutical cemposition acco
`
`it is an aqueous composition.
`
`
`
`a mixture of methyl parahydrombenzoate
`
`u d ethyl parahydroxyhenzoate 0r
`
`
`parahydroxybenzoate. ethyl parahydroxyb .. oate , propyl parahydroxybenzoate ,
`
`1' of methyl parahydroxybenzoate and
`
`propyl parahydroxybenzoate , and a -
`
`propyl parahydroxybenzoate.
`
`‘
`
`
`
`preservatives selected in the range of 0.01 .=‘ d 1.4 mg/ml of the composition.
`
`A liquid pharmaceutical composifiOn aeco
`
`the phannaceutical composition contains .-
`
`
`
`the range of 0.2 and 1.125 rug/m1.
`A liquid pharmaceutical composition accor ‘ g to claim 6, characterized in that
`
`the pharmaceutical cornposition contains .
`‘
`amount of preservatives selected in
`
`
`
`the range of 0.3 and 1 mg/ml.
`
`
`the range of 0.375 to 0.75 mg/ml of the co.
`
`A liquid pharmaceutical Composition accar
`
`characterized in that the active substance
`
`
`
`Empf.zeit:14/D7/2004 12:03 ,
`
`
`Apotex, mpg
`
`amppgmom, Ex. 1016, p. 017
`
`Apotex, Inc. (IPR2019-00400), Ex. 1016, p. 017
`
`

`

`14. JUL. 2004 12:01
`
`UCB [PD 32 2 5599409
`
`ABSTRACT
`
`
`
`N9644
`
`P.
`
`25
`
`The present invenfion relates to a liquid ‘ nmpusition containing an active
`substance belonging to the family of subsfituted '- enzhydryl piperazines with reduced
`
`amounfs of preservatives.
`
`Empf .zeit:14/D7/2004 12:03
`
`Apotex, Iaspfc"13;%fi11$v,@@§00),Ex. 1016, p. 018
`
`Apotex, Inc. (IPR2019-00400), Ex. 1016, p. 018
`
`

`

`PCT/EP200 5 / 0
`
`73 at)
`
`17.80.WO
`
`Pharmaceutical composition of piperazine derivatives
`
`The present invention relates to a liquid pharmaceutical composition
`
`containing an active substance such as cetin'zine, levocetin'zine and efletin'zine.
`
`A number of substances belonging to the family of substituted benzhydryl
`
`piperazines are known to be substances with useful pharmacological properties.
`
`European Patent EP 58146, filed in the name of UCB, S.A., describes
`
`substituted benzhydryl piperazines having the general formula
`
`X
`
`X,
`
`,—\
`
`N
`N
`\_/
`
`//o
`(CH2)n—CE'm—H2c—c
`\L
`
`in which L stands for an -OH or -NH2 group, X and X’, taken separately, stand for a
`
`hydrogen atom, a halogen atom, a linear or branched alkoxy radical at C1 or C4, or a
`
`trifluoromethyl radical, m equals 1 or 2, n equals 1 or 2, as well as their
`
`pharmaceutically acceptable salts.
`
`Of these compounds, 2-[2-[4-[(4—chloropheny1)phenylmethyl]—l-
`
`piperazinyllethoxy] acetic acid, also known under the name of cetin'zine, and its
`
`dichlorohydrate are well known for their antihistaminic properties.
`
`The active substances belonging to the family of substituted benzhydryl
`
`piperazines specifically include 2-[2—[4—[(4-chloropheny1)phenylmethyl]-1-
`
`piperazinyllethoxyl—acetic acid (cetin'zine), 2—[2-[4—[bis(4-fluorophenyl)methyl]—1-
`
`piperazinyllethoxylacetic acid (efletirizine), their optically active isomers when
`
`applicable, as well as their pharmaceutically acceptable salts.
`
`In the pharmaceutical filed, solutions and drOps are generally produced as
`
`germ—free compositions during their production processes. However, once the seal of
`
`the containers is broken, and the pharmaceutical compositions are completely used
`
`over a period of time, these pharmaceutical compositions are continuously exposed to
`
`ApoteX, Inc. (IPR2019—00400), EX. 1016, p. 019
`
`EONFIRMATION COPY
`
`10
`
`15
`
`20
`
`25
`
`30
`
`Apotex, Inc. (IPR2019-00400), Ex. 1016, p. 019
`
`

`

`the risk of being contaminated by the microorganisms existing in the environment or
`
`the human body, each time the containers are used and their covers are opened or
`
`closed.
`
`It has now surprisingly been found that the active substances belonging to the
`
`family of substituted benzhydryl piperazines possess a preservative effect in aqueous
`
`solutions.
`
`The purpose of the invention concerns a liquid pharmaceutical composition
`
`containing an active substance belonging to the family of substituted benzhydryl
`
`piperazines chosen among cetirizine, levocetirizine and efletirizine, and a reduced
`
`10
`
`amount of preservatives.
`
`The present invention is based on the unexpected recognition that a
`
`pharmaceutical composition comprising an active substance belonging to the family of
`
`substituted benzhydryl piperazines and a reduced amount of preservatives is stable
`
`during a long period of time. Stability means the capacity to resists to microbial
`contamination.
`
`15
`
`The present invention encompasses a pharmaceutical composition comprising
`
`an active substance belonging to the family of substituted benzhydryl piperazines and
`
`an amount of parahydroxybenzoate esters used as preservatives less than 3 mg/ml of
`
`the composition, a normal concentration to preserve a