[N THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`In re application of
`
`Masayo HIGASHIYAMA
`
`Serial No. 10;"500,354
`
`Filed June 30, 2004
`
`AQUEOUS LIQUID PREPARATIONS
`AND LIGHT-STABILIZED AQUEOUS
`LIQUID PREPARATIONS
`
`Confirmation No. 2612
`
`Group Art Unit 161 l
`
`Attorney Docket No. 2004_1016A
`
`:
`
`:
`
`Examiner Charlesworth E. Rae
`
`Mail Stop: Amendment
`
`AMENDMENT
`
`Commissioner for Patents
`
`P.O. Box 1450
`
`Alexandria, VA 22313-1450
`
`Sir:
`
`Responsive to the Official Action dated August 5, 2008, the time for responding thereto
`
`being extended for two months in accordance with a Petition for extension submitted
`
`concurrently herewith, please amend the above-identified application as follows:
`
`MYLAN EX. 1023, Page1
`
`MYLAN Ex. 1023, Page1
`
`

`
`Amendments to the Claims
`
`1. (Currently am ended) An aqueous liquid preparation comprising, in an agueous solution,
`
`(+)-(S)-4-[4-[(4-chloropheny1)(2-pyridyl)methoxy]piperidino]butyric acid or a
`
`pharmacologically acceptable acid addition salt thereof, and a water-soluble metal chloride as-i_n
`
`a light-stabilizing fiective amount.
`
`2. (Original) The aqueous liquid preparation of claim 1, wherein the metal chloride has a
`
`concentration selected from the range of a lower limit concentration of 0.15 w/v% and an upper
`
`limit concentration of 1.5 w/'v%.
`
`3. (Previously presented) The aqueous liquid preparation of claim 1, wherein the metal
`
`chloride is at least one kind selected from sodium chloride, potassium chloride and calcium
`
`chloride.
`
`4. (Previously presented) The aqueous liquid preparation of claim 1, wherein the (+)-(S)-4—[4-
`
`[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino]butyric acid or the pharrnacologically
`
`acceptable acid addition salt thereof has a concentration selected from the range of a lower limit
`
`concentration of 0.1 wJ'v% and an upper limit concentration of 2.0 w/v%.
`
`5. (Previously presented)
`
`The aqueous liquid preparation of claim 1, which is an acid
`
`addition salt of (+)-(S)-4-[4-[(4—chlorophenyl)(2-pyridyl)methoxy]piperidino]butyric acid.
`
`6. (Original) The aqueous liquid preparation of claim 5, wherein the acid addition salt is
`
`monobenzenesulfonate.
`
`7. (Previously presented) The aqueous liquid preparation of claim 1, wherein the aqueous
`
`liquid preparation has a pH in the range of 4-8.5.
`
`8. (Previously presented) The aqueous liquid preparation of claim 1, which is an eye drop.
`
`MYLAN EX. 1023, Page2
`
`MYLAN Ex. 1023, Page2
`
`

`
`9. (Previously presented) The aqueous liquid preparation of claim 1, which is a nasal drop.
`
`10. (Currently amended) An aqueous eye drop comprising, in an agueous solution, (+)-(S)-4-
`
`[4—[(4-chIorophenyl)(2-pyridyDmethoxy]piperidino]butyric acid monobenzenesulfonate and
`
`sodium chloride at not less than 0.2 w:'v% and not more than 0.8 w/v% as-i_n_a light-stabilizing
`
`- Hective amount.
`
`11. (Cancelled)
`
`MYLAN EX. 1023, Page3
`
`MYLAN Ex. 1023, Page3
`
`

`
`REMARKS
`
`Favorable reconsideration is respectfully requested in View of the foregoing amendments
`
`and following remarks.
`
`Applicants confirm with thanks the Examiner’s indication during the telephone
`
`conference held on August 18, 2008 that the finality of the last Office Action is withdrawn.
`
`Applicants wish to express their sincere appreciation of the Examiner Charlesworth Rae
`
`and his supervisor, Supervisory Examiner Sharmila Landau, for their courtesy and assistance
`
`provided during the personal interview held on August 21, 2003.
`
`Claims 1 and 10 have been amended as discussed during the interview. Specifically,
`
`claims 1 and 10 have been amended to clarify that the water-soluble metal chloride is contained
`
`in the aqueous solution in a light-stabilizing effective amount. Claims 1 and 10 have also been
`
`amended to clarify that the aqueous liquid preparation comprises the claimed ingredients in an
`
`aqueous solution. Claim 11 is cancelled without prejudice to expedite allowance.
`
`Claims 1-10 solely rejected under 35 USC l03(a) as unpatentable over Koida et al. in
`
`view of Kita et al. and Rernington’s. This ground of rejection is respectfully traversed as applied
`
`to the amended claims.
`
`As discussed during the interview, the combined teachings of the cited references fail to
`
`render obvious the claimed invention as amended. The cited Koida teaches the claimed
`
`compound but does not teach the compound in combination with any water-soluble metal
`
`chloride. The compound is only combined with mannitol, sucrose, lactose and polyethylene
`
`glycol.
`
`Similarly, Kita teaches the claimed compound but does not teach the compound in
`
`combination with any water-soluble metal chloride.
`
`Remington’s teaches a long list of isotonicity agents which can be used to adjust the
`
`isotonicity of eye and nasal drops. Remington fails to disclose any of these agents in
`
`combination with the claimed compound. The inventors have surprisingly discovered that a
`small group of these isotonicity agents, namely the water-soluble metal chlorides, unexpectedly
`
`stabilize the claimed compound from light. The Examiners appeared to be persuaded by these
`
`facts during the interview.
`
`During the interview, the Declaration of record was reviewed to detennine if the
`
`comparative experiments were satisfactory to the Examiners for showing unexpected results for
`
`MYLAN EX. 1023, Page4
`
`MYLAN Ex. 1023, Page4
`
`

`
`the claims. The Examiners appeared satisfied that the experiments support the unexpected light
`
`stability of the claimed compound by the claimed group of water soluble metal chlorides, based
`
`upon the results of Experiment 1 of sodium chloride, potassium chloride and calcium chloride.
`
`Experiment 2 of the Declaration compares the light stabilizing effect of sodium chloride
`
`to the combination of glycerin and boric acid. Experiment 4 compares the light stabilizing effect
`
`of sodium chloride to glycerin. The experiment also discusses replacing glycerin with glucose or
`
`marmitol in Fonnulation 16, however the Table 4 does not reflect this fact.
`
`However the Examiners suggested a side-by-side comparison of the claimed invention
`
`with the closest prior art. The closest prior art is Koida. Koida teaches combining the claimed
`
`compound with marmitol, sucrose, lactose or polyethylene glycol. The Examiners recommended
`
`that a Supplemental Declaration be filed comparing the light stabilizing activity of a claimed
`
`water soluble metal chloride with any one of mannitol, sucrose, lactose or polyethylene glycol.
`
`Submitted herewith is a Supplemental Declaration to establish the unobviousness of the
`
`present invention from Koida et al., by clarifying the description of Experiment 4 in the earlier
`
`Declaration, which was pointed out to be indefinite by the Examiner during the interview.
`
`Koida 'et al. disclose a method of preventing racemization of bepotastine, which includes
`
`addition of sugars to an oral solid preparation. As reported in the Declaration, Formulation 7
`
`(containing 0.6% w/v% sodium chloride) remained pale-yellow and clear even after exposure to
`
`light, but Fonnulation 18 (containing 3.3 W/v% glucose) and Formulation 19 (containing 3.3
`
`w:’v% mannitol) both turned black green.
`
`It has thus been clearly established that the bepotastine-stabilizing effect achieved by the
`
`addition of water-soluble metal chloride to an aqueous solution containing bepotastine carmot be
`
`achieved by the addition of sugars. As mentioned above, stabilization of bepotastine by the
`
`addition of sugars is different from stabilization of bepotastine by the addition of water-soluble
`
`metal chloride, and those of ordinary skill in the art carmot easily conceive stabilization of
`
`bepotastine achieved by the present invention by the addition of water-soluble metal chloride,
`
`from the technique of Koida et al.
`
`In summary, it is respectfully submitted that the prior art fails to suggest the unexpected
`
`light stabilization of the claimed compound using a water-soluble metal chloride.
`
`MYLAN EX. 1023, Page5
`
`MYLAN Ex. 1023, Page5
`
`

`
`In View of the foregoing, it is believed that each ground of rejection set forth in the
`
`Official Action has been overcome, and that the application is now in condition for allowance.
`
`Accordingly, such allowance is solicited.
`
`Respectfully submitted,
`
`Masayo HIGASHIYAMA
`
`By:
`Warren M. Cheek
`
`Registration No. 33,367
`Attorney for Applicant
`
`WMCfakl
`
`Washington, D.C. 20006-1021
`Telephone (202) 721-8200
`Facsimile (202) 721-8250
`January 5, 2009
`
`MYLAN EX. 1023, Page6
`
`MYLAN Ex. 1023, Page6