00
`
`US005641805A
`
`United States Patent 19
`5,641,805
`Jun. 24, 1997
`[45] Date of Patent:
`Hayakawaetal.
`
`(111 Patent Number:
`
`[54] TOPICAL OPHTHALMIC FORMULATIONS
`FOR TREATING ALLERGIC EYE DISEASES
`
`[75]
`
`Inventors: Eiji Hayakawa, Susono; Masashi
`Nakakura, Shizuoka-ken, both of
`Japan; Stella M. Robertson, Arlington;
`John Michael Yanni, Burleson, both of
`Tex.
`
`[73] Assignees: Alcon Laboratories, Inc., Fort Worth,
`Tex.; Kyowa Hakko Kogyo Co. Ltd.,
`Tokyo, Japan
`
`[21] Appl. No.: 469,729
`
`[22] Filed:
`
`Jun. 6, 1995
`
`Lint, CUS acccccssccsssssscccucnsesssesnseeessssseseess A61K 31/335
`[511
`[52] US. CL.
`cessescssscsscssssonsonssncsrscessssccnssseseececsesseeeeess §14/450
`[58] Biel of Search ou...sssssscesseccesssssssssssseesnees 514/450
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`..eccsccsecsseses 549/354
`10/1989 Lever, Jr. et al.
`4,871,865
`
`5/1990 Lever, Jr. et al...
`eecsscscsseese 514/450
`4,923,892
`5/1992 Oshima et al...cccssssecceoreee 514/450
`5,116,863
`FOREIGN PATENT DOCUMENTS
`
`0048023A2
`0214779A1
`0235796A2
`
`3/1982 European Pat. Off. .
`3/1987 European Pat. Off. .
`9/1987 European Pat. Off.
`.
`
`OTHER PUBLICATIONS
`
`Kamei et al., “Effects of Certain Antiallergic Drugs on
`Experimental Conjunctivitis in Guinea Pigs,” Atarashi
`Ganka, vol. 11(4), pp. 603-605 (1994) (abstract only).
`Kameietal., “Effect of (Z)-11-[3—(Dimethylamino) propy-
`lidene|-6,11-dihydrodibenz[b,e]oxepin—2—acetic
`Acid
`Hydrochloride on Experimental Allergic Conjunctivitis and
`Rhinitis in Rats and Guinea Pigs,” Arzneimittelforschung,
`vol. 45(9), pp. 1005-1008 (1985).
`Ohsima et al., “Synthesis and Antiallergic Activity of
`11+Aminoalkylidene)-6,11,dihydrodibenz[b,e]oxepin
`Derivatives,” J. Medicinal Chemistry, vol. 35(11), pp.
`2074-1084 (1992).
`Sharif et al., “Characterization of the Ocular Antiallergic and
`Antihistaminic Effects of Olopatadine (AL-4943A), a Novel
`Drug for Treating Ocular Allergic Diseases,” J. ofPharma-
`cology and Experimental Therapeutics, vol. 278(3), pp.
`1252-1261 (1996).
`Sharif et al., “Olopatadine (AL~4943A): Pharmacological
`Profile of a Novel Anti-histaminic/Anti-allergic Drug for
`Use in Allergic Conjunctivitis,” Investigative Ophthalmol-
`ogy & Visual Science, vol. 37(3), p. 1027 (1996) (abstract
`only).
`
`Spitalny et al., “Olopatadine Ophthalmic Solution Decreases
`Itching and Redness Associated with Allergic Conjunctivi-
`tis,” Investigative Ophthalmology & Visual Science, vol.
`37(3), p. 593 (1996) (abstract only).
`Yanni et al., “The In Vitro and In Vivo Ocular Pharmacology
`of Olopatadine (AL-4943A), An Effective Anti-allergic/
`Antihistamlinic Agent,” Investigative Ophthalmology &
`Visual Science, vol. 37(3), p. 1028 (1996) (abstract only).
`Zhang et al., “Optically Active Analogues of Ebastine:
`Synthesis and Effect of Chirality on Their Antihistaminic
`and Antimuscarinic Activity,” Chirality, vol. 6(8), pp.
`631-641 (1994).
`Church, “Is Inhibition of Mast Cell Mediator Release Rel-
`evant to the Clinical Activity of Anti-allergic Drugs?,”
`Agents and Actions, vol. 18, 3/4, pp. 288-293 (1986).
`Clegget al., “Histamine Secretion from Human Skin Slices
`Induced by Anti-IgE and Artificial Secretagogues and the
`Effects of Sodium Cromoglycate and Salbutanol,” Clin
`Allergy, vol. 15, pp. 321~328 (1985).
`Hamilton et al., “Comparison of a New Antihistaminic and
`Antiallergic Compound KW 4679 with Terfenadine and
`Placebo on Skin and Nasal Provocation in Atopic Individu-
`als,” Clinical and Experimental Allergy, vol. 24, pp.
`955-959 (1994).
`Ikeda et al., “Effects of Oxatomide and KW-—4679 on
`Acetylcholine-Induced Responses in the Isolated Acini of
`Guinea Pig Nasal Glands,” Int. Arch. Allergy Immunol., vol.
`106, pp. 157-162 (1995).
`Trani et al., “Mast Cell Heterogeneity,” Clinical and Experi-
`mental Allergy, vol. 19, pp. 143-155 (1989).
`Pearce et al., “Effect Disodium Cromoglycate on Antigen
`Evoked Histamine Release in Human Skin,” Clinical Exp.
`Immunol.,vol. 17, pp. 437-440 (1974).
`Siraganian, “An Automated Continuous Flow System forthe
`Extraction and Fluorometric Analysis of Histamine,” Anal.
`Biochem., vol. 57, pp. 383-394 (1974).
`“The Lung,”Scientific Foundations, RavenPress, Ltd., New
`York, Ch. 3.4.11 (1991), Schwartz, pp. 601-615.
`Kamei et al. “Effect of Certain Antirallergic Drugs on
`Experimental Conjunctivitis in Guinea Pigs”, Atarashii
`Ganka 11(4) pp. 603-605 1994 (month unavailable).
`
`Primary Examiner—Jeffrey C. Mullis
`Attorney, Agent, or Firm—Patrick M. Ryan
`
`[57]
`
`ABSTRACT
`
`Topical ophthalmic formulations of the invention contain as
`an active ingredient 11-(3-dimethylaminopropylidene)-6,11-
`dihydrodibenz[b,e]oxepin-2-acetic acid or a pharmaceuti-
`cally acceptable salt thereof. The formulations are useful for
`treating allergic eye diseases such as allergic conjunctivitis,
`vernal conjunctivitis, vernal-keratoconjunctivitis, and giant
`papillary conjunctivitis.
`
`12 Claims, No Drawings
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1007, Page 1
`
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1007, Page 1
`
`

`

`5,641,805
`
`1
`TOPICAL OPHTHALMIC FORMULATIONS
`FOR TREATING ALLERGIC EYE DISEASES
`
`BACKGROUND OF THE INVENTION
`1. Field of the Invention
`The present invention relates to topical ophthalmic for-
`mulations used for treating allergic eye diseases, such as
`allergic conjunctivitis, vernal conjunctivitis, vernal
`keratoconjunctivitis, and giant papillary conjunctivitis.
`More particularly, the present invention relates to therapeu-
`tic and prophylactic topical use of 11-(3-
`dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]
`oxepin-2-acetic acid for treating and/or preventingallergic
`eye diseases.
`2. Description of the Related Art
`Astaught in U.S.Pat. Nos. 4,871,865 and 4,923,892, both
`assigned to Burroughs Wellcome Co.
`(“the Burroughs
`Wellcome Patents”), certain carboxylic acid derivatives of
`doxepin, including 11-(3-dimethylaminopropylidene)-6,11-
`dihydrodibenz[b,e]oxepine-2-carboxylic acid and 11-(3-
`dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]
`oxepine-2(E)-acrylic acid, have antihistamine and
`antiasthmatic activity. These two patents classify the car-
`boxylic acid derivatives of doxepin as mast cell stabilizers
`with antihistaminic action because they are believed to
`inhibit the release of autacoids (i.e., histamine, serotonin,
`and the like) from mast cells and to inhibit directly hista-
`mine’s effects on target tissues. The Burroughs Wellcome
`Patents teach various pharmaceutical formulations contain-
`ing the carboxylic acid derivatives of doxepin; Example 8 (1)
`in both of the patents discloses an ophthalmic solution
`formulation.
`Although both of the Burroughs Wellcome Patents claim
`that the variety of pharmaceutical formulations disclosed are
`effective both for veterinary and for human medical use,
`neither patent contains an example demonstrating that the
`carboxylic acid derivatives of doxepin have activity in
`humans. Example 7 in the Burroughs Wellcome Patents
`demonstrates antihistamine activity in male guinea pigs and
`Example G demonstrates anaphylactoid activity in Wistar
`rats.
`
`It is now well established, however, that the types of mast
`cells which exist in rodents are different from those in
`humans. See, for example, THE LUNG: Scientific
`Foundations, Raven Press, Ltd., New York, Ch. 3.4.11
`(1991). Moreover, mast cell populations exist within the
`same species that differ in phenotype, biochemical
`properties, functional and pharmacological responses and
`ontogeny. These recognized differences in mast cells both
`between and within species are referred to as mast cell
`heterogeneity. See for example, Irani et al., “Mast Cell
`Heterogeneity,” Clinical and ExperimentalAllergy, Vol. 19,
`pp. 143-155 (1989). Because different mast cells exhibit
`different responses to pharmacological agents,
`it is not
`obvious that compounds claimed to be anti-allergic (“mast
`cell stabilizers”) will have clinical utility in specific mast
`cell populations. The assumption that mast cells are a
`homogeneous population and that therefore the effects of
`anti-allergic drugs observed in experiments in rat mast cells
`would be predictive of those in human cells is known to be
`incorrect. Church, “Is Inhibition of Mast Cell Mediator
`Release Relevant to the Clinical Activity of Anti-Allergic
`Drugs?,” Agents and Actions, Vol. 18, 3/4, 288-293, at 291
`(1986).
`Examples exist in the art in which mast cell stabilizing
`drugs inhibit only select populations of mastcells. Disodium
`
`10
`
`15
`
`20
`
`25
`
`35
`
`45
`
`50
`
`2
`cromoglycate is an anti-allergic drug whose local effects are
`believed to be due to inhibition of mast cell degranulation
`(Church, Agents and Actions, at 288). This drug was shown
`to inhibit rodent mast cell degranulation. In human trials,
`100 uM of the drug inhibited mast cells obtained from
`bronchoalveolar lavage fluid. In dispersed human lung mast
`cell preparations, 1000 uM of the drug was required to
`inhibit only 25% to 33% of histamine release. Finally,
`histamine release from human skin mast cells was not
`inhibited at all by disodium cromoglycate. Pearce et al.,
`“Effect of Disodium Cromoglycate on Antigen Evoked
`Histamine Release in Human Skin,” Clinical Exp. Immunol.,
`Vol. 17, 437-440 (1974); and Clegg et al., “Histamine
`Secretion from Human Skin Slices Induced by Anti-IgE and
`Artificial Secretagogues and the Effects of Sodium Cro-
`moglycate and Salbutanol,” Clin. Allergy, Vol. 15, 321-328
`(1985). These data clearly indicate that classification of a
`drug as ananti-allergic does not predict that the drug possess
`inhibitory effects on all mast cell populations.
`Topical ophthalmic formulations which contain drugs
`having conjunctival mast cell activity may only need to be
`applied once every 12-24 hours instead of once every 2-4
`hours. One disadvantage to the ophthalmic use of reported
`anti-allergic drugs which in fact have no human conjunctival
`mast cell stabilizing activity is an increased dosage fre-
`quency. Because the effectiveness of ophthalmic formula-
`tions containing drugs which do not have conjunctival mast
`cell activity stems primarily from a placebo effect, more
`frequent doses are typically required than for drugs which do
`exhibit conjunctival mast cell activity.
`US. Pat. No. 5,116,863, assigned to Kyowa Hakko
`Kogyo Co., Ltd., (“the Kyowa patent”), teaches that acetic
`acid derivatives of doxepin and, in particular, the cis form of
`the compound having the formula
`
`;
`
`CH2CH2N(CH3)2
`
`|
`
`Oo
`
`;
`
`CH)COOH
`
`(i.e., Z-11-(3-dimethylaminopropylidene)-6,11-
`dihydrodibenz[b,e]oxepin-2-acetic acid), have anti-allergic
`and anti-inflammatory activity.
`The Kyowa patent demonstrates anti-allergic activity and
`anti-inflammatory activity in Wistar male rats. Medicament
`forms taught by the Kyowa patent for the acetic acid
`derivatives of doxepin include a wide range of acceptable
`carriers; however, only oral and injection administration
`forms are mentioned. In the treatmentof allergic eye disease,
`such as allergic conjunctivitis, such administration methods
`require large doses of medicine.
`What is needed are topically administrable drug com-
`pounds which have demonstrated stabilizing activity on
`mast cells obtained from human conjunctiva, the target cells
`for treating allergic eye diseases. What is also needed are
`local administration methods for the treatment of allergic
`eye disease.
`
`SUMMARY OF THE INVENTION
`
`65
`
`The present invention provides a method for treating an
`allergic eye disease characterized by administering to the
`eye a topical ophthalmic formulation which contains a
`therapeutically effective amount of 11-(3-
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1007, Page 2
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`

`5,641,805
`
`3
`-6,11-dihydrodibenz[b,e]
`dimethylaminopropylidene)
`oxepin-2-acetic acid (referred to as “Compound A”
`hereinafter) or a pharmaceutically acceptable salt thereof.
`The formulation may contain the cis isomer of Compound A
`(Z-11-(3-dimethylaminopropylidene)-6,11-dihydrodibenz
`[b,e]oxepin-2-acetic acid), the trans isomer of Compound A
`(E-11-(3-dimethylaminopropylidene)-6,11-dihydrodibenz
`[b,e]oxepin-2-acetic acid), or a combination of both the cis
`and the trans isomers of Compound A, and unless specified
`otherwise,“11-(3-dimethylaminopropylidene)-6,
`11-dihydrodibenz[b,e]oxepin-2-acetic acid” or “Compound
`A” means the cis isomer, the trans isomer or a mixture of
`both. “Cis isomer” means the cis isomer substantially free of
`the trans isomer; “trans isomer” means the trans isomer
`substantially free of the cis isomer. One isomer is “substan-
`tially free” of the other isomerif less than about two percent
`of the unwanted isomeris present.
`CompoundA has human conjunctival mastcell stabilizing
`activity, and may be applied as infrequently as once or twice
`a day in somecases. In addition to its mast cell stabilizing
`activity, Compound A also possesses significant antihista-
`minic activity. Thus, in addition to a prophylactic effect,
`Compound A will also have a therapeutic effect.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`Compound A is a known compound and both the cis and
`the trans isomers of Compound A can be obtained by the
`methods disclosed in U.S. Pat. No. 5,116,863, the entire
`contents of which are hereby incorporated by reference in
`the present specification.
`Examples of the pharmaceutically acceptable salts of
`Compound A include inorganic acid salts such as
`hydrochloride, hydrobromide, sulfate and phosphate;
`organic acid salts such as acetate, maleate, fumarate, tartrate
`and citrate; alkali metal salts such as sodium salt and
`potassium salt; alkaline earth metal salts such as magnesium
`salt and calcium salt; metal salts such.as aluminum salt and
`zinc salt; and organic amine addition salts such as triethy-
`lamine addition salt (also known as tromethamine), mor-
`pholine addition salt and piperidine addition salt.
`Theinhibitory effects of reported anti-allergic, mast cell
`stabilizing drugs on mast cells obtained from human con-
`junctiva (the target cells for topical ophthalmic drug prepa-
`tations claimed useful in treating allergic conjunctivitis)
`were tested according to the following experimental method.
`Human conjunctival
`tissues obtained from organ/tissue
`donors were weighed and transferred to petri dishes con-
`taining RPMI 1640 culture medium supplemented with heat
`inactivated fetal bovine serum (20%, v/v), L-glutamine (2
`mM), penicillin (100 units/ml), streptomycin (100 pg/ml),
`amphotericin B (2.5 pg/ml) and HEPES (10 mM) and
`equilibrated overnight at 37° C. (5% CO,).
`Post equilibration, tissues were placed in Tyrode’s buffer
`(in mM:137 NaCl, 2.7 KCL, 0.35 Na H,PO,,1.8 CaCL, 0.98
`MgCl,, 11.9 Na HCO3,5.5 glucose) containing 0.1% gelatin
`(TGCM)and incubated with 200 U each of collagenase
`(Type IV) and hyaluronidase (Type I-S) per gram of tissue
`for 30 minutes at 37° C. Following enzymedigestion,tissues
`were washed with an equal volume of TGCM over Nitex®
`filter cloth (Tetko, Briarcliff Manor, N-Y.). Intact tissues
`were placed in TGCM for further enzymatic digestions.
`Theflitrate obtained from each digestion was centrifuged
`(825 g, 7 minutes) and pelleted cells were resuspended in
`calcium/magnesium free Tyrode’s buffer (TG). Pooled cells
`from all digestions were centrifuged (825 g, 30 minutes)
`
`3
`
`15
`
`20
`
`25
`
`35
`
`45
`
`50
`
`55
`
`60
`
`65
`
`4
`over a 1.058 g/L Percoll® cushion. Mast cell enriched cell
`pellets were resuspended and washed in TG buffer. Viability
`and number of mast cells were determined by vital dye
`exclusion and toluidine biue 0 staining of the harvested cell
`suspensions. Mast cell containing preparations were placed
`in supplemented RPMI 1640 culture medium and allowed to
`equilibrate at 37° C. prior to challenge with anti-human IgE
`(goat derived IgG antibody).
`Cell suspensions containing 5000 mast cells were added
`to TGCM containing tubes and challenged with anti-human
`IgE. The final volume of each reaction tube was 1.0 mL.
`Tubes were incubated at 37° C. for 15 minutes post chal-
`lenge. The release reaction was terminated by centrifugation
`(500 g, 7 minutes). Supernatants were collected and stored
`(-20° C.) until mediator analyses.
`Initially, supernatants were analyzed for histamine con-
`tent by both the automated fluorimetric method described by
`Siraganian,“An Automated Continuous Flow System for the
`Extraction and Fluorometric Analysis of Histamine,” Anal.
`Biochem., Vol. 57, 383-94 (1974), and a commercially
`available radioimmunoassay (RIA) system (AMAC, Inc.,
`Westbrook, Me.). Results from these assays were positively
`correlated (r=0.999): therefore, the remainder of histamine
`analyses were performed by RIA.
`Each experiment included an anti-human IgE (plus
`vehicle) positive release control, a spontaneous/vehicle
`release and a total histamine release control. Total histamine
`release was determined by treatment with Triton X-100®
`(0.1%). The experiments also included a non-specific goat
`IgG control. Test compounds are administered to the mast
`cell cultures either 1 or 15 minutes before stimulation with
`anti-human IgE. Inhibition of histamine release resulting
`from challenge of drug treated mast cells was determined by
`direct comparison with histamine release from vehicle
`treated, anti-IgE challenged mast cells using Dunnett’s t-test
`(Dunnett, “A multiple comparison procedure for comparing
`treatments with a control, ” J. Amer. Stat Assoc., Vol. 50,
`1096-1121 (1955)). The results are reported in Table 1,
`below.
`
`AsTable | clearly shows,the anti-allergic drugs disodium
`cromoglycate and nedocromil failed to significantly inhibit
`human conjunctival mast cell degranulation. In contrast,
`Compound A (cis isomer) produced concentration-
`dependentinhibition of mast cell degranulation.
`
`TABLE 1
`
`Compound Effect on Histamine Release from Human
`Conjunctival Tissue Mast Cells upon anti-Human IgH Challenge.
`Treatment
`Compound
`Dose (uM)
`(min)
`Inhibition (%)
`
`
`Cromolyn sodium
`
`Cromolyn sodium
`
`Nedocromil sodium
`
`1000
`300
`100
`30
`10
`1000
`300
`100
`30
`10
`1000
`300
`100
`30
`10
`3
`1
`
`15
`15
`15
`15
`15
`1
`1
`1
`1
`1
`15
`15
`15
`15
`15
`15
`15
`
`~15.4
`6.9
`-1.2
`18
`10.6
`9.4
`-18
`12
`0.1
`-0.9
`7.2
`3
`28.2*
`15.2
`9.2
`13.2
`10.7
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1007,
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`Page 3
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`IPR2018-01020 and IPR2018-01021, Exhibit 1007, Page 3
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`

`

`5,641,805
`
`5
`
`TABLE1-continued
`
`Nedocromil sodium
`
`Compound Effect on Histamine Release from Human
`Conjunctival Tissue Mast Cells upon anti-Human IgE Challenge.
`Treatment
`
`Compound
`Dose (4M)
`(main)
`Inhibition (%)
`0.3
`15
`3.7
`0.1
`15
`8.7
`1000
`1
`-1.1
`300
`1
`4.0
`100
`i
`6.7
`30
`1
`0.9
`10
`1
`-6.5
`3
`1
`0.8
`1
`1
`48
`0.3
`1
`8.8
`0.1
`1
`17.4
`2000
`15
`92.6*
`1000
`15
`66.7*
`600
`15
`47,.5*
`300
`15
`29.6*
`100
`15
`13.0
`
`1530 3.9
`
`
`Compound A
`
`*p < 0.05, Dunnett’s t-test
`
`Dunnett’s t-test, is a statistical test which compares mul-
`tiple treatment groups with one control group. In the assay
`described above, histamine released from drug treated mast
`cells are compared to histamine released from the anti-
`humanIgE plus vehicle treated mast cells which serve as the
`positive control. Statistically significant inhibition is deter-
`mined using this procedure. The probability level of 0.05 is
`accepted as the level of significance in biomedical research.
`Data indicated as significant have a low probability (0.05) of
`occurring by chance, indicating that the inhibition observed
`is an effect of the drug treatment.
`The effects of the cis and trans isomers of Compound A
`on histamine release from human conjunctival tissue mast
`cells upon anti-human IgE challenge are compared in Table
`2. The same experimental method used in Table 1 was used
`in Table 2. The results in Table 2 indicate that there is no
`statistically significant difference between the conjunctival
`mast cell activity of the two isomers at the indicated dose
`level.
`
`TABLE 2
`
`
`Tsomeric Effect of Compound A on In-Vitro Histamine Release
`from Human Conjunctival Tissue Mast Cells upon anti-Human
`IgE Challenge.
`Treatment
`Compound
`Dose (uM)
`(min)
`Inhibition (%)
`
`
`29.7*—
`15
`500
`Compound A (cis)
`
`
`
`500 15Compound A (trans) 26.2"
`*p < 0.05, Dunnett’s t-test compared to anti-[gE positive control.
`not significantly different; p > 0.05 Studentized Range comparison of
`indicated doses
`
`The topical activity of Compound A was tested in a
`passive anaphylaxis assay performed in rat conjunctiva. This
`assay indicates whether a topically applied compoundeffec-
`tively prevents or decreases the local allergic response in the
`conjunctiva. This assay allows an assessment of bioavail-
`ability following topical dosing. Briefly, male Sprague Daw-
`ley rats (6/group) were passively sensitized by subconjunc-
`tival injection of a rat serum containing IgE specific for
`ovalbumin (OA). Twenty-four hours post sensitization, test
`compound prepared in saline (0.9% NaCl) or saline vehicle
`was applied topically onto the sensitized eye. Twenty (20)
`
`6
`minutes after dosing, rats were challenged intravenously via
`the lateral tail vein with 1.0 ml of a solution containing OA
`(1.0 mg/ml) and Evans Blue dye (2.5 mg/ml). Thirty (30)
`minutes post antigen challenge, animals were killed, skin
`wasreflected, and the size of the resulting wheal and the
`intensity of the extravasated dye were determined. The
`wheal area multiplied by the dye intensity produced the
`individual response score. Scores for each group of animals
`were compared with the scores of the saline treated group
`using Dunnett’s test and are listed in Table 3.
`
`TABLE3
`
`In-Vivo Effects of Compound A on Passive Conjunctival
`Anaphylaxis in Rats
`
`Permeability
`
`Compound
`Conc. (%, wiv)
`Score (x + §.D.)
`% Change
`NaCl
`09
`239 + 22
`_
`Compound B
`0.1
`133 + 53*
`55
`Compound C
`0.1
`139 + 36*
`53
`Compound A
`0.1
`55 + 56*@
`86
`(cis)
`Compound A
`0.1
`43 + 34*@
`-81
`(trans)
`
`
`*p < 0.01, Dunnett’s test
`@p < 0.05, Studentized Range Comparison Procedure, significantly different
`from Compounds B and C.
`Compound B = (Z)-11-(3-Dimethylaminopropylidene)-6,11-dihydrodibenz
`[b,eJoxepin-2-carboxylic acid
`~
`Compound C = (Z)-11-(3-Dimethylaminopropylidene)-6, 11-<dihydrodibenz
`[b,eJoxepin-2-acrylic acid
`
`Compound A may be administered to the eye by means of
`conventional
`topical ophthalmic formulations, such as
`solutions, suspensions or gels. The preferred formulation for
`topical ophthalmic administration of Compound A is a
`solution. The solution is administered as eye drops. The
`preferred form of Compound A in the topical ophthalmic
`formulations of the present invention is the cis isomer. A
`general method of preparing the eye drops of the present
`invention is described below.
`Compound A and an isotonic agent are addedtosterilized
`purified water, and if required, a preservative, a buffering
`agent, a stabilizer, a viscous vehicle and the like are added
`to the solution and dissolved therein. The concentration of
`CompoundA is 0.0001 to 5 w/v %, preferably 0.001 to 0.2
`w/v %, and most preferably about 0.1 w/v %, based on the
`sterilized purified water. After dissolution, the pH is adjusted
`with a pH controller to be within a range which allowsthe
`use as an ophthalmologic medicine, preferably within the
`range of 4.5 to 8.
`Sodium chloride, glycerin or the like may be used as the
`isotonic agent; p-hydroxybenzoic acid ester, benzalkonium
`chloride or
`the like as the preservative; sodium
`hydrogenphosphate, sodium dihydrogenphosphate, boric
`acid or the like as the buffering agent; sodium edetate or the
`like as the stabilizer; polyvinyl alcohol, polyvinyl
`pyrrolidone, polyacrylic acid or the like as the viscous
`vehicle; and sodium hydroxide, hydrochloric acid or the like
`as the pH controller.
`If required, other ophthalmologic chemicals such as
`epinephrine, naphazoline hydrochloride, berberine chloride,
`sodium azulenesulfonate, lysozyme chloride, glycyrrhizate
`and the like may be added.
`The eye drops produced by the above method typically
`need only be applied to the eyes a few times a day in an
`amount of one to several drops at a time, though in more
`severe cases the drops may be applied several times a day.
`A typical drop is about 30 pl.
`
`5
`
`10
`
`15
`
`25
`
`30
`
`45
`
`50
`
`55
`
`65
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1007, Page 4
`
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1007, Page 4
`
`

`

`5,641,805
`
`10
`
`15
`
`20
`
`8
`4. The method of claim 3 wherein the amount of 11-3-
`dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]
`oxepin-2-acetic acid is about 0.1% (w/v).
`5. The method of claim 1 wherein the 11-G-
`dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]
`oxepin-2-acetic
`acid
`is
`(Z)-11-(3-
`dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]
`oxepin-2-acetic acid, substantially free of (E)-11-3-
`dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]
`oxepin-2-acetic acid.
`6. The method of claim 5 wherein the amountof (Z)-11-
`(3-dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]
`oxepin-2-acetic acid is from about 0.0001 to about 5%
`(w/y).
`7. The method of claim 6 wherein the amountof (Z)-11-
`(3-dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]
`oxepin-2-acetic acid is from about 0.001 to about 0.2%
`(w/v).
`8. The method of claim 7 wherein the amountof (Z)-11-
`(3-dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]
`oxepin-2-acetic acid is 0.1% (w/v).
`9. The method of claim 1 wherein the 11-(3-
`dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]
`oxepin-2-acetic
`acid
`is
`(E)-11-(3-
`dimethylaminopropylidene) -6,11 -dihydrodibenz[b,e]
`oxepin-2-acetic acid, substantially free of (Z)-11-(-
`dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]
`oxepin-2-acetic acid.
`10. The method of claim 9 wherein the amount of
`(E)-11-(3-dimethylaminopropylidene)-6,11-dihydrodibenz
`[b,e]oxepin-2-acetic acid is from about 0.0001 to about 5%
`(w/v).
`11. The method of claim 10 wherein the amount of
`(E)-11-(3-dimethylaminopropylidene)-6,11-dihydredibenz
`[b,e]oxepin-2-acetic acid is from about 0.001 to about 0.2%
`(w/v).
`12. The method of claim 11 wherein the amount of
`(E)-11-(3-dimethylaminopropylidene)-6,11-dihydrodibenz
`40 [b,e]oxepin-2-acetic acid is about 0.1% (w/v).
`
`25
`
`30
`
`35
`
`7
`Certain embodiments of the inventionare illustrated in the
`following examples.
`
`Example 1: Preferred Topical Ophthalmic Solution Formulation
`
`
` Ingredient Concentration (W/V %)
`Compound A.HC1
`0.111*
`Dibasic Sodium Phosphate
`0.5
`(Anhydrous), USP
`0.65
`Sodium Chloride, USP
`0.01
`Benzalkonium Chloride
`q.s. pH = 7.0
`Sodium Hydroxide, NF
`q.s. pH = 7.0
`Hydrochloric Acid, NF
`
`Purified Water q.s. 100
`
`*0.111% Compound A.HC1 is equivalent to 0.1% Compound A
`Example 2: Topical Opthalmic Gel Formulation
`
`
`
` Ingredient Concentration (W/V 9%)
`
`0.11*
`Compound A.HC1
`08
`Carbopol 974 P
`0.01
`Disodium EDTA.
`0.05
`Polysorbate 80
`0.01 +5 xs
`Benzalkonium Chloride, Solution
`q.s. pH 7.2
`Sodium Hydroxide
`q.s. pH 7.2
`Hydrochloric acid
`
`Water for Injection qs. 100
`
`*0.11% Compound A.HC]Iis equivalent to 0.1% Compound A
`
`Whatis claimedis:
`1. A method for treating allergic eye diseases in humans
`comprising stabilizing conjuctival mast cells by topically
`administering to the eye a composition comprising a thera-
`peutically
`effective
`amount
`of
`11-(3-
`dimethylaminopropylidene)-6,11-dihydrodibenz(b,e)
`oxepin-2-acetic acid or a pharmaceutically acceptable salt
`thereof.
`2. The method of claim 1 wherein the composition is a
`solution
`and
`the
`amount
`of
`11-(3-
`dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]
`oxepin-2-acetic acid is from about 0.0001 w/v. % to about
`5% (wiv).
`3. The method of claim 2 wherein the amount of 11-(3-
`dimethylaminopropylidene)-6,11-dihydrodibenz[b.e]
`oxepin-2-acetic acid is from about 0.001 to about 0.2%
`(wy).
`
`*
`
`oe
`
`ok FF
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1007, Page 5
`
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1007, Page 5
`
`

`

`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`CERTIFICATE OF CORRECTION
`
`PATENTNO.
`DATED
`INVENTOR(S)
`
`:
`>
`:
`
`5,641,805
`June 24, 1997
`Hayakawa et al.
`
`It is certified that error appears in the above-identified patent and that said Letters Patent is hereby
`corrected as shown below:
`
`On the title page:
`
`under “United States Patent
`[19)”, “Hayakawaetal.” should read “Yanni et al.”
`
`Item
`
`[75]
`
`Inventors:
`
`John Michael Yanni, Burleson:
`Stella M. Robertson, Arlington, both of Texas:
`Eiji Hayakawa, Susono;
`Masashi Nakakura, Shizuoka-ken, both of Japan
`
`
`
`Attest:
`
`Signed and Sealed this
`
`Eighteenth Dayof August, 1998
`
`Ns¢Noe b,lyMh.
`
`BRUCE LEHMAN
`
`Alttesting Officer
`
`Commissioner of Patents and Trademarks
`
`
`
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1007, Page 6
`
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1007, Page 6
`
`

`

`a2, EX PARTE REEXAMINATION CERTIFICATE(10045th)
`United States Patent
`(io) Number:
`US 5,641,805 C1
`Yanniet al.
`(45) Certificate Issued:
`Feb. 13, 2014
`
`
`US005641805C1
`
`(54) TOPICAL OPHTHALMIC FORMULATIONS
`FOR TREATING ALLERGIC EYE DISEASES
`
`(75)
`
`73) A
`
`:
`
`Inventors: John Michael Yanni, Burleson, TX
`(US); Stella M. Robertson, Arlington,
`TX (US); Eiji Hayakawa, Susono (IP):
`Masashi Nakakura, Shizuoka-ken (JP)
`se
`: K
`Hakko Kirin
`Co. Ltd.
`Assignee Ont,nachi Chiy dcKa Tokyo (IP)
`(73)
`Reexamination Request:
`No. 90/012,720, Nov. 16, 2012
`Reexamination Certificate for:
`:
`Patent No.:
`5,641,805
`ae . ° a
`Issued:
`Jun. 24, 1997
`Appl. No.:
`08/469,729
`Filed:
`Jun. 6, 1995
`
`(2006.01)
`(2006.01)
`(2006.01)
`
`AG6IK 31/00 (2013.01
`( oe»?
`
`AGIK 31/35
`CO7D 313/12
`C07D 313/00
`(52) U.S. Cl.
`CPC
`teresoesesenecasseneeesenseseeanecneseees
`(58) Field of Classification Search
`None
`See application file for complete search history.
`References Cited
`(56)
`To view the complete listing of prior art documents cited
`during the proceeding for Reexamination Control Number
`90/012,720, please refer to the USPTO’s public Patent
`ue
`Application Information Retrieval (PAIR) system under the
`Display Ref
`b
`Isplay Relerences tab.
`Primary Examiner — Dwayne Jones
`
`Certificate of Correction issued Aug. 18, 1998
`
`(51)
`
`Int. Cl.
`A6IK 31/00
`A6IK 31/335
`A6IK 31/45
`A6IP 27/00
`A6IP 27/02
`AG6IP 27/14
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`(57)
`
`ABSTRACT
`
`Topical ophthalmic formulations of the invention contain as
`an active ingredient 11-(3-dimethylaminopropylidene)-6,11-
`dihydrodibenz[b,e]oxepin-2-acetic acid or a pharmaceuti-
`cally acceptable salt thereof. The formulations are useful for
`treating allergic eye diseases such as allergic conjunctivitis,
`vernal conjunctivitis, vernal keratoconjunctivitis, and giant
`papillary conjunctivitis.
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1007, Page 7
`
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1007, Page 7
`
`

`

`US 5,641,805 C1
`
`1
`EX PARTE
`
`REEXAMINATION CERTIFICATE
`
`ISSUED UNDER35 U.S.C. 307
`
`NO AMENDMENTS HAVE BEEN MADE TO
`THE PATENT
`
`AS A RESULT OF REEXAMINATION, IT HAS BEEN
`DETERMINED THAT:
`
`10
`
`The patentability of claims 4 and 8 is confirmed.
`Claims 1-3, 5-7 and 9-12 were not reexamined.
`*
`*
`*
`*
`*
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1007, Page 8
`
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1007, Page 8
`
`