Case 1:14-cv-01453-LPS Document 43-11 Filed 10/22/15 Page 1 of 127 PageID #: 713
`Case 1:14—cv—O1453—LPS Document 43-11 Filed 10/22/15 Page 1 of 127 Page|D #: 713
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`EXHIBIT 26
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`EXHIBIT 26
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`Case 1:14-cv-01453-LPS Document 43-11 Filed 10/22/15 Page 2 of 127 PageID #: 714
`Case 1:14—cv—O1453—LPS Document 43-11 Filed 10/22/15 Page 2 of 127 Page|D #: 714
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`Case 1:14-cv-01453-LPS Document 43-11 Filed 10/22/15 Page 3 of 127 PageID #: 715
`Case 1:14—cv—O1453—LPS Document 43-11 Filed 10/22/15 Page 3 of 127 Page|D #: 715
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`APOTEX_AZFL 0061478
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`Case 1:14-cv-01453-LPS Document 43-11 Filed 10/22/15 Page 4 of 127 PageID #: 716
`Case 1:14—cv—O1453—LPS Document 43-11 Filed 10/22/15 Page 4 of 127 Page|D #: 716
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`APOTEX_AZFL 0061479
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`Case 1:14-cv-01453-LPS Document 43-11 Filed 10/22/15 Page 5 of 127 PageID #: 717
`Case 1:14—cv—O1453—LPS Document 43-11 Filed 10/22/15 Page 5 of 127 Page|D #: 717
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`Case 1:14-cv-01453-LPS Document 43-11 Filed 10/22/15 Page 6 of 127 PageID #: 718
`Case 1:14—cv—O1453—LPS Document 43-11 Filed 10/22/15 Page 6 of 127 Page|D #: 718
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`

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`Case 1:14-cv-01453-LPS Document 43-11 Filed 10/22/15 Page 7 of 127 PageID #: 719
`Case 1:14—cv—O1453—LPS Document 43-11 Filed 10/22/15 Page 7 of 127 Page|D #: 719
`
`EXHIBIT 27
`
`EXHIBIT 27
`
`
`
`

`
`Case 1:14-cv-01453-LPS Document 43-11 Filed 10/22/15 Page 8 of 127 PageID #: 720
`_ ' I. {egg Q-1]/4}T.fv-01453-LPS Document 43—lJT1_|l=€i:|ed 10/22/15 Page80f-“E27 P899‘?
`PatentsAct1977
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`ofthis (can. You can also
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`5'
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`CPW/20632
`
`
`
`
`2. Patent application number
`(77z£_Patent Otfice will fill in this part)
`
`1
`
`. 6
`
`3. Full name, address and postcode of the or of
`each applicant (underline all surnames)
`
`CIPLA LINHTED
`
`Patents ADP number (lfyou knowit)
`
`289 BELLASIS ROAD
`MUMBAI CENTRAL
`MUMBAI 400 008
`INDIA
`
`-
`‘T7557! ‘O20 6
`
`\
`
`If the applicant is a corporate body, give the
`country/state of its incorporation
`
`INDIA
`
`4. Title of the invention
`
`PHARMACEUTICAL COMPOSITIONS
`
`5. Name of your agent (lryou have one)
`
`“Address for service" in t.he United Kingdom
`to which all correspondence should be sent
`findudmgthepostwdei
`
`A A THORNTON & CO
`
`235 I—flGH HQLBORN
`LONDON WCIV 7LE
`
`/"
`
`K
`
`6.
`
`7.
`
`8.
`
`Patents ADP number (ifyau know It)
`Ifyou are declaring priority from one or more
`earlier patent applications, give the country
`and the date of filing of the or of each of these
`earlier applications and (lfyou know it) the or
`each application number
`
`If this application is divided or otherwise
`derived from an earlier UK application,
`give the number and the filing date of
`the earlier application
`
`Is a statement of inventorship and of right
`to grant of a patent required in support of
`this request? Mnswer ’Yes'1f."
`a) any applicant named In part 3 is not an inventor, or
`b)
`there is an invmtar who is not named as an
`applicant or
`
`c) any named applicant is a corporate body.
`See note (d))
`
`0000075001
`Country
`
`Priority application number
`(lfyau knowIt)
`
`Date offiling
`(day/month /year)
`
`Number of earlier application
`
`Date of filing
`(day/month /year)
`
`r
`
`Patents Form 1/77
`
`MED_DYM_00000082
`
`

`
`Case 1:14-cv-01453-LPS Document 43-11 Filed 10/22/15 Page 9 of 127 PageID #: 721
`Case 1:11./4'1’-__(I3V-01453-LPS Document 43-11 Filed 10/22/15 Page 9 Of 127 Page|D #2 721
`. P
`t9. Enter the number ofsheets for an
`e
`D
`'
`
`following items you are filing with this form.
`Do not count copies of the same document
`
`Continuation sheets of this form
`
`eA
`
`7 /
`
`Description
`
`Drawing (5)
`
`
`10. If you are also filing any of the following,
`state how many against each item.
`
`Priority documents
`
`Translations of priority documents
`
`Statement of inventorship and right
`to grant of a patent (Patents Form 7/777
`
`Request for preliminary examination
`and search (PatentsForm 9/77)
`
`0
`)[E/
`
`Request for substantive examination
`(Patents Fonn l0/7D
`
`Any other documents
`azlease specify)
`
`1 1.
`I/We request the grant of a patent on the basis of this application.
`Signature /4 A %\" '4\
`Date 14/5/07/
`
`A. A. Thornton & Co.
`14th June 2002
`
`12. Name and daytime telephone number of
`,
`_
`,
`person to contact in the United Kingdom
`Ph-‘hp A- Curtls ‘ 020 7440 6860
`
`Warning
`After an application for a patent has been filed, the Comptroller ofthe Patent Oflice will consider whetherpublication
`or communication ofthe invention should be prohibited or restricted under Section 22 ofthe Patents Act I977. You
`will be informed ifit is necessary to prohibit or restrictyour invention in this way. Furthermore, ifyou live in the
`United Kingdom, Section 23 ofthe Patents Act I.977stopsyou from applying for a patent abroad without firstgetting
`written permission from the Patent Oiiice unless an application has been filed at least 6‘ weeks beforehand in the
`United Kingdom for a patent for the same invention and either no direction prohibiting publication or
`communication has been given, or any such direction has been revoked
`
`Notes
`a) Ifyou need help to fillin this form oryou have any questions, please contact the Patent 0fi‘ice on 0645 500505.
`b) Write your answers in capital letters using black ink oryou may type them.
`c)
`Ifthere is not enough space for all the relevant details on anypart ofthis form, please continue on a separate
`sheet ofpaper and write “see continuation sheet" in the relevantpart(s). Any continuation sheet should be
`attached to dzis form.
`
`d) Ifyou have answered 'Yes'Patents Form 7/77 will need to be filed.
`e) Once you have filled in the form you must remember to sign and date it.
`1‘) For details of the fee and ways to payplease contact the Patent Ofiice.
`
`Patents Form 1/7
`
`MED_DYM_00000083
`
`

`
`Case 1:14-cv-01453-LPS Document 43-11 Filed 10/22/15 Page 10 of 127 PageID #: 722
`. ‘age 1:14-cv-01453-LPS Document 43-11 Filed 10/22/15 Page 10 of 127 Page|D #: 722
`
`i.
`
`+
`
`..
`
`-
`
`.
`
`-
`
`DUPLECATQ
`
`-1-
`
`PHARMACEUTICAL COMPOSITIONS
`
`This invention relates to pharmaceutical compositions. More particularly this
`invention relates to pharmaceutical compositions usefill for preventing or minimising
`allergic reactions. More particularly, but not exclusively,
`this invention relates to
`pharmaceutical compositions for nasal and ocular use.
`
`Such allergic reactions commonly comprise the allergy-related and vasomotor-
`related symptoms and the rhinovirus-related symptoms.
`It is known to use antihistamines in nasalsprays and eye drops to treat allergy-
`related conditions. Thus, for example, it is known to use the antihistamine azelastine
`(usually as the hydrochloride salt) as a nasal spray against seasonal or perennial allergic
`rhinitis, or as eye drops against seasonal and perennial allergic conjunctivitis.
`
`nasal use are, for example, beclomethasone, mometasone, fluticasone, budesonide and
`cyclosenide.
`Corticosteroids known for ocular anti-inflammatory use
`include
`betamethasone sodium, dexamethasone sodium and prednisolone acetate, for example.
`It would be highly desirable, however, to provide a treatment that combines the
`effects of anti-histamine treatments and steroid treatments,
`in a pharmaceutically
`acceptable composition, which is tolerated in situ, without significantly disrupting the
`potency of.the constituent pharmaceuticals.
`
`(4-[(4-
`azelastine
`surprisingly,
`very
`that,
`now found
`have
`We
`Chlorophenyl)methyl]-2-(hexahydro-1-methy1-1H-azepin-4-yl)-1(2I-I)-phthalazinone) , or
`a salt thereof, can advantageously be combined with a steroid to provide a stable, very
`effective combination composition for nasal or ocular treatment. The combination
`provides, in a single administration, the antihistaminic properties of azelastine and the
`anti-inflammatory (and/or other) properties of the steroid, without any significant
`interference between the two, or adverse reaction in situ.
`
`MED_DYM_00000084
`
`

`
`Case 1:14-cv-01453-LPS Document 43-11 Filed 10/22/15 Page 11 of 127 PageID #: 723
`Base 1:14—cv—O1453—LPS Document 43-11 Filed 10/22/15 Page 11 of 127 Page|D #: 723
`
`-2-
`
`In one aspect the invention provides a pharmaceutical composition comprising
`
`azelastine or a salt thereof and a steroid, preferably a corticosteroid, the composition
`
`being in a form suitable for administration nasally or ocularly.
`
`The preferred forms of compositions of the invention are nasal drops, eye drops,
`
`nasal sprays, nasal inhalation solutions or aerosols or insufilation powders.
`
`Preferred embodiments of the invention comprise stable aqueous solutions of
`
`azelastine or one or more of its salts, in combination with steroids which may be
`
`beclomethasone, mometasone, fluticasone, budesonide or cyclosenide, which can be used
`in the form of inhalation solution, pressurized aerosol, eye drops or nasal drops, and in a
`
`particular preferred embodiment, in the form of a spray (preferably a nasal spray). The
`
`spray can, for example, be formed by the use of a conventional spray-squeeze bottle or a
`
`pump vaporizer.
`
`In addition, it is also possible to use compressed gas aerosols.
`
`In a
`
`preferred embodiment, 0.03 to 3 mg of azelastine base and 0.05 to 0.15 mg of the steroid
`
`should be released per individual actuation.
`
`The compositions preferably contain a preservative and/or stabilizer. These
`
`include, for example: ethylene djamine tetra-acetic acid (edetic acid) and its alkali salts
`
`(for example dialkali salts such as disodium salt, calcium salt, calcium-sodium salt),
`lower alkyl p—hydroxybenzoates, chlorohexidine (for example in the form of the acetate
`
`or gluconate), phenyl mercury borate. Other suitable preservatives are: pharmaceutically
`
`usefiil quaternary ammonium compounds,
`
`for example cetylpyridinium chloride,
`
`tetradecyltrimethyl
`
`ammonium bromide,
`
`generally
`
`known
`
`as
`
`“cetrimide”,
`
`benzyldimethyl-[2-[2-[p-(l,1,3,3-tetramethyl-butyl)phenoxy]ethoxy]—arnmonium
`
`chloride, generally known as “benzethonium chloride” and myristyl-:-picolinium
`
`chloride. Each of these compounds may be used in a concentration of 0.002 to 0.05%, for
`
`example 0.02% (weight/volume in liquid fonnulations, otherwise weight/weight).
`
`Preferred preservatives among the quaternary ammonium compounds are, however,
`
`alkylbenzyl dirnethyl ammonium chloride and mixtures thereof,
`
`for example the
`
`compounds generally known as “benzalkonium chloride”.
`
`The total amounts of preservatives in the formulations (solutions, ointments, etc.)
`
`is preferably from 0.001 to 0.l0g, preferably 0.01 g per l00rnl of solution/suspension or
`
`100g of formulation.
`
`MED_DYM_00000085
`
`

`
`_
`
`_
`
`Case 1:14-cv-01453-LPS Document 43-11 Filed 10/22/15 Page 12 of 127 PageID #: 724
`Case 1:14—cv—O1453—LPS Document 43—11- Filed 10/22/15 Page 12 of 127 Page|D #: 724
`
`‘
`
`‘
`
`-3-
`
`In the case of preservatives, the following amounts of individual substances can,
`
`for example, be used: thimero sal 0.002-0.02%; benzalkonium chloride 0.002 to 0.02%
`
`(in combination with thimero sal the amount of thimero sal is, for example =0.002 to
`
`0.005%;); chlorhexidine acetate or gluconate 0.01 to 0.02%; phenyl mercuric/nitrate,
`
`borate, acetate 0.002-0.004%; p-hydroxybenzoic acid ester (for example, a mixture of the
`
`methyl ester and propyl ester in the ratio 7:3): preferably 0.05-0.15, more preferably
`
`0.1%.
`
`The preservative used is preferably a combination of edetic acid (for example, as
`
`the disodium salt) and benzalkonium chloride. In this combination, the edetic acid is
`
`preferably used in a concentration of 0.05 to 0.1%, benzalkonium chloride preferably
`
`being used in a concentration of 0.005 to 0.05%, more preferably 0.01%.
`
`In the case of solutions/suspensions reference is always made to percent by
`
`weight/volume,
`
`in the case of solid or semi-solid formulations to percent by
`
`weight/weight of the formulation.
`
`Further auxiliary substances which may, for example, be used for the fonnulations
`
`of the invention are: polyvinyl pyrrolidone, sorbitan fatty acid esters such as sorbitan
`
`trioleate, polyethoxylated sorbitan fatty acid esters (for example polyethoxylated sorbitan
`
`trioleate), sorbimacrogol oleate, synthetic amphotensides (tritons), ethylene oxide ethers
`
`of octylphenolfonnaldehyde condensation products, phosphatides such as lecithin,
`
`polyethoxylated fats, polyethoxylated oleotriglycerides, polyethoxylated fatty alcohols. In
`
`this context, polyethoxylated means that the relevant substances contain polyoxyethylene
`chains, the degree of polymerisation of which is generally between 2 to 40, in particular
`
`between 10 to 20. These substances are preferably used to improve the solubility of the
`azelastine component.
`
`It is optionally possible to use additional isotonization agents. Isotonization agents
`
`which may, for. example, be used are: saccharose, glucose, glycerine, sorbitol, 1,2-
`
`propylene glycol, NaCl.
`
`The isotonization agents adjust the osmotic pressure of the formulations to the
`
`same osmotic pressure as nasal secretion. For this purpose these substances are in each
`
`case to be used in such amount that, for example, in the case of a solution, a reduction in
`
`the freezing point of 0.50 to 0.56 degree C is attained in comparison to pure water.
`
`MED_DYM_00000086
`
`

`
`Case 1:14-cv-01453-LPS Document 43-11 Filed 10/22/15 Page 13 of 127 PageID #: 725
`sage 1:14—cv—O1453—LPS Document 43-11 Filed 10/22/15 Page 13 of 127 Page|D #: 725
`
`-4-
`
`In Example 1, it is possible to use instead of NaCl per 100 ml of solution, for
`
`example: Glucose 1H2O 3.81 g; saccharose 6.35g; glycerine 2.2g; 1,2-propylene glycol
`1.6l7g; sorbitol 3.84g (in the case of mixtures of these substances correspondingly less
`
`may optionally be used).
`
`Moreover, it is possible to add thickening agents to the solutions to prevent the
`
`solution from flowing out of the nose too quickly and to give the solution a viscosity of
`
`about 1.5 to 3, preferably 2 mPa.
`
`_
`
`Such thickening agents may, for example, be: cellulose derivatives (for example
`
`cellulose ether) in which the cel1u1ose—hydroxy groups are partially etherified with lower
`
`unsaturated aliphatic alcohols and/or
`
`lower unsaturated aliphatic oxyalcohols (for
`
`example ‘methyl cellulose, carboxymethyl cellulose, hydroxypropylmethylcellulose),
`gelatin, polyvinylpyrrolidone, tragacanth, ethoxose (water soluble binding and thickening
`
`agents on the basis of ethyl cellulose), alginic acid, polyvinyl alcohol, polyacrylic acid,
`
`pectin and equivalent agents. Should these substances contain acid groups,
`
`the
`
`corresponding physiologically acceptable salts may also be used.
`
`In the event of the use of hydroxypropyl cellulose, 0.1% by weight of the
`
`formulation, for example, is used for this purpose.
`
`In the event of the use of Avicel RC 591 or CLll, 0.65-3.0% by Weight of the
`
`composition, for example, is used for the purpose.
`
`It is also possible to add to the formulations buffer substances such as citric
`
`acid/sodium
`
`hydrogensulphate
`
`borate
`
`buffer,
`
`phosphates
`
`(sodium
`
`hydrogenorthophosphate, disodium hydrogenphosphate),
`
`trometamol or equivalent
`
`conventional buffers in order, for example, to adjust the formulations to a pH value of 3
`
`to 7, preferably 4.5 to 6.5.
`
`The amount of citric acid is, for example, 0.01 to 0.14g, preferably 0.04 to 0.05g,
`
`the amount of disodium hydrogenphosphate 0.1 to 0.5g, preferably 0.2 to 0.3 g per 100 ml
`of solution.‘ The weights given relate in each case to the anhydrous substances.
`
`In the case of solutions and suspensions, the maximum total concentration of
`
`active agent and buffer
`
`is preferably less than 5%,
`
`in particular
`
`less than 2%
`
`(weight/volume).
`
`MED_DYM_00000087
`
`

`
`Case 1:14-cv-01453-LPS Document 43-11 Filed 10/22/15 Page 14 of 127 PageID #: 726
`Case 1:14—cv—O1453—LPS Document 43-11 Filed 10/22/15 Page 14 of 127 Page|D #: 726
`'0"
`0
`o
`
`For the nasal application a solution or suspension is preferably used which is
`
`applied as an aerosol, i.e. in the form of a fine dispersion in air or in another conventional
`
`carrier gas, for example by means of a conventional pump vaporizer.
`
`Application as a dosage aerosol is, however, also possible. Dosage aerosols are
`
`defined as being pressure packings which contain the azelastine or its salts in combination
`
`with steroid, in the form of a solution or suspension in a so-called propellant. The
`
`propellant may be a pressurized liquid chlorinated, fluorinated hydrocarbon or mixtures
`
`of various chlorinated, fluorinated hydrocarbons as well as propane, butane, isobutene or
`
`mixtures of these among themselves or with chlorinated, fluorinated hydrocarbons which
`
`are gaseous at atmospheric pressure and room temperature. Hydrofluorocarbons (‘HFCs),
`
`such as I-IFC 134a, can also be used, if desired. The pressure packing has a dosage valve
`
`which, on actuation, releases a defined amount of the solution or suspension. of the
`
`medicament. The subsequent very sudden vaporization of the propellant tears the solution
`
`or suspension of azelastine into the finest droplets or minute particles which can be
`
`sprayed in the nose or which are available for inspiration into the nose. Certain plastic
`
`applicators may be used to actuate the valve and to convey the sprayed suspension into
`
`the nose.
`
`I
`
`i
`
`In the case of application as an aerosol, it is also possible to use a conventional
`
`adapter.
`
`In the case of insufflatable powder, the maximum particle size of the substance
`
`preferably does not exceed lOp.m.'Aze1astine or its salts and the steroid may be mixed
`
`with inert carrier substances or drawn up onto inert carrier substances. Carrier substances
`
`which may, for example, be used are: sugars such as glucose, saccharose, lactose and
`
`fructose. Also starches or
`
`starch derivatives, oligosaccharides such as dextrins,‘
`
`cyclodextrins and their derivatives, polyvinylpyrrolidone, alginic acid, tylose, silicic acid,
`
`cellulose, cellulose derivatives (for example cellulose ether), sugar alcohols such as
`
`marmitol or sorbitol, calcium carbonate, calcium phosphate, etc.
`
`In one embodiment, the steroid has a particle size of less than about l0um,
`
`preferably less than 5 pm.
`
`MED_DYM_00000088
`
`

`
`Case 1:14-cv-01453-LPS Document 43-11 Filed 10/22/15 Page 15 of 127 PageID #: 727
`(Die 1:14—cv—O1453—LPS ‘ Document 43-11 Filed 10/22/15 Page 15 of 127 Page|D 35¢: 727
`
`DETAILED DESCRIPTION OF PREFERRED ENIBODIIVIENTS
`
`The invention is illustrated by the following examples.
`
`EXAMPLE 1
`
`Nasal spray or nasal drops with 0.1% azelastine hydrochloride as active ingredient and
`
`steroid 0.1%
`
`
`
`OUANTITY
`NAME OF INGREDIENTS
`S.NO.
`'
`'
`%w/V
`
`
`1.
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`8.
`
`9.
`
`'
`
`*
`
`Azelastine hydrochloride
`Steroid
`
`‘
`
`Disodium edetate
`
`Sodium chloride .
`
`Benzalkonium chloride
`
`Avicel RC 591
`
`.
`
`‘
`
`Citric acid monohydrate
`
`’ Disodium hydrogen phosphate dodecahydrate
`
`Purified water
`
`0. 1%
`0.1%
`
`0.005%
`
`0.9%
`
`0.001%
`
`1.2%
`
`0.2%
`
`0.1%
`
`EXAMPLE 2
`
`Dosage aerosol giving off 0.5 mg of azelastine hydrochloride and 50 micrograms of
`
`Beclomethasone dipropionate freon solvate per stroke.
`
`MED_DYM_00000089
`
`

`
`1"’
`
`0
`
`Case 1:14-cv-01453-LPS Document 43-11 Filed 10/22/15 Page 16 of 127 PageID #: 728 Case 1:14-cv-01453-LPS Document43-11 Filed 10/22/15 Pagel
`0
`age
`
`0
`
`5
`
`-7-
`
`About 8.0 kg of a mixture of 70 parts by weight of difluorodichloromethane and
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`30 parts by Weight of 1,2d.ichlorotetra.fluoroethane are cooled to about -55 degree C in an
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`appropriate cooling vessel. A mixture of 0.086 kg of pre—cooled sorbitantrioleate and
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`0.8600 kg of pre-cooled trichlorofluoromethane are dissolved with stirring into the
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`mixture at —55 degrees C, 0.0688 kg of micronized azelastine hydrochloride, 0.00688 kg
`
`of Beclomethasone dipropionate freon solvate and 0.0688 kg of micronized lactose are
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`then incorporated in portions into the solution thereby obtained with intensive stirring.
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`The total weight of the suspension thereby obtained is made up to 9.547 kg through
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`addition of more of the mixture of 70 parts by weight of difluorodichloromethane and 30
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`parts by weight of 1,2-dichlorotetrafluoroethane cooled to about —55 degree C.
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`Following closure of the cooling vessel the suspension is again cooled to about
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`-5 5 degrees C under intensive stirring. It is then ready to be filled.
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`MED_DYM_00000090
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`

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`Case 1:14-cv-01453-LPS Document 43-11 Filed 10/22/15 Page 17 of 127 PageID #: 729
`sage 1:14—cv—O1453—LPS Document 43-11 Filed 10/22/15 Page 17 of 127 Page|D,#: 729
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`CLAIIVIS:
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`1
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`A pharmaceutical composition which comprises azelastine or a salt thereof, and a
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`steroid, the composition being in a form suitable for nasal or ocular administration.
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`2
`
`3
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`A composition according to claim 1, which is an aqueous suspension or solution.
`
`A composition according to claim 1 or 2, which is in the form of an aerosol, an
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`ointment, eye drops, nasal drops, a nasal spray or an inhalation solution.
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`4
`
`A composition according to claim 1, which is in the form of an insufflation
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`powder.
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`5
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`A composition according to any of claims
`
`1
`
`to 4, wherein the steroid is
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`beclomethasone or an ester thereof, mometasone or an ester thereof, fluticasone or an
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`ester