PTO-1390 (Rev. 07-2005)
`Approved for use through 3/31/2007. OMB 0651-0021
`US. Patent and Trademark Office; US. DEPARTMENT OF COMMERCE
`Under the Paperwork Reduction Act of 1995, no persons are required to respond to a collection of information unless it displays a valid OMB control number.
`
`TRANSMITTAL LETTER TO THE UNITED STATES
`DESIGNATED/ELECTED OFFICE (DO/EO/US)
`CONCERNING A SUBMISSION UNDER 35 U.S.C. 371
`
`06-796
`
`INTERNATIONAL APPLICATION NO.
`
`INTERNATIONAL FILING DATE
`
`PR|QR|TY DATE CLAIMED
`
`PCT/EP2005/007340
`TITLE OF INVENTION
`Pharmaceutical Comoosition Of Pioerazine Derivatives
`APPLICANT(S) FOR DO/EO/US
`Domenico Fanara et al.
`
`7 July 2005 (07.07.2005)
`
`14 Jul 2004 14.07.2004
`
`Applicant herewith submits to the United States Designated/Elected Office (DO/EO/US) the following items and other information:
`
`This is a FIRST submission of items concerning a submission under 35 U.S.C. 371.
`
`This is a SECOND or SUBSEQUENT submission of items concerning a submission under 35 U.S.C. 371.
`
`This is an express request to begin national examination procedures (35 U.S.C. 371 (f)). The submission must include items
`(5), (6), (9) and (21) indicated below.
`
`The US has been elected (Article 3).
`
`A copy of the International Application as filed (35 U.S.C. 371 (c)(2))
`
`a.
`
`b.
`
`IE is attached hereto (required only if not communicated by the International Bureau).
`
`IX has been communicated by the International Bureau.
`
`0. D is not required, as the application was filed in the United States Receiving Office (RO/US).
`
`An English language translation of the International Application as filed (35 U.S.C. 371 (c)(2)).
`
`a. D is attached hereto.
`
`b. D has been previously submitted under 35 U.S.C. 154(d)(4).
`
`Amendments to the claims of the International Application under PCT Article 19 (35 U.S.C. 371(c)(3))
`
`a. D are attached hereto (required only if not communicated by the International Bureau),
`
`b. D have been communicated by the International Bureau.
`
`0. D have not been made; however, the time limit for making such amendments has NOT expired.
`
`d.
`
`IX have not been made and will not be made.
`
`An English language translation of the amendments to the claims under PCT Article 19 (35 U.S.C. 371 (c)(3)).
`
`An oath or declaration of the inventor(s) (35 U.S.C. 371 (c)(4))
`
`An English language translation of the annexes of the International Preliminary Examination Report under PCT
`Article 36 (35 U.S.C. 371(c)( )).
`
`Items 11 to 20 below concern documents) or information included:
`An Information Disclosure Statement under 37 CFR 1.97 and 1.98.
`
`
`
`DDDDDEEDE
`
`An assignment document for recording. A separate cover sheet in compliance with 37 CFR 3.28 and 3.31 is included.
`
`A preliminary amendment.
`
`An Application Data Sheet under 37 CFR 1.76.
`
`A substitute specification.
`
`A power of attorney and/or change of address letter.
`
`A computer-readable form of the sequence listing in accordance with PCT Rule 13ter.2and 37 CFR 1821- 1.825.
`
`second copy of the published International Application under 35 U.S.C. 154(d)(4).
`
`A second copy of the English language translation of the international application under 35 U.S.C. 154(d)(4).
`
`This collection of information is required by 37 CFR 1.414 and 1491-1492. The information is required to obtain or retain a benefit by the public, which is to file (and by the
`USPTO to process) an application. Confidentiality is governed by 35 U.S.C. 122 and 37 CFR 1.11 and 1.14. This collection is estimated to take 15 minutes to complete,
`including gathering information, preparing, and submitting the completed form to the USPTO. Time will vary depending upon the individual case. Any comments on the amount
`of time you require to complete this form and/or suggestions for reducing this burden, should be sent to the Chief Information Officer, US. Patent and Trademark Office, US.
`Department of Commerce, PO. Box 1450, Alexandria, VA 22313-1450. DO NOT SEND FEES OR COMPLETED FORMS TO THIS ADDRESS. SEND TO: Mail Stop PCT,
`Commissioner for Patents, P.0. Box 1450, Alexandria, VA 22313-1450.
`.
`
`Appatgnglglc. (IPR2019—00400), EX. 1013,
`
`a
`
`015 ‘ “”F°"“"°°"‘
`
`Apotex, Inc. (IPR2019-00400), Ex. 1013, p. 001
`
`

`

`PTO-1390 (Rev. 07-2005)
`Approved for use through 3/31/2007. OMB 0651-0021
`US. Patent and Trademark Office; US. DEPARTMENT OF COMMERCE
`Under the Paperwork Reduction Act of 1995, no persons are required to respond to a collection of information unless it displays a valid OMB control number.
`
`U.S. APPLICATION NO. (if known, see 37 CFR 1.5)
`
`INTERNATIONAL APPLICATION NO.
`PCT/E P2005/007340
`
`ATTORNEY'S DOCKET NUMBER
`06-796
`
`20.
`
`Other items or information.
`
`Form PTO/SB/OSA and International Search Report
`
`CALCULATIONS
`PTO USE ONLY
`$
`300.00_
`
`
`
`The following fees have been submitted
`21. IX Basic national fee (37 CFR 1.492(a)) ...............................................................$300
`22. IX Examination fee (37 CFR 1.492(c))
`
`If the written opinion prepared by ISA/Us or the international preliminary examination report prepared
`by IPEA/US indicates all claims satisfy provisions of PCT Article 33(1)-(4) ............... $0
`All other situations
`$200
`
`23. IX Search fee (37 CFR 1.492(b))
`If the written opinion prepared by ISA/Us or the international preliminary examination repOIt prepared by
`IPEA/US indicates all claims satisfy provisions of PCT Article 33(1)-(4) .................... $0
`Search fee (37 CFR 1.445(a)(2)) has been paid on the international application to the USPTO as an
`International Searching Authority .............................................................................. $100
`International Search Report prepared by an ISA other than the US and provided to the Office or
`previously communicated to the USA by the IB ........................................................ $400
`All other situations ................................................................................................................ $500
`TOTAL OF 21, 22 and 23-—
`E Additional fee for specification and drawings filed'In paper over 100 sheets(e(xc|uding
`sequence listing in compliance with 37 CFR 1. 821(c)0 r(e) or computer program listing in an
`electronic medium) 37 CFR 1. 492()
`The fee'Is $250 for each additionalJ 50 sheets of paper or fraction thereof.
`Total Sheets
`Extra Sheets
`Number of each additional 50 or fraction
`thereof round u - to a whole number
`
`RATE
`
`Surcharge of $130. 00 for furnishing any of the search fee examination fee or the oath or declaration
`after the date of commencement of the national stage((37 CFR 1 .4.92(h))
`CLAIMS
`NUMBER FILED
`NUMBER EXTRA
`
`RATE
`
`—_—_
`Independent claims
`X
`$200
`
`MULTIPLE DEPENDENT CLAIM(S) (if applicable)
`
`$360
`+
`TOTAL OF ABOVE CALCULATIONS =
`
`D Applicant claims small entity status. See 37 CFR 1.27. Fees above are reduced by 1/2.
`SUBTOTAL:
`
`Processing fee of $130.00 for furnishing the English translation later than 30 months from the earliest
`claimed priority date (37 CFR 1.492(i)).
`
`+
`TOTAL NATIONAL FEE:
`
`Fee for recording the enclosed assignment (37 CFR 1 .2.1(h)) The assignment must be accompanied
`by an appropriate cover sheet (37 CFR 3. 28 3. 31) $40. 00 per property
`
`200_00
`
`40000
`
`900.00—
`
`$
`
`$
`
`$
`
`$
`
`$ A
`
`mount to be
`refunded:
`
`TOTAL FEES ENCLOSED:
`
`charged:
`
`FORM PTO-1390 (Rev. 07-2005)
`
`Page 2 of 3
`
`American LegalNet Inc.
`www. USCourtForms.com
`
`Apotex, Inc. (IPR2019—00400), EX. 1013, p. 002
`
`Apotex, Inc. (IPR2019-00400), Ex. 1013, p. 002
`
`

`

`PTO-1390 (Rev. 07-2005)
`Approved for use through 3/31/2007. OMB 0651-0021
`US. Patent and Trademark Office; US. DEPARTMENT OF COMMERCE
`Under the Paperwork Reduction Act of 1995, no persons are required to respond to a collection of information unless it displays a valid OMB control number.
`
`A check in the amount of $
`
`to cover the above fees is enclosed.
`
`Please charge my Deposit Account No. 13-2490 in the amount of $900.00 to cover the above fees.
`A duplicate copy of this sheet is enclosed.
`
`The Commissioner is hereby authorized to charge any additional fees which may be required, or credit any overpayment to Deposit
`Account No. 13-2490. A duplicate copy of this sheet is enclosed.
`
`Fees are to be charged to a credit card. WARNING: Information on this form may become public. Credit card information should not
`be included on this form. Provide credit card information and authorization on PTO-2038.
`
`REGISTRATION NUMBER
`
`NOTE: Where an appropriate time limit under 37 CFR 1.495 has not been met, a petition to revive (37 CFR 1.137(a) or (b)) must be filed
`and granted to restore the International Application to pending status.
`
`SEND ALL CORRESPONDENCE TO:
`Michael S. Greenfield
`
`McDonnell Boehnen Hulbert & Berghoff LLP
`300 South Wacker Drive
`Suite 3100
`
`/Michael S. Greenfield/
`SIGNATURE
`
`Michael S Greenfield
`NAME '
`
`Chicago, Illinois 60606
`
`37,142
`
`FORM PTO-1390 (Rev. 07-2005)
`
`Page 3 of 3
`
`American LegalNet, Inc.
`www.USCourtForms.com
`
`ApoteX, Inc. (IPR2019—00400), EX. 1013, p. 003
`
`Apotex, Inc. (IPR2019-00400), Ex. 1013, p. 003
`
`

`

`PTO-1390 (Rev. 07-2005)
`Approved for use through 3/31/2007. OMB 0651-0021
`US. Patent and Trademark Office; US. DEPARTMENT OF COMMERCE
`Under the Paperwork Reduction Act of 1995, no persons are required to respond to a collection of information unless it displays a valid OMB control number.
`
`TRANSMITTAL LETTER TO THE UNITED STATES
`DESIGNATED/ELECTED OFFICE (DO/EO/US)
`CONCERNING A SUBMISSION UNDER 35 U.S.C. 371
`
`06-796
`
`INTERNATIONAL APPLICATION NO.
`
`INTERNATIONAL FILING DATE
`
`PR|QR|TY DATE CLAIMED
`
`PCT/EP2005/007340
`TITLE OF INVENTION
`Pharmaceutical Comoosition Of Pioerazine Derivatives
`APPLICANT(S) FOR DO/EO/US
`Domenico Fanara et al.
`
`7 July 2005 (07.07.2005)
`
`14 Jul 2004 14.07.2004
`
`Applicant herewith submits to the United States Designated/Elected Office (DO/EO/US) the following items and other information:
`
`This is a FIRST submission of items concerning a submission under 35 U.S.C. 371.
`
`This is a SECOND or SUBSEQUENT submission of items concerning a submission under 35 U.S.C. 371.
`
`This is an express request to begin national examination procedures (35 U.S.C. 371 (f)). The submission must include items
`(5), (6), (9) and (21) indicated below.
`
`The US has been elected (Article 3).
`
`A copy of the International Application as filed (35 U.S.C. 371 (c)(2))
`
`a.
`
`b.
`
`IE is attached hereto (required only if not communicated by the International Bureau).
`
`IX has been communicated by the International Bureau.
`
`0. D is not required, as the application was filed in the United States Receiving Office (RO/US).
`
`An English language translation of the International Application as filed (35 U.S.C. 371 (c)(2)).
`
`a. D is attached hereto.
`
`b. D has been previously submitted under 35 U.S.C. 154(d)(4).
`
`Amendments to the claims of the International Application under PCT Article 19 (35 U.S.C. 371(c)(3))
`
`a. D are attached hereto (required only if not communicated by the International Bureau),
`
`b. D have been communicated by the International Bureau.
`
`0. D have not been made; however, the time limit for making such amendments has NOT expired.
`
`d.
`
`IX have not been made and will not be made.
`
`An English language translation of the amendments to the claims under PCT Article 19 (35 U.S.C. 371 (c)(3)).
`
`An oath or declaration of the inventor(s) (35 U.S.C. 371 (c)(4))
`
`An English language translation of the annexes of the International Preliminary Examination Report under PCT
`Article 36 (35 U.S.C. 371(c)( )).
`
`Items 11 to 20 below concern documents) or information included:
`An Information Disclosure Statement under 37 CFR 1.97 and 1.98.
`
`
`
`DDDDDEEDE
`
`An assignment document for recording. A separate cover sheet in compliance with 37 CFR 3.28 and 3.31 is included.
`
`A preliminary amendment.
`
`An Application Data Sheet under 37 CFR 1.76.
`
`A substitute specification.
`
`A power of attorney and/or change of address letter.
`
`A computer-readable form of the sequence listing in accordance with PCT Rule 13ter.2and 37 CFR 1821- 1.825.
`
`second copy of the published International Application under 35 U.S.C. 154(d)(4).
`
`A second copy of the English language translation of the international application under 35 U.S.C. 154(d)(4).
`
`This collection of information is required by 37 CFR 1.414 and 1491-1492. The information is required to obtain or retain a benefit by the public, which is to file (and by the
`USPTO to process) an application. Confidentiality is governed by 35 U.S.C. 122 and 37 CFR 1.11 and 1.14. This collection is estimated to take 15 minutes to complete,
`including gathering information, preparing, and submitting the completed form to the USPTO. Time will vary depending upon the individual case. Any comments on the amount
`of time you require to complete this form and/or suggestions for reducing this burden, should be sent to the Chief Information Officer, US. Patent and Trademark Office, US.
`Department of Commerce, PO. Box 1450, Alexandria, VA 22313-1450. DO NOT SEND FEES OR COMPLETED FORMS TO THIS ADDRESS. SEND TO: Mail Stop PCT,
`Commissioner for Patents, P.0. Box 1450, Alexandria, VA 22313-1450.
`.
`
`Appatgnglglc. (IPR2019—00400), EX. 1013,
`
`a
`
`015 “”F°"“"°°"‘
`
`Apotex, Inc. (IPR2019-00400), Ex. 1013, p. 004
`
`

`

`PTO-1390 (Rev. 07-2005)
`Approved for use through 3/31/2007. OMB 0651-0021
`US. Patent and Trademark Office; US. DEPARTMENT OF COMMERCE
`Under the Paperwork Reduction Act of 1995, no persons are required to respond to a collection of information unless it displays a valid OMB control number.
`
`U.S. APPLICATION NO. (if known, see 37 CFR 1.5)
`
`INTERNATIONAL APPLICATION NO.
`PCT/E P2005/007340
`
`ATTORNEY'S DOCKET NUMBER
`06-796
`
`20.
`
`Other items or information.
`
`Form PTO/SB/OSA and International Search Report
`
`CALCULATIONS
`PTO USE ONLY
`$
`300.00_
`
`
`
`The following fees have been submitted
`21. IX Basic national fee (37 CFR 1.492(a)) ...............................................................$300
`22. IX Examination fee (37 CFR 1.492(c))
`
`If the written opinion prepared by ISA/Us or the international preliminary examination report prepared
`by IPEA/US indicates all claims satisfy provisions of PCT Article 33(1)-(4) ............... $0
`All other situations
`$200
`
`23. IX Search fee (37 CFR 1.492(b))
`If the written opinion prepared by ISA/Us or the international preliminary examination repOIt prepared by
`IPEA/US indicates all claims satisfy provisions of PCT Article 33(1)-(4) .................... $0
`Search fee (37 CFR 1.445(a)(2)) has been paid on the international application to the USPTO as an
`International Searching Authority .............................................................................. $100
`International Search Report prepared by an ISA other than the US and provided to the Office or
`previously communicated to the USA by the IB ........................................................ $400
`All other situations ................................................................................................................ $500
`TOTAL OF 21, 22 and 23-—
`E Additional fee for specification and drawings filed'In paper over 100 sheets(e(xc|uding
`sequence listing in compliance with 37 CFR 1. 821(c)0 r(e) or computer program listing in an
`electronic medium) 37 CFR 1. 492()
`The fee'Is $250 for each additionalJ 50 sheets of paper or fraction thereof.
`Total Sheets
`Extra Sheets
`Number of each additional 50 or fraction
`thereof round u - to a whole number
`
`RATE
`
`Surcharge of $130. 00 for furnishing any of the search fee examination fee or the oath or declaration
`after the date of commencement of the national stage((37 CFR 1 .4.92(h))
`CLAIMS
`NUMBER FILED
`NUMBER EXTRA
`
`RATE
`
`—_—_
`Independent claims
`X
`$200
`
`MULTIPLE DEPENDENT CLAIM(S) (if applicable)
`
`$360
`+
`TOTAL OF ABOVE CALCULATIONS =
`
`D Applicant claims small entity status. See 37 CFR 1.27. Fees above are reduced by 1/2.
`SUBTOTAL:
`
`Processing fee of $130.00 for furnishing the English translation later than 30 months from the earliest
`claimed priority date (37 CFR 1.492(i)).
`
`+
`TOTAL NATIONAL FEE:
`
`Fee for recording the enclosed assignment (37 CFR 1 .2.1(h)) The assignment must be accompanied
`by an appropriate cover sheet (37 CFR 3. 28 3. 31) $40. 00 per property
`
`200_00
`
`40000
`
`900.00—
`
`$
`
`$
`
`$
`
`$
`
`$ A
`
`mount to be
`refunded:
`
`TOTAL FEES ENCLOSED:
`
`charged:
`
`FORM PTO-1390 (Rev. 07-2005)
`
`Page 2 of 3
`
`American LegalNet Inc.
`www. USCourtForms.com
`
`Apotex, Inc. (IPR2019—00400), EX. 1013, p. 005
`
`Apotex, Inc. (IPR2019-00400), Ex. 1013, p. 005
`
`

`

`PTO-1390 (Rev. 07-2005)
`Approved for use through 3/31/2007. OMB 0651-0021
`US. Patent and Trademark Office; US. DEPARTMENT OF COMMERCE
`Under the Paperwork Reduction Act of 1995, no persons are required to respond to a collection of information unless it displays a valid OMB control number.
`
`A check in the amount of $
`
`to cover the above fees is enclosed.
`
`Please charge my Deposit Account No. 13-2490 in the amount of $900.00 to cover the above fees.
`A duplicate copy of this sheet is enclosed.
`
`The Commissioner is hereby authorized to charge any additional fees which may be required, or credit any overpayment to Deposit
`Account No. 13-2490. A duplicate copy of this sheet is enclosed.
`
`Fees are to be charged to a credit card. WARNING: Information on this form may become public. Credit card information should not
`be included on this form. Provide credit card information and authorization on PTO-2038.
`
`REGISTRATION NUMBER
`
`NOTE: Where an appropriate time limit under 37 CFR 1.495 has not been met, a petition to revive (37 CFR 1.137(a) or (b)) must be filed
`and granted to restore the International Application to pending status.
`
`SEND ALL CORRESPONDENCE TO:
`Michael S. Greenfield
`
`McDonnell Boehnen Hulbert & Berghoff LLP
`300 South Wacker Drive
`Suite 3100
`
`/Michael S. Greenfield/
`SIGNATURE
`
`Michael S Greenfield
`NAME '
`
`Chicago, Illinois 60606
`
`37,142
`
`FORM PTO-1390 (Rev. 07-2005)
`
`Page 3 of 3
`
`American LegalNet, Inc.
`www.USCourtForms.com
`
`ApoteX, Inc. (IPR2019—00400), EX. 1013, p. 006
`
`Apotex, Inc. (IPR2019-00400), Ex. 1013, p. 006
`
`

`

`{12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19} World Intellectual Property Organization ,
`International Bureau
`
`(43) International Publication Date
`19 January 2006 (19.01.2006)
`
`(51)
`
`International Patent Clntisil'iention:
`C071) 487/04 (2006.01)
`
`I.
`
`
`
`lllllllllllllllllllllllllllllllllllIlllllllllllillillllillllllllllllllllIllllllllllllllill
`
`(10) International Publication Number
`
`WO 2006/005507 A2
`
`(74)
`
`(81)
`
`Agent: LECHHEN, Nlonique; UCB, S A, Alice do la
`Recherche 60, 134010 Bruxelles (BE),
`
`Designated States (unless otizenuise indicated, for every
`kind of national protection available): AE, AG, AL, Alvl,
`AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN,
`CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI,
`GB, GD, GE, Gl-l, GM, HR, l-lU, ID, IL, IN, IS, JP, KE,
`KG, KM, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA,
`MD, RIG, MK, MN, MW, MX, MZ, NA, NG, NI, NO, NZ,
`OM, PG, PH, Pl, PT, 110, RU, SC, SIT), SE, SCI, SK, SL,
`SM. SY, TJ. TM, TN, TR. TY, TZ, UA, UG, US, UZ, VC.
`VN, YU, ZA, ZM, ZW
`
`(34)
`
`Designated States (union artist-wire iridinatou’, jhr every
`.tcinur of regional protection available): Alill’CJ (BW, Glut,
`GM, KE, LS, MW, MZ, NA, SD, St, SZ, TZ, UG, ZM,
`ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, 'I‘J, TM),
`European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FE,
`FR, GB, GR, l‘IU, IE, IS, IT, LT, LU, i..V, MC, NL, PL, PT,
`RO, SE, SI, SK, '1 R), OAI’I (BF, BJ, CF, CG, Cl, CM, GA,
`GN, GQ, GW, ML, MR, NE, SN, TD, TG),
`Published:
`without international search report and to be republished
`upon receipt ojthat report
`
`Fortwodetter codes and other abbreviations, refer to the "Guid-
`tmce Note t on Codes and Abbreviations "appearing at the begin-
`ning of each regular is tut? oftitr.’ PCT Gazette.
`
`(11)
`
`(22)
`
`(15)
`
`International Application Number:
`I’CT/Ei’2005/007340
`
`International Fiiing Date:
`
`'1' Juiy 2005 (07.07 2005)
`
`Filing Language:
`
`(26)
`
`Publication Language:
`
`(311)
`
`Priority Data:
`040165193
`
`English
`
`Engiisit
`
`t4 July 2004 (14.07 2004)
`
`IEP
`
`(71)
`
`(72)
`(‘75)
`
`Applicant (for at! designated States except US): UCB
`FARCHIM SA [CI-It'Ci-i']; Zl Pianchy, Chemist do Croix
`Blanche 10, CAP, 42 1. Cit—1630 Bulle (CID
`
`Inventors; and
`FANARA,
`only):
`(for US
`Inventor'sft'tpplieonL-s
`Domenico [117813; Rue Pont do Soleil, 2A, 13-4520
`Wnnze (BE). SCOUVART, Jenn [BE/BE]; Tit nux Pi—
`geons, 72, B—llSO Brussels (BE) POULAIN, Cluit'e
`[FR/BE]; 23 rue do Jouker, 13-1060 Brussels (BE). DEEL~
`ERS, Michel [BE/BE]; Square des braves,
`i2, B«i630
`Linkebeeic (BE)
`
`
`
`(54) TitEc: l’l'l'ARMACEUTICAL COMPOSTI‘ION OF’ PIPERAZINE DERIVATIVES
`
`(57) Abstract: The present invention rciatcs to a liquid composition containing an active substance belonging to the family of
`substituted benzhydryl pipcmzines with reduced amounts of preservatives
`
`Apotex, Inc. (IPR2019—00400), EX. 1013, p. 007
`
`
`
`W02006/005507A2IlllllIllllllllIlllllllllllllllllllllllllllllllllllllllllllllIlllIlllllllllllllllllllllllllll
`
`Apotex, Inc. (IPR2019-00400), Ex. 1013, p. 007
`
`

`

`‘WO 2006/005507
`
`PCT/EPflHB/GO‘YISJO
`
`17.80.WO
`
`Pharmaceutical composition of piperazine derivatives
`
`The present invention relates to a liquid pharmaceutical composition
`
`containing an active substance such as cetirizme, levocetirizine and efletirizine.
`
`5
`
`A number of substances belonging to the family of substituted benzhydryl
`
`piperazines are known to be substances with useful phaimacological properties.
`
`European Patent EP 58146. filed in the name of" UCB, SA... describes
`
`substituted benzhydryl piperazines having the general formula
`
`10
`
`X
`
`X;
`
`N
`N
`\___/
`
`(CH2)n—aE—H2C—*C//
`\L
`
`o
`
`15
`
`in which L stands for an -OH or —l\ll-I2 group, X and X’. taken separately. stand for a
`
`hydrogen atom. a halogen atom. a linear or branched alltoxy radical at C; or C4, or a
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`trifluoromethyl radical. m equals 1 or 2. :1 equals 1 or 2. as well as their
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`pharmaceutically acceptable salts.
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`Of thesa compounds, 2—[2—[4—[[4~chlorophenyllphenylmethyl]~1—
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`piperazinyliethoxy] acetic acid, also known under the name of cetirizioe. and its
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`dichlorohydrate are well known for their antihistaminic properties.
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`The active substances belonging to the family of substituted benzhydryl
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`piperazines specifically include 24244—[ta—chlorophenyllphenylmethy11~l~
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`piperazinyllethoxyluacetic acid [cetirlzineL 2—12—[4-{bis{4-fluorophenyllmetliyll-1—
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`piperazinyllethowlacetic acid (efletirizine). their optically active isomers when
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`applicable. as well as their pharmaceutically acceptable salts.
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`In the pharmaceutical filed, solutions and drops are generally produced as
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`germwfree compositions during their production processes. Howaver. once the seal of
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`the containers is broken. and the pharmaceutical compositions are completely used
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`over a period of time. these pharmaceutical compositions are continuously exposed to
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`CONFIRMATION COPY
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`the risk of being contaminated by the microorganisms existing in the environment or
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`the human body, each time the containers are used and their coVers are opened or
`closed.
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`It has new surprisingly been found that the active substances belonging to the
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`family of substituted benzhydryi piperazines possess a preservative effect in aqueous
`solutions;
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`The purpose of the invention concerns a liquid pharmaceutical composition
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`containing an active substance belonging to the family of substituted benzhydryl
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`piperazines chosen among cetirizine. levocetirizine and efletirizine. and a reduced
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`amount of preservatives
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`The present invention is based on the unexpected recognition that a
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`pharmaceutical composition comprising an active substance belonging to the family of
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`substituted benzhydryl piperazines and a reduced amount of preservatives is stable
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`during a tong period of time. Stability means the capacity to resists to microbial
`contamination
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`The present invention encompasses a pharmaceutical composition comprising
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`an active substance belonging to the family of substituted benzhydryl piperszines and
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`an amount of parahydroxybenzoate esters used as preservatives less than 3 rag/ml of
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`the composition. a normal concentration to preserve aqueous solutions
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`The present invention encompasses a pharmaceutical composition comprising
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`an active substance chosen among cetirizine. levocetirizine and efletirizine and at least
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`one preservative. wherein the amount of preservative is in the case of
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`parahydroxybenzoate esters more than 0 and less than 1.5 rug/ml of the composition,
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`and in the case of other preservatives corresponds to the bactericidal effect of a
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`parahydroxybenzoate esters concentration of more than 0 and less than 1.5 rug/ml.
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`Generally. the phannaceutical composition of the invention is liquid and
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`preferably aqueous“
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`In the pharmaceutical composition of the invention, the active substance is
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`generally selected from the group of cetirizine. ievocetirizine. efietirizine. and their
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`pharmaceutically acceptable salts. Preferably. the active substance is selected from the
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`group of ceb‘n’zine. levocetirizine, and their pharmaceutically acceptable salts,
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`The term "cetirizine" refers to the racemate of [244%(4
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`ch10rophenylmhenylrnethyl] ~lwpiperazinyIIBthoml-acefic acid and its dihydrochloride
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`salt which is well known as cetirizine dihydr‘ochloride; its levorotatory and
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`dextrorotatory enantiorners are imowu as ievocetirizine and dextroceijrizme. Processes
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`for preparing cetirizine, an individual optical isomer thereof or a pharmaceutically
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`acceptable salt thereof have been described in European Patent 0 058 146. Great
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`Britain Patent 2.225.320, Great Britain Patent 2225.321, United States Patent
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`“’0 20061005507
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`PCTIEP2005I'007340
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`5,478,941, European Patent application 0 601 02.8. European Patent Applicaijon 0 801
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`064 and International Patent Application WO 97/379812.
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`The term "levocetirizine" as used herein means the levorotatory enantiomer of
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`cetirizine. More precisely, it means that the active substance comprises at least 90%
`
`by weight, preferably at least 95% by Weight. of one individual optical isomer of
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`cetirizine and at most 10% by weight. preferably at most 5% by weight, of the other
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`individual optical isomer of cetirizine. Each individual optical isomer may be obtained
`
`by conventional means, lie” resolution from the corresponding racemic mixture or by
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`asymmetric synthesis Each individual optical isomer may be obtained from 1E
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`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
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`disclosed in US. Patents No. 4,800,162 and 5,057,427.
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`The term “efletirizine” as used herein refers to 2»[2—[4—[his[4—
`
`fluor’ophenyl)methyll—1—piperazinyllethoxylacetic acid“ Efletlrizine is encompassed
`
`within general formula I of" European patent No. 58146. which relates to substituted
`
`benzhydrylpiperazine derivatives. Eiletirizine has been found to possess excellent
`
`antiliistaminic properties. It belongs to the pharmacological class of histamine H}—
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`recepior antagonists and shown in vitro high affinity and selectivity for H1~receptors
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`It is useful as an antiallergic, and antiliistaniinic agent. Two pseudopolyuiorphic
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`crystalline forms of efletirizine dihydrochioride, namely anhydrous efletin‘zine
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`dihyclrochloride and efletirizine diliydrochlorlde monohyclrate, are described in the
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`European patent No. 1 034 171, and another pseudopolymorphic form of efletirizine
`
`diliydr‘ochloride is described in the international patent application W0 03/009849.
`
`Processes for preparing efletirizine or a pharmaceutically acceptable salt thereof have
`
`been described in European Patent 1 034 171, and in the international patent
`
`applications WO 97737982 and W0 03/009849.
`
`The term ”pharmaceutically acceptable salts“ as used herein refers not only to
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`addition salts with pharmaceutically acceptable non—toxic organic and inorganic acids.
`
`such as acetic. citric, maleic, succinic, ascorbic, hydrochloric, hydrobronuc. sulfuric.
`
`and phosphoric acids and the like. but also its metal salts [for example sodium or
`
`potassium salts) or ammonium salts. the amine salts and the aminoacid salts. The
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`best results have been obtained with dihydrochioride salts“
`
`By preservatives we understand a chemically substance that inhibits the
`
`development of microorganisms or, in an ideal instance, kills them: so antinucrobial
`
`agent able to limit or avoid the growth of microorganisms such as bacteria, yeast and
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`moulds in a solution, Preservatives will comply with Eur P. and USP requirements: for
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`a product incubated Willi a large number ofbacteria and fungi. the preservative must
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`kill and reduce a required amount of bacteria and fungi within a prescribed time
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`period.
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`Examples of preservatives are pahydroxybenzoate esters (methyl
`
`parahydroxybcnzoatc. ethyl parahydroxybenzoate . propyl parahydroxybenzoate , butyl
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`parahydmxybenzoate , Cl~C20 alkyl parahydroxybenzoate and their sodium salts),
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`acrinol. methyl rosaniline chloride, henzalkonium chloride. benzethonlum chloride,
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`cetylpyridlnium chloride. cetylpyrodium bromide. chlorohexldine, chloroheiddine
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`acetate, benzylalcohol, alcohol, chlorobutanoi. isopropanol. ethanol. thimerosal.
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`phenol. sorbic acid, potassium and calcium sorbate, bemoic acid. potassium and
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`calcium benzoate, sodium benzoate, calcium acetate, calcium disodium
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`ethylenediaminetctraacetate. calcium propionate, calcium sorbate, diethyl
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`pyrocarbonate, sulphur dioxide, sodium sulphite. sodium bisulfite. horic acid. sodium
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`tetr'aborate, propionic acid, sodium and calcium propionate, sodium thiosulfate. or a
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`mixture therefore. Generally, the preservative is selected fitom the group ofthimerosal.
`
`chlorohexidine acetate, benzylalcohol, benzalltonium chloride, p—hydroxybenzoatc
`
`esters (methyl parahydroig/benzoate, ethyl parahyclroxybenzoate . propyl
`
`parahydroxybenzoate , butyl parahydroxybenzoate , (31—020 alltyl
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`parahydroxybenzoate or a mixture thereof. Preferably the preservative is selected from
`
`the group of methyl parahydrombenzoate, ethyl parahydroiqrhenzoate , propyl
`
`par ahydrowbenzoate . a mixture of methyl parahydroxvh enzoate and ethyl
`
`parahydroxybenzoate or propyl parahydroxybenzoate , and a mixture of methyl
`
`parahydroxybenzoate and propyl parahydroxybenzoate. Best results have been
`
`obtained with a mixture of methyl parahydroxybenzoate and propyl
`
`parahydroxyhenzoate in a ratio of 9/ 1 expressed in Weight.
`
`In a particular embodiment ofthe invention, the pharmaceutical composition
`
`contains an amount of’p—hydroxybenzoate esters (methyl p-hydroxybenzoate/propyl p—
`
`hydroxybenzoate in a ratio of 9/ 1 expressed in weight] selected in the range of 0.0001
`
`and 1.5 mg] ml of the composition. Preferably, it contains an amount selected in the
`
`range of 0.01 and 1,125 mg] ml. More preferably it contains an amount of
`
`preservatives selected in the range of 0.1 and 1 mg/mL
`
`In a particular embodiment of the invention. the pharmaceutical composition
`
`contains an amount of thirnerosal selected in the range of 0.0001 and 0.05 trig/ml of
`
`the composition. Preferably, it contains an amount selected in the range of 0.005 and
`
`0.035 orig/ml, More preferably it contains an amount of preservatives selected in the
`
`range of 0007 and 0.025 rag/ml.
`
`In a particular embodiment of the invention. the pharmaceutical composition
`
`contains an amount of chlorhexidlne acetate selected in the range of 0.0001 and 005
`
`trig/m1 of the composition Preferably. it contains an amount selected in the range of
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`Apotex, Inc. (IPR2019—00400), EX. 1013, p. 011
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`‘WO 2006/005507
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`PCT/EP2005f0073'40
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`0.005 and 0.035 nag/ml. More preferably it contains an amount of preservatives
`
`selected in the range of 0.007 and 0.025 mg/ml.
`
`In a particular embodiment of the invention, the pharmaceutical composiiion
`
`contains an amount of benzylalcohol selected in the range of 0.0001 and 10 mg/ml of
`
`the composition. Preferably. it contains an amount selected in the range of 0.05 and
`
`7.5 rug/ml. More preferably it contains an amount of preservatives selected in the
`
`range of l and 5 mg/ml.
`
`in a particular embodiment of the invention, the pharmaceutical composition
`
`contains an amount ofbenzalkoniurn chloride selected in the range of 0.0001 and 0.05
`
`mg/ml of the composition. Pref