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`
`Patent Assignment Abstract of Title
`
`Total Assignments: 1
`Patent #: 8859623 Issue Dt: 10/14/2014
`Filing Dt: 11/14/2013
`Application #: 14080771
`Publication #: NONE
`Pub Dt:
`Intl Reg #:
`PCT #: NONE
`Inventors: Patrick H. Witham, Lauren Mackensie-Clark Bluett, Sailaja Machiraju
`Title: METHODS AND COMPOSITIONS OF STABLE PHENYLEPHRINE FORMULATIONS
`
`Assignment: 1
`Reel/Frame: 031813
`/ 0424 Received: 12/18/2013 Recorded: 12/18/2013 Mailed: 12/19/2013 Pages: 4
`Conveyance: ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS).
`
`Assignors: WITHAM, PATRICK H
`
`MACHIRAJU, SAILAJA
`
`Exec Dt: 11/25/2013
`
`Exec Dt: 11/14/2013
`
`BLUETT, LAUREN MACKENSIE-CLARK
`
`Exec Dt: 11/14/2013
`
`Assignee: PARAGON BIOTECK, INC.
`4640 SW MACADAM AVENUE
`SUITE 80
`PORTLAND, OREGON 97239
`
`Correspondent: WILSON, SONSINI, GOODRICH, & ROSATI
`12235 EL CAMINO REAL
`SUITE 200
`SAN DIEGO, CA 92130
`
`f™ ‰ Šƒ Š• RQQSN q‚ ˆ † U ‡ WRX
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`US Patent & Trademark Office
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`US 8,859,623
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`Due at 3.5 years
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`Due at 7.5 years
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`Due at 11.5 years
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`2
`
`3
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`
`Small
`Entity
`
`Attorney
`Docket No.
`
`0.00
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`0.00
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`0.00
`
`0.00
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`MISSING PAGE(S) FROM THE
`U.S. PATENT OFFICE
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`(Note: This page is not a part of the official USPTO record.)
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`f™ ‰ Šƒ Š• RQQSN q‚ ˆ † W ‡ WRX
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`

`
`METHODS AND COMPOSITIONS OF STABLE PH ENYL-EPH RINE FORMULATIONS
`
`WSGR Docket No. 44630-701.201
`
`|'nVc'nt0'r(s):
`
`Patrick H. Witham,
`Citizen of U.S.A._, Residing at
`5563 Jeffrey Way
`Eugene, OR 97402
`
`Sailaja Machiraju
`Citizen of India, Residing at
`l627"5 NW Sc-hendel Ave, #16D
`
`Beaverton, OR 97006
`
`Lauren Maekensie-Clark Bluett
`
`Citizen of U.S.A., Residing at
`2585 SE Martha Ct
`
`Milwaukie, OR 9?222
`
`Assignee:
`
`Paragon BioTec-k, Inc-.
`4640 SW Macadam Ave, Suite 80
`
`Portland, or 97239
`
`Entity:
`
`A small business concern
`
`WER
`
`Rosati
`Wilson Sons:in.i Gecsdricli
`?‘ iii) ."_-"i‘.'
`ii.) N6 3. <'.'2i).l{.I"ii'r]iL.-'\'f.19??
`
`650 Page Mill Road
`Palo Alto, CA 94304
`(650)493-9300 (Main)
`(650) 493-681 I (Facsimile)
`
`Certificate of Electronic Filing
`
`Ihereby certify that the attached Non-Provisional Application and all marked
`attac-hniems are being deposited by Electronic Filing on .\Ioveml1er 14, 2013 by using
`the EFS Web patent tiling system and addressed to C-ornrnissioner for Patents, PO.
`Box 1450, Alexandria, VA 22313-1450.
`
`/\dr1‘ana Serrano
`
`By:
`
`.»9’ldriar.rtar. Serrc.mo,-”
`
`f™ ‰ Šƒ Š• RQQSN q‚ ˆ † X ‡ WRX
`Exhibit 1002- Page 7 of 617
`
`

`
`METHODS AND COMPOSITIONS OF STABLE PHENYLEPHRINE FORMULATIONS
`
`BACKGROUND OF THE INVENTION
`
`[0001] Phenylephrine is a selective o.l -adrenergic receptor agonist used primarily as a decongestant,
`
`as an agent to dilate the pupil, and to increase blood pressure. Phenylephrine is marketed as a
`
`substitute for the decongestant pseudoephedrine, though clinical studies d'iffe'r regarding
`
`phenylephrine's efi'"ect-iveness in this role.
`
`SUMMARY OF THE INVENTION
`
`[0002] In accordance with the present invention, the present invention provide a composition
`
`comprising at least 95% R-phenylephrine hydrochloride and an aqueous buf‘Fer, wherein the
`
`composition su.bstantially maintains an initial chiral purity of R-phenylephrine hydrochloride for at
`
`least 6 months stored between -10 to 10 degree Celsius.
`
`[0003]
`
`In another aspect, provided herein are methods of stabilizing a phenylephrine hydrochloride
`
`composition comprising storing a solution of aqueous R-phenylephrine hydrochloride at less than 10
`
`degree Celsius, wherein the composition substantially maintains the initial chiral purity of R-
`
`phenylephrine hydrochloride for at least 6 months.
`
`[0004] In one aspect, provided herein are methods of assaying chiral purity of R-phenylephrine
`
`hydrochloride, wherein the chiral purity is determined. by chiral column chromatography, optical
`
`rotation, capillary electrophoresis, circular dichroism, or Nuclear Magnetic Resonance.
`
`[0005] In another aspect provides compositions comprising R-phenylephrine hydrochloride, wherein
`
`the composition substantially maintains the initial chiral purity of R-phenylephrine hydrochloride for
`
`at least 6 months.
`
`[0006]
`
`In another aspect provides methods of dilating the pupil comprising administering a
`
`composition comprising R-phenylephrine hydrochloride topically to a mammal, wherein the
`
`composition substantially maintains the initial chiral purity of R-phenylephrine hydrochloride for at
`
`least 6 "months.
`
`[0007] In another aspect provides methods of treating Uveitis in a subject comprising administering
`
`a composition comprising R-phenylephrine hydrochloride to said subject, wherein the composition
`
`substantially maintains the initial chiral purity of R-phenylephrine hydrochloride for at least 6
`
`months
`
`[0008] In another aspect provides methods of performing certain ocular testing such as
`
`ultrasonography, provocative closed angle glaucoma test, Retinoscopy, compromised circulation
`
`(i.e._. blanching test), Refraction, Fundus examination comprising administering a composition
`
`'2'
`
`f™ ‰ Šƒ Š• RQQSN q‚ ˆ † Y ‡ WRX
`Exhibit 1002- Page 8 of 617
`
`

`
`comprising R-phenylephrine hydrochloride, wherein the composition substantially maintains the
`
`initial chiral purity of R-phenylephrine hydrochloride for at least 6 months.
`
`[0009] In another aspect provides method.s of aiding surgical procedures requiring visualization of
`
`the posterior chamber comprising administering a composition comprising R-phenylephrine
`
`hydrochloride to a subject, wherein the composition substantially maintains the initial chiral purity
`
`of R-phenylephrine hydrochloride for at least 6 months.
`
`INCORPORATION BY REFERENCE
`
`[0010] All publications, patents, and patent applications mentioned. in this specification are herein
`
`incorporated. by reference to the same extent as if each individual public-ation, patent, or patent
`
`application was specifically and individually indicated. to be incorporated. by reference.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`[0011] The novel features of the invention are set forth with particularity in the appended claims. A
`
`better understanding of the features and advantages of the present invention will be obtained by
`
`reference to the following detailed description that sets forth illustrative embodiments, in which the
`
`principles of the invention are utilized, and the accompanying drawings of which:
`
`[0012] Figure l shows a HPLC ehromatogram of rac-emic R-phenylephrine hydrochloride by a chiral
`
`column purification (OJ-RH (l 50><4.6) mm). Two peaks at the retention time 5.225 minutes and
`
`6.444 minutes are shown.
`
`[0013] Figure 2 shows a HPL-C chromatogram of the exemplary R-Phenylephrine Hydrochloride
`
`Opthalmic Solution (10%) before storage. The chiral purity was determined to be 99.3% ee based
`
`on the peaks at 5.184 minutes (area: 993 l .84) and at 6.425 minutes (area: 32.5748).
`
`[0014] Figure 3 shows a HPLC ehromatogram of the exemplary R-Phenylephrine Hydrochloride
`
`Opthalmic Solution (10%) stored at 2 to 8 "C after 6 months. The chiral purity was determined. to be
`
`99.3% ee based. on the peaks at 5.089 minu.tes (area: 8454.34) and at 6.363 minutes (area: 30.7874).
`
`[0015] Figure 4 shows a HPLC ehromatogram of the purified. “impurity” which is a S-Phenylephrine
`
`Hydrochloride. The chiral purity was determined to be 82.4% ee based on the peaks at 5.183
`
`minutes (area: 255.971) and at 6.347 minutes (area: 2851.08).
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`[0016] Phenylephrine differs chemically from epinephrine only in lacking one hydroxyl group (OH)
`
`in the four position on the benzene ring. It is a bitter-tasting crystalline material solu.ble in water and
`
`alcohols, with a melting point of 1408-145“ C. Chemically it is Benzenemethanol, 3- hydroxy-or
`
`'3'
`
`f™ ‰ Šƒ Š• RQQSN q‚ ˆ † Z ‡ WRX
`Exhibit 1002- Page 9 of 617
`
`

`
`[(methylamino)methyl]-, hydrochlorid.e or (R)- (-)-m-hydroxy-o.-[methylamino)methyl]benzyl
`
`alcohol hydrochloride with the following chemical structure.
`
`Ho
`
`H OH
`,
`
`H
`N__
`
`CH3
`
`-
`
`HCI
`
`[0017] It is known in the art that a Phenylephrine Hydrochloride solution shou.ld. be stored. protected.
`
`from light. The benzylic hydrogen is acid.ic and can be d.eprotonated easily. The hydroxyl grou.p
`
`may be oxidized to form a carbonyl moiety conjugated with phenyl group, especially with help of
`
`the adjacent basic amino group. Thus, it is known in the art that a Phenylephrine Hydrochloride
`
`solution should be stored protected from light. For example, an insert from a commercially available
`
`Phenylephrine Hydrochloride Ophthalmic Solution provides that the solution should be stored at 20°
`
`to 25 "C (USP controlled. room temperature) and keep container tightly closed.. Do not use if
`
`solution is brown or contains precipitate. (AKORN Package Insert)
`
`[0018] However, a solution under such condition often turns brown over time despite of carefully
`
`keeping container tightly closed. at 20" to 25 "C (USP controlled room temperature). Those packages
`
`containing the brown solution cannot be used and thus create waste.
`
`[0019] The present invention provides the improvement to overcome such instability problem.
`
`[0020] In some embodiments, there are provided a composition comprising at least 95% R-
`
`phenylephrine hydrochloride and. an aqueous buffer for substantially maintaining chiral purity ofR-
`
`phenylephrine hydrochloride for at least 6 months, the improvement comprising storing the
`
`composition between -10 to 10 degree Celsius. In certain embodiments, the composition is stored.
`
`between 2 to 8 degree Celsius.
`
`In certain embodiments, the composition comprises at least 99% or
`
`99.3%, R-phenylephrine hydrochloride.
`
`In certain embodiments, the chiral purity of R-
`
`phenylephrine hydrochloride is at least 95%, 9?'%, 99%, or 99.5% of the initial chiral purity after 6
`
`months.
`
`In certain embodiments, the composition comprises 2.5% W/v or "I 0% wfv R-phenylephrine
`
`hydrochloride by weight.
`
`In Certain embodiments, the composition further comprises a preservative
`
`such as benzalkonium chloride, stearalkonium chloride, polyaminopropyl biguanide, or the like. In
`
`some embodiments, the composition is in a 1-15 ml plastic or glass bottle.
`
`In some embodiments,
`
`the composition is in a glass or plastic bottle of about 2 ml, about 3 ml, about 5 ml, about 10 ml or
`
`about "I 5 ml.
`
`In certain embodiments, the plastic or glass bottle is opaque.
`
`'4'
`
`f™ ‰ Šƒ Š• RQQSN q‚ ˆ † RQ ‡ WRX
`Exhibit 1002- Page 10 of 617
`
`

`
`[0021] In some embod.iments provide method.s of stabilizing a phenylephrine hydrochloride
`
`composition su.ch as a solu.tion of aqueous R-phenylephrine hydrochloride at less than 10 degree
`
`Celsiu.s wherein the composition su.bstantially maintains the initial chiral purity of R-phenylephrine
`
`hydrochlorid.e for at least 6 months.
`
`[0022] In some embodiments provide herein compositions comprising R-phenylephrine
`
`hydrochlorid.e, wherein the composition su.bstantially maintains the initial chiral purity of R-
`
`phenylephrine hydrochloride for at least 6 months.
`
`[0023] In some embodiments, the composition is stored at -10 to 10 degree Celsius. In certain
`
`embodiments, the composition is stored at -5 to 10 degree Celsius. In certain embodiments, the
`
`composition is stored. at 0 to 10 degree Celsius. In certain embodiments, the composition is stored at
`
`2 to 8 degree Celsius.
`
`[0024] The term “substantial” or “substantially “maintains” described herein refers to not more than
`
`15% deviation of the initial purity. In some embodiments, the chiral purity of the composition is at
`
`least 85%, 90%, 95%, 9?%_. 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 993%, 99.8% or
`
`99.9% of the initial chiral purity.
`
`[0025] In some embodiments provide herein methods of assaying chiral purity of R-phenylephrine
`
`hydrochloride, wherein the chiral purity is determined by chiral column chromatography, optical
`
`rotation, capillary electrophoresis, circular dichroism, or Nuclear Magnetic Resonance.
`
`[0026] In certain embodiments, the chiral purity is determined by chiral column chromatography.
`
`Chiral Column Chromatography
`
`[0027] Chiral column chromatography is a Variant of column chromatography in which the
`
`stationary phase contains a single enantiomer of a chiral compound rather than being achiral. The
`
`two enantiomers of the same analyte compound. differ in affinity to the single-enantiomer stationary
`
`phase and. therefore they exit the column at different times.
`
`[0028] The chiral stationary phase can be prepared by attaching a suitable chiral compound. to the
`
`surface of an achiral support such as silica gel, which creates a Chiral Stationary Phase (CSP). Many
`
`common chiral stationary phases are based on oligosac-c-harides such as cellulose or cyc-lodextrin (in
`
`particular with [3-cyc-lodextrin, a seven sugar ring molecule). As with all chromatographic methods,
`
`various stationary phases are particularly suited to specific types of analytes.
`
`[0029] The packing material of the chiral column may be amylose tris(3,5-
`
`dimethylphenylcarbamate), [3-c-yclodextrin, cellobiohydrolase, selector R-(-)—N-(3_,5-
`
`dinitrobenzoyl)-phenylglycine, cellulose tris(3,5-dimethylphenylcarbamate), cellulose tris(3_,5-
`
`dic-hlorophenylcarbamate), or combinations thereof. In some embodiments, the chiral column for
`
`'5'
`
`f™ ‰ Šƒ Š• RQQSN q‚ ˆ † RR ‡ WRX
`Exhibit 1002- Page 11 of617
`
`

`
`analytical purpose is packed with amylose tris(3,5- d.ichlorophenylcarbamate). The column may
`
`have a packing particle of a size of about 3 um to about 50 um. In some embodiments, the column
`
`has a packing particle a size of about 3 um, 5 um, 10 um, 20 um, 30 um, 40 um, or 50 um. In
`
`certain embodiments, the column has a packing particle a size of about 3 um. In some embod.iments,
`
`when using a chiral column system, the first mobile phase is non-polar solvent such as n-hexane, n-
`
`pentane, and. the like, and. the second. mobile phase is polar solvent such as isopropanol, ethanol,
`
`methanol, or the like. In certainly embodiments, the mobile phase comprises small amount of amine
`
`such as ethylened.iamine. The first mobile phase may be present in an amount of about ?'5% to about
`
`95% by volume and the second. mobile phase is present in an amount of about 5% to about 25% by
`
`volume. In some embodiments, the first mobile phase is present in an amount of about 85% by
`
`volume and. the second mobile phase is present in an amount of about 15% by volume with or
`
`Without ethylenediamine.
`
`Other Chiral Compound Analysis Methods
`
`[0030] There are several chiral compound purification and analysis methods available besides chiral
`
`column chromatography. For example, it is known in the art chiral purity can be determined by
`
`optical rotation.
`
`In some embodiments, the chiral purity of R-phenylephrine hydrochloride in the
`
`stabilized compositions and methods thereof can be determined by comparison of optical rotation of
`
`pure R-phenylephrine hydrochloride.
`
`Optical Purity Measured by Optical Rotation
`
`[0031] Molecules with chrial centers cause the rotation of plane polarised light and are said to be
`
`"optically active" (hence the term optical isomers). Enantiomeric molecules rotate the plane in
`
`opposite directions but with the same magnitude. This provides a means ofmeasuring the "optical
`
`purity" or "enantiomerie excess (ee)" of a sample of a mixture of enantiomers.
`
`[0032] Specific rotation is a physical property like boiling point and. can be looked up in references.
`
`It is defined. according to the following equation based. on the experimental measurements: Specific
`
`rotation [u]D = rt,,b,fcl where "am" is the experimentally observed rotation, "c" is the concentration
`
`in g/ml and "1" is the path length of the cell used expressed in dm (10 em).
`
`[0033] A non-raeemic mixture of two enantiomers will have a net optical rotation. It is possible to
`
`determine the specific rotation of the mixture and, with knowledge of the specific rotation of the
`
`pure enantiomer, the optical purity can be d.etermined..
`
`" 0 Optical purity of sample = 100 * (specific rotation of sample) I (specific rotation of a pure
`
`enantiomer)
`
`'6'
`
`f™ ‰ Šƒ Š• RQQSN q‚ ˆ † RS ‡ WRX
`Exhibit 1002- Page 12 of617
`
`

`
`[0034] In some embod.iments, there are provid.ed methods of assaying chiral purity of R-
`
`phenylephrine hydrochloride, wherein the chiral purity is determined by optical rotation. In certain
`
`embodiments, the optical rotation is determined. by comparison of optical rotation of pure R-
`
`phenylephrine hydrochloride.
`
`Capillary electrophoresis
`
`[0035] Capillary electrophoresis (CE), also known as capillary zone electrophoresis (CZE), can be
`
`used to separate ionic species by their charge and frictional forces and hydrodynamic radius.
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`[0036] Capillary electrophoresis (CE) in general offers highly efficient separations. To achieve
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`chiral separation, the capillary is filled. with a separation buffer containing a chiral ad.ditive.
`
`Although many chiral selectors have been used successfully, the most comprehensive separation
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`strategies have been achieved. with highly su.lfated. c-yc-lodextrins. In some embodiments, the chiral
`
`purity of the compositions provided herein is determined by capillary electrophoresis.
`
`In certain
`
`embodiments, the capillary electrophoresis uses cyclodextrin or its derivatives (such as sulfated
`
`cyclodextrins).
`
`Chiral Purity Measured by Circular Dichroism
`
`[0037] Circular dichroism (CD) refers to the differential absorption of left and right circularly
`
`polarized light. This phenomenon is exhibited in the absorption bands of optically active chiral
`
`molecules. CD spectroscopy has a wide range of applications in many different fields. For example,
`
`vibrational circular dichroism, which uses light from the infrared energy region, is used for structural
`
`studies of small organic “molecules, and most recently proteins and DNA.
`
`In general, this
`
`phenomenon will be exhibited in absorption bands of any optically active molecule. As a
`
`consequence_. circular dichroism is exhibited by biological molecules, because of their dextrorotary
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`and. levorotary components. Even more important is that a secondary structure will also impart a
`
`distinct CD to its respective molecules.
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`[0038] Optical rotation and circular dichroism stem from the same quantum mechanical phenomena
`
`and one can be derived. mathematically from the other if all spectral information is provided. In
`
`some embodiments, the chiral purity is determined. by circular dichroism. In certain embodiments,
`
`the chiral purity is determined. by Fourier transform infrared vibrational circular dichroism (FTIR-
`
`VCD). A skilled person in the art can readily apply the general knowledge and procedure to
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`determine chirality of the compositions provided herein.
`
`NMR spectroscopy of stereoisomers
`
`[0039] It is known in the art that NMR spectroscopy techniques can detennine the absolute
`
`configuration of stereoisomers such as cis or trans alkenes, R or S enantiomers, and R,R or RS
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`Exhibit 1002- Page 13 of 617
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`diastereomers. In a mixture of enantiomers, these method.s can help qu.antify the optical purity by
`
`integrating the area under the NMR peak correspond.ing to each stereoisomer. Accuracy of
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`integration can be improved. by inserting a chiral derivatizing agent with a nucleus other than
`
`hydrogen or carbon, then reading the heteronu.clear NMR spectrum: for example fluorine-19 NMR
`
`or phosphorus-31 NMR. Mosher's acid contains a -CF3 group, so ifthe adduct has no other fluorine
`
`atoms, the 19F NMR of a racemic mixture shows just two peaks, one for each stereoisomer. In some
`
`embodiments, the chiral purity of the compositions provided. herein is determined. by Nuclear
`
`Magnetic Resonance Spectroscopy (NMR). In certain embodiments, a chirally pure eomplexing
`
`reagent (i.e., a chiral d.erivatizing agent) is used. in measuring NMR. A skilled. person in the art can
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`readily utilize NMR and any suitable chiral complexing agent to detennine the chirality of the
`
`compositions provid.ed herein.
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`DOSAGE FORMS AND STRENGTHS
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`[0040] In some embodiments, the stabilized compositions provided herein comprise a solution of
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`2.5% wfv or 10% wfv R-phenylephrine hydrochloride by Weight.
`
`In certain embodiments, the
`
`compositions further comprise sodium phosphate monobasic, sodium phosphate dibasic, boric acid
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`and benzall<onium chloride. The followings are non-limited exemplary compositions:
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`[0041] Phenylephrine Hydrochloride Ophthalmic Solution, 2.5% is a clear, colorless to yellowish,
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`sterile topical ophthalmic solution containing phenylephrine hydrochloride 2.5%.
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`[0042] Phenylephrine Hydrochloride Ophthalmic Solution, '1 0% is a clear, colorless to yellowish,
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`sterile topical ophthalmic solution containing phenylephrine hydrochloride 10%.
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`Application of the Stabilized Compositions Comprising R- Phenylephrine hydrochloride
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`[0043] It has been established that Phenylephrine Hydrochloride Ophthalmic Solution is
`
`recommended as a vasoconstrictor, decongestant, and. mydriatic in a variety of ophthalmic
`
`conditions and procedures. Some of its uses are for pu.pillary dilation in u.veitis (to prevent or aid. in
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`the disruption of posterior synechia formation), for many ophthalmic surgical procedures and. for
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`refraction without cycloplegia. Phenylephrine Hydrochloride Ophthalmic Solution may also be used.
`
`for funduscopy and other diagnostic procedures.
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`[0044] For example, R-Phenylephrine is used to dilate the iris through (1-adrenergic stimulation of
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`the iris dilator "muscle. Sympathetic stimulation ofthe ciliary muscle is believed to be inhibitory,
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`decreasing accommodative amplitude. R-Phenylephrine is formulated in an eye drop to dilate the
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`pu.pil in order to facilitate visualization of the retina. It is often used. in combination with tropicamid.e
`
`as a synergist when tropicamide alone is not sufficient. Surprisingly it was found that S-
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`Phenylephrine dilated the eye only slightly more than that was untreated. Thus it is important that an
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`Exhibit 1002- Page 14 of 617
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`

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`eye drop containing Phenylephrine Hydrochloride used for dilation of the pu.pil contains
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`pred.ominantly the R-isomer in order to maintain maximum efficacy of the ophthalmic solution.
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`[0045] Sympathetic innervation leads to pu.pillary dilation. It is innervated by the sympathetic
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`system, which acts by releasing noradrenaline, which acts on 0:1-receptors causing dilation.
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`[0046] The alpha-1 (0.1) adrenergic receptor is a G protein-coupled receptor (GPCR) associated with
`
`the Gq heterotrimeric G-protein. It consists of three highly homologou.s su.btypes, including rim-
`
`, (£113,-, and. um-adrenergic. Catecholamines like norepinephrine (noradrenaline)
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`and. epinephrine (adrenaline) signal through the 0..-adrenergic receptor in the central and peripheral
`
`nervous systems.
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`[0047] Phenylephrine is a selective 0..-adrenergic receptor agonist used primarily as a d.econgestant,
`
`as an agent to dilate the pupil, and to increase blood pressure. Dilation is controlled by the dilator
`
`pupillae, a group of -muscles in the peripheral 2;-’3 of the iris. Sympathetic i'n'nervatio'n begins at the
`
`cortex with the first synapse at the cilliospinal center (also known as Budge's center after German
`
`physiologist Julius Ludwig Budge). Post synaptic "neurons travel down all the Way through the brain
`
`stem and finally exit through the cervical sympathetic chain and the superior cervical ganglion. They
`
`synapse at the superior c-ervic-al ganglion where third-ord.er neurons travel through the carotid plexus
`
`and enter into the orbit through the first division of the trigeminal nerve.
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`[0048] In the anesthetized rats, infusion of large amount of (+)-epinephrine, (+)-"norepinephrine,
`
`epinine, and (-)-or (+')—phenylephri-ne induces tachyphylaxis to vasopressor effect of (-)-epinephrine,
`
`(-)-norepinephrine, and tetraethy1am'mo'niu'm. The tachyphylactic potency of the amines was (-)-
`
`phenylephrine (R-phenylephrine) > epinine > (+')—norepi'nephri'ne = (+')-epinephrine > (+)-
`
`phenylephrine.
`
`[0049] Two ophthalmic formulations, formulated. 10% Phenylephrine hydrochloride (S-isomer) and.
`
`the exemplary invention composition, 10% Phenylephrine hydrochloride (R-isomer) were tested. for
`
`their ocular activity in NZW rabbits. It was observed that formulated. S-isomer showed
`
`minimal d.ilation, responded. to light exposure and. c-onstric-ted. slightly more slowly than the untreated.
`
`eye, where as the exemplary invention composition, 10% Phenylephrine hydrochloride showed
`
`maximal dilation with in '15 min of dosing and the pupil did not respond to light and
`
`remained dilated for 4 hrs.
`
`[0050] According to the above stu.dy it could be postulated that, when an ophthalmic solution of
`
`phenylephrine hydrochloride, (R-isomer) containing S-isomer as an impurity is u.sed for dilation of
`
`pupil, the s-isomer may cau.se the saturation of the a-adrenergic rec-eptors res u.lting in the decrease in
`
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`Exhibit 1002- Page 15 of 617
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`

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`the response of the drug after its administration (tachyphylasis). Furthermore, the presence of S-
`
`isomer in the ophthalmic solution may lead to poor,-*’ delayed. dilation of the pu.pil.
`
`[0051] In some embod.iments provid.e methods of dilating the pupil comprising administering a
`
`composition comprising R-phenylephrine hydrochloride topically to a mammal, wherein the
`
`composition substantially maintains the initial chiral purity of R-phenylephrine hydrochloride for at
`
`least 6 months. It is evident from the literature that the pharmacological evaluation of both R & S-
`
`Phenylephrine hydrochloride is not same. R-Phenylephrine is referenced. as useful synthetic
`
`adrenergic drug.
`
`Uveitis
`
`[0052] Uveitis is, broadly, inflammation of the u.vea. The u.vea consists of the midd.le, pigmented.,
`
`vascular structures of the eye and. includes the iris, ciliary body, and. choroid. Uveitis requires an
`
`urgent referral and thorough examination by an ophthalmologist or Optometrist and urgent treatment
`
`to control the inflammation. Anterior uveitis (iritis) affects the front portion of the eye, intermediate
`
`uveitis (cyelitis) affects the ciliary body, and posterior uveitis (ehoroidi ti s) affects the back portion
`
`of the uvea. Diffuse uveitis affects all portions of the uvea. Anterior uveitis commonly occurs in
`
`conjunction with juvenile rheumatoid arthritis, but does not manifest in all juvenile arthritis patients.
`
`Uveitis is most likely to be present in juvenile arthritis patients with pauciarticular disease (fewer
`
`than five joints involved), a positive anti-"nuclear antibody test, and a "negative rheumatoid factor test.
`
`It has been demonstrated that after phenylephrine hydrochloride ophthalmic solution instillation,
`
`flare intensity and pain were significantly decreased only in eyes with iridocyclitis and without
`
`fibrinoid reaction (FR). The decreasing level of flare intensity, and paralysis of the pupil after
`
`phenylephrine instillation seem to alleviate pain in those eyes. See e.g., Zaczek, et. al., Acta
`
`Ophthalmol Scand. 2000 Oc-t,78(5):5l6-8