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`Docket No. 200 4_1o1 6A
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`Group Art Unit 1611
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`Examineri Rae, Charlesworth E
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`In re application of
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`Masayo HIGASHIYAMA
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`
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`,/r C
`' as. :s»
`‘~~”
`.
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`Filed on June 30, 2004
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`For: AQUEOUS LIQUID PREPARATIONS AND LIGHT-STABILIZED AQUEOUS
`LIQUID PREPARATIONS
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`DECLARATION UNDER 37 CFR §1.132
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`Honorable Commissioner of
`Patents,
`P.O. Box 1450
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`Alexandria, Virginia 22313-1450
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`Sirs:
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`I, Masayo HIGASHIYAMA, citizen of Japan and residing in
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`Suita—shi, Osaka, Japan, sincerely declare;
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`That my education and employment history is as follows:
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`1.
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`I graduated from Nagoya City University, Japan,
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`Graduate School of Pharmaceutical Sciences,
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`in March 1995,
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`2.
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`I received a Doctor's degree in Engineering from
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`Kyushu Institute of Technology, Japan,
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`in September 2007,
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`and
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`A
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`3. since April 1995 up to this time, I have been an
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`employee of Senju Pharmaceutical Co., Ltd., and engaged
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`in the pharmaceutical research of ophthalmic formulation;
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`That I am a member of the Pharmaceutical Society of Japan
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`since.November 1993, and the Controlled Release Society
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`since January 2002;
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`That I am a co—author of the following papers:
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`1. Yasueda S, Higashiyama M, Yamaguchi M,
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`Isowaki A,
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`Ohtori A; Corneal critical barrier against the
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`penetration of dexamethasone and lomefloxacin
`hydrochloride: evaluation by the activation energy for
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`drug partition and diffusion in cornea, Drug Dev Ind
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`H Pharm., 2007, 33(8), 805-11,
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`2. Higashiyama M,
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`Inada K, Ohtori A, Kakehi K; NMR
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`1
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`MYLAN EX. 1022, Page1
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`MYLAN Ex. 1022, Page1
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`analysis of ion pair formation between timolol and sorbic
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`acid in ophthalmic preparations, J Pharm Biomed Anal.,
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`2007, 43(4), 1335-42,
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`3. Higashiyama M, Tajika T,
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`Inada K, Ohtori A;
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`Improvement of the ocular bioavailability of carteolol by
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`ion pair, J'Ocul Rharmacol Ther., 2006, 22(5), 333-9,
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`Inada K, Ohtori
`4. Yasueda S, Higashiyama M, Shirasaki Y,
`A; An HPLC method to evaluate purity of a steroidal drug,
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`loteprednol etabonate, J'Rharm Biomed Anal., 2004, 36(2),
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`g
`309-16, and
`Improvement
`Inada K, Ohtori A, Tojo K:
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`5. Higashiyama
`of the ocular bioavailability of timolol by sorbic acid,
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`Int J Pharm., 2004, 272(l—2), 91-8;
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`That I am the sole inventor of the above-identified U.S.
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`patent application SN 10/500,354; and
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`That I conducted the following experiment to demonstrate
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`the unexpected superior effect of the present invention that
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`(+)—
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`(S)—4—[4—[(4—chlorophenyl)(2—pyridyl)methoxylpiperidino]butyric
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`acid and a pharmacologically acceptable acid addition salt
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`thereof, particularly bepotastine besilate, can be light-
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`stabilized in water by adding water—soluble metal chloride,
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`the
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`results of which follow hereunder.
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`ggpgriment
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`Effect of water—soluble metal chloride on light—stability of
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`bepotastine besilate in aqueous solution as compared to the
`effect of glucose or mannitol
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`Test method
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`The aqueous liquid preparations (Formulations 7, 18 and 19)
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`shown in the following Table 1, which contained bepotastine
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`besilate, were prepared according to conventional methods and
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`filled in glass ampoules by 5 mL each. Using the Xenon long—life
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`fade meter
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`(FAL-25AX—Ec manufactured by SUGA TEST INSTRUMENTS Co.,
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`Ltd.), a light corresponding to not less than 200 W-h/n3 in a
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`total near—ultraviolet radiation energy was irradiated
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`MYLAN EX.-1022, Page2
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`MYLAN Ex. 1022, Page2
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`(irradiation time: 23-34 hr), and the appearance of each
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`formulated liquid preparation was observed. The amount of light
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`exposure was measured by a quinine chemical actinometry system
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`described in the Drug Approval and Licensing Procedures in Japan
`2001.
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`Formulation
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`bepotastine besilate
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`sodium dihydrogen
`phosphate dihydrate
`sodium chloride
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`glucose — 3-3
`mannitol —
`benzalkonium chloride
`o_oo5 .
`o_oo5 .
`sodium hydroxide
`S:;:::ie
`suitable amount
`total ‘amount
`100 mL
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`o_oo5 .
`suitable amount
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`irradiation
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`appearance after ligh
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`tpale—yellow black green,
`and
`containing
`precipitate
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`black green,
`containing
`precipitate
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`Test results
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`The appearance after light irradiation did not change from
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`that immediately after preparation and was pale yellow and clear
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`for Formulation 7, comprising 0.6 w/v% sodium chloride. Meanwhile,
`the appearance after light irradiation turned black green for
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`Formulation 18 and Formulation 19, comprising 3.3 w/v% glucose
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`and 3.3 w/v% mannitol, and a precipitate was observed. The
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`results indicate that a water—soluble metal chloride in a light
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`stabilizing effective amount
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`improves light—stability of
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`bepotastine besilate, and saccharides such as glucose and
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`mannitol do not improve light—stability of bepotastine besilate.
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`I further declare that all statements made herein of my own
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`knowledge are true and that all statements made on information
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`and belief are believed to be true; and further that these
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`statements were made with the knowledge that willful false
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`MYLAN EX. 1022, Page3
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`MYLAN Ex. 1022, Page3
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`statements and the like so made are punishable by fine or
`imprisonment, or both, under Section 1001 of Title 18 of the
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`United States Code and that such willful false statements may
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`jeopardize the validity of the application or any patent issuing
`thereon.
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`Signed at.C%qAh Japan on this «K2 day of December, 2008
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`.' .
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`Masayo HIGASHIYAMA
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`MYLAN Ex; 1022, Page4
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`MYLAN Ex. 1022, Page4