(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY(PCT)
`
`(19) World Intellectual Property
`Organization
`International Bureau
`
`
`
`(43) International Publication Date
`17 June 2004 (17.06.2004)
`
`(10) International Publication Number
`WO 2004/050094 Al
`
`(51) International Patent Classification’:
`A61P 37/00
`
`A61K 31/495,
`
`(21) International Application Number:
`PCT/EP2003/00549 1
`
`(81) Designated States (national): AE, AG, AL, AM,AT, AU,
`AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CO, CR, CU,
`CZ, DE, DK, DM, DZ, EC, EE, ES, FI, GB, GD, GE, GH,
`GM, HR, HU,ID,IL,IN, IS, JP, KE, KG, KP, KR, KZ, LC,
`LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW,
`MX, MZ, NO, NZ, OM,PH,PL, PT, RO, RU, SD, SE, SG,
`(22) International Filing Date:=26 May 2003 (26.05.2003)
`SK, SL, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VN,
`YU, ZA, ZM, ZW.
`
`
`
`
`
`Wo2004/050094A./IIMTNININNIINIINTIITNTITIINIHNN
`
`(72) Inventor; and
`
`(75) Inventor/Applicant (for US only):|REVIRRON,
`Published:
`Christophe [FR/CH]; Rossistrasse 25, CH-1735 Giffers
`(CH).
`
`(25) Filing Language:
`
`English
`
`(26) Publication Language:
`
`English
`
`(30) Priority Data:
`2080064.5
`
`3 December 2002 (03.12.2002)
`
`EP
`
`(71) Applicant(for all designated States except US): UCB,S.A.
`[BE/BE]; Allée de la Recherche 60, B-1070 Brussels (BE).
`
`(84) Designated States (regional): ARIPO patent (GH, GM,
`KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZM, ZW),
`Eurasian patent (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
`European patent (AT, BE, BG, CH, CY, CZ, DE, DK, EE,
`ES, FI, FR, GB, GR, HU, IE, IT, LU, MC, NL, PT, RO,
`SE, SI, SK, TR), OAPI patent (BF, BJ, CF, CG, CI, CM,
`GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG).
`
`with international search report
`
`(74) Agent: LECHIEN, Monique; UCB, S.A., Intellectual
`Property Dept., Allée de la Recherche 60, B-1070 Brussels
`(BE).
`
`For two-letter codes and other abbreviations, refer to the "Guid-
`ance Notes on Codes and Abbreviations" appearing at the begin-
`ning of each regular issue of the PCT Gazette.
`
`(54) Title: USE OF LEVOCETIRIZINE FOR THE TREATMENTOF PERSISTENT ALLERGIC RHINITIS
`
`(57) Abstract: The present invention relates to a pharmaceutical use of levocetirizine for the treatmentof persistent allergic rhinitis.
`
`Apotex,Inc. (IPR2019-00400), Ex. 1007, p. 001
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`Apotex, Inc. (IPR2019-00400), Ex. 1007, p. 001
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`

`

`WO 2004/050094
`
`PCT/EP2003/005491
`
`USE OF LEVOCETIRIZINE FOR THE TREATMENT OF PERSISTENT ALLERGIC RHINITIS
`
`The present invention relates to the use of levocetirizine for the preparation of
`
`drugs effective for the treatmentof the persistent allergic rhinitis.
`
`International patent application 94/06429 describes a method utilising
`
`levocetirizine for the treatment of seasonal and perennial allergic rhinitis.
`
`It has now surprisingly been found that levocetirizine possesses therapeutic
`
`properties which renderit particularly useful in the treatment of persistent allergic
`
`rhinitis. These activities are not observed in the dextrocetirizine.
`
`10
`
`The purpose of the invention concerns the treatment of persistent allergic
`
`rhinitis.
`
`The present invention is based on the unexpected recognition that
`
`administration of pharmaceutical compositions comprising levocetirizine, or a
`
`pharmaceutically acceptable salt thereof to a patient treats the persistent allergic
`
`15
`
`rhinitis.
`
`The present invention encompasses a method for treating persistent allergic
`
`rhinitis which comprises administering to a patient a therapeutically effective amount
`
`of levocetirizine or a pharmaceutically acceptable salt thereof.
`
`The present invention also encompasses the use of levocetirizine or a
`
`20
`
`pharmaceutically acceptable salt thereof for the preparation of a medicament intended
`
`for the treatment of persistent allergic rhinitis.
`
`The present invention relates to the use of levocetirizine or a pharmaceutically
`
`acceptable salt thereof for the preparation of a medicamentintended for decreasing the
`
`symptomsof persistent allergic rhinitis and improving the quality of life.
`
`25
`
`In another aspect, the present invention relates to a methodof treating in a
`
`patient persistent allergic rhinitis by administering an effective dose of levocetirizine or
`
`a pharmaceutically acceptable salt thereof.
`
`The term "cetirizine" refers to the racemate of [2-[4-|(4
`
`chlorophenyl)phenylmethyl] -1-piperazinyllethoxy]-acetic acid and its dihydrochloride
`
`30
`
`salt which is well known as cetirizine dihydrochloride; its levorotatory and
`
`dextrorotatory enantiomers are known as levocetirizine and dextrocetirizine. Processes
`
`for preparing cetirizine, an individual optical isomer thereof or a pharmaceutically
`
`acceptable salt thereof have been described in European Patent 0 058 146, Great
`
`Britain Patent 2.225.320, Great Britain Patent 2.225.321, United States Patent
`
`35
`
`5,478,941, European Patent application 0 601 028, European Patent Application 0 801
`
`064 and International Patent Application WO 97/37982.
`
`The term "levocetirizine" as used herein meansthelevorotatory enantiomerof
`
`cetirizine. More precisely, it means that the active substance comprises at least 90%
`
`KONRMATOMR98%5-00400), Ex. 1007, p. 002
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`Apotex, Inc. (IPR2019-00400), Ex. 1007, p. 002
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`WO 2004/050094
`
`PCT/EP2003/005491
`
`by weight, preferably at least 95% by weight, of one individual optical isomer of
`cetirizine and at most 10% by weight, preferably at most 5% by weight, of the other
`individual optical isomerof cetirizine. Each individual optical isomer may be obtained
`by conventional means, i.e., resolution from the corresponding racemic mixture or by
`asymmetric synthesis. Each individual optical isomer may be obtained from its
`racemic mixture by using conventional means such as disclosed in British patent
`application No. 2,225,321. Additionally, each individual optical isomer can be
`
`prepared from the racemic mixture by enzymatic biocatalytic resolution, such as
`
`disclosed in U.S. Patents No. 4,800,162 and 5,057,427.
`
`10
`
`The term "pharmaceutically acceptable salts" as used herein refers not only to
`addition salts with pharmaceutically acceptable non-toxic organic and inorganic acids,
`such asacetic, citric, maleic, succinic, ascorbic, hydrochloric, hydrobromic, sulfuric,
`and phosphoric acids and thelike, but also its metal salts (for example sodium or
`
`potassium salts) or ammonium salts, the amine salts and the aminoacid salts. The
`
`15
`
`best results have been obtained with levocetirizine dihydrochloride.
`
`By patient, we understand children, adolescents and adults.
`
`20
`
`25
`
`30
`
`By the term "allergic rhinitis", we understand a symptomatic disorder of the
`
`nose induced by an IgE-mediated inflammation after allergen exposureof the
`
`membraneof the nose. Symptomsof allergic rhinitis include rhinorrhea, nasal
`obstruction, nasal itching, sneezing, ocular pruritis. The term "persistent allergic
`rhinitis", as used herein, refers to a disease when symptomslast more than 4 days per
`
`week and for more than 4 weeks. It is subdivided into mild and moderate-severe
`
`rhinitis. It is said "mild" when there are normal sleep, or no impairment of normal
`daily activities, sport, leisure, normal work and school, or no troublesome symptoms.
`It is said "moderate-severe" when there are abnormal sleep, or impairmentof daily
`
`activities, sport, leisure, or problems caused at work or school, or troublesome
`
`symptoms.
`
`A therapeutically effective amountof levocetirizine or a pharmaceutically
`acceptable salt thereof is used to treat or alleviate the effects of persistent allergic
`rhinitis. The dosage dependsessentially on the specific method of administration and
`
`on the purposeof the treatment. Thesize of the individual doses and the
`
`administration program can best be determined based on an individual assessmentof
`
`the relevant case. The methods required to determine the relevant factors are familiar
`
`to the expert.
`
`35
`
`A preferred daily dosage provides from about 0,0005 mg to about 2 mg of
`
`levocetirizine or a pharmaceutically acceptable salt thereof, per kg of body weight per
`patient. A particularly preferred daily dosage is from about 0,001 to about 2 mg per
`kg of body weight per patient. The best results have been obtained with a daily dosage
`
`Apotex, Inc. (IPR2019-00400), Ex. 1007, p. 003
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`Apotex, Inc. (IPR2019-00400), Ex. 1007, p. 003
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`

`WO 2004/050094
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`PCT/EP2003/005491
`
`3
`
`from about 0,005 to 1 mg per kg of body weight per patient. The dosage may be
`administered once per day of treatment, or divided into smaller dosages, for examples
`1 to 4 times a day, and preferably 1 to 3 times a day, and administrated over about a
`
`24 hourstime period to reach a total given dosage. Bests results have been obtained
`
`with an administration of a compositions of the invention are twice a day for children;
`
`and 5 mg once a day for adults. The exact dosages in which the compositions are
`administrated can vary according to the type of use, the modeof use, the requirements
`of the patient, as determined by a skilled practitioner. The exact dosage for a patient
`may be specifically adapted by a skilled person in view of the severity of the condition,
`
`10
`
`the specific formulation used, and other drugs which may beinvolved.
`
`Pharmaceutical compositions used according to the present invention may be
`
`administered by any conventional means. The routes of administration include
`
`intradermal, transdermal, slow release administration, intramuscular, oral and
`
`intranasal routes. Any other convenient route of administration can be used, for
`
`15
`
`example absorption through epithelial or mucocutaneouslinings.
`
`The pharmaceutical forms according to the present invention may be prepared
`according to conventional methods used by pharmacists. The forms can be
`
`administered together with other components orbiologicaly active agents,
`pharmaceutically acceptable surfactants, excipients, carriers, diluents and vehicles.
`
`20
`
`The pharmaceutical compositions of the invention include any conventional
`
`therapeutical inert carrier. The pharmaceutical compositions can contain inert as well
`
`as pharmacodynamically active additives. Liquid compositions can for example take
`the form of a sterile solution which is miscible with water. Furthermore, substances
`
`conventionally used as preserving, stabilizing, moisture-retaining, and emulsifying
`
`25
`
`agents as well as substances such as salts for varying the osmotic pressure,
`
`substances for varying pH such as buffers, and other additives can also be present. If
`
`desired an antioxidant can be included in the pharmaceutical compositions.
`
`30
`
`Pharmaceutical acceptable excipients or carriers for compositions include saline,
`buffered saline, dextrose or water. Compositions may also comprise specific stabilizing
`agents such as sugars, including mannose and mannitol. Carrier substances and
`diluents can be organic or inorganic substances, for example water, gelatine, lactose,
`starch, magnesium stearate, talc, gum arabic, polyalkylene glycol and thelike. A
`
`prerequisite is that all adjuvants and substances used in the manufacture of the
`
`pharmaceutical compositions are nontoxic.
`
`35
`
`Pharmaceutical compositions can be administered by spray inhalation. Any
`
`conventional pharmaceutical composition for spray inhalation administration may be
`
`used. Another preferred mode of administration is by aerosol.
`
`Apotex, Inc. (IPR2019-00400), Ex. 1007, p. 004
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`Apotex, Inc. (IPR2019-00400), Ex. 1007, p. 004
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`WO 2004/050094
`
`PCT/EP2003/005491
`
`4
`
`The pharmaceutical composition of the invention can also be formulated for
`
`topical application. The composition for topical application can be in the form of an
`
`aqueoussolution, lotion or jelly, an oily solution or suspension or a fatty or emulsion
`
`ointment.
`
`The pharmaceutical composition of the invention can also be used for slow
`
`prolonged release with a transdermal therapeutic system in polymer matrix or with an
`
`appropriate formulation for oral slow release.
`
`The pharmaceutical compositions according to the present invention may also
`
`be administered orally or rectally. They may also be administered by nasal instillation,
`
`10
`
`aerosols or in the form of unguents or creams. The pharmaceutical compositions
`
`which can be used for oral administration may be solid or liquid, for example, in the
`
`form of uncoated or coated tablets, pills, dragees, gelatine capsules, solutions, syrups
`
`and thelike. For administration by the rectal route, the compositions containing the
`
`compoundsof the present invention are generally used in the form of suppositories.
`
`15
`
`The pharmaceutical forms, such as tablets, drops, suppositories and thelike,
`
`are prepared by conventional pharmaceutical methods. The compoundsof the present
`
`invention are mixed with a solid or liquid, non-toxic and pharmaceutically acceptable
`
`carrier and possibly also mixed with a dispersing agent, a disintegration agent, a
`
`stabilizing agent and the like. If appropriate, it is also possible to add preservations,
`
`20
`
`sweeteners, coloring agents andthelike.
`
`Preferably, the pharmaceutical compositions of the invention is administered in
`
`traditional form for oral administration, as film coated tablets, lozenges, dragees, and
`
`oral liquid preparation such as syrup.
`
`Best results have been obtained with an oral dosage form, in particular liquid
`
`25
`
`formulations such as syrup for children, and film-coated tablet for adults. For
`
`example, patients can receive 2 doses of 0,25 mg/kg (total daily dose : 0,50
`
`mg/kg/day) of an oral solution of levocetirizine dihydrochloride 10 mg/ml per day; one
`
`mi of the solution contains 20 drops and onedrop oflevocetirizine dihydrochloride
`
`solution contains 0,5 mg.
`
`30
`
`As an Example of a composition according to the present invention, the
`
`following formulation of a film coated tablet is preferred: levocetirizine dihydrochloride,
`
`magnesium stearate, cellulose, lactose and silicon dioxide.
`
`As an Example of a composition according to the present invention, the
`
`following formulation of a syrup is preferred: levocetirizine dihydrochloride, methyl-
`
`35
`
`and propylparaben, saccharinum, and purified water.
`
`Pharmaceutical compositions of the invention are useful to treat the persistent
`
`allergic rhinitis. These compositions can alleviate the effects of the persistent allergic
`
`rhinitis.
`
`Apotex, Inc. (IPR2019-00400), Ex. 1007, p. 005
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`Apotex, Inc. (IPR2019-00400), Ex. 1007, p. 005
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`WO 2004/050094
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`PCT/EP2003/005491
`
`Another advantage of the invention is the ability of the process to improve
`
`quality of life and all symptomsof persistent allergic rhinitis.
`
`The method of the invention is believed particularly suited to use in patients
`
`susceptible to suffer from persistent allergic rhinitis.
`
`Another advantage of the invention is that levocetirizine dihydrochloride has an
`
`effect on rhinitis up to 6 months.
`
`It is shown that levocetirizine dihydrochloride has an effect on quality of life up
`
`to 6 months.
`
`It is shown that levocetirizine dihydrochloride has an effect on nasal congestion
`
`10
`
`after 3 months.It lasts through 3 months.
`
`The invention is further defined by reference to the following example.
`
`Example
`
`The aim of the study relative to the clinical effect of levocetirizine
`
`dihydrochloride was to establish on the intention to treat (ITT population) whether a 6
`
`15
`
`month levocetirizine dihydrochloride treatment can improve the quality of life and
`
`clinical symptoms from adult patients suffering from persistentallergic rhinitis, when
`
`compared to placebo. For clinical symptoms,it was considered that a 1 point score
`
`reduction is clinically relevant. For health-related quality oflife, it was considered that
`
`a 0.36 point score reduction is relevant. Secondary parameters of efficacy included
`
`20
`
`different durations of treatment, different symptoms,different quality oflife
`
`questionnaires, the incidence of co-morbidities suspected to be linked to allergic
`
`rhinitis and pharmaco-economic variables. The safety of this long-term treatment with
`
`levocetirizine dihydrochloride has also been evaluated.
`
`Thetarget population of this example consisted of adults aged more than 18
`
`25
`
`years suffering from persistent allergic rhinitis [WHOInitiative on Allergic Rhinitis and
`
`its Impact on Asthma (ARIA), 2000, pages S147-S149]. To be enrolled, the subjects
`
`needed to have sufficient rhinitis symptoms during the selection period. Excluded
`
`were patients with ENT or eye infection during the 2-weeks precedinginitial visit.
`
`The study was a prospective, randomized, double blind, parallel group, and
`
`30
`
`placebo-controlled study with levocetirizine dihydrochloride.
`
`The severity of clinical symptoms wasrated by the T5SS (sneezing, rhinorrhea,
`
`nasal pruritus, ocular pruritus and nasal congestion) evaluated each by a score from
`
`0 to 3. The impact on health related quality of life was measured using the
`
`Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) (E. JUNIPER and G.H.
`
`35
`
`GUYATT, Development and testing of a new measure of health statusfor clinical trials
`
`in rhinoconjunctivitis, Clinical and Experimental Allergy 1991; 21:77-83; E. JUNIPER,
`
`Measuring Health Related Quality of Life in rhinitis, J. Allergy Clin. Immunol. 1997;
`
`99:5742-9).
`
`Apotex, Inc. (IPR2019-00400), Ex. 1007, p. 006
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`Apotex, Inc. (IPR2019-00400), Ex. 1007, p. 006
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`WO 2004/050094
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`Study treatment lasted for 6 months. After the treatmentperiod, patients
`
`entered a 1-week follow-up period.
`
`The primary end-point for efficacy was a decrease of the T5SSoverthefirst 4
`
`weeksof at least 1 unit of score. The primary end-point for quality oflife was a
`
`decrease of RQLQ after 4 weeks of at least 0.36 unit of the total score.
`
`Secondary parameters of efficacy included the mean TS5SS, the RQLQ and the
`
`SF-36 questionnaire at the different time points of the study, and the incidence and
`
`the duration of rescue medication over 6 months.
`
`Exploratory parameters of efficacy included the mean of each individual
`
`10
`
`rhinitis score, each RQLQ domain and each scale of the SF-36 questionnaire at the
`
`different time points of the study, the Global Evaluation Scale after 4 weeks and 6
`
`months, the incidence of co-morbidities suspected to be linked to allergic rhinitis and
`
`the pharmaco-economic direct and indirect costs over 6 months.
`
`At each of the eightvisits, diary book entries (T5SS, ROLQ, SF-36, indirect cost
`
`15
`
`pharmaco-economic parameters, concomitant medication, outpatient consultations
`
`and adverse events) were verified and transferred into the Clinical Record Form and
`
`direct cost pharmaco-economic parameters were recorded. Patients underwent a
`
`physical examination, including the measurementofvital signs. At the beginning and
`
`at the end of the study they also underwenta safety lab test, including pregnancy test
`
`20
`
`for females, and at Visits 4 and 7, they filled-in a Global evaluation scale.
`
`Adverse events were recorded by the patients on diary cards and discussed
`
`with the investigator at each visit. Serious adverse events had to be reported
`
`immediately.
`
`Oral tablets of levocetirizine dihydrochloride (5 mg) and matching placebo,
`
`25
`
`similar in appearance, shape and taste were used. The recommended study dosage
`
`was 1 tablet per day.
`
`Sample size was based on 40% relative improvement over placebo in the RQLQ
`
`questionnaire, assuming an improvement from baseline for placebo of 0.9. For this
`
`questionnaire this correspondsto a difference of 0.36 vs. placebo.
`
`30
`
`The baseline characteristics of the two treatment groups, including
`
`demographic data, were comparable.
`
`The study showsthat treatment with levocetirizine dihydrochloride improves
`
`the symptomsof persistent allergic rhinitis (Difference of T5SS overthefirst 4 weeks:
`
`1.14, p < 0.001; this difference being maintained over the whole study period) and the
`
`35
`
`QOL(Change from baseline of the ROLQ Overall Score at first 4 weeks: 0.48,
`
`p < 0.001; this difference being maintained over the whole study period). A
`
`statistically significant improvement is also observed at all time points for sneezing,
`
`rhinorrhea, nasal pruritus and ocular pruritus. In addition, an improvement of nasal
`
`Apotex, Inc. (IPR2019-00400), Ex. 1007, p. 007
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`Apotex, Inc. (IPR2019-00400), Ex. 1007, p. 007
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`WO 2004/050094
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`PCT/EP2003/005491
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`7
`
`obstruction is observed, which becomesstatistically different from 3 months onwards
`(Difference vs. placebo: 0.15, p = 0.009). Moreover, the long-term administration of
`levocetirizine did not involve particular safety concerns.
`
`This study provides evidenceof activity of levocetirizine in persistent allergic
`rhinitis. Levocetirizine is shown to be active on nasal obstruction after a long term
`treatment (equal or more than 3 months).
`
`Table I
`
`Mean T5S5 overthe first four weeks of treatment
`
`10
`
`(ITT population)
`
`
`
`Baseline
`(SD)
`Adjusted
`Diff. vs.
`
`
`
`placebo®)
`
`mean® (SE)
`Mean
`
`
`
`
`Placebo (0.15) sararexs)!coon8.90 2.26)| 6.61 2.47)| 6.56
`
`
`
`
`
`Ietz 5mg [276] (0.15)| 1.14 [0.75, 1.52]|< 0.0019.02 (2.28)| 5.53 (2.52)| 5.43
`
`
`
`
`
`
`
`
`
`
`
`p-value)
`
`(95 % CD
`
`
`
`
`
`Mean adjusted for baseline score and country.
`
`()) Placebo minuslevocetirizine dihydrochloride (Lctz) 5mg.
`
`() p-value was obtained from an ANCOVAwith baseline score as covariate and
`
`15
`
`country and treatmentas factors.
`
`In table I it is shown that treatment with levocetirizine dihydrochloride
`
`improves the symptoms of persistent allergic rhinitis.
`
`20
`
`TableII
`
`Change from baseline of the RQLQ Overall Score after first 4 weeks of treatment
`
`(ITT population)
`
`
` |STBaseline_|Change
`Treatment] N Mean (SD)|Mean® (SE) placebo®) p-value®)
`
`(95 % CD
`
`
`
`
`
`
`
`
`
`Q© Ol E
`g
`
`
`|257| 3.04 (0.92)|-1.50 (1.18)|
`
`(0.07)| 0.48 [0.29, 0.67]}]
`-1.49
`
`
`< 0.001
`
`‘ Mean adjusted for baseline score and country.
`
`25
`
`(>) Placebo minus levocetirizine dihydrochloride 5mg.
`
`() p-value was obtained from an ANCOVA with baseline score as covariate and
`
`country and treatmentas factors.
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`Apotex, Inc. (IPR2019-00400), Ex. 1007, p. 008
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`Apotex, Inc. (IPR2019-00400), Ex. 1007, p. 008
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`WO 2004/050094
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`PCT/EP2003/005491
`
`In tableII it is shown that treatment with levocetirizine dihydrochloride
`
`improves the quality oflife.
`
`Table Til
`
`Nasal congestion symptoms evaluated over the 24 hours,
`
`over the first week and first 4 weeks, 3, 4.5 and 6 months of treatment
`
`(ITT population)
`
`
`
`
`
`
`
`
`
`Leitz 5 mg|271/1.90 (0.69)} (0.04)|0.07 [-0.04; 0.18]|0.2031.61 (0.83)] 1.58
`
`Adjusted
`
`Diff. vs.
`
`-
`
`
`Mean Mean 5)|5% cno(SD)
`
`Baseline
`
`
`
`
`
`
`
`
`
`
`
`4 weeks Letz 5mg|276 (0.04)|0.08 [-0.02; 0.19]|0.12311.91 (0.69)| 1.44 (0.78)| 1.40
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`4.5months|Pi8eeo 270|1.85 (©.04)0.1510.04;0.261|0.007(0.71)| 1.29 (0.74)| 1.27.
`Letz 5 mg|276 (0.04)|0.15 [0.04; 0.26]|0.007{1.91 (0.69)| 1.17 (0.77)| 1.11
`
`
`
` 6 months 270|1.85 6.005|Leiz 5mg|276 (0.71)| 1.26 (0.74)| 1.24 (0.04)
`
`
`
`
`
`
`
`
`}1.91 (0.69)}1.13 0.16 [0.05;0.27]|0.005(0.76)} 1.08 (0.04)}
`10
`
`
`
`
`
`
`
`
`
`
`
`
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`
`
`Leiz 55mg|276/]1.91 (0.69)} 1.16—(0.04)} 0.15 [0.04; 0.26]|0.0091.22 (0.78)|
`
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`
`@) On study Mean adjusted for baseline score and country.
`
`) Placebo minuslevocetirizine dihydrochloride.
`
`() p-value was obtained from an ANCOVA with baseline score as covariate and
`
`country and treatmentas factors.
`
`15
`
`In table Iit is shown that levocetirizine dihydrochloride is shown to be active
`
`on nasal obstruction after a long term treatment.
`
`The following abbreviations are used in the example:
`
`TS5SS
`
`Total 5 Symptoms Score
`
`20
`
`25
`
`30
`
`IIT
`
`N
`
`SD
`
`SE
`
`Diff.
`
`vs.
`
`CI
`
`P
`
`Intention-to-Treat
`
`Number
`
`Standard Deviation
`
`Standard Error of the Mean
`
`Difference
`
`versus
`
`Confidence Interval
`
`probability that the observed difference is only by chance
`
`RQLQ
`
`Rhinoconjunctivitis Quality of Life Questionnaire
`
`ANCOVA
`
`Analysis of Covariance
`
`ENT
`
`SF-36
`
`Letz
`
`Ear-Nose-Throat
`
`Medical Outcomes Survey Short Form 36
`
`levocetirizine dihydrochloride.
`
`Apotex, Inc. (IPR2019-00400), Ex. 1007, p. 009
`
`Apotex, Inc. (IPR2019-00400), Ex. 1007, p. 009
`
`

`

`WO 2004/050094
`
`PCT/EP2003/005491
`
`A long duration of effect is noted. The positivity of the trial is due to the lack of
`
`tachyphylaxis, i.e there’s no "adjustement" of the dosing schedule needed during 6
`
`months. The recommended dosageis effective constantly throughoutthetrial.
`
`An improvement of quality of life (QoL) is clearly noted during the trial. It is
`
`central to ARIA. This is the first time that a drug is able to change the QoL of patients
`
`for such a long duration. This is as close as possible to a "disease modifying"effect.
`
`Nasal congestion is treated during the trial. Interestingly, nasal congestion is a
`
`symptom relief that appear duringthetrial, i.e the effect is gradual, this is congruent
`
`with the observation that QoL is improving.
`
`10
`
`It is demonstrated that levocetirizine dihydrochloride is able to treat persistent
`
`rhinitis as long as it is administered, but also able to modify daily activities of patients,
`
`going beyond the simple symptom relief observed in short duration trials so far.
`
`Apotex, Inc. (IPR2019-00400), Ex. 1007, p. 010
`
`Apotex, Inc. (IPR2019-00400), Ex. 1007, p. 010
`
`

`

`WO 2004/050094
`
`PCT/EP2003/005491
`
`10
`
`CLAIMS
`
`1.
`
`Use oflevocetirizine or a pharmaceutically acceptable salt thereof for the
`
`preparation of a medicament intended for treating the persistent allergic
`rhinitis.
`
`2.
`
`Use oflevocetirizine or a pharmaceutically acceptable salt thereof for the
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`8.
`
`9.
`
`10
`
`15
`
`20
`
`25
`
`preparation of a medicament intended for decreasing the symptomsof
`
`persistent allergic rhinitis and improving the quality oflife.
`
`Useoflevocetirizine or a pharmaceutically acceptable salt thereof for the
`preparation of a medicament intended for treating the rhinorrhea.
`
`Useoflevocetirizine or a pharmaceutically acceptable salt thereof for the
`
`preparation of a medicament intended for treating the nasal obstruction.
`
`Use oflevocetirizine or a pharmaceutically acceptable salt thereof for the
`
`preparation of a medicament intended for treating the nasal itching.
`
`Use oflevocetirizine or a pharmaceutically acceptable salt thereof for the
`
`preparation of a medicament intended for treating the sneezing.
`Useoflevocetirizine or a pharmaceutically acceptable salt thereof for the
`
`preparation of a medicament intendedfor treating the ocular pruritis.
`
`Use according to any one of claims 1 to claim 7, wherein the salt is the
`
`levocetirizine dihydrochloride.
`
`Use according to any one of claims 1 to 8, wherein the medicamentis adapted
`for administration of a daily dosage from about 0,0005 mg to about 2 mg of
`said levocetirizine or said pharmaceutically acceptable salt thereof, per kg of
`body weightper patient.
`
`Apotex, Inc. (IPR2019-00400), Ex. 1007, p. 011
`
`Apotex, Inc. (IPR2019-00400), Ex. 1007, p. 011
`
`

`

`Domingues, H
`
`"Xyzal (Levocetirizine) Jaunched in
`England for Allergic Rhinitis"
`INTERNET,
`‘Online!
`1 October 2001 (2001-10-01), XP002240083
`Retrieved from the Internet:
`<URL: http://www. psigroup.com/dg/207766.htm
`http: //www.pslgroup.com/dg/207766.htm>
`‘retrieved on 2003-05-05!
`the whole document
`
`_-/--
`
`Further documents are listed in the continuation of box C.
`
`Patent family membersarelisted in annex.
`
`° Special categories of cited documents:
`
`"A" documentdefining the general state of the art which is not
`consideredto beof particular relevance
`“E" earlier document but published onor after the international
`filing date
`"L" document which may throw doubts onpriority claim(s) or
`whichis cited to establish the publication date of another
`citation or other special reason (as specified)
`"O" documentreferring to an oraldisclosure, use, exhibition or
`other means
`
`"P" documentpublishedpriorto the international
`later than thepriority date claimed
`
`filing date but
`
`"T" later document published after the internationalfiling date
`or priority date and not in conflict with the application but
`cited to understandthe principle or theory underlying the
`invention
`
`"X" documentof particular relevance; the claimed invention
`cannotbe considered novel or cannot be considered to
`involve an inventive step when the documentis taken alone
`"¥" documentof particular relevance; the claimed invention
`cannot be consideredto involve an inventive step when the
`documentis combined with one or more other such docu-
`ments, such combination being obvious to a personskilled
`in
`the art.
`“&" document memberof the samepatentfamily
`
`Date of the actual completion of the international search
`
`Date of mailing of the international search report
`
`15 September 2003
`
`Name and mailing address of the ISA
`European Patent Office, P.B. 5818 Patentlaan 2
`NL - 2280 HV Rijswijk
`Tel. (431-70) 340-2040, Tx. 31 651 eponl,
`Fax: (+31-70) 340-3016
`
`Form PCT/ISA/210 (second sheet) {July 1992)
`
`23/09/2003
`
`Authorized officer
`
`Apotex, Inc. (IPR2019dg@400)F 2x. 1007, p. 012
`
`INTERNATIONAL SEARCH REPORT
`
`Intern
`al Application No
`PCT/EP 03/05491
`
`A I
`
`CLASSIFICATION OFS'
`BJECT MATTER
`A61K31/495
`A61P37/00
`PC 7
`
`Accordingto International Patent Classification (IPC) or to both nationalclassification and IPC
`B. FIELDS SEARCHED
`
`Minimum documentation searched (classification system followedbyclassification symbols)
`IPC 7
`A61K A6I1P
`
`Documentation searched other than minimum documentation to the extent that such documentsare included in the fields searched
`
`Electronic data base consulted during the international search (name of data base and, wherepractical, search terms used)
`
`EPO-Internal, MEDLINE, BIOSIS, EMBASE, CHEM ABS Data
`
`Cc. DOCUMENTS CONSIDERED TO BE RELEVANT
`
`Category °
`
`Citation of document, with indication, where appropriate, of the relevant passages
`
`WO 94 06429 A (SEPRACOR INC)
`31 March 1994 (1994-03-31)
`cited in the application
`page 1-7
`page 15
`page 20 -page 21
`
`Relevant to claim No.
`
`1-9
`
`Apotex, Inc. (IPR2019-00400), Ex. 1007, p. 012
`
`

`

`Category °|Citation of document, with indication,where appropriate, of the relevant passages
`
`"Germany Approves Antihistamines Xyzal"
`INTERNET,
`‘Online!
`16 January 2001 (2001-01-16), XP002240084
`Retrieved from the Internet:
`<URL: http://www. pslgroup.com/dg/lefc66.htm
`http: //www.pslgroup.com/dg/lefc66. htm>
`‘retrieved on 2003-05-05!
`the whole document
`
`
`
`Interng
`al Application No
`INTERNATIONAL SEARCH REPORT
`PCT/EP 03/05491
`
`
`
`C.(Continuation) DOCUMENTS CONSIDERED TO BE RELEVANT
` Relevantto claim No.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Form PCT/ISA/210 (continuation of second sheet) (July 1992)
`
`Apotex, Inc. (IPR2019QQ4000F Ex. 1007, p. 013
`
`"Levocetirizine:
`GENSTHALER BM:
`R-enantiomer against allergies"
`PHARMAZEUTISCHE ZEITUNG,
`vol. 146, no. 7,
`15 February 2001 (2001-02-15), pages
`35-36, XP001147797
`page 35
`page 35 -page 36
`
`"A double-blind,
`GRANT J ANDREW ET AL:
`randomized, single-dose, crossover
`comparison of levocetirizine with
`ebastine, fexofenadine,
`loratadine,
`mizolastine, and placebo: suppression of
`histamine-induced wheal-and-flare response
`during 24 hours in healthy male subjects."
`ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY:
`OFFICIAL PUBLICATION OF THE AMERICAN
`COLLEGE OF ALLERGY, ASTHMA, & IMMUNOLOGY.
`UNITED STATES FEB 2002,
`vol. 88, no. 2, February 2002 (2002-02),
`pages 190-197, XP009010299
`ISSN: 1081-1206
`abstract
`page 195 -page 196
`
`"Lack of effect of
`GANDON J M ET AL:
`single and repeated doses of
`levocetirizine, a new antihistamine drug,
`on cognitive and psychomotor functions in
`healthy volunteers.”
`BRITISH JOURNAL OF CLINICAL PHARMACOLOGY,
`vol. 54, no. 1, July 2002 (2002-07), pages
`51-58, XP002240086
`=bjcp July, 2002
`ISSN: 0306-5251
`abstract
`page 52
`page 56 -page 58
`
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`
`Apotex, Inc. (IPR2019-00400), Ex. 1007, p. 013
`
`

`

`INTERNATIONAL SEARCH REPORT
`
` Intern;
`
`al Application No
`
`PCT/EP 03/05491
`
`Patent document
`cited in search report
`
`Publication
`date
`
`Patent family
`member(s)
`
`
`Publication
`date
`
`WO 9406429
`
`A
`
`31-03-1994
`
`
`
`
`
`
`
`15-09-1998
`170749 T
`12-04-1994
`4932093 A
`07-10-1999
`711212 B2
`21-05-1998
`5934398 A
`31-03-1994
`2145410 Al
`15-10-1998
`69320975 Di
`12-05-1999
`69320975 T2
`07-06-1999
`663828 T3
`
`26-07-1995
`0663828 Al
`
`20-10-1999
`0950412 A2
`
`16-12-1998
`2122042 T3
`
`20-02-1996
`8501561 T
`
`08-04-2002
`90898 AQ
`
`31-03-1994
`9406429 Al
`
`16-12-1997
`5698558 A
`
`
`
`
`Form PGT/SA/210 (patent family annex) (July 1992)
`
`Apotex, Inc. (IPR2019-00400), Ex. 1007, p. 014
`
`Apotex, Inc. (IPR2019-00400), Ex. 1007, p. 014
`
`