IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
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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_1016A
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`Confirmation N0. 2612
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`Group Art Unit 1611
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`Examiner Barbara S. Frazier
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`Mail Stop: AMENDMENT
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`SUPPLEMENTAL AMENDMENT
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`Commissioner for Patents
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`P.O. Box 1450
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`Alexandria, VA 22313-1450
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`Sir:
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`In further response to the final Office Action of November 30, 2011, the Advisory Action
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`of May 2, 2012, and in view of the personal interview with the Examiner held June 26, 2012,
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`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. 1028, Page 1
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`MYLAN Ex. 1028, Page 1
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`

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`U.S. Serial No. 10/500,354
`Attorney Docket No. 2004_l0 1 6A
`September 14, 2012
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`AMENDMENTS TO THE CLAIMS
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`1. (Previously presented) An aqueous liquid preparation consisting essentially of, in an
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`aqueous solution, an active ingredient consisting of (+)-(S)-4-[4-[(4-chlorophenyl)(2-
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`pyridyl)methoxy]piperidino] butyric acid or a pharrnacologically acceptable acid addition salt
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`thereof, and a water-soluble metal chloride in a light-stabilizing effective amount, wherein the
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`metal chloride has a concentration selected from the range of a lower limit concentration of 0.2
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`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. 1028, Page 2
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`MYLAN Ex. 1028, Page 2
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`U.S. Serial No. 10/500,354
`Attorney Docket No. 2004_1016A
`September 14, 2012
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`10. (Currently amended) An aqueous eye drop ''
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`consisting essentially of, in an
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`aqueous solution, (+)-(S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino]butyric acid
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`monobenzenesulfonate, as the only active ingredient, and sodium chloride at not less than 0.2
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`w/v% and not more than 0.8 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. (Previously presented) 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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`pharmacologically 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 selected from the range of
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`a lower limit concentration of 0.2 w/v% and an upper limit concentration of 1.2 w/v%.
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`14. (Previously presented) An aqueous liquid preparation consisting 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, a water-soluble metal chloride in a light-stabilizing effective amount, wherein the metal
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`chloride has a concentration selected from the range of a lower limit concentration of 0.2 w/v%
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`and an upper limit concentration of 1.2 w/v%, benzalkonium chloride, sodium
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`dihydrogenphosphate dihydrate, sodium hydroxide and water.
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`MYLAN EX. 1028, Page 3
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`MYLAN Ex. 1028, Page 3
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`U.S. Serial No. 10/500,354
`Attorney Docket No. 2004_1016A
`September 14, 2012
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`REMARKS
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`Claims 1, 3, 5-10 and 12-14 are pending in this application.
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`Claim 10 has been amended to recite “consisting essentially of’ in order to be consistent
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`with claims 1 and 13.
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`1.
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`Personal Interview
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`Applicant appreciates the courtesies extended to Applicant’s attorneys by Examiner
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`Frazier and Supervisory Examiner Blanchard during the personal interview held June 26, 2012.
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`Applicant’s attorneys traversed the outstanding prior art rejection based upon the
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`arguments presented in the Amendment After Final Rejection filed April 24, 2012, and presented
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`new arguments to traverse the Examiner’s arguments presented in the Advisory Action dated
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`May 2, 2012 (discussed below).
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`Examiner Frazier maintained the rejection, and asserted that even though there is a
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`showing of unexpected results in Example 1 of the specification, and claims 1 and 13 recite
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`“consisting essentially of’ language to exclude Carbopol, the primafacie case of obviousness
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`has not been overcome.
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`In addition, Examiner Frazier stated that she has performed another prior art search, and
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`found that US 2003/0139436 teaches to use a water-soluble metal chloride for light-stabilizing
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`effects.
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`New claim 14 was also discussed. Examiner Frazier stated that she has not fully
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`examined this claim to determine whether it is patentable over the art, but it appears allowable
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`over the references of record.
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`Applicant greatly appreciates the Examiners’ comments, and has considered these
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`comments in preparing this Supplemental 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. § 103(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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`A.
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`The Examiner’s Position
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`The Examiner has asserted that Kita et al. disclose (+)-(S)-4-[4-[(4-chlorophenyl)(2-
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`pyridyl)methoxy]piperidino] butyric acid or a benzenesulfonic acid salt thereof (hereinafter,
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`“bepotastine”), but do not disclose how a composition comprising bepotastine is formulated and
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`MYLAN EX. 1028, Page 4
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`MYLAN Ex. 1028, Page 4
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`l0/500,354
`U.S. Serial No.
`Attorney Docket No. 2004_l0 l 6A
`September l4, 2012
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`do not disclose a composition comprising bepotastine and a water-soluble metal chloride in a
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`light-stabilizing effective amount of 0.2 w/v% to 1.2 w/v%. The Examiner applies Lehmussaari
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`et al. for disclosing sodium chloride and potassium chloride in an amount of 0.01 to 2.0% by
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`weight. See final Office Action, pages 2-3.
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`B.
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`Carbopol
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`Claims l, l0 and l3 each recite the transitional phrase “consisting essentially of’, which
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`limits the scope of a claim to the specified materials or steps and those that do not materially
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`affect the basic and novel characteristic(s) of the claimed invention (see MPEP 2l l l .03).
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`The composition of Lehmussaari et al. requires the inclusion of an ion sensitive,
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`hydrophilic polymer having viscosity, such as Carbopol, to control the formation of the polymer
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`film on the cornea of the eye, and each of the reference’s examples contain Carbopol (please see
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`col. 2, line 57 to col. 3, line 6, and the Examples).
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`Carbopol is degraded by light. This is clear fiom the Chemical Abstract reference dated
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`January 3, l972 enclosed with the Amendment filed April 24, 2012, and the enclosed Declaration
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`under 37 CFR l.l32. As requested by the Examiner, the Chemical Abstract reference is
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`submitted again herewith in an Information Disclosure Statement.
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`As discussed in the Declaration, the reference states “CARBOXYVINYL POLYMERS of
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`the type Carbopol 940. . .and 941 were degraded by light, type 941 presenting the highest
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`DEGRADATION” (emphasis in original). This clearly teaches that it was known that Carbopol
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`is degraded by light well-prior to the U.S. filing date of the present application (2003).
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`Using an ion sensitive, hydrophilic polymer, such as Carbopol, in the aqueous liquid
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`preparation of claim l and the eye drops of claims l0 and l3 would materially affect the basic
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`and novel characteristics of the claimed compositions, because it would introduce a component
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`that degrades in light into a composition that is designed to be “light-stabilized” by a water-
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`soluble metal chloride.
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`As a result, an ion sensitive, hydrophilic polymer is excluded from the aqueous liquid
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`preparation of claim l and the eye drops of claims l0 and 13. Therefore, a person of ordinary
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`skill in the art could not have arrived at the presently claimed invention from the combination of
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`Kita et al., disclosing bepotastine, and Lehmussaari et al., disclosing a metal chloride in a
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`composition with Carbopol, with any reasonable expectation of success.
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`MYLAN EX. 1028, Page 5
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`MYLAN Ex. 1028, Page 5
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`U.S. Serial No. 10/500,354
`Attorney Docket No. 2004_1016A
`September 14, 2012
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`C.
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`Unexpected Results
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`In the Advisory Action, the Examiner has asserted that even though Applicant has
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`demonstrated a critical range in which sodium chloride, potassium chloride or calcium chloride
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`impart a light-stabilizing effect on bepotastine, a person of ordinary skill in the art would have
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`arrived at 0.2-1.2 w/v% of the metal chloride by routine experimentation.
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`However, under MPEP 2144.05.Il.B, “[a] particular parameter must first be recognized as
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`a result-effective variable, i.e., a variable which achieves a recognized result, before the
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`determination of the optimum or workable ranges of said variable might be characterized as
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`routine experimentation”.
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`The Lehmussaari et al. reference provides no teaching that varying the salt concentration
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`would be helpful for light-stabilization or viscosity optimization. The reference states,
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`“[a]ccording to the invention we have shown that it is the amount of polymer in the
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`composition, rather than the viscosity of the composition as such, which are important from
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`the point of view of obtaining good absorption of drug into the eye”. Fig. 3 shows that by using
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`the same amount of polymer, in compositions that have different viscosities, the compositions
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`provide for substantially the same absorption. Fig. 4 shows that compositions containing
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`different amounts of polymer but the same viscosities and pH’s have stronger absorption over the
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`composition with the higher polymer concentration. See col. 2, lines 19-34.
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`One skilled in the art might have recognized that the result-effective variable in the
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`reference is the amount of polymer (carbopol), but could not have recognized at all that the
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`amount of salt is a result-effective variable. Therefore, one skilled in the art would not consider
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`the salt concentration to be a result-effective variable, and would not have determined the
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`optimum concentration by routine experimentation.
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`In addition, in Experimental Example 1 of the specification, Formulation 2, comprising
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`0.1 W/v% of a metal chloride (sodium chloride) fails to light-stabilize bepotastine besilate,
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`because after light irradiation it was slightly dark green-pale yellow and produced a precipitate.
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`On the other hand, Formulations 3-6, comprising 0.2 to 1.18 W/v% of a metal chloride (i.e.,
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`sodium chloride, potassium chloride or calcium chloride), provide an unexpected light-
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`stabilizing effect, because after light irradiation the formulations were pale yellow and clear and
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`no precipitate was formed.
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`MYLAN EX. 1028, Page 6
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`MYLAN Ex. 1028, Page 6
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`U.S. Serial No. 10/500,354
`Attorney Docket No. 2004_1016A
`September 14, 2012
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`The fact that Formulation 2, comprising 0.1 w/v% of a metal chloride (sodium chloride),
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`does not light stabilize the composition, even though it falls within the reference’s broad range,
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`is evidence that the reference’s salt range (0.01-2.0 %) would not be expected to light-stabilize a
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`composition comprising bepotastine.
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`Therefore, the Examiner has failed to consider the showing of unexpected results.
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`D.
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`Conclusion of Non-Obviousness
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`As stated in MPEP 2145, the Examiner must consider all rebuttal arguments and
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`evidence presented by Applicant (citing In re Sam’, 54 F.3d 746, 750, 34 USPQ2d 1684, 1687
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`(Fed. Cir. 1995)).
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`Claims 1, 10 and 13 recite “consisting essentially of”, which clearly excludes the required
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`ingredient of Carpobol of Lehmussaari et al., because it would materially affect the basic and
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`novel characteristics of the claimed invention.
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`Furthermore, the present specification demonstrates that a water-soluble metal chloride in
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`an amount of 0.2 w/v% to 1.2 w/v% has an unexpected light-stabilizing effect.
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`Therefore, claims 1, 10 and 13 would not have been obvious over the combination of
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`Kita et al. and Lehmussaari et al.
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`Claims 3, 5-9 and 12 depend from directly or indirectly from claim 1, and thus also
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`would not have been obvious over the references.
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`Accordingly, reconsideration and withdrawal of the rejection are respectfully requested.
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`III.
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`Araki et al.
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`During the interview, the Examiner cited Araki et al. (U.S. Patent Application Publication
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`No. 2003/0139436). Applicant submits the enclosed Declaration, which includes the following
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`remarks to distinguish over this reference.
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`A.
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`The Differences Between Bepotastine and Sitafloxacin
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`Araki et al. disclose a composition comprising sitafloxacin (see abstract). Sitafloxacin
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`has a completely different chemical structure and has completely different chemical properties as
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`compared to bepotastine, which is contained in the claimed compositions.
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`MYLAN EX. 1028, Page 7
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`MYLAN Ex. 1028, Page 7
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`l0/500,354
`U.S. Serial No.
`Attorney Docket No. 2004_l0 l 6A
`September l4, 2012
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`Sitafloxacin has the following chemical structure:
`0
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`N
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`N
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`C1 A/F
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`1::-,\=
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`Bepotastine has the following chemical structure:
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`
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`The compounds clearly have different chemical structures, and Virtually no similar
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`chemical moieties. For example, sitafloxacin has an oxoquinoline core bonded to a cyclopropyl
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`group and a azaspiro[2,4]heptan group. On the other hand, bepotastine does not have any
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`bicyclic or spiro rings, and has separate pyridine and piperidine rings. There are no common
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`chemical groups in the two compounds that would suggest they share any similar activity or have
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`any similar properties.
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`Araki et al. disclose light stabilization of sitafloxacin by sodium chloride. Sodium
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`chloride is generally used for isotonization.
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`Since sitafloxacin has a completely different chemical structure and completely different
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`chemical properties as compared to bepotastine, as discussed above, there is no predictability or
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`correlation of light stabilization of bepotastine by sodium chloride.
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`Therefore, one skilled in the art would not expect a metal chloride to have a light-
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`stabilizing effect on bepostatine in View of the light stabilizing effect of sodium chloride on
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`sitafloxacin.
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`MYLAN EX. 1028, Page 8
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`MYLAN Ex. 1028, Page 8
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`U.S. Serial No. 10/500,354
`Attorney Docket No. 2004_1016A
`September 14, 2012
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`B.
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`There is No Reasonable Expectation that Sodium Chloride Would
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`Suppress Coloration and Precipitation of Bepotastine in view of Araki et al.
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`Araki et al. state the following:
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`[0100] As is understood from Table 1, the aqueous sitafloxacin solutions without sodium
`chloride or containing D-sorbitol in place of sodium chloride undergo reductions in pH,
`transmission and sitafloxacin content and an increase of related substances when
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`irradiated.
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`[0101] However, it is apparent that addition of sodium chloride suppresses these
`unfavorable changes due to irradiation, showing improvement on sitafloxacin stability
`against light.
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`The reference is silent on the suppression of coloration and precipitation. While Araki et
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`al. teach that the addition of sodium chloride results in the suppression of changes in
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`transmission, the reference does not teach or suggest that sodium chloride causes coloration, and,
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`likewise, does not mention the suppression of coloration by sodium chloride.
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`On the other hand, the present application demonstrates that when an aqueous bepotastine
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`solution free of sodium chloride was subjected to light irradiation, the solution turned black
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`green, and a precipitate was produced (see specification, page 8, lines 8-9, Formulation 1). A
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`person of ordinary skill in the art with the goal of reducing or eliminating this phenomenon
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`would not refer to the teachings Araki et al. and would not have been motivated by the teachings
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`to Araki et al. to include a metal chloride in a bepotastine composition, because the reference
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`provides no description regarding coloration and precipitation.
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`Accordingly, there would have been no reasonable expectation of success of arriving at
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`the claimed invention from the disclosure of Araki et al.
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`Therefore, the aqueous liquid preparation of claim 1 and the eye drops of claims 10 and
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`13 would not have been obvious over Araki et al. in view of Kita et al. and/or Lehmussaari et al.,
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`or in view of any other reference.
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`IV.
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`Claim 14
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`Claim 14 recites “consisting of ’. The transitional phrase “consisting of ’ excludes any
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`element, step, or ingredient not specified in the claim (see MPEP 2111.03).
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`As recognized by the Examiner, none of the references disclose an aqueous liquid
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`preparation consisting of, in an aqueous solution, an active ingredient consisting of (+)-(S)-4-[4-
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`[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino] butyric acid or a pharmacologically acceptable
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`MYLAN EX. 1028, Page 9
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`MYLAN Ex. 1028, Page 9
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`U.S. Serial No. 10/500,354
`Attorney Docket No. 2004_1016A
`September 14, 2012
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`acid addition salt thereof, a water-soluble metal chloride in a light-stabilizing effective amount,
`
`wherein the metal chloride has a concentration selected from the range of a lower limit
`
`concentration of 0.2 w/V% and an upper limit concentration of 1.2 w/V%, benzalkonium chloride,
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`sodium dihydrogenphosphate dihydrate, sodium hydroxide and water.
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`Therefore, claim 14 is patentable over the cited references.
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`V.
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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 HIGASHIYAMADigitally signed by /Andrew B.
`B.
`Freistein/
`DN: cn:/Andrew B. Freistein/, o:WLP,
`ou:WLP, emai|:afreistein@wenderoth.
`Date: 2012.09.14 13:06:32 —04'00'
`
`By Freistein/
`Andrew B. Freistein
`
`Registration No. 52,917
`Attorney for Applicant
`
`ABF/cso
`Washington, D.C. 20005-1503
`Telephone (202) 721-8200
`Facsimile (202) 721-825 0
`September 14, 2012
`
`Enclosures: Declaration under 37 CFR 1.132 and Information Disclosure Statement
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`10
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`MYLAN EX. 1028, Page 10
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`MYLAN Ex. 1028, Page 10