43
`
`
`
`IN THE UNITED STATES EATENT AND TRADEMARK OFFICE
`
`In re application of
`
`Masayo HIGASHIYAMA
`
`Docket No. 2004_1016A
`
`Serial No. 10/500,354
`
`Group Art Unit 1614
`
`Filed on June 30, 2004
`
`_
`
`2
`
`Examiner: Rae, Charlesworth E
`
`For: AQUEOUS LIQUID PREPARATIONS AND LIGHT-STABILIZED AQUEOUS
`LIQUID PREPARATIONS
`
`DECLARATION UNDER 37 CFR §1.132
`
`L
`
`Honorable Commissioner of
`Patents,
`P.O. Box 1450
`
`Alexandria, Virginia 22313-1450
`
`Sirs:
`
`I, Masayo HIGASHIYAMA, citizen of Japan and residing in
`
`Kobe—shi, Hyogo—ken, Japan, sincerely declare;
`
`That my education and employment history is as follows:
`
`1.
`
`I graduated from Nagoya City University, Japan,
`
`Graduate School of Pharmaceutical Sciences,
`
`in March 1995,
`
`. 2.
`
`I received a Doctor's degree in Engineering from
`
`Kyushu Institute of Technology, Japan,
`and
`
`in September 2007,
`
`3. since April 1995 up to this time,
`
`I have been an
`
`employee of Senju Pharmaceutical Co.; Ltd., and engaged
`
`in the pharmaceutical research of ophthalmic formulation;
`
`That I am a member of the Pharmaceutical Society of Japan
`
`since November 1993, and the Controlled Release Society
`
`since January 2002;
`
`That I am a co—author of the following papers:
`
`1. Yasueda S, Higashiyama M, Yamaguchi M,
`
`Isowaki A,
`
`Ohtori A; Corneal critical barrier against the
`
`penetration of dexamethasone and lomefloxacin
`
`hydrochloride: evaluation by the activation energy for
`
`drug partition and diffusion in cornea, Drug Dev Ind
`
`Pharm., 2007, 33(8), 805-11,
`
`2. Higashiyama M,
`
`Inada K, Ohtori A, Kakehi K; NMR
`
`1
`
`MYLAN EX. 1019, Page 11
`
`MYLAN Ex. 1019, Page 11
`
`
`
`
`
`IN THE UNITED STATES EATENT AND TRADEMARK OFFICE
`
`In re application of
`
`Masayo HIGASHIYAMA
`
`Docket No. 2004_1016A
`
`Serial No. 10/500,354
`
`Group Art Unit 1614
`
`Filed on June 30, 2004
`
`_
`
`2
`
`Examiner: Rae, Charlesworth E
`
`For: AQUEOUS LIQUID PREPARATIONS AND LIGHT-STABILIZED AQUEOUS
`LIQUID PREPARATIONS
`
`DECLARATION UNDER 37 CFR §1.132
`
`L
`
`Honorable Commissioner of
`Patents,
`P.O. Box 1450
`
`Alexandria, Virginia 22313-1450
`
`Sirs:
`
`I, Masayo HIGASHIYAMA, citizen of Japan and residing in
`
`Kobe—shi, Hyogo—ken, Japan, sincerely declare;
`
`That my education and employment history is as follows:
`
`1.
`
`I graduated from Nagoya City University, Japan,
`
`Graduate School of Pharmaceutical Sciences,
`
`in March 1995,
`
`. 2.
`
`I received a Doctor's degree in Engineering from
`
`Kyushu Institute of Technology, Japan,
`and
`
`in September 2007,
`
`3. since April 1995 up to this time,
`
`I have been an
`
`employee of Senju Pharmaceutical Co.; Ltd., and engaged
`
`in the pharmaceutical research of ophthalmic formulation;
`
`That I am a member of the Pharmaceutical Society of Japan
`
`since November 1993, and the Controlled Release Society
`
`since January 2002;
`
`That I am a co—author of the following papers:
`
`1. Yasueda S, Higashiyama M, Yamaguchi M,
`
`Isowaki A,
`
`Ohtori A; Corneal critical barrier against the
`
`penetration of dexamethasone and lomefloxacin
`
`hydrochloride: evaluation by the activation energy for
`
`drug partition and diffusion in cornea, Drug Dev Ind
`
`Pharm., 2007, 33(8), 805-11,
`
`2. Higashiyama M,
`
`Inada K, Ohtori A, Kakehi K; NMR
`
`1
`
`MYLAN EX. 1019, Page 11
`
`MYLAN Ex. 1019, Page 11
`
`
`
`analysis of ion pair formation between timolol and sorbic
`
`acid in ophthalmic preparations, J Pharm Biomed Anal.,
`
`2007, 43 (4) , 1335-42‘,
`
`3. Higashiyama M, Tajika T,
`
`Inada K, Ohtori A;
`
`Improvement of the ocular bioavailability of carteolol by
`
`ion pair, J Ocul Pharmacol Ther., 2006, 22(5), 333-9,
`
`4. Yasueda S, Higashiyama M, Shirasaki Y,
`
`Inada K, Ohtori
`
`‘ A; An HPLC method to evaluate purity of a steroidal drug,
`
`loteprednol etabonate, J Pharm Biomed Anal., 2004, 36(2),
`
`309-16;'and
`
`5. Higashiyama M,
`
`Inada K, Ohtori A, Tojo K;
`
`Improvement
`
`of the ocular bioavailability of timolol by sorbic acid,
`
`Int J Pharm., 2004, 272(1—2), 91-8;
`
`That I am the sole inventor of the above—identified U.S.
`
`patent application SN 10/500,354; and
`
`That I conducted the following experiments 1-4 to
`
`demonstrate the unexpected superior effect of the present
`
`invention that
`
`(+)—(S)—4—{4-[(4—chlorophenyl)(2-
`
`pyridyl)methoxy]piperidino]butyric acid and a pharmacologically
`
`acceptable acid addition salt thereof, particularly bepotastine
`
`besilate, can be light—stabili2ed in water by adding water-
`
`soluble metal chloride,
`
`the results of which follow hereunder.
`
`ggggriments
`
`Experiment 1 Effect of water—soluble metal chloride on light-
`
`stability of bepotastine besilate
`Test method
`
`The aqueous liquid preparations (Formulations 1-6)
`
`shown in
`
`the following [Table 1], which contained bepotastine besilate,
`were prepared according to conventional methods and filled in
`
`glass ampoules by 5 mL each. Using a xenon long-life fade meter
`
`(FAL—25AX—Ec manufactured by SUGA TEST INSTRUMENTS Co., Ltd.), a
`
`light corresponding to not less than 500 W-h/HF in a total near-
`ultraviolet radiation energy was irradiated (irradiation time:
`
`23-34 hr), and the appearance of each formulated liquid
`
`MYLAN EX. 1019, Page 12
`
`MYLAN Ex. 1019, Page 12
`
`
`
`preparation was observed. The amount of light exposure was
`
`measured by a quinine chemical aotinometry system described in
`
`the Drug Approval and Licensing Procedures in Japan 2001.
`
`Table 1
`
`1.5 g
`
`sodium
`
`chloride 1-
`
`0.3 g
`
`1o
`
`potassium
`chloride
`calcium
`chloride
`
`2H2O
`sodium
`
`hydroxide
`total
`amount
`
`suitable
`
`suitable
`
`suitable suitable
`
`suitable
`
`suitable
`
`amount
`
`amount
`
`amount
`
`amount
`
`amount
`
`amount
`
`100 mL .
`
`Test results
`
`The appearance after light irradiation was black green in
`
`Formulation 1, and a precipitate was observed.
`
`It was slightly
`
`dark green - pale yellow in Formulation 2, and a precipitate was
`
`slightly observed. The appearance of Formulations 3-6 did not
`
`change from that immediately after preparation and were pale
`
`yellow and clear. The results indicate that addition of a water—
`
`soluble metal chloride in not less than 0.2 w/v% improves
`
`stability of bepotastine besilate under light irradiation
`conditions.
`
`Experiment 2 Effect of boric acid and glycerin on light-stability
`
`of bepotastine besilate
`Test method
`
`The aqueous liquid preparations (Formulations 7—9)
`
`shown in
`
`the following [Table 2], which contained bepotastine besilate,
`were prepared according to conventional methods and processed in
`
`the same manner as in Experiment 1, and the appearance of each
`
`formulated liquid preparation was observed.
`
`MYLAN EX. 1019, Page 13
`
`MYLAN Ex. 1019, Page 13
`
`
`
`7
`—“
`bepotastine be silate
`1.5 g
`1.5 g
`sodium dihydrogen
`phosphate dihydrate
`
`Table 2
`
`0.1 g
`
`-
`1.5 g
`
`
`
`
`
`
`
`1.0 g
`
`0.5 g
`
`j b
`
`enzalkonium chloride
`sodium hydroxide
`
`g
`suitable
`amount
`
`g
`suitable
`amount
`
`g
`suitable
`amount
`
`
`
`100 mL
`100 mL
`m
`
`Test results
`
`The appearance after light irradiation did not change from
`
`"that imediately after preparation and was pale yellow and clear
`
`for Formulation 7 comprising sodium chloride, but black green for
`Formulations 8 and 9 comprising boric acid and glycerin and a‘
`precipitate was observed. The results indicate that addition of '
`
`boric acid and glycerin fails to improve stability of bepotastine
`
`besilate under light irradiation conditions.
`
`Experiment 3 Effect of pH and bepotastine besilate concentration
`
`on light-stability of bepotastine besilate
`Test method
`
`The aqueous liquid preparations (Formulations 10-12)
`
`shown
`
`in the following [Table 3], which contained bepotastine besilate,
`
`were prepared according to conventional methods and processed in
`
`the same manner as in Experiment 1, and the appearance of each
`
`formulated liquid preparation was observed.
`
`MYLAN EX. 1019, Page 14
`
`MYLAN Ex. 1019, Page 14
`
`
`
`Table 3
`
`
`
`1
`
`beP°taStine besilate
`sodium dihydrogen
`
`
`
`
`
`S°di“m °h1°ride @113 0.82 g
`benzalkonium chloride O_005 g O_005 g
`0_O05 g
`sodium hydroxide
`suitable suitable suitable
`amount
`amount
`amount
`
`100mL
`100mL
`100 ml»
`he
`
`
`
`
`
`
`
`Test results
`
`The appearance after light irradiation did not change from
`
`that immediately after preparation and was pale yellow and clear
`
`for Formulation 10 (pH 4) and Formulation 11 (pH 8.5) comprising
`
`sodium chloride.
`
`In addition,
`
`the appearance did not change from
`
`that imediately after preparation and was colorless and clear
`
`for Formulation 12 having a bepotastine besilate concentration of
`
`0.1 w/v%. These results and the results of Formulation 7
`
`(pH 6.8)
`
`in Experiment 2 indicate that addition of sodium chloride, which
`
`is a water—soluble metal chloride,
`
`improves light stability of
`
`bepotastine besilate at pH 4-8.5.
`
`In addition,
`
`they indicate that
`
`the 1ight—stabi1ity of bepotastine besilate is improved in the
`
`concentration range of 0.1 w/v% — 1.5 w/v%.
`
`Experiment 4 Effect of bepotastine besilate concentration and pH
`
`on light-stability of bepotastine besilate in aqueous preparation
`
`comprising glycerin
`Test method
`
`The aqueous liquid preparations (Formulations 13-17)
`
`shown
`
`in the following [Table 4], which contained bepotastine besilate,
`
`were prepared according to conventional methods and processed in
`
`the same manner as in Experiment 1, and the appearance of each
`
`formulated liquid preparation was observed.
`
`MYLAN EX. 1019, Page 15
`
`MYLAN Ex. 1019, Page 15
`
`
`
`
`
`Table 4
`
`0.1
`
`g
`
`0.1
`
`g
`
`0.1
`
`g
`
`0.1
`
`g
`
`0.1
`
`g
`
`0.005 g
`
`0.005 g
`
`0.005 g
`
`0.005 g
`
`0.005 g
`
`suitable suitable suitable suitable suitable
`amount
`amount
`amount
`amount
`amount
`
`
`
`
`
`
`be otastine
`
`sodium dihydrogen
`Phosphate
`dihydrate
`
`benzailkonium
`chloride
`
`sodium hydroxide
`’
`
`
`
`
`
`
`
`
`
`100 mL
`100 mL
`100 mL
`100 mi.
`100 mL
`
`
`Test results
`
`.The appearance after light irradiation was pale black green
`
`for Formulation 13 and black green for Formulation 14, and a
`
`precipitate was observed in both Formulations. The results
`
`indicate that addition of glycerin results in coloration of
`
`bepotastine besilate into black green even at a low concentration.
`
`Formulation 15 (pH 4)
`
`turned blue and a precipitate was
`
`observed. Formulation 16 (pH 6.8)
`
`turned black green and a
`
`turned yellow
`precipitate was observed. Formulation 17 (pH 8.5)
`brown but no precipitation was observed. The results indicate
`
`that bepotastine besilate is extremely unstable at a pH near
`
`neutral. The results also indicate that glycerin does not improve
`
`light—stability of bepotastine besilate in the range of pH 4-8.5.
`
`When 3.3 w/v% of glucose or mannitol was added instead of
`
`glycerin of Formulation 16, black green was developed and a
`
`precipitate was observed. These results indicate that a water-
`
`soluble metal chloride improves light—stability of bepotastine
`
`besilate, and isotonic agents such as glycerin, saccharides and
`
`the like do not improve light-stability of bepotastine besilate.
`
`I further declare that all statements made herein of my own
`
`knowledge are true and that all statements made on information
`
`and belief are believed to be true; and further that these
`
`statements were made with the knowledge that willful false
`
`statements and the like so made are punishable by fine or
`
`MYLAN EX. 1019, Page 16
`
`MYLAN Ex. 1019, Page 16
`
`
`
`
`
`imprisonment, or both, under Section 1001 of Title 18 of the
`
`United States Code and that such willful false statements may
`
`jeopardize the validity of the application or any patent issuing
`thereon.
`
`Signed at Kobe, Japan on this étladay of November, 2007
`
`. r.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`Masayo HIGASHIYAMA
`
`MYLAN EX. 1019, Page 17
`
`MYLAN Ex. 1019, Page 17
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