IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`(Atty. Docket No. 06-796)
`
`In the Application of:
`
`Fanaraetal.
`
`Serial No.
`
`10/599,451
`
`Filing Date:
`
`September 28, 2006
`
`For:
`
`Pharmaceutical Composition of Piperazine
`Derivatives
`
`
`
`
`
`NoweNewerNewerneeneeeeeeeeeeeee”
`
`Examiner: Timothy P. Thomas
`
`Art Unit: 1614
`
`Confirmation No.: 9142
`
`RESPONSE TO THE FINAL OFFICE ACTION MAILED FEBRUARY25,2009
`
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`DearSir:
`
`Please consider the following amendments and remarksin responseto the final Office
`
`Action mailed February 25, 2009. No fees are believed to be due, but the Office is nevertheless
`
`authorized to charge any fees necessary to maintain the pendencyofthis application to Deposit
`
`Account, No. 13-2490.
`
`Amendmentsto the claims begin on page 2 of this paper.
`
`Remarksbegin on page 5 ofthis paper.
`
`CERTIFICATE OF TRANSMISSION(37 C.F.R.1.8)
`I hereby certify that this correspondence is being transmitted to the USPTOvia the USPTO EFS on April 24, 2009.
`
`Date: April 24, 2009
`
`/Michael S. Greenfield/
`Michael S. Greenfield
`
`Apotex (IPR2019-00400) Ex. 1026, p. 001
`
`Apotex (IPR2019-00400) Ex. 1026, p. 001
`
`

`

`Amendments to the Claims
`
`The following listing of claims will replace all prior versions andlistings of claims in the
`
`application.
`
`Listing of Claims:
`
`1.
`
`(Currently amended) A liquid pharmaceutical composition comprising (i) levocetirizine
`
`or a pharmaceutically acceptable salt of levocetirizine, and (ii) at least one preservative, wherein
`
`the preservative is a mixture of methyl parahydroxybenzoate and propyl parahydroxybenzoate in
`
`a ratio of 9/1 expressed in weight, said mixture being present in an amount of more than 0 and
`
`less than +31 mg/ml of the composition.
`
`2.
`
`(Previously presented) The liquid pharmaceutical composition accordingto claim 1,
`
`wherein the composition is aqueous.
`
`3.
`
`4.
`
`5.
`
`(Canceled)
`
`(Canceled)
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`(Currently amended) The liquid pharmaceutical composition accordingto claim 1,
`
`wherein the amount of thep-hydroxybenzoateesters is in the range of 0.0001 and +31 mg/ml of
`
`the composition.
`
`6.
`
`(Withdrawn) The liquid pharmaceutical composition according to claim 1, wherein the
`
`pharmaceutical composition contains an amount of thimerosal in the range of 0.0001 and 0.05
`
`mg/ml of the composition.
`
`7.
`
`(Withdrawn) The liquid pharmaceutical composition according to claim 1, wherein the
`
`pharmaceutical composition contains an amount of chlorhexidine acetate in the range of 0.0001
`
`and 0.05 mg/ml of the composition.
`
`8.
`
`(Withdrawn) The liquid pharmaceutical composition according to claim 1, wherein the
`
`pharmaceutical composition contains an amountof benzylalcoholin the range of 0.0001 and 10
`
`mg/ml of the composition.
`
`McDonnell Boehnen Hulbert & Berghoff LLP
`300 South Wacker Drive
`Chicago, Illinois 60606
`312-913-0001
`
`2
`
`Response to Office Action Mailed February 25, 2009
`Application No. 10/599,451
`Attorney Docket No. 06-796
`
`Apotex (IPR2019-00400) Ex. 1026, p. 002
`
`Apotex (IPR2019-00400) Ex. 1026, p. 002
`
`

`

`9.
`
`(Withdrawn) The liquid pharmaceutical composition according to claim 1, wherein the
`
`pharmaceutical composition contains an amount of benzalkonium chloridein the range of 0.0001
`
`and 0.05 mg/ml of the composition.
`
`10.
`
`(Withdrawn) The liquid pharmaceutical composition according to claim 1, wherein the
`
`active substanceis cetirizine.
`
`11.=(Canceled)
`
`12.
`
`(Previously presented) The liquid pharmaceutical composition accordingto claim 1,
`
`wherein the composition is in the form oforal solutions, nasal drops, eye drops or ear drops.
`
`13.
`
`14.
`
`(Canceled)
`
`(Previously Presented) The liquid pharmaceutical composition according to claim 13,
`
`wherein the pharmaceutically acceptable salt of levocetirizine is a hydrochloridesalt.
`
`15.
`
`(Previously Presented) The liquid pharmaceutical composition according to claim 14,
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`wherein the hydrochloride salt of levocetirizine is present in amount of 0.5 mg/ml and the
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`mixture of methyl p-hydroxybenzoate and propyl p-hydroxybenzoate is present in amount of
`
`0.75 mg/ml.
`
`16.
`
`17.
`
`(Canceled)
`
`(Previously presented) The liquid pharmaceutical composition accordingto claim 1,
`
`which composition comprises levocetirizine or a pharmaceutically acceptable salt that is at least
`
`95% by weight of the levorotatory enantiomerofcetirizine.
`
`18.
`
`(Withdrawn-currently amended) A method of making a liquid pharmaceutical
`
`composition according to claim 1 comprising combining,
`
`a)
`
`b)
`
`cetirizine, levocetirizine, efletirizine, or a pharmaceutically acceptable salt of
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`cetirizine, levocetirizine, or efletirizine, and
`
`parahydroxybenzoate ester in an amount of more than 0 and less than 45-1mg/ml
`
`of the composition.
`
`McDonnell Boehnen Hulbert & Berghoff LLP
`300 South Wacker Drive
`Chicago, Illinois 60606
`312-913-0001
`
`3
`
`Response to Office Action Mailed February 25, 2009
`Application No. 10/599,451
`Attorney Docket No. 06-796
`
`Apotex (IPR2019-00400) Ex. 1026, p. 003
`
`Apotex (IPR2019-00400) Ex. 1026, p. 003
`
`

`

`19.
`
`(Withdrawn) The method according to claim 18, comprising mixing levocetirizine or a
`
`pharmaceutically acceptable salt thereof with a mixture of methyl p-hydroxybenzoate and propyl
`
`p-hydroxybenzoate.
`
`20.
`
`(Withdrawn) The method according to claim 19, comprising mixing a pharmaceutically
`
`acceptable salt of levocetirizine with a mixture of methyl p-hydroxybenzoate and propyl p-
`
`hydroxybenzoate, wherein the methyl p-hydroxybenzoate and propyl p-hydroxybenzoate are
`
`presentin a ratio of 9:1.
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`21.
`
`(Withdrawn) The method according to claim 20, wherein the pharmaceutically acceptable
`
`salt of levocetirizine is a hydrochloridesalt.
`
`22.
`
`(Withdrawn) In a methodoftreating a patient with cetirizine, levocetirizine, efletirizine,
`
`or a pharmaceutically acceptable salt of cetirizine, levocetirizine, or efletirizine, the improvement
`
`comprising administering a liquid composition according to claim 1.
`
`23.
`
`(Withdrawn) The method according to claim 23, wherein the liquid composition
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`comprises levocetirizine or a pharmaceutically acceptable salt thereof and a mixture of methyl p-
`
`hydroxybenzoate and propyl p-hydroxybenzoate.
`
`24.
`
`(Withdrawn) The method according to claim 23, wherein the pharmaceutically acceptable
`
`salt of levocetirizine is a hydrochloridesalt.
`
`25.
`
`(Withdrawn) The method according to claim 24, wherein the hydrochloridesalt of
`
`levocetirizine is present in amount of 0.5 mg/ml and the mixture of methyl p-hydroxybenzoate
`
`and propyl p-hydroxybenzoate is present in amount of 0.75 mg/ml.
`
`26.
`
`(Withdrawn) The method according to claim 25, wherein the methyl p-hydroxybenzoate
`
`and propyl p-hydroxybenzoate are presentin a ratio of 9:1 by weight.
`
`McDonnell Boehnen Hulbert & Berghoff LLP
`300 South Wacker Drive
`Chicago, Illinois 60606
`312-913-0001
`
`4
`
`Response to Office Action Mailed February 25, 2009
`Application No. 10/599,451
`Attorney Docket No. 06-796
`
`Apotex (IPR2019-00400) Ex. 1026, p. 004
`
`Apotex (IPR2019-00400) Ex. 1026, p. 004
`
`

`

`REMARKS
`
`Claims, claim objection, and rejection of claims 1-2, 5, 12, and 17 under 35 USC § 112,
`second paragraph
`
`Claims 1 and 5 were amendedto recited an upperlimit on the amountofp-
`
`hydroxybenzoate esters of 1 mg/ml. Support for these amendmentsis found onp. 4, Il. 25-30, of
`
`the application.
`
`The claims were objected to and rejected as indefinite for the recitation of “p-
`
`hydroxybenzoate esters” in claim 5, the Office alleging that the recitation of this term in
`
`dependentclaim 5 was seen as broadening the scope of the claim beyond that of independent
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`claim 1 from which claim 5 depends. While the applicants respectfully traverse, in order to
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`clarify claim 5 and expedite prosecution, claim 5 has been amended byinserting the definite
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`article “the” before the recitation of “p-hydroxybenzoate esters.” This amendmentclarifies that
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`the “p-hydroxybenzoate esters” referred to in claim 5 are the methyl parahydroxybenzoate and
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`propyl parahydroxybenzoate recited in claim 1. It is respectfully submitted that this amendment
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`merely clarifies claim 5 and does not narrow its scope.
`
`In view of the foregoing, the applicants respectfully request reconsideration and
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`withdrawalof this rejection.
`
`Rejection of claims 1-2, five, 12, and 17 under 35 USC 103
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`Claims 1-2, 5, 12, and 17 were rejected as obvious over DeLongueville et al. (WO
`
`02/47689 A2) and Doronet al. The Office relied on DeLongueville for its teaching ofcetirizine
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`or an optical isomer (levocetirizine being identified as an optical isomerofcetirizine), liquid
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`pharmaceutical compositions containing them, and a syrup containing cetirizine and methyl- and
`
`propylparaben. The Office notes that DeLongueville does not specifically teach an embodiment
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`comprising levocetirizine and a mixture of methyl- and propylparaben northe total amount of
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`parabensortheir ratios. The office relies on Doronforits teachings of the antibacterial effects of
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`methylparaben (MP) and propylparaben (PP) with concentration ratios of [MP]:[PP] up to 8.33:1
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`and the synergistic antibacterial effects of combinations of parabens. For the following reasons,
`
`the applicants respectfully traverse.
`
`The presently amendedclaimsrecite liquid levocetirizine compositions comprising
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`[MP]:[PP] = 9:1 with a total urban concentration of [MP] + [PP] < 1 mg/ml. The lowesttotal
`
`McDonnell Boehnen Hulbert & Berghoff LLP
`300 South Wacker Drive
`Chicago, Illinois 60606
`312-913-0001
`
`5
`
`Response to Office Action Mailed February 25, 2009
`Application No. 10/599,451
`Attorney Docket No. 06-796
`
`Apotex (IPR2019-00400) Ex. 1026, p. 005
`
`Apotex (IPR2019-00400) Ex. 1026, p. 005
`
`

`

`concentration of the combination of MP and PP taught by Doron to be completely antibacterial is
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`1.55 mg/ml. The applicants respectfully submit that it would have been nonobviousto reduce the
`
`concentrations of parabensto less than 1.55 mg/ml, let alone by more than 35%, downto 1
`
`mg/ml. This is because those of ordinary skill in the art understand that for pharmaceutical
`
`compositions there can be zero tolerance for bacterial growth. There must be 100% certainty that
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`each and every dosage form will be completely bacteria-free. But, following the teachings of
`
`Doron,one of ordinary skill in the art would avoid using smaller concentrations(i.¢e., below 1.5
`
`mg/ml) because they would believe or reasonably expect that concentrations such as those
`
`recited in the present claims would render a composition susceptible to bacterial growth. While,
`
`as the Office noted, Doron teaches that combinations of parabens have a synergistic effect on
`
`planktonic bacteria, in the very same sentence Doronstates, “although a complete antibacterial
`
`effect is not always achieved.” The significance ofthis statement cannot be over-emphasized
`
`becauseto be safe, useful, and achieve regulatory approval, a complete antibacterial effect must
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`be achieved. Furthermore, the antibacterial efficacy of a pharmaceutical composition must be
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`continuously maintained over long periods of time and multiple potential exposures to bacteria.
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`While liquid pharmaceutical formulations are manufactured to be bacteria-free and sealed, they
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`maybe repeatedly exposedto the risk of bacterial contamination each time the containeris
`
`opened(such as with drops). And acceptable pharmaceutical formulation must be completely
`
`bacterial resistant under such circumstances throughoutthe life of the product.
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`Doron reports that solutions with [MP] + [PP] < 1.55 mg/ml(all of which, by the way,
`
`have a [MP]:[PP] < 2) show planktonic bacterial growth. While the same combinations of
`
`parabens have complete antibacterial effect at 0.9 mg/ml on immobilized bacteria, Doron
`
`expressly states that there is a stronger antibacterial effect on immobilized bacteria comparedto
`
`planktonic bacteria. So, one of ordinary skill in the art would understand from Doron that higher
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`concentrations of parabensare required for liquid compositions.
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`In summary, the applicants respectfully submit that one of ordinary skill in the art could
`
`not have predicted or had a reasonable expectation that a liquid levocetirizine-containing solution
`
`would be completely antibacterial with concentrations of the combination of methyl- and
`
`propylparabensofless than 1 mg/ml because,
`
`McDonnell Boehnen Hulbert & Berghoff LLP
`300 South Wacker Drive
`Chicago, Illinois 60606
`312-913-0001
`
`6
`
`Response to Office Action Mailed February 25, 2009
`Application No. 10/599,451
`Attorney Docket No. 06-796
`
`Apotex (IPR2019-00400) Ex. 1026, p. 006
`
`Apotex (IPR2019-00400) Ex. 1026, p. 006
`
`

`

`1.
`
`The lowest completely antibacterial concentration of the combination of MP + PP
`
`disclosed by Doronis > 1.5 mg/ml, the lower concentrations tested being reported
`
`to have bacterial growth;
`
`2.
`
`3.
`
`Doron teaches that a complete antibacterial effect of a combination of parabensis
`
`not alwaysachieved; and
`
`Doron teaches that antibacterial efficacy of parabens is weaker against planktonic
`
`bacteria compared to immobilized bacteria.
`
`It is therefore unexpected and nonobviousthat compositions according to the claims
`
`would have such antibacterial efficacy. The unexpected efficacy of the claimed compositionsis
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`manifested in Tables 15-20 of Example 4 of the present application, which show that
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`levocetirizine compositions according to claim 1 with total paraben concentrations ([MP] + [PP])
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`of from 0.375 mg/ml up to 1.125 mg/ml (and [MP]:[PP] = 9) are free of Pseudomonas
`
`aeruginosa, E. coli, and Staphylococcus aureus bacteria 14 and 28 days following inoculation
`with these bacteria, respectively.’
`
`In view of the foregoing, the applicants respectfully request reconsideration and
`
`withdrawal of this obviousnessrejection.
`
`If there are any questions or comments regarding this application, the Examineris
`
`encouraged to contact the undersigned in order to expedite prosecution.
`
`Date: April 24, 2009
`
`Respectfully submitted,
`
`/Michael S. Greenfield/
`Michael S. Greenfield
`Registration No. 37,142
`
`Telephone:
`Facsimile:
`
`312-913-0001
`312-913-0002
`
`McDonnell Boehnen Hulbert & Berghoff LLP
`300 South Wacker Drive
`Chicago, IL 60606
`
`' Candida albicans and Aspergillus niger are fungi.
`McDonnell Boehnen Hulbert & Berghoff LLP
`300 South Wacker Drive
`Chicago, Illinois 60606
`312-913-0001
`
`7
`
`Response to Office Action Mailed February 25, 2009
`Application No. 10/599,451
`Attorney Docket No. 06-796
`
`Apotex (IPR2019-00400) Ex. 1026, p. 007
`
`Apotex (IPR2019-00400) Ex. 1026, p. 007
`
`