(19)
`
`(12)
`
`Europäisches Patentamt
`
`European Patent Office
`
`Office européen des brevets
`
`*EP001321142A1*
`EP 1 321 142 A1
`
`(11)
`
`EUROPEAN PATENT APPLICATION
`
`(43) Date of publication:
`25.06.2003 Bulletin 2003/26
`
`(21) Application number: 01403339.3
`
`(22) Date of filing: 21.12.2001
`
`(51) Int Cl.7: A61K 31/404, A61K 9/20
`
`(84) Designated Contracting States:
`AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU
`MC NL PT SE TR
`Designated Extension States:
`AL LT LV MK RO SI
`
`(72) Inventors:
`• Vitzling, Christian, c/o Novartis AG
`4000 Basel (CH)
`• Aubert, Jérome, c/o Novartis AG
`4000 Basel (CH)
`
`(71) Applicant: Novartis AG
`4056 Basel (CH)
`
`(54)
`
`Solid pharmaceutical composition for oral administration of Tegaserod
`
`(57)
`A solid pharmaceutical composition for oral adminstration comprising tegaserod in base or salt form in an
`amount of up to 10% by weight a bulking agent in an amount of 70 to 90% by weight a disintegrant in an amount of
`less than 14% by weight a glidant and a lubricant,
`
`Printed by Jouve, 75001 PARIS (FR)
`
`EP1 321 142A1
`
`1
`
`EX 1005
`IPR of U.S. Pat. No. 7,829,595
`
`

`
`1
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`EP 1 321 142 A1
`
`2
`
`Description
`
`Field of the invention
`
`troporesis and chronic constipution.
`[0008] A preferred agent is tegaserod, a 5-HT4 partial
`agonist of formula
`
`[0001] The present invention relates to pharmaceuti-
`cal compositions, in particular to compositions for ad-
`ministering a 5-HT4-receptor partial agonist as active
`agent. More particularly, the present invention relates to
`pharmaceutical compositions for administering tegase-
`rod and to processes for manufacturing such composi-
`tions.
`
`Background of the invention
`
`[0002] Tegaserod (3-(5-methoxy-1H-indol-3-yl-meth-
`ylene)-N-pentylcarbazimidamide) or a pharmaceutically
`acceptable salt thereof is known from EP 505322 and
`under the trade marks ZELMAC and ZELNORM. Pub-
`lished PCT Application WO 00/10526 describes tegas-
`erod compositions, e.g. solid oral pharmaceutical com-
`positions and use in anal incontinence.
`[0003] Despite the merits of the above-mentioned
`compositions, there remains a need for more economic
`and stable compositions which can be formulated effec-
`tively.
`
`Summary of the invention
`
`[0004]
`In one aspect this invention provides a solid
`pharmaceutical composition for oral adminstration com-
`prising
`a 5-HT4 partial agonist in base or salt form in an
`amount of up to 10% by weight,
`a diluent in an amount of 70 to 90% by weight, and
`the disintegrant in an amount of less than 15% by
`weight,
`wherein the amounts by weight are based on the
`total weight of the composition.
`[0005] The term "disintegrant" is understood to mean
`a substance or mixture of substances which facilitates
`disintegration of the composition after administration in
`order that the active ingredient be released from the
`composition as efficiently as possible to allow for its rap-
`id dissolution (see e.g. "Remington's Pharmaceutical
`Science" 18th edition (1990). The Theory and Practice
`of Industrial Pharmacy" Lachman et al. Lea & Febiger
`(1970)).
`[0006] The active agent used in compositions accord-
`ing to the present invention is a serotonergic active
`agent acting on the gastro-intestinal system as partial
`agonist of the 5-HT4 receptor. It is poorly soluble and
`acid sensitive and preferably in salt form, e.g., hydrogen
`maleate or hydrochloride or in free form.
`[0007]
`5-HT4 receptor partial agonists are useful for
`the prevention and treatment of gastro-intestinal motility
`disorders, e.g., Irritable Bowel Syndrome (IBS), Gastro-
`Esophageal Reflux Disease (GERD), Functional Dys-
`pepsia (FD), Post Operative Ileus (POI), Diabetic gas-
`
`5
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`10
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`15
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`20
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`25
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`30
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`40
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`2
`
`or pharmaceutically acceptable salt form thereof, e.g.
`the hydrogen maleate (hereinafter "hml") salt. Tegaser-
`od has a solubility of about 0.02% at 25°C in water and
`is acid sensitive. We have found that compositions
`thereof may be produced which provide good absorp-
`tion even in the stomach.
`[0009]
`In one embodiment, the composition of the in-
`vention comprises less than 15%, e.g. less than 14% or
`12% or less, e.g. 10% or less, e.g. 5 to 10% by weight
`of disintegrant based on the total weight of the compo-
`sition. We have observed that the use of such a small
`percentage of disintegrant
`improves the dissolution
`rate.
`[0010] The diluent may comprise lactose, mannitol,
`sucrose, calcium sulphate, calcium phosphate or micro-
`crystalline cellulose (MCC USP (AvicelTM PH-102,
`FMC Corp.) The diluent may be present in an amount
`from 50 to 90 %, preferably from 70 to 90 % more pref-
`erably from 75 to 85%. Preferably the diluent is lactose
`consisting of α-lactose monohydrate and amorphous
`material (Spray dried lactoseTM, Formost Corp.).
`[0011] As disintegrant the composition of the present
`invention may comprise:
`
`-
`
`-
`
`crospovidone (molecular weight >106 Daltons), e.
`g. Polyplasdone XL®, Kollidon CL®, Polyplasdone
`XL-10®,
`pregelatinized starch (MW 30000-120000 Daltons),
`e.g., starch 1500™ (Colorcon UK).
`
`[0012] Preferably, the disintegrant Is crospovidone
`which is preferably water insoluble. Ideally the disinte-
`grant rapidly exhibits high capillary or pronounced hy-
`dration capacity with little tendency to gel formation.
`The particle size of the disintegrant may be from about
`1 to 500 micrometers. A preferred particle size distribu-
`tion is from 10 to 400 e.g. less than 400 micrometers, e.
`g., for Polyplasdone XL® less than 80 micrometers, e.
`g., less than 74 micrometers for, e.g., Polyplasdone XL-
`10®, approximately 50% greater than 50 micrometers
`and maximum of 1% greater than 250 micrometers in
`size for, e.g., Kollidon CL®. A preferred crospovidone is
`Polyplasdone XL®, e.g., with a density of about 0.213
`
`2
`
`

`
`3
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`EP 1 321 142 A1
`
`4
`
`g/cm3 (bulk) or 0.273 g/cm3 (tapped).
`[0013] The composition of the present invention may
`further comprise a glidant e.g. Colloidal silicon dioxide
`(Aerosil, Degussa).
`[0014] The composition may further comprise one or
`more lubricants, e.g., in an amount within the range of
`from 3 to 7%, e.g. from 4 to 6% by weight of the com-
`position.
`[0015] Examples of such lubricants include:
`
`- magnesium stearate (Faci),
`-
`sodium benzoate
`-
`glyceryl mono fatty acid, e.g. having a molecular
`weight of from 200 to 800 Daltons e.g. gylceryl mon-
`ostearate (e.g., Danisco, UK),
`glyceryl dibehenate (e.g., CompritolATO888™,
`Gattefossé France)
`glyceryl palmito-stearic ester (e.g. Precirol™, Gat-
`tefossé France)
`polyoxyethylene glycol (PEG, BASF)
`hydrogenated cotton seed oil (Lubitrab, Edward
`Mendell Co Inc),
`castor seed oil (Cutina HR, Henkel)
`
`-
`
`-
`
`-
`-
`
`-
`
`[0016]
`In a preferred embodiment the lubricant is glyc-
`eryl dibehenate. We have observed that the use of glyc-
`eryl dibehenate improves lubrication properties and
`avoids tablet adhesion.
`[0017] Further there is no or negligible impact on te-
`gaserod in vitro dissolution rate and tablet disintegration
`of the composition.
`[0018] The composition of the invention may com-
`prise one or more binders, e.g., in an amount in the
`range of from 1 to 10%, e.g., 2 to 8%, e.g. 3% by weight.
`Particularly the following binders may be used:
`
`-
`
`-
`-
`
`(HPMC2910,
`cellulose
`hydroxy-propyl-methyl
`Pharmacoat603TM, Shin-Etsu Chemical Co Ltd)
`copolyvidone (KollidonTM VA64, BASF)
`potato starch, wheat starch, com starch, e.g., hav-
`ing a molecular weight of from 30000 to 120000,
`
`or a mixture thereof.
`[0019] Other conventional exciplents which may op-
`tionally be present in the composition of the invention
`include preservatives, stabilisers, anti-adherents or sil-
`ica flow conditioners or glidants, e.g., silicon dioxide (e.
`g., Syloid®, Aerosil®) as well as FD&C colours such as
`ferric oxides.
`[0020] Other excipients disclosed in the literature, as
`for instance in Fiedler's "Lexicon der Hilfstoffe", 4th Edi-
`tion, ECV Aulendorf 1996 and "Handbook of Pharma-
`ceutical Excipients" Wade and Weller Ed.(1994), the
`contents of which are incorporated herein by reference,
`may be used in the pharmaceutical compositions ac-
`cording to the invention.
`[0021] A preferred composition of the invention may
`comprise from about 0.5 to 15% by weight of tegaserod,
`
`less than 15 % by weight of disintegrant e.g. crospovi-
`done, from 3 to 7% by weight of lubricant, e.g. glyceryl
`dibehenate, from 50 to 90% by weight of diluent, e.g.
`lactose, from 0.1 % to 1% by weight of glidant and op-
`tionally from 1 to 10% of binder, e.g. hydroxypropylme-
`thyl cellulose (HPMC)
`[0022] The compositions of this invention may be free
`or substantially free of surfactant.
`[0023]
`In a further aspect the present Invention pro-
`vides an oral, e.g. tablet composition comprising the ac-
`tive agent tegaserod.
`[0024] Daily dosages required in practising the meth-
`od of the present invention will vary depending upon, for
`example the mode of administration and the severity of
`the condition to be treated. An indicated daily dose is in
`the range of from about 1 to about 30 mg of active agent
`for oral use, conveniently administered once or in divid-
`ed dosages.
`[0025]
`In one embodiment the present invention pro-
`vides a round shaped tablet with a diameter of 6 to 9
`mm, preferably 7 mm.
`[0026]
`In a further aspect the present invention pro-
`vides a process for the production of the compositions
`of the invention. The compositions of the invention may
`be prepared by working up active agent with excipients.
`The following processes A,B and C are contemplated:
`
`5
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`20
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`25
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`Process A
`
`30
`
`[0027] The composition of the invention may be ob-
`tained by
`
`(i) preparing a mixture of tegaserod, diluent and lu-
`bricant,
`(ii) sieving the mixture
`(iii) adding the disintegrant, glidant, lubricant and
`optionally binder and blending the sieved mixture of
`step (ii) and
`(iv) forming tablets by direct compression.
`
`[0028] Part of the lubricant may be added in mixture
`of step (i), the rest in the final mixture of step (iii) or the
`total amount of lubricant may be added in the final mix-
`ture of step (iii).
`[0029] The resulting powder blends of step iii) are
`compressed on either a single punch press (Korsh
`EKO), 6 station-rotary press (Korsh PH106), 17 station-
`rotary press (Korsh PH 230) or 43 station-rotary press
`(Fette PT2090).
`[0030] All components may be mixed together, sieved
`through and mixed again. Tablets are then formed by
`direct compression.
`
`Process B
`
`[0031] The compositions of the invention may be ob-
`tained by
`
`35
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`3
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`

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`5
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`EP 1 321 142 A1
`
`6
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`(i) preparing a mixture of Tegaserod and diluent,
`(ii) sieving the mixture,
`(iii) adding the disintegrant, glidant and optionally
`binder and blending the sieved mixture of step (ii),
`and
`(iv) adding the lubricant by spray lubrication when
`forming tablets by direct compression.
`
`[0032] A 43 station rotary press (Fette PT 2090) with
`a magnesium stearate spraying system may be conven-
`iently used to carry out step (iv).
`[0033] The components may be mixed together,
`sieved and mixed again. The lubricant is added by spray
`lubrication when the tablets are formed by direct com-
`pression.
`
`5
`
`10
`
`15
`
`Process C
`
`[0034]
`In another embodiment the compositions of
`the invention may be obtained by
`
`20
`
`This blend is sieved and the mixture is blended again.
`The resulting powder blends are compressed using a
`17 station-rotary press (Korsh PH 230) equipped with 7
`mm, round upper punches.
`
`Example 2
`
`[0039] A 6 mg tablet is prepared using the direct com-
`pression method with in situ spray lubrication.
`
`Component
`
`Quantitiy
`(125 mg tablet)
`% w/w
`
`Tegaserod maleate
`
`Lactose spray dried
`
`HPMC
`
`Crospovidone
`
`Aérosil
`
`Magnesium stearate
`
`6.65
`
`84.85
`
`3.00
`
`5.00
`
`0.50
`
`< 0.3
`
`(i) preparing a mixture of Tegaserod, diluent, disin-
`tegrant, glidant and optionally binder,
`(ii) compacting the mixture of step (i) by roller com-
`paction,
`(iii) milling the mixture of step (ii), and
`(iv) forming tablets by compression or adding the
`lubricant by spray lubrication when forming tablets
`by direct compression.
`
`[0035] Tablets may be formed by compressing the re-
`sulting powder on a single punch press (Korsh EKO), 6
`station-rotary press (Korsh PH106), 17 station-rotary
`press (Korsh PH 230), a 43 station-rotary press (Fette
`PT2090) or a 43 station rotary press (Fette PT 2090)
`with the magnesium stearate spraying system.
`[0036] Following Is a description by way of example
`only of compositions and processes of the invention.
`
`Example 1
`
`[0037] A 6 mg tablet is prepared using the direct com-
`pression method.
`
`Component
`
`Quantitiy
`(125 mg tablet)
`% w/w
`
`Tegaserod maleate
`
`Lactose spray dried
`
`Crospovidone
`
`Aérosil
`
`Compritol ATO 800
`
`6.65
`
`82.85
`
`6.00
`
`0.50
`
`4.00
`
`[0038] A blend is formed by mixing tegaserod
`maleate, lactose, crospovidone, aérosil and compritol.
`
`[0040] A blend is formed by mixing tegaserod
`maleate, lactose, crospovidone, aérosil and compritol.
`This blend and the mixture is blended again. The lubri-
`cant magnesium stearate is added by spray lubrication.
`The resulting powder blends are compressed using a
`43 station-rotary press (Fette PT 2090) equipped with 7
`mm, round upper punches.
`
`25
`
`30
`
`Example 3
`
`[0041] A 6 mg tablet is prepared using roller compac-
`tion
`
`35
`
`Component
`
`Quantitiy
`(125 mg tablet)
`% w/w
`
`Tegaserod maleate
`
`Lactose spray dried
`
`Crospovidone
`
`Aerosil
`
`Compritol ATO 888
`
`6.65
`
`76.85
`
`10.00
`
`0.50
`
`< 0.3
`
`[0042] Compositions are prepared by mixing tegase-
`rod maleate, lactose, crospovidone, aerosil and compri-
`tol. This mixture is compacted by roller compaction and
`milled. Tablets are formed by compression.
`[0043] The present invention this provides a solid oral
`pharmaceutical composition comprising a 5-HT4-recep-
`tor partial agonist and a lower amount of disintegrant
`than witherto used.
`[0044] This invention provides tegaserod composi-
`tions with fewer components than hitherto known and a
`
`40
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`45
`
`50
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`55
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`4
`
`4
`
`

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`7
`
`EP 1 321 142 A1
`
`8
`
`simple dry process without granulation. The formula-
`tions of the present invention are less hygroscopic, over-
`come adhesion problems and provide complete or sub-
`stantially complete dissolution within 30 minutes.
`
`Claims
`
`1. A solid pharmaceutical composition for oral admin-
`stration comprising
`a 5-HT4 partial agonist in base or salt form in
`an amount of up to 10% by weight,
`a diluent in an amount of 70 to 90% by weight,
`a disintegrant in an amount of less than 15%
`by weight, and
`wherein the amounts by weight are based on
`the total weight of the composition.
`
`5
`
`10
`
`15
`
`2. A composition as claimed in claim 1 wherein the
`5-HT4 partial agonist is tegaserod.
`
`20
`
`3. A composition as claimed in claim 1 or 2 further
`comprising a glidant.
`
`4. A composition as claimed in any preceding claim
`further comprising a lubricant.
`
`25
`
`5. A composition as claimed in any preceding claim
`further comprising a binder.
`
`6. A composition as claimed in any of claims 2 - 5
`wherein tegaserod is in the form of the maleate salt.
`
`7. A composition as claimed in any preceding claim
`wherein the diluent is selected from the group con-
`sisting of lactose, mannitol, sucrose, calcium phos-
`phate or microcrystalline cellulose.
`
`30
`
`35
`
`8. A composition as claimed In any preceding claim
`wherein the diluent is lactose.
`
`40
`
`9. A composition as claimed in any preceding claim
`wherein the disintegrant is present in an amount
`less than 10% by weight based on the total weight
`of the compostion
`
`10. A composition as claimed in any preceding claim
`wherein the disintegrant is crospovidone.
`
`11. A pharmaceutical composition as claimed in any of
`claims 4 to 10 claim wherein the lubricant is present
`in an amount of 3 to 7% based on the total weight
`of the composition.
`
`12. A pharmaceutical composition as claimed in any of
`claims 4 to 11 wherein the lubricant is glycerol mon-
`ostearate or glycerol behenate.
`
`45
`
`50
`
`55
`
`5
`
`13. A pharmaceutical composition as claimed in any of
`claims 3 to 12 wherein the glidant is colloidal silica
`dioxide.
`
`14. A process for the production of a composition as
`claimed In any preceding claim which process is
`carried out under substantially dry conditions using
`granulation.
`
`15. A process for the production of a composition as
`claimed in any preceding claim which process com-
`prises:
`
`(i) preparing a mixture of 5-HT4-partial agonist,
`e.g. tegaserod, diluent and lubricant,
`(ii) sieving the mixture,
`(iii) adding the disintegrant, glidant and option-
`ally binder and blending the sieved mixture of
`step (ii), and
`(iv) forming tablets by direct compression.
`
`16. A process for the production of a composition as
`claimed in claim 5 wherein the components are
`mixed with tegaserod, sieved and mixed again be-
`fore tabletting.
`
`17. A process for the production of a composition as
`claimed in any of claims 1 to 13 which process com-
`prises:
`
`(i) preparing a mixture of 5-HT4 partial agonist,
`e.g. tegaserod, and diluent
`(ii) sieving the mixture
`(iii) adding the disintegrant, glidant and option-
`ally binder and blending the sieved mixture of
`step (ii)
`(iv) adding the lubricant by spray lubrication
`when forming tablets by direct compression.
`
`18. A process for the production of a composition as
`claimed in claim 17 wherein all the components are
`mixed with tegaserod, sieved through and mixed
`again before tabletting.
`
`19. A process for the production of a composition as
`claimed in any of claims 1 to 13 which process com-
`prises:
`
`(i) preparing a mixture of 5-HT4 partial agonist
`e.g.
`tegaserod, diluent, disintegrant, glidant
`and optionally binder
`(ii) compacting the premix of step (i) by roller
`compaction
`(iii) milling the mixture of step (ii) and
`(iv) forming tablets by compression.
`
`20. A solid pharmaceutical composition for oral admin-
`stration consisting of or consisting essentially of
`
`5
`
`

`
`9
`
`EP 1 321 142 A1
`
`10
`
`tegaserod in base or salt form in an amount of up
`to10% by weight,
`a diluent in an amount of 70 to 90% by weight,
`a disintegrant in an amount of less than 15% by
`weight, e.g. 2 to 10%
`a glidant and a lubricant,
`wherein the amounts are by weight based on the
`total weight of the composition.
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
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`45
`
`50
`
`55
`
`6
`
`6
`
`

`
`EP 1 321 142 A1
`EP 1 321 142 A1
`
`European Patent
`Office
`
`Application Number
`PARTIAL EUROPEAN SEARCH REPORT
`which under Rule 45 ot the European Patent Conventiongp 01 40 3339
`shall be considered, for the purposes of subsequent
`proceedings, as the European search report
`
`DOCUMENTS CONSIDERED TO BE RELEVANT
`Citation of document with indication, where appropriate,
`of relevant Eassages
`
`NO 00 57857 A (YUHAN CORP)
`5 October 2000 (2000-10-05)
`
`line 5 - line 9 *
`* page 6,
`* page 6 — page 7; example 6 *
`* page 15; claims 1-3 *
`
`W0 00 10526 A (NOVARTIS ERFIND VERNALT
`GMBH ;NOVARTIS AG (CH); ZUEGER OTHMAR
`(CH)) 2 March 2000 (2000-03-02)
`* page 2, paragraph 4 =I=
`* page 18 ~ page 20; examples 1,2 *
`* page 25 - page 26; claims 1,2,6-11 *
`
`(:LAsslr-'lCATloN OF THE
`APPLICATION (lnt.Cl.7')
`
`A61K31/404
`A61K9/20
`
`TECHNICAL FIELDS
`SEARCHED
`(|nt.Cl.7]
`
`INCOMPLETE SEARCH
`The Search Division considers that the present application, or one or more of its claims, does/do
`not comply with the EPC to such an extent that a meaningful search into the state of the an cannot
`be canted out, or can only be carried out partially. for these claims.
`Claims searched completely :
`
`Claims searched incompletely :
`
`Claims not searched :
`
`Reason for the limitation ot the search;
`
`see sheet C
`
`Place of search
`
`Date oi completion of the search
`
`Examiner
`
`
`
` 7EPOFORM15030382(P04C07)
`
`VON EGGELKRAUT,
`17 April 2002
`THE HAGUE
`T 2 theory or principle underlying the invention
`CATEGORY OF CITED DOCUMENTS
`E : earlier patent document, but published on, or
`afterthe filing date
`X : particularly relevant if taken alone
`D : document cited in the application
`Y : particularly relevant it combined with another
`L : document cited for other reasons
`document ol the same category
`A : technological background
`& : member or the same patent family, corresponding
`0 : non—written disclosure
`document
`P : intermediate document
` _%_?_.:}
`
`8
`
`7
`
`7
`
`

`
`EP 1 321 142 A1
`EP 1 321 142 A1
`
`0) EuropeanPatent
`J °“‘°°
`
`SHEET c
`
`ApplicationNumber
`EP 01 40 3339
`
`Claim(s) searched completely:
`2,6,16,18,20
`
`Claim(s) searched incompletely:
`1,3—5,7-15,17,19
`
`Reason for the limitation of the search:
`
`Present claims 1,3—5,7—15,17,19 relate to a product defined by reference
`to a property, namely the activity as 5—HT4 partial agonist.
`The claims cover all products having this property, whereas the
`application provides support within the meaning of Article 84 EPC and
`disclosure within the meaning of Article 83 EPC for only a very limited
`number of such products.
`In the present case,
`the claims so lack support,
`and the application so lacks disclosure, that a meaningful search over
`the whole of the claimed scope is impossible.
`Independent of the above
`reasoning,
`the claims also lack clarity (Article 84 EPC). An attempt is
`made to define the product by reference to a result to be achieved.
`Again,
`this lack of clarity in the present case is such as to render a
`meaningful search over the whole of the claimed scope impossible.
`Consequently,
`the search has been carried out for those parts of the
`claims which appear to be clear, supported and disclosed, namely those
`parts relating to the 5—HT4 partial agonist tegaserod claimed in claims
`2,6,16,18,20 and to the concept of "5—HT4 agonists".
`
`8
`
`8
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`EP 1 321 142 A1
`EP 1 321 142 A1
`
`ANNEXTOTHEEUROPEANSEARCHREPORT
`ON EUROPEAN PATENT APPLICATION NO.
`
`EP 01 40 3339
`
`This annex lists the patent family membersrelating to the patent documents cited in the above—mentioned European search report.
`The members are as contained in the European Patent Office EDP file on
`The European Patent Office is in no way liable for these particulars which are menelygiven for the purpose of information.
`17-04-2002
`
`Patent document
`cited in search report
`
`NO 0057857
`
`NO 0010526
`
`A
`
`A
`
`Publication
`date
`
`05-10-2000
`
`02-03-2000
`
`Patent family
`member(s)
`
`3574500 A
`0057857
`
`5623299
`105257
`9913135
`1323200
`0010526
`1104289
`2799123
`2782454
`2784899
`MI991826
`20010863
`346764
`2432001
`200100361
`
`Publication
`date
`
`16-10-2000
`05-10-2000
`
`14-03-2000
`30-11-2001
`08-05-2001
`21-11-2001
`02-03-2000
`06-06-2001
`06-04-2001
`25-02-2000
`28-04-2000
`19-02-2001
`26-03-2001
`25-02-2002
`11-09-2001
`21-06-2001
`
`EPOFORMP0459 For more details about this annex : see Official Journal of the European Patent Office, No. 12/82
`
`9
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