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`EXHIBIT 66
`
`EXHIBIT 66
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`
`
`

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`(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization
`International Bureau
`
`
`
`(43) International Publication Date
`25 October 2001 (25.10.2001)
`
`(10) International Publication Number
`
`PCT
`
`WO 01/78739 A1
`
`(51)
`
`International Patent Classification7: A6lK 31/575,
`31/46, A61P 11/06 // (A61K 31/575, 31:46)
`
`(21)
`
`International Application Number:
`
`PCT/GB01/01631
`
`(22)
`
`International Filing Date:
`
`11 April 2001 (11.04.2001)
`
`(25)
`
`Filing Language:
`
`(26)
`
`Publication Language:
`
`(30)
`
`Priority Data:
`0009606.5
`
`English
`
`English
`
`18 April 2000 (18.04.2000)
`
`GB
`
`(71)
`
`(72)
`(75)
`
`Applicant for all designated States except US): GLAXO
`GROUP LIMITED [GB/GB]; Glaxo Wellcome House,
`Berkeley Avenue, Greenford, Middlesex UB6 ONN (GB).
`
`Inventor; and
`Inventor/Applicant 0"or US only): GAVIN, Brian,
`Charles [IE/IE]; GlaXoSmithKline, PO Box 700, Grange
`Road, Rathfarnfam, 16 Dublin (IE).
`
`(81) Designated States (national): AE, AG, AL, AM, AT, AU,
`AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CO, CR, CU,
`CZ, DE, DK, DM, DZ, EE, ES, FI, GB, GD, GE, GH, GM,
`HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK,
`LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX,
`MZ, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL,
`TJ, TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZW.
`
`(84) Designated States (regional): ARIPO patent (GH, GM,
`KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZW), Eurasian
`patent (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European
`patent (AT, BE, CH, CY, DE, DK, ES, FT, FR, GB, GR, IE,
`IT, LU, MC, NL, PT, SE, TR), OAPI patent (BF, BJ, CF,
`CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG).
`
`Published:
`
`with international search report
`before the expiration of the time limit for amending the
`claims and to be republished in the event of receipt of
`amendments
`
`(74)
`
`Agent: LEAROYD, Stephanie, Anne; GlaxoSmithKline,
`Corporate Intellectual Property, Two New Horizons Court,
`Brentford, Middlesex TW8 9EP (GB).
`
`For two—letter codes and other abbreviations, refer to the ”Guid—
`ance Notes on Codes andAbbreviations " appearing at the begin-
`ning ofeach regular issue ofthe PCT Gazette.
`
`(54) Title: MEDICAL COMBINATIONS COMPRISING TIOTROPIUM AND FLUTICASONE PROPRIONATE
`
`(57) Abstract: The present invention is concerned with pharmaceutical formulations comprising a combination of tiotropium and
`fluticasone propionate and the use of such formulations in medicine, particularly in the prophylaxis and treatment of respiratory
`diseases.
`
`MED_DYM_00007791
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`WO01/78739A1||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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`

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`MEDICAL COMBINATIONS COMPRISING TIOTROPIUM AND FLUTICASONE PROPRIONATE
`
`The present invention is concerned with combinations of tiotropium and
`
`fluticasone propionate, particularly compositions containing a combination of
`
`5
`
`tiotropium and fluticasone propionate and the use of such compositions in
`
`medicine, particularly in the prophylaxis and treatment of respiratory diseases.
`
`Tiotropium i.e. (1oc,2[3,4l3,5oc,7B)—7—[(hydroxydi—2—thienylacetyl)oxy]—9,9—dimethyl-
`
`3-oxa-9-azoniatricyc|o[3.3.2.0]nonane and particularly its bromide salt is a well-
`
`10
`
`known anti—cho|inergic agent, described in EP418,716 for the treatment of
`
`bronchial asthma and related disorders.
`
`Fluticasone propionate is an anti—inflammatory corticosteroid, described in GB
`
`2088877, and is systematically named S—fluoromethyl—6oc,9oc—difluoro—1 18-
`
`15
`
`hydroxy-16oc-methyl—17oc—propionyloxy—3-oxoandrosta-1 ,4-diene-17(3-
`
`carbothioatew Fluticasone propionate is now used clinically for the treatment of
`bronchial asthma and related disorders.
`‘
`
`Although tiotropium bromide and fluticasone propionate may be effective
`
`20
`
`therapies, there exists a clinical need for asthma therapies having potent and
`
`selective action and having an advantageous profile of action.
`
`Therefore, according to the present invention there is provided a combination of
`
`tiotropium or a pharmaceutically acceptable salt, solvate, or physiologically
`
`25
`
`‘ functional derivative thereof and fluticasone propionate or a pharmaceutically
`
`acceptable salt, solvate, or physiologically functional derivative thereof.
`
`It will be appreciated that the compounds of the combination may be
`
`administered simultaneously, either in the same or different pharmaceutical
`formulations or sequentially.
`If there is sequential administration, the delay in
`
`administering the second compound should not be such as to lose the beneficial
`
`therapeutic effect of the combination.
`
`According to a further aspect of the present invention, there is provided a
`pharmaceutical formulation comprising tiotropium or a pharmaceutically
`
`30
`
`35
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`MED_DYM_00007792
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`

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`acceptable salt, solvate, or physiologically functional derivative thereof and
`
`fluticasone propionate or a pharmaceutically acceptable salt, solvate, or
`
`physiologically functional derivative thereof, and a pharmaceutically acceptable
`
`carrier or excipient, and optionally one or more other therapeutic ingredients.
`
`5
`
`According to a preferred aspectof the present invention, there is provided a
`pharmaceutical formulation comprising tiotropium bromide and fluticasone
`
`propionate, and a pharmaceutically acceptable carrier or excipient, and
`
`In the most preferred
`optionally one or more other therapeutic ingredients.
`aspect, theabove pharmaceutical formulations are suitable for administration by
`inhalation.
`
`10
`
`it
`
`is to be understood that the present invention covers all combinations of
`
`particular and preferred aspects of the invention described herein.
`
`15
`
`By the term “physiologically functional derivative” is meant a chemical derivative
`
`of tiotropium or fluticasone propionate having the same physiological function as
`the free compound, for example,’ by being convertible in the body thereto.
`According to the present invention, examples of physiologically functional
`derivatives include esters.
`
`20
`
`Suitable salts according to the invention include those formed with both organic
`and inorganic acids. Pharmaceutically acceptable acid addition salts include but
`are not limited to those formed from hydrochloric, hydrobromic, sulphuric, citric,
`
`tartaric, phosphoric, lactic, pyruvic, acetic, trifluoroacetic, succinic, oxalic,
`
`25
`
`A
`
`fumaric, maleic, oxaloacetic, methanesulphonic, ethanesulphonic, p-
`toluenesulphonic, benzenesulphonic, isethionic, and naphthalenecarboxylic,
`such as 1-hydroxy—2—naphthalenecarboxylic acids.‘
`
`Pharmaceutically acceptable esters of tiotropium or fluticasone propionate may
`
`30
`
`have a hydroxyl group converted to a C1-5alky|, aryl, aryl C1_5 alkyl, or amino acid
`ester.
`
`As mentioned above, both tiotropium and fluticasone propionate and their
`
`pharmaceutically acceptable salts, solvates, and physiologically functional
`
`35
`
`derivatives have been described for use in the treatment of respiratory diseases.
`
`MED_DYM_00007793
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`Therefore, formulations of tiotropium and fluticasone propionate and their .
`
`pharmaceutically acceptable salts, solvates, and physiologically functional
`
`derivatives have use in the prophylaxis and treatment of clinical conditions for
`which anticholinergic agent and/or an antiinflammatory corticosteroid is
`
`indicated. Such conditions include diseases associated with reversible airways ‘
`obstruction such as asthma, chronic obstructive pulmonary diseases (COPD)
`(e.g. chronic and wheezy bronchitis, emphysema), respiratory tract infection and
`
`upper respiratory tract disease.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`1 Accordingly, the present invention provides a method for the prophylaxis or
`
`treatment of a clinical condition in a mammal, such as a human, for which an
`
`anticholinergic agent and/or antiinflammatory corticosteroid is indicated,'which
`comprises administration of a therapeutically effective amount of a combination
`
`of tiotropium or a pharmaceutically acceptable salt, solvate, or physiologically
`
`functional derivative thereof and fluticasone propionate or a pharmaceutically
`
`acceptable salt, solvate, or physiologically functional derivative thereof. The
`
`present invention further provides a method for the prophylaxis or treatment of a
`
`clinical condition in a mammal, such as a human, for which an anticholinergic
`
`agent and/or antiinflammatory corticosteroid is indicated, which comprises
`
`administration of a therapeutically effective amount of a pharmaceutical
`
`formulation comprising tiotropium or a pharmaceutically acceptable salt, solvate,
`
`or physiologically functional derivative thereof and fluticasone propionate or a
`
`pharmaceutically acceptable salt, solvate, or physiologically functional derivative
`
`thereof, and a pharmaceutically acceptable carrier or excipient.
`
`In a preferred
`
`aspect, there is provided such a method which comprises administration of a
`
`therapeutically effective amount of a pharmaceutical formulation comprising
`tiotropium bromide and fluticasone propionate, and a pharmaceutically
`
`acceptable carrier or excipient.
`
`In particular, the present invention provides
`
`such methods for the prophylaxis or treatment of a disease associated with
`
`reversible ainlvays obstruction such as asthma, chronic obstructive pulmonary
`
`disease (COPD), respiratory tract infection or upper respiratory tract disease.
`
`In the alternative, there is provided a combination of tiotropium or a
`pharmaceutically acceptable salt, solvate, or physiologically functional derivative
`
`thereof and fluticasone propionate or a pharmaceutically acceptable salt,
`
`MED_DYM_00007794
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`

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`4
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`solvate, or physiologically functional derivative thereof, for use in therapy,
`particularly for use in the prophylaxis or treatment of a clinical condition for which
`
`an anticholinergic agent and/or antiinflammatory corticosteroid is indicated.
`
`In
`
`particular, there is provided a pharmaceutical formulation comprising tiotropium
`
`or a pharmaceutically acceptable salt, solvate, or physiologically functional
`
`derivative thereof (suitably, tiotropium bromide) and fluticasone propionate or a
`
`pharmaceutically acceptable salt, solvate, or physiologically functional derivative
`
`thereof, and a pharmaceutically acceptable carrier or excipient for use in
`
`therapy, particularly for use in the prophylaxis or treatment of a clinical condition
`
`for which an anticholinergic agent and/or antiinflammatory corticosteroid is
`indicated.
`In a preferred aspect, the invention is concerned with the prophylaxis
`
`or treatment of a disease associated with reversible airways obstruction such as
`asthma, chronicobstructive pulmonary disease (COPD), respiratory tract
`
`infection or upper respiratory tract disease.
`
`The amount of tiotropium and fluticasone propionate, or a pharmaceutically
`
`acceptable salt, solvate or physiologically functional derivative thereof which is
`
`required to achieve a therapeutic effect will, of course, vary with the particular
`
`compound, the route of administration, the subject under treatment, and the
`
`particular disorder or disease being treated. As a monotherapy, tiotropium
`
`bromide is generatly administered to adult humans by aerosol inhalation at a
`
`dose of 10mcg to 200mcg twice daily. As a monotherapy, fluticasone propionate
`
`is administered to adult humans, by aerosol inhalation at a dose of from 100mcg
`
`to 1000mcg twice daily, preferably 200mcg to 500mcg.
`
`10
`
`,15
`
`20
`
`25
`
`While it is possible for the active ingredients of the combination to be
`administered as the raw chemical, it is preferable to present them as a
`
`pharmaceutical formulation. When the individual compounds of the combination
`
`are administered separately, they are generally each presented as a
`
`30
`
`pharmaceutical formulation as described previously in the art.
`
`Pharmaceutical formulations are often prescribed to the patient in "patient
`
`packs" containing the whole course of treatment in a single package. Patient
`packs have an advantage over traditional prescriptions, where a pharmacist
`divides a patient's supply of a pharmaceutical from a bulk supply, in that the
`
`35
`
`MED_DYM_00007795
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`

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`patient always has access to the package insert contained in the patient pack,
`
`normally missing in traditional prescriptions. The inclusion of a package insert
`
`has been shown to improve patient compliance with the physician's instructions
`
`and, therefore, lead generally to more successful treatment.
`
`It will be
`
`understood that the administration of the combination of the invention by means
`
`of a single patient pack, or patient packs of each component compound, and
`
`containing a package insert instructing the patient to the correct use of the
`
`invention is a desirable additional feature of the invention.
`
`Hereinafter, the term “active ingredients” means tiotropium or a pharmaceutically
`acceptable salt, solvate, or physiologically functional derivative thereof,
`
`preferably tiotropium bromide, and fluticasone propionate, or a pharmaceutically
`
`acceptable salt, solvate, or physiologically functional derivative thereof.
`
`Suitably, the pharmaceutical formulations which are suitable for inhalation
`
`according to the invention comprise the active ingredients in amounts such that
`
`each actuation provides therapeutically effective dose, for example, a dose of
`
`tiotropium of 10mcg to 200mcg, preferably 20mcg to 100mcg and a dose of
`
`fluticasone propionate of 50mcg to 1.0mg, preferably 100mcg to 500mcg.
`
`The pharmaceutical formulations according to the invention may further include
`
`other therapeutic agents for example anti—inflammatory agents such as other
`corticosteroids (e.g. beclomethasone dipropionate, mometasone furoate,
`
`triamcinolone acetonide or budesonide) or NSA|Ds (e.g. sodium cromoglycate,
`
`nedocromil sodium,. PDE-4 inhibitors, leukotriene antagonists, iNOS inhibitors,
`
`tryptase and elastase inhibitors, beta-2 integrin antagonists and adenosine 2a
`agonists)) or, [3g—adrenoreceptor agonists (such as salbutamol, formoterol,
`
`salmeterol, fenoterol or terbutaline and salts thereof), or other anticholinergic
`
`agents (such as ipratropium).
`
`The formulations include those suitable for oral, parenteral (including
`
`subcutaneous, intradermal, intramuscular, intravenous and intraarticular),
`
`intranasal, inhalation (including fine particle dusts or mists which may be
`
`generated by means of various types of metered dose pressurised aerosols,
`
`nebulisers or insufflators), rectal and topical (including dermal, buccal, sublingual
`
`10
`
`15
`
`20
`
`25
`
`30
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`35
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`MED_DYM_00007796
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`

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`and intraocular) administration although the most suitable route may depend
`
`upon for example the condition and disorder of the recipient. The formulations
`
`may conveniently be presented in unit dosage form and may be prepared by any
`
`of the methods well known in the art of pharmacy. All methods include the step
`
`5
`
`of bringing the active ingredients into association with the carrier which
`constitutes one or more accessory ingredients.
`in general the formulations are
`
`prepared by uniformly and intimately bringing into association the active
`
`ingredients with liquid carriers or finely divided solid carriers or both and then, if
`necessary, shaping the product into the desired formulation,
`
`10
`
`_
`
`Formulations for inhalation include powder compositions which will preferably
`contain lactose, and spray compositions which may be formulated, for example,
`as aqueous solutions or suspensions or as aerosols delivered from pressurised
`
`packs, with the use of a suitable propellant, e.g. dichlorodifluoromethane,
`
`15
`
`trichlorofluoromethane, dichlorotetrafluoroethane, 1,1,1,2,3,3,3—
`
`heptafluoropropane, 1,1,1 ,2-tetrafluoroethane, carbon dioxide or other suitable
`
`gas. Suitable aerosol formulations include those described in EP 0372777 and
`
`W093/11743. For suspension aerosols, the active ingredients should be
`
`micronised so as to permit inhalation of substantially all of the active ingredients
`
`20
`
`into the lungs upon administration of the aerosol formulation, thus the active
`
`ingredients will havea particle size of less than 100 microns, desirably less than
`20 microns, and preferably in the range 1 to 10 microns, for example, 1 to 5 .
`microns.
`
`25
`
`lntranasal sprays may be formulated with aqueous or non-aqueous vehicles with
`
`the addition of agents such as thickening agents, buffer salts or acid or alkali to
`
`adjust the pH, isotonicity adjusting agents or anti-oxidants.
`
`Capsules and cartridges or for example gelatin, or blisters of for example
`
`30 _
`
`laminated aluminium foil, for use in an inhaler or insuflator may be formulated
`
`containing a powder mix of the active ingredients and a suitable powder base
`
`such as lactose or starch.
`
`In this aspect, the active ingredients are suitably
`
`micronised so as to permit inhalation of substantially all of the active ingredients
`into the lungs upon administration of the dry powder formulation, thus the active
`
`MED_DYM_00007797
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`ingredients will have a particle size of less than 100 microns, desirably less than
`
`20 microns, and preferably in the range 1 to 10 microns.
`
`‘
`
`Solutions for inhalation by nebulation may be formulated with an aqueous
`
`5
`
`vehicle with the addition of agents such as acid or alkali, buffer salts, isotonicity
`
`adjusting agents or antimicrobials. They may be sterilised by filtration or heating
`
`in an autoclave, or presented as a non-sterile product.
`
`Preferred unit dosage formulations are those containing a pharmaceutically
`effective dose, as hereinbefore recited, or an appropriate fraction thereof, of the
`
`active ingredient. Thus, in the case of formulations designed for delivery by
`
`metered dose pressurised aerosols, one actuation of the aerosol may deliver
`
`half of the therapeutically effective amount such that two actuations are
`
`necessary to deliver the therapeutically effective dose.
`
`10
`
`15
`
`It should be understood that in addition to the ingredients particularly mentioned
`above, the formulations of this invention may include other agents conventional
`in the art having regard‘ to the type of formulation in question. Furthermore, the
`
`claimed formulations include bioequivalents as defined by the US Food and
`
`20
`
`Drugs Agency.
`
`For a better understanding of the invention, the following Examples are given by
`
`way of illustration.
`
`25
`
`EXAMPLES
`
`,
`
`A: Metered Dose Inhalers
`
`Example 1
`
`
`tiotropium bromide
`
`
`fluticasone propionate
`
`
`
`1,1,1,2-Tetrafluoroethane
`
`30
`
`MED_DYM_00007798
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`

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`The micronised active ingredients are weighed into an aluminium can, 1,1,1,2—
`
`tetrafluoroethane is then added from a vacuum flask and a metering valve is
`
`crimped into place.
`
`Similar methods may be used for the formulation of Examples 2 to 4:
`
`Example 2
`
`— t
`
`iotropium bromide
`
`200 microgram
`
`100 microgram
`
`to 75.0mg
`
`
`
`fluticasone propionate
`
`1,1,1 ,2-Tetrafluoroethane
`
`
`
`
`
`
`
`
`10
`
`Example 3
`
`
`
`
`
`_
`
`
`
`
`
`1,1 ,1 ,2-Tetrafluoroethane
`
`Example 4
`
`15
`
`
`
`tiotropium bromide
`
`
`
`fluticasone propionate
`
`
`
`20
`
`1,1,1 ,2-Tetrafluoroethane
`
`to 75.0mg
`
`9 microgram
`
`'
`
`100 microgram
`
`
`
`
`
`
`MED_DYM_00007799
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`

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`Bi Diy Powder Inhalers
`
`Example 5
`
`— Per cartridge or buster
`
`
`
`
`200 microgram
`
`or to 25.0mg
`
`tiotropium bromide
`
`fluticasone propionate
`
`’
`
`
`
`The active ingredients are micronised and bulk blended with the lactose’ in the
`
`proportions given above. The blend is filled into hard gelatin capsules or
`
`cartridges or in specifically constructed double foil blister packs to be
`administered by an inhaler such as a Rotahaler, Diskhaler, or Diskus inhaler
`(each of these being a Trademark of Glaxo Group Limited).
`
`‘Similar methods may be used tor the formulations of Examples 6 to 8:
`
`Example 6
`
`10
`
`15
`
`’
`
`.
`
`
`
`Per cartridge or blister
`
`tiotropium bromide
`
`200 microgram
`
`fluticasone propionate
`
`100 microgram
`
`Lactose Ph. Eur.
`
`A
`
`to 12.5mg
`
`or to 25.0mg
`
`Example 7
`
`Per cartridge or blister
`
`tiotropium bromide
`
`18 microgram
`
`fluticasone propionate
`
`100 microgram
`
`Lactose Ph. Eur.
`
`to 12.5mg
`
`‘
`
`‘ orto 25.0mg
`
`
`
`
`
`
`
`MED_DYM_00007800
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`WO 01/78739
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`PCT/GB01/01631
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`10
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`Example 8
`
`
`
`
`
`— Per cartridge or buster
`trotroprum bromide
`fluticasone propionate
`
`4 100 microgram
`
`
`
`Lactose Ph. Eur
`
`to 12.5mg
`
`* or to 25.0mg
`
`MED_DYM_00007801
`
`

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`WO 01/78739
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`PCT/GB01/01631
`
`1 1
`
`Claims
`
`1.
`
`A pharmaceutical formulation comprising tiotropium or a
`
`pharmaceutically acceptable salt, solvate, or physiologically functional
`
`derivative thereof and fluticasone propionate or a pharmaceutically
`acceptable salt, solvate, or physiologically functional derivative thereof,
`
`and a pharmaceutically acceptable carrier or excipient, and optionally
`
`one or more other therapeutic ingredients.
`
`10
`
`15
`
`2.
`
`A pharmaceutical formulation comprising tiotropium bromide and
`
`fluticasone propionate, and a pharmaceutically acceptable carrier or
`
`excipient, and optionally one or more other therapeutic ingredients.
`
`3.
`
`A pharmaceutical formulation according to claim 1 or 2 which is suitable
`
`for administration by inhalation.
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`4.
`
`A pharmaceutical formulation according to any of claims 1 to 3 wherein
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`the pharmaceutically acceptable carrier or excipient is lactose.
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`20
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`5.
`
`A pharmaceutical formulation according to any of claims 1 to 3 wherein
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`the pharmaceutically acceptable carrier or excipient comprises 1,1,1,2-
`
`tetrafluoroathane and/or 1,1,1,2,3,3,3—heptaf|uoropropane.
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`25
`
`30
`
`6.
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`A method for the prophylaxis or treatment of a clinical condition in a
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`mammal, such as a human, for which an anticholinergic agent and/or
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`antiinflammatory corticosteroid is indicated, which comprises
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`administration of a therapeutically effective amount of a pharmaceutical
`
`formulation according to any one of claims 1 to 5.
`
`7.
`
`A method according to claim 6 wherein the clinical condition is a disease
`
`associated with reversible ain/vays obstruction such as asthma, chronic
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`obstructive pulmonary disease (COPD), respiratory tract infection or
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`upper respiratory tract.disease.
`
`MED_DYM_00007802
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`

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`EXHIBIT 67
`
`EXHIBIT 67
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`
`
`

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`(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization
`International Bureau
`
`
`
`(43) International Publication Date
`25 October 2001 (25.10.2001)
`
`(10) International Publication Number
`
`PCT
`
`WO 01/78745 A1
`
`(51)
`
`International Patent Classif1cation7: A6lK 31/575,
`31/167, A61P 11/06 // (A61K 31/575, 312167)
`
`(21)
`
`International Application Number:
`
`PCT/GB01/01649
`
`(22)
`
`International Filing Date:
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`11 April 2001 (11.04.2001)
`
`(25)
`
`Filing Language:
`
`(26)
`
`Publication Language:
`
`English
`
`English
`
`(30)
`
`Priority Data:
`0009591.9
`
`18 April 2000 (18.04.2000)
`
`GB
`
`(71)
`
`Applicant (for all designated States except US): GLAXO
`GROUP LIMITED [GB/GB]; Glaxo Wellcome House,
`Berkeley Avenue, Greenford, Middlesex UB6 0NN (GB).
`
`(72)
`(75)
`
`Inventors; and
`Inventors/Applicants (for US only): GAVIN, Brian,
`Charles [IE/IE]; GlaxoSmithKline, PO Box 700, Grange
`Road, Rathfarnfam, 16 Dublin (IE). GARRETT, Ronique,
`Nichele [US/US]; GlaXoSmithKline, Five Moore Drive,
`Research Triangle Park, Durham County, NC 27709 (US).
`ROCHE, Trevor, Charles [GB/GB]; GlaxoSmithKline,
`Park Road, Ware, Hertfordshire SG12 0DP (GB).
`
`(74) Agent: LEAROYD, Stephanie, Anne; GlaxoSmithKline,
`Corporate Intellectual Property, Two New Horizons Court,
`Brentford, Middlesex TW8 9EP (GB).
`
`(81) Designated States (national): AE, AG, AL, AM, AT, AU,
`AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CO, CR, CU,
`CZ, DE, DK, DM, DZ, EE, ES, FT, GB, GD, GE, GH, GM,
`HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK,
`LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX,
`MZ, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL,
`TJ, TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZW.
`
`(84) Designated States (regional): ARIPO patent (GH, GM,
`KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZW), Eurasian
`patent (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European
`patent (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE,
`IT, LU, MC, NL, PT, SE, TR), OAPI patent (BF, BJ, CF,
`CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG).
`
`Published:
`
`with international search report
`before the expiration of the time limit for amending the
`claims and to be republished in the event of receipt of
`amendments
`
`For two-letter codes and other abbreviations, refer to the ”Guid-
`ance Notes on Codes andAbbreviations " appearing at the begin-
`ning ofeach regular issue ofthe PCT Gazette.
`
`(54) Title: MEDICAL COMBINATIONS COMPRISING FORMOTEROL AND FLUTICASONE PROPRIONATE
`
`(57) Abstract: The present invention is Concerned with pharmaceutical formulations comprising a combination of formoterol and
`flutieasone propionate and the use of such formulations in medicine, particularly in the prophylaxis and treatment of respiratory
`diseases.
`
`MED_DYM_00008003
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`
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`WO01/78745A1|||||||||||||||||||||||||||||||I||||||||||||||||||||||||||||||||||||||||||||||||
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`

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`WO 01/78745
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`PCT/GB01/01649
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`MEDICAL COMBINATIONS COMPRISING FORMOTEROL AND FLUTICASONE PROPRIONATE
`
`1
`
`The present invention is concerned with combinations of formoterol and
`
`fluticasone propionate, particularly compositions containing a combination of
`
`5
`
`formoterol and fluticasone propionate and the use of such compositions in
`medicine, particularly in the prophylaxis and treatment of respiratory diseases.
`
`Formoterol, i.e. 2'-hydroxy-5'-[(RS)~1-hydroxy-2{[(RS)-p-methoxy—oc—
`
`methylphenethy|]amino}ethy|]formanilide, particularly its fumarate salt is a well-
`
`_1O
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`known adrenoreceptor agonist which is now used clinically in the treatment of
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`bronchial asthma and related disorders.
`
`Fluticasone propionate is an anti-inflammatory corticosteroid, described in GB .
`
`2088877, and is systematically named S—f-luoromethyl-6oc,90¢-difluoro—1 113-
`
`15
`
`hydroxy—160¢-methyl-17oz-propionyloxy-3-oxoandrosta—’l ,4-diene-17B-
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`carbothioate. Fluticasone propionate is now used clinically for the treatment of
`bronchial asthma and related disorders.
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`20
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`25
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`Although formoterol fumarate and fluticasone propionate may be effective
`
`therapies, there exists a clinical need for asthma therapies having potent and
`selective action and having an advantageous profile of action.
`
`Therefore, according to the present invention there is provided a combination of
`formoterol or a pharmaceutically.acceptable salt, solvate, or physiologically
`functional derivative thereof and fluticasone propionate or a pharmaceutically
`
`acceptable salt, solvate, or physiologically functional derivative thereof.
`
`It will be appreciated that the compounds of the combination may be
`
`administered simultaneously, either in the same or different pharmaceutical
`
`30
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`formulations or sequentially.
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`If there is sequential administration, the delay in
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`administering the second compound should not be such as to lose thebeneficial
`
`therapeutic effect of the combination.
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`According to a further aspect of the present invention, there is provided a
`
`35
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`pharmaceutical formulation comprising formoterol or a pharmaceutically
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`MED_DYM_00008004
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`

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`WO 01/78745
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`PCT/GB01/01649
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`acceptable salt, solvate, or physiologically functional derivative thereof and
`
`fluticasone propionate or a pharmaceutically acceptable salt, solvate, or
`
`physiologically functional derivative thereof, and a pharmaceutically acceptable
`
`carrier or excipient, and optionally one or more other therapeutic ingredients.
`
`5
`
`According to a preferred aspect of the present invention, there is provided a
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`pharmaceutical formulation comprising formoterol fumarate and fluticasone
`
`propionate, and a pharmaceutically acceptable carrier or excipient, and
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`optionally one or more other therapeutic ingredients.
`
`in the most preferred
`
`aspect, the above pharmaceutical formulations are suitable for administration by
`inhalation.
`
`10
`
`It
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`is to be understood that the present invention covers all combinations of
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`particular and preferred aspects of the invention described herein.
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`15
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`As would be appreciated by the skilled person, formoterol includes two
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`asymmetric centres. The present invention includes each isomer of formoterol
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`either in substantially pure form or admixed in any proportions, particularly the
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`(R,R)— isomer. The enantiomers of formoterol have been described previously,
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`for example, in W098/21175 and US5795564.
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`20
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`By the term "physiologically functional derivative” is meant a chemical derivative
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`of formoterol or fluticasone propionate having the same physiological function as
`
`the free compound, for example, by being convertible in the body thereto.
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`According to the present invention, examples of physiologically functional
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`25
`
`. derivatives include esters.
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`Suitable salts according to the invention include those formed with both organic '
`
`and inorganic acids. Pharmaceutically acceptable acid addition salts include but
`are not limited to those formed from hydrochloric, hydrobromic, sulphuric, citric,
`
`30
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`tartaric, phosphoric, lactic, pyruvic, acetic, trifluoroacetic, succinic, oxalic,
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`fumaric, maleic, oxaloacetic, methanesulphonic, ethanesulphonic, p-
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`toluenesulphonic, benzenesulphonic, isethionic, and naphthalenecarboxylic,
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`such as 1—hydroxy—2—naphthalenecarboxylic acids.
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`MED_DYM_00008005
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`WO 01/78745
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`PCT/GB01/01649
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`3
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`Pharmaceutically acceptable esters of formoterol or fluticasone propionate may
`have a hydroxyl group converted to a C1_5alkyl, aryl, aryl C1_5 alkyl, or amino acid
`ester.
`
`5
`
`As mentioned above, both formoterol and fluticasone propionate and their
`
`pharmaceutically acceptable salts, solvates, and physiologically functional
`
`‘
`
`derivative