IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
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`RESPONSE UNDER 37 CFR § 1.116
`EXPEDITED PROCEDURE
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`EXAMINING GROUP 1611
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`In re application of
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`Masayo HIGASHIYAMA
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`Serial No. 10/500,354
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`Filed June 30, 2004
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`AQUEOUS LIQUID PREPARATIONS AND
`LIGHT-STABILIZED AQUEOUS LIQUID
`PREPARATIONS
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`Attorney Docket No. 2004_l0l6A
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`Confirmation N0. 2612
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`Group Art Unit l6ll
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`Examiner Barbara S. Frazier
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`Mail Stop: AF
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`AMENDMENT AFTER FINAL REJECTION
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`Commissioner for Patents
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`P.O. Box l450
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`Alexandria, VA 22313-1450
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`Sir:
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`In response to the Office Action of November 30, 201 l, the time for responding thereto
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`being extended for two months in accordance with payment of an extension of time fee
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`submitted herewith, please amend the above-identified application as follows:
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`The USPTO is hereby authorized to charge anyfees under 37 C.F.R. §§ 1.16, 1.17, and 1.492, which may be required by this
`paper to Deposit Account No. 23-0975.
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`MYLAN EX. 1032, Page 1
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`MYLAN Ex. 1032, Page 1
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`

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`U.S. Serial No. 10/500,354
`Attorney Docket No. 2004_l0 1 6A
`April 24, 2012
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`AMENDMENTS TO THE CLAIMS
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`1. (Currently amended) An aqueous liquid preparation consisting essentially of, in an aqueous
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`solution, an active ingredient consisting of (+)-(S)-4-[4-[(4-chlorophenyl)(2-
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`pyridyl)methoxy]piperidino] butyric acid or a pharmacologically acceptable acid addition salt
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`thereof, and a water-soluble metal chloride in a light-stabilizing effective amount
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`mere, wherein the metal chloride has a concentration selected from the range of a lower limit
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`concentration of 0.2 w/v% and an upper limit concentration of 1.2 w/v%.
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`2. (Cancelled)
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`3. (Previously presented) The aqueous liquid preparation of claim 1, wherein the metal
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`chloride is at least one kind selected from sodium chloride, potassium chloride and calcium
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`chloride.
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`4. (Cancelled)
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`5. (Previously presented) The aqueous liquid preparation of claim 1, which is an acid addition
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`salt of (+)-(S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino]butyric acid.
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`6. (Original) The aqueous liquid preparation of claim 5, wherein the acid addition salt is
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`monobenzenesulfonate.
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`7. (Previously presented) The aqueous liquid preparation of claim 1, wherein the aqueous
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`liquid preparation has a pH in the range of 4-8.5.
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`8. (Previously presented) The aqueous liquid preparation of claim 1, which is an eye drop.
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`9. (Previously presented) The aqueous liquid preparation of claim 1, which is a nasal drop.
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`MYLAN EX. 1032, Page 2
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`MYLAN Ex. 1032, Page 2
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`U.S. Serial No. 10/500,354
`Attorney Docket No. 2004_l0 l 6A
`April 24, 2012
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`10. (Previously presented) An aqueous eye drop comprising, in an aqueous solution, (+)—(S)-4-
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`[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino]butyric acid monobenzenesulfonate, as the
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`only active ingredient, and sodium chloride at not less than 0.2 w/v% and not more than 0.8
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`w/v% in a light-stabilizing effective amount.
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`1 1. (Cancelled)
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`12. (Previously presented) The aqueous liquid preparation of claim 1, wherein the metal
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`chloride is at least one kind selected from alkali metal chlorides and alkaline earth metal
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`chlorides.
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`13. (Currently amended) An aqueous eye drop consisting essentially of an active ingredient
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`consisting of (+)-(S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino]butyric acid or a
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`pharrnacologically acceptable acid addition salt thereof, which is light-stabilized with a water-
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`soluble metal chloride- wherein the metal chloride has a concentration
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`selected from the range of a lower limit concentration of 0.2 w/v% and an upper limit
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`concentration of 1.2 w/v%.
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`MYLAN EX. 1032, Page 3
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`MYLAN Ex. 1032, Page 3
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`

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`U.S. Serial No. 10/500,354
`Attorney Docket No. 2004_1016A
`April 24, 2012
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`REMARKS
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`Further and favorable reconsideration is respectfully requested in view of the foregoing
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`amendments and following remarks.
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`Entry of the amendments is proper under 37 CFR §1.116, because the amendments place
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`the application in condition for allowance and do not raise any new issue requiring further search
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`and/or consideration. The amendments are necessary and were not earlier presented, because
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`they are made in response to arguments raised in the final rejection. Entry of the amendments is
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`thus respectfully requested.
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`Claims 1 and 13 have been amended to recite “wherein the metal chloride has a
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`concentration selected from the range of a lower limit concentration of 0.2 w/v% and an upper
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`limit concentration of 1.2 w/v%”. Support for these amendments can be found on page 5, lines
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`17-21 of the specification. As a result, claims 2 and 4 have been cancelled.
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`I.
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`Telephonic Interview
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`Applicant appreciates the courtesies extended to Applicant’s attorney by Examiner
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`Frazier during the telephonic interview held April 6, 2012.
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`During the interview, Applicant’s attorney proposed to amend claims 1 and 13 to limit
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`the concentration of the water-soluble metal chloride to 0.2-1.2 w/v%. The Examiner stated that
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`these amendments would overcome the rejection in view of Experimental Example 1 of the
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`specification (comparing Formulation 2 to Formulations 3-6 in Table 1), because this is a critical
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`range that provides unexpected light-stabilizing effects on (+)-(S)-4-[4-[(4-chlorophenyl)(2-
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`pyridyl)methoxy]piperidino] butyric acid (hereinafter, “bepotastine”) or a salt thereof over the
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`art.
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`The Examiner also agreed to enter an Amendment After Final Rejection with these claim
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`amendments. However, she will need to update her prior art search, and did not agree to allow
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`the claims during the interview.
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`In addition, Applicant’s attorney presented a reference stating that Carbopol is degraded
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`by light. The Examiner agreed that a person of ordinary skill in the art would have expected
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`Carbopol to impair the claimed invention, because Carbopol is degraded by light. As a result,
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`Applicant’s attorney maintained the position that using an ion sensitive, hydrophilic polymer,
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`such as Carbopol, in the aqueous liquid preparation of claim 1 and the eye drop of claim 13
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`MYLAN EX. 1032, Page 4
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`MYLAN Ex. 1032, Page 4
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`U.S. Serial No. 10/500,354
`Attorney Docket No. 2004_1016A
`April 24, 2012
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`would materially affect the basic and novel characteristics of the claimed compositions.
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`Applicant’s attorney also pointed out that each example of Lehmussaari et al. (US 5,795,913)
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`includes Carbopol.
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`In addition, Applicant’s attorney stated that (1) Applicant should only be required to
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`demonstrate unexpected results over Kita et al. (US 6,307,052), rather than a combination of Kita
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`et al. and Lehmussaari et al., in View of MPEP 716.02(e)IH; (2) adding a water-soluble metal
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`chloride provides unexpected light-stabilization properties to a composition containing
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`bepotastine based upon Experimental Example 4 of the specification; (3) the compounds
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`disclosed in Lehmussaari et al. do not share any structural similarity and do not share a common
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`structural feature that demonstrates light-stability; (4) the problems addressed by Lehmussaari et
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`al. are completely different from the problems addressed by the present application; and (5) the
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`position taken by the Examiner in the paragraph bridging pages 7-8 of the Office Action is
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`clearly based upon Applicant’s own specification and is therefore impermissible hindsight.
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`The Examiner did not specifically comment on items (1)-(5) above, but requested
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`Applicant to include these items in a formal response to the Office Action.
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`Applicant has carefully considered the Examiner’s comments and suggestions in
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`preparing this Amendment.
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`11.
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`Claim Re°ection Under 35 U.S.C.
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`103
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`The Examiner has rejected claims 1-10, 12 and 13 under 35 U.S.C. § l03(a) as being
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`unpatentable over Kita et al. (US 6,307,052) in view of Lehmussaari et al. (US 5,795,913). As
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`applied to the amended claims, Applicant respectfully traverses the rejection.
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`The Concentration of the Metal Chloride
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`Kita et al. teach a medical composition comprising bepotastine, but the reference does not
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`specifically teach how the composition is formulated and does not specifically teach a water-
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`soluble metal chloride in a light-stabilizing effective amount.
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`As discussed above, claims 1 and 13 have been amended to recite that the concentration
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`of the water-soluble metal chloride is 0.2-1.2 w/v%, and, as agreed during the interview, this is a
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`critical range that provides unexpected light-stabilizing effects over the art. Moreover, claim 10
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`has an even narrower metal chloride concentration of 0.2-0.8 w/v%. Thus, as demonstrated by
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`Experimental Example 1 of the specification, Formulation 2, comprising 0.1 w/v% of a metal
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`MYLAN EX. 1032, Page 5
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`MYLAN Ex. 1032, Page 5
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`U.S. Serial No. 10/500,354
`Attorney Docket No. 2004_1016A
`April 24, 2012
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`chloride (sodium chloride) fails to light-stabilize bepotastine besilate, because after light
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`irradiation it was slightly dark green-pale yellow and produced a precipitate. On the other hand,
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`Formulations 3-6, comprising 0.2 to 1.18 w/v% of a metal chloride (i.e., sodium chloride,
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`potassium chloride or calcium chloride), provide an unexpected light-stabilizing effect, because
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`after light irradiation the formulations were pale yellow and clear and no precipitate was formed.
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`Moreover, sodium chloride, potassium chloride and calcium chloride, as recited in claim
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`3, are generally added to eye drops as tonicity agents. However, as demonstrated in
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`Experimental Example 4 of the specification, glycerin, glucose and mannitol, which are
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`generally used tonicity agents other than metal chlorides, fail to demonstrate a light-stabilizing
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`effect. Therefore, the effect of light-stabilizing an aqueous bepotastine solution with a metal
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`chloride is completely unexpected.
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`Accordingly, as agreed during the interview, the concentration of 0.2-1 .2 w/v% is a
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`critical range that provides unexpected results in terms of light-stabilization over Kita et al. (see
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`MPEP 2144.05.111 and 716.02(e)111).
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`Carbopol
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`In addition, claims 1 and 13 recite the transitional phrase “consisting essentially of”,
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`which limits the scope of a claim to the specified materials or steps and those that do not
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`materially affect the basic and novel characteristic(s) of the claimed invention (see MPEP
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`21 1 1.03).
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`As agreed during the interview, the composition of Lehmussaari et al. requires the
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`inclusion of an ion sensitive, hydrophilic polymer having viscosity, such as Carbopol, to control
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`the formation of the polymer film on the cornea of the eye, and each of the reference’s examples
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`contain Carbopol (please see col. 2, line 57 to col. 3, line 6, and the Examples). However, a
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`person of ordinary skill in the art would recognize that Carbopol is degraded by light, as
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`evidenced by the enclosed Chemical Abstract reference, which states “CARBOXYVINYL
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`POLYMERS of the type Carbopol 940. . .and 941 were degraded by light, type 941 presenting the
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`highest DEGRADATION” (emphasis in original).
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`Therefore, using an ion sensitive, hydrophilic polymer, such as Carbopol, in the aqueous
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`liquid preparation of claim 1 and the eye drop of claim 13 would materially affect the basic and
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`novel characteristics of the claimed compositions. As a result, an ion sensitive, hydrophilic
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`polymer is excluded from the claimed compositions, and a person of ordinary skill in the art
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`MYLAN EX. 1032, Page 6
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`MYLAN Ex. 1032, Page 6
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`U.S. Serial No. 10/500,354
`Attorney Docket No. 2004_l0 1 6A
`April 24, 2012
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`could not have arrived at the presently claimed invention fiom the combination of Kita et al. and
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`Lehmussaari et al. with any reasonable expectation of success.
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`Difference of Problems
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`Furthermore, the objective of Lehmussaari et al. is “to provide an ophthalmic
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`composition with a sufficiently high concentration of poly er to control the formation of the
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`polymer film on the cornea of the eye, but which composition is still fluid enough for ocular
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`topical application” (see col. 1, line 65 to col. 2, line 3).
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`On the other hand, the objective of the claimed invention is to light-stabilize bepotastine
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`or a salt thereof in an aqueous solution. A person of ordinary skill in the art would recognize that
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`the light-stabilization of a drug and the viscosity control of a composition for local
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`administration are completely different problems. Accordingly, there would have been no reason
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`or rationale to combine Kita et al. with Lehmussaari et al. to obtain light-stabilization of
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`bepotastine.
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`Difference in Compounds
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`In addition, Lehmussaari et al. describe, as an active ingredient containing a basic group,
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`about 30 compounds having completely different chemical structures (see col. 3, line 66 to col. 4,
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`line 27). In general, chemical properties, such as light-stability, vary according to the chemical
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`structure. There is no reasonable basis for these compounds, having no structural similarity, to
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`have uniform light-stability from the teachings of the reference. Thus, a person of ordinary skill
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`in the art would not have had any reason to use the compounds disclosed in Lehmussaari et al. to
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`light-stabilize bepotastine, as in the presently claimed invention.
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`Hindsight
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`In the paragraph bridging pages 7-8 of the Office Action, the Examiner has asserted that
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`one skilled in the art would have been motivated to manipulate the amount of salt disclosed in
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`Lehmussaari et al. by routine experimentation in order to optimize the viscosity reducing effects,
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`and such amount would necessarily be a light-stabilizing effective amount, as evidenced by
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`Applicant’s own specification.
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`However, as discussed above, Lehmussaari et al. teach to use an agent that is degraded by
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`light in each example (Carbopol) and teach a wide-range of compounds with no structural
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`similarity and no effect on light-stability. Accordingly, the Examiner’s position is based solely
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`on Applicant’s own specification, which teaches that a water-soluble metal chloride has a light-
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`MYLAN EX. 1032, Page 7
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`MYLAN Ex. 1032, Page 7
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`U.S. Serial No. 10/500,354
`Attorney Docket No. 2004_1016A
`April 24, 2012
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`stabilizing effect on bepotastine. Therefore, the EXaminer’s position is based upon
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`impermissible hindsight reasoning.
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`Conclusion of Non-Obviousness
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`Accordingly, in view of the foregoing amendments and remarks, claims 1, 10 and 13
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`would not have been obvious over Kita et al. in view of Lehmussaari et a1.
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`Claims 3, 5-9 and 12 depend directly or indirectly from claim 1, and thus also would not
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`have been obvious over the references.
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`Therefore, reconsideration and withdrawal of the rejection are respectfully requested.
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`III.
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`Conclusion
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`For these reasons, Applicant takes the position that the presently claimed invention is
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`clearly patentable over the applied references.
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`Therefore, in view of the foregoing amendments and remarks, it is submitted that the
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`rejection set forth by the Examiner has been overcome, and that the application is in condition
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`for allowance. Such allowance is solicited.
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`Respectfully submitted,
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`Masayo HIGASHIYAMA
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`/Andrew B.
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`ou:WLP, emai|:afreis(ein@wenderoth.
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`By FreIsteIn/
`Andrew B. Freistein
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`Registration No. 52,917
`Attorney for Applicant
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`ABF
`Washington, D.C. 20005-1503
`Telephone (202) 721-8200
`Facsimile (202) 721-825 0
`April 24, 2012
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`MYLAN EX. 1032, Page 8
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`MYLAN Ex. 1032, Page 8