IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
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`(Case No. 06-796)
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`In the Application of:
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`Fanara et al.
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`Serial No.
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`10/599,451
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`Filing Date:
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`September 28, 2006
`
`For:
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`Pharmaceutical Composition of Piperazine
`Derivatives
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`VVVVVVVVVV
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`Examiner: Timothy P. Thomas
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`Art Unit: 1614
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`Confirmation No.2 9142
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`RESPONSE TO THE OFFICE ACTION MAILED SEPTEMBER 25, 2008
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`Commissioner for Patents
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`PO. Box 1450
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`Alexandria, VA 22313—1450
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`Dear Sir:
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`Please consider the following amendments and remarks in response to the Office
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`communication mailed September 25, 2008. No fees are believed to be due, but the Office is
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`nevertheless authorized to charge any fees necessary to maintain the pendency of this application
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`to Deposit Account, No. 13-2490.
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`Amendments to the claims begin on page 2 of this paper.
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`Remarks begin on page 5 of this paper.
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`1
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`Apotex (11311201900400) EX. 1025, p. 001
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`Apotex (IPR2019-00400) Ex. 1025, p. 001
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`

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`Amendments to the Claims
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`The following listing of claims will replace all prior versions and listings of claims in the
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`application.
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`Listing of Claims:
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`1.
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`(Currently Amended) A liquid pharmaceutical composition comprising (i) eetirizine;
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`levocetirizinerefletirizifie; or a pharmaceutically acceptable salt of eetirizine, levocetirizinerer
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`efletirizine, and (ii) at least one preservative, wherein the preservative is (a)—a
`
`
`
`-
`
`I
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`u
`
`in.
`
`.
`
`-v c
`
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`I
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`
`II.
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`
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`
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`
`
`
`WWW—Ma mixture of methyl parahydroxybenzoate
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`and propyl parahydroxybenzoate in a ratio of 9/1 expressed in weightd said mixture beingpresent
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`in an amount of more than 0 and less than 1.5 mg/ml of the composition.
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`2.
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`(Previously presented) The liquid pharmaceutical composition according to claim 1,
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`wherein the composition is aqueous.
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`3.
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`4.
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`5.
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`(Canceled)
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`(Canceled)
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`(Currently amended) The liquid pharmaceutical composition according to claim [[4]] 1,
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`wherein the amount of p—hydroxybenzoate esters is in the range of 0.0001 and [[1,4]] _1_._§ mg/ml
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`of the composition.
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`6.
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`(Withdrawn) The liquid pharmaceutical composition according to claim 1, wherein the
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`pharmaceutical composition contains an amount of thimerosal in the range of 0.0001 and 0.05
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`mg/ml of the composition.
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`7.
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`(Withdrawn) The liquid pharmaceutical composition according to claim 1, wherein the
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`pharmaceutical composition contains an amount of chlorhexidine acetate in the range of 0.0001
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`and 0.05 mg/ml of the composition.
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`2
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`Apotex (11311201900400) Ex. 1025, p. 002
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`Apotex (IPR2019-00400) Ex. 1025, p. 002
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`8.
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`(Withdrawn) The liquid pharmaceutical composition according to claim 1, wherein the
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`pharmaceutical composition contains an amount of benzylalcohol in the range of 0.0001 and 10
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`mg/ml of the composition.
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`9.
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`(Withdrawn) The liquid pharmaceutical composition according to claim 1, wherein the
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`pharmaceutical composition contains an amount of benzalkonium chloride in the range of 0.0001
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`and 0.05 mg/ml of the composition.
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`10.
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`(Withdrawn) The liquid pharmaceutical composition according to claim 1, wherein the
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`active substance is cetirizine.
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`1 1.
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`(Canceled)
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`12.
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`(Previously presented) The liquid pharmaceutical composition according to claim 1,
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`wherein the composition is in the form of oral solutions, nasal drops, eye drops or ear drops.
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`13.
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`(Canceled)
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`14.
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`(Previously Presented) The liquid pharmaceutical composition according to claim 13,
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`wherein the pharmaceutically acceptable salt of levocetirizine is a hydrochloride salt.
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`15.
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`(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
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`0.75 mg/ml.
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`16.
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`(Canceled)
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`17.
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`(Previously presented) The liquid pharmaceutical composition according to claim 1,
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`which composition comprises levocetirizine or a pharmaceutically acceptable salt that is at least
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`95% by weight of the levorotatory enantiomer of cetirizine.
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`18.
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`(Withdrawn) A method of making a liquid pharmaceutical composition according to
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`claim 1 comprising combining,
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`a)
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`cetirizine, levocetirizine, efletirizine, or a pharmaceutically acceptable salt of
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`cetirizine, levocetirizine, or efletirizine, and
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`3
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`Apotex (IPR2019-00400) EX. 1025, p. 003
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`Apotex (IPR2019-00400) Ex. 1025, p. 003
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`

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`b)
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`parahydroxybenzoate ester in an amount of more than 0 and less than 1.5 mg/ml
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`of the composition.
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`19.
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`(Withdrawn) The method according to claim 18, comprising mixing levocetirizine or a
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`pharmaceutically acceptable salt thereof with a mixture of methyl p—hydroxybenzoate and propyl
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`p~hydroxybenzoate.
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`20.
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`(Withdrawn) The method according to claim 19, comprising mixing a pharmaceutically
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`acceptable salt of levocetirizine with a mixture of methyl p~hydroxybenzoate and propyl p-
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`hydroxybenzoate, wherein the methyl p-hydroxybenzoate and propyl p—hydroxybenzoate are
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`present in a ratio of 9: 1.
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`21.
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`(Withdrawn) The method according to claim 20, wherein the pharmaceutically acceptable
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`salt of levocetiriZine is a hydrochloride salt.
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`22.
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`(Withdrawn) In a method of treating a patient with cetirizine, levocetirizine, efletirizine,
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`or a pharmaceutically acceptable salt of cetirizine, levocetirizine, or efletirizine, the improvement
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`comprising administering a liquid composition according to claim 1.
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`23.
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`(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—
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`hydroxybenzoate and propyl p—hydroxybenzoate.
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`24.
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`(Withdrawn) The method according to claim 23, wherein the pharmaceutically acceptable
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`salt of levocetirizine is a hydrochloride salt.
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`25.
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`(Withdrawn) The method according to claim 24, wherein the hydrochloride salt of
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`levocetirizine is present in amount of 0.5 mg/ml and the mixture of methyl p—hydroxybenzoate
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`and propyl p—hydroxybenzoate is present in amount of 0.75 mg/ml.
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`26.
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`(Withdrawn) The method according to claim 25, wherein the methyl p-hydroxybenzoate
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`and propyl p-hydroxybenzoate are present in a ratio of 9:1 by weight.
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`4
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`Apotex (11311201900400) Ex. 1025, p. 004
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`Apotex (IPR2019-00400) Ex. 1025, p. 004
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`REMARKS
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`Claims 1-26 are pending in this case. Claims 18-26 are withdrawn as directed to the non—
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`elected Group II and Group III inventions. Claims 6-10 are withdrawn as directed to non-elected
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`species.
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`The limitations of claims 4 and 11 have been incorporated into claim 1, and claims 4 and
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`11 have been canceled accordingly. Claims 3, 13, and 16 have been canceled as redundant in
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`view of the amendment to claim 1. Claim 5 has been amended to depend from claim 1, and to
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`correct a typographical error. Support for this amendment is found in the specification as
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`originally filed at page 4, line 25-28. The claims remaining under consideration are 1, 2, 5, 12,
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`14, 15, and 17. In the prior response, it was stated that the elected species was covered by claims
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`1-5 and 11. As the elected species is also covered by claims 12, 14, 15, and 17, it is requested
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`that those claims also be considered at this time.
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`Oath/Declaration
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`The examiner’s objection to the Declaration submitted in this application is respectfully
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`not understood. The Declaration has two alterations on the second page, one to inventor Claire
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`Poulain’s citizenship and the other to her address. In both cases, the inventor’s dated signature
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`appears immediately adjacent to the alterations. Thus, the date “28 June 07” and her signature
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`“C Poulain” appear three times on that page: once in the space for the Inventor’s signature, once
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`next to the corrected citizenship, and once next to the corrected address. Applicants respectfully
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`request the Examiner to explain what else, if anything, is required.
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`Claim rejection —- 35 USC 112
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`The claims were rejected as indefinite with respect to the use of “or” in two separate
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`instances in claim 1. This language has been deleted from amended claim 1, thereby overcoming
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`this ground of rejection.
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`Claim rejection -— 35 USC 103
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`The present invention is generally directed to a liquid pharmaceutical composition
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`comprising an active ingredient and a preservative. Pursuant to the amendments herein, the
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`5
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`Apotex (IPR2019-00400) Ex. 1025, p. 005
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`Apotex (IPR2019-00400) Ex. 1025, p. 005
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`present claims are directed to the liquid composition wherein the active ingredient is
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`levocetirizine or a pharmaceutically acceptable salt thereof, and the preservative is a mixture of
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`methyl parahydroxybenzoate and propyl parahydroxybenzoate in a ratio of 9/1 expressed in
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`weight, the mixture being present in an mount of more than 0 and less than 1.5 mg/ml of the
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`composition. The amendments find support in the specification at least at page 3, lines 3-13;
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`page 4, lines 3-5; and page 4, lines 25-28.
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`The claims stand rejected as obvious over Deitrich, (US 2004/0058896 A1). Dietrich is
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`directed to a pharmaceutical compositions in which a coated pellet of an active ingredient can
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`retain a desired functionality, even when subjected to further processing. In particular, Dietrich
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`is directed to a preparation made of coated pellets of active ingredients in which the
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`functionalities of the pellet coatings are maintained when the pellets are processed to dosage
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`forms, such as by being shaped into tablets with excipients (Dietrich paras. [0002]—[0003]).
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`Dietrich teaches (para. [0004]) that this can be accomplished by a preparation in which an active
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`ingredient is essentially uniformly dispersed in an excipient matrix composed of one or more
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`excipients selected from the group of fatty alcohol, triglyceride, partial glyceride and fatty acid
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`ester. The composition of Dietrich is not limited to any particular active ingredient; in fact,
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`Dietrich’s list of possible active ingredients spans page 2, paragraph [0013] — page 18, paragraph
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`[0401] of the reference. Hundreds of compounds are listed. Levocetirizine is one of the active
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`ingredients listed, but it is not included in any of the examples or otherwise singled out.
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`Preservatives are discussed only at paragraph [043 9]. Nothing in that discussion suggests to one
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`skilled in the art to use as a preservative a mixture of methyl parahydroxybenzoate and propyl
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`parahydroxybenzoate in a ratio of 9/1 expressed in weight as presently claimed.
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`Dietrich’s discussion of preservatives is part of a broader discussion of general
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`excipients, also including flavorings, buffers, and emulsifiers, and the general amounts of each
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`that can be used in the formed tablets. With regard to preservatives, Dietrich says, “The
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`proportion depends on the preservative used and is normally from 0.1 to 4% by weight based on
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`the solution or suspension ready for use.” This is not a teaching of the use of the specific
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`preservatives, in the specific proportions, with the particular active ingredient, as set forth in the
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`amended claims. Indeed, Dietrich’s broad disclosure teaches the opposite of the claimed
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`invention, namely, that the choice of preservatives and their quantities is not critical. By
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`6
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`Apotex (IPR2019-00400) EX. 1025, p. 006
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`Apotex (IPR2019-00400) Ex. 1025, p. 006
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`contrast, one aspect of the present invention is based on the discovery that the selection of the
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`particular combination of preservatives and their proportion is indeed critical to the long term
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`stability of this particular active ingredient.
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`One skilled in the art, searching for a solution to the problem of the stability of
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`levocetirizine would not have turned to Dietrich, which teaches how to protect the functionalities
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`of pellet coatings when the pellets are compressed or otherwise processed into tablets, or used in
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`other pharmaceutical preparations. There is no motivation in the reference to choose
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`levocetirizine as the active ingredient, as required in the amended claims, from among Dietrich’s
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`long list of possible active ingredients, or to use the particular preservatives in the particular
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`proportions as claimed in the present application.
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`Even if one skilled in the art had read the Dietrich reference, he would not have had the
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`idea to use a reduced amount of preservatives in order to obtain a levocetirizine composition
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`stable over a long period of time. (specification, page 2, lines 11-15)
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`It is respectfully
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`submitted that the claims as amended are not obvious over the Dietrich reference.
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`The applicants’ selection of the particular preservatives and amounts is not merely a
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`routine selection by one of ordinary skill in the art based on the teachings of Dietrich. These
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`particular preservatives and amounts lead to a result that is not suggested by the prior art, i.e.,
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`enhanced stability of the active ingredient, levocetirizine. Dietrich provides no reason to make
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`the particular invention now being claimed, nor does Dietrich provide any teachings from which
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`one of ordinary skill in the art could have reasonably predicted the results.
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`For all of the foregoing reasons, the applicants respectfully request reconsideration and
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`withdrawal of this obviousness rejection. Further, should claim 1 as amended be found to be
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`allowable, it is respectfully requested that withdrawn species claims 69 be considered as well.
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`Date: November 19, 2008
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`Respectfully submitted,
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`/Sandra B. Weiss/
`Sandra B. Weiss
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`Registration No. 30,814
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`Telephone: 312-913—0001
`Facsimile: 312—913-0002
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`McDonnell Boehnen Hulbert & Berghoff LLP
`300 South Wacker Drive
`Chicago, IL 60606—6709
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`7
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`Apotex (IPR2019-00400) EX. 1025, p. 007
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`Apotex (IPR2019-00400) Ex. 1025, p. 007
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