APPLICATION
`NUMBER
`61/487,789
`
`FILING or
`37l(c)DATE
`05/19/2011
`
`GRPART
`UNIT
`
`FIL FEE REC'D
`220
`
`26356
`ALCON
`IP LEGAL, TB4-8
`6201 SOUTH FREEWAY
`FORT WORTH, TX 76134
`
`Ul\TfED STATES DEPA RTME'IT OF COMMERCE
`United States Patent and Trademark Office
`Adm"'· COMMISSIO'JER FOR PATENTS
`PO Box 1450
`Alexandria, Virgmia 22313-1450
`\VVi\V.USpto.gov
`
`ATTY.DOCKET.NO
`3988 US Pr
`
`TOT CLAIMS IND CLAIMS
`
`CONFIRMATION NO. 4778
`FILING RECEIPT
`111111111111111111111111]~!l]~~1~~1~~11~UHi~11111111111111111111111111
`
`Date Mailed: 06/30/2011
`
`Receipt is acknowledged of this provisional patent application. It will not be examined for patentability and will
`become abandoned not later than twelve months after its filing date. Any correspondence concerning the application
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`to the Notice, the USPTO will generate another Filing Receipt incorporating the requested corrections
`
`Applicant( s)
`
`Laman Alani, Fort Worth, TX;
`Malay Ghosh, Fort Worth, TX;
`Francisco Javier Galan, Teia, SPAIN;
`Nuria Carreras Perdiguer, Caldes de Montbui, SPAIN;
`Power of Attorney:
`Scott Chapple--46287
`
`If Required, Foreign Filing License Granted: 06/29/2011
`The country code and number of your priority application, to be used for filing abroad under the Paris Convention,
`is US 61/487,789
`Projected Publication Date: None, application is not eligible for pre-grant publication
`Non-Publication Request: No
`Early Publication Request: No
`Title
`
`High Concentration Olopatadine Ophthalmic Composition
`
`PROTECTING YOUR INVENTION OUTSIDE THE UNITED STATES
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`page 1of3
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`APOTEX EX1010
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`Page 1
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`

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`Title 35, United States Code, Section 184
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`Page 2
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`page 3 of 3
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`Page 3
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`Doc Code: TR.PROV
`Document Description: Provisional Cover Sheet (SB16)
`
`PTOISB/16 (11-08)
`Approved for use through 09/30/2010 OMB 0651-0032
`U.S. Patent and Trademark Office: U.S. DEPARTMENT OF COMMERCE
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`Provisional Application for Patent Cover Sheet
`This is a request for filing a PROVISIONAL APPLICATION FOR PATENT under 37 CFR 1.53(c)
`
`lnventor(s)
`
`Inventor 1
`
`Given Name
`
`Middle Name
`
`Family Name
`
`City
`
`State
`
`Laman
`
`Inventor 2
`
`Alani
`
`Fort Worth
`
`TX
`
`Given Name
`
`Middle Name
`
`Family Name
`
`City
`
`State
`
`I Remove I
`Country
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`us
`
`I Remove I
`Country
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`Ghosh
`
`Fort Worth
`
`TX
`
`us
`
`Malay
`
`Inventor 3
`
`I Remove I
`Country
`
`Given Name
`
`Middle Name
`
`Family Name
`
`City
`
`State
`
`Francisco
`
`Javier
`
`Galan
`
`Teia
`
`ES
`
`Inventor 4
`
`Given Name
`
`Middle Name
`
`Family Name
`
`City
`
`State
`
`I Remove I
`Country
`
`Nuria
`
`Carreras
`
`Perdiguer
`
`Caldes de Mo1j
`
`ES
`
`All Inventors Must Be Listed -Additional Inventor Information blocks may be
`generated within this form by selecting the Add button.
`
`I Add
`
`I
`
`Title of Invention
`
`High Concentration Olopatadine Ophthalmic Composition
`
`Attorney Docket Number (if applicable)
`
`3988 US Pr
`
`Correspondence Address
`
`Direct all correspondence to (select one):
`
`0 The address corresponding to Customer Number
`
`0 Firm or Individual Name
`
`Customer Number
`
`26356
`
`i
`
`i
`
`i
`
`i
`
`The invention was made by an agency of the United States Government or under a contract with an agency of the United
`States Government.
`0 No.
`0 Yes, the name of the U.S. Government agency and the Government contract number are:
`
`EFS - Web 1.0.1
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`Page 4
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`

`
`Doc Code: TR.PROV
`Document Description: Provisional Cover Sheet (SB16)
`
`PTOISB/16 (11-08)
`Approved for use through 09/30/2010 OMB 0651-0032
`U.S. Patent and Trademark Office: U.S. DEPARTMENT OF COMMERCE
`Under the Paperwork Reduction Act of 1995, no persons are required to respond to a collection of information unless it displays a valid OMB control number
`
`Entity Status
`Applicant claims small entity status under 37 CFR 1.27
`0 Yes, applicant qualifies for small entity status under 37 CFR 1.27
`® No
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`Signature
`
`Please see 37 CFR 1.4(d} for the form of the signature.
`
`Signature
`
`/Scott A. Chapple, Reg. #46,287/
`
`Date (YYYY-MM-DD)
`
`2011-05-19
`
`First Name
`
`Scott
`
`Last Name
`
`Chapple
`
`Registration Number
`(If appropriate)
`
`46287
`
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`

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`Page 6
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`

`
`Atty. Docket No.: 3988 US Pr
`
`HIGH CONCENTRATION OLOP A TADINE
`OPHTHALMIC COMPOSITION
`
`s Technical Field of the Invention
`
`The present invention relates to an ophthalmic composition containing a
`relatively high concentration of olopatadine. More particularly, the present
`invention relates to an ophthalmic aqueous solution containing a relatively high
`concentration of solubilized olopatadine wherein the solution is capable of
`providing enhanced relief from symptoms of ocular allergic conjunctivitis in the
`early phase, the late phase or preferably both phases.
`
`Background of the Invention
`
`from ocular allergic conjunctivitis experience
`suffering
`Individuals
`symptoms such as ocular irritation, itchiness, redness and the like.
`It has been
`found that these symptoms are significantly reduced using topical ophthalmic
`solutions containing olopatadine. Such solutions are sold under the tradenames
`PATANOL® and PATADAY®, which are both commercially available from
`Alcon Research Ltd., Fort Worth, TX.
`
`Recently, and as discussed further below, it has been discovered that
`relatively high concentration solutions of olopatadine provide significantly
`improved reduction of late phase ocular allergic conjunctivitis symptoms in
`addition to relief from early phase symptoms. Such discovery is significant since
`relief from such late phase symptoms is particularly desirable for individual
`suffering from ocular allergic conjunctivitis. Further, it has been discovered that
`relief from these late phase symptoms can be achieved through once a day dosing
`of relatively high concentration olopatadine solution as opposed to greater dosing
`frequencies. A voiding more frequent dosing is more convenient for patients and
`helps assure better compliance with a simpler dosing regimen.
`
`The discovery that relatively high concentration solutions of olopatadine
`provides hope to sufferers of ocular allergic conjunctivitis that a single dose of
`olopatadine per day could provide a substantial degree of full day relief from
`symptoms of ocular allergic conjunctivitis. However, the development of a multi-
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`Atty. Docket No.: 3988 US Pr
`
`includes high concentrations of olopatadine
`that
`dose ophthalmic solution
`necessary to achieve desired levels of efficacy is extremely difficult and complex.
`
`Solubilizing high concentrations of olopatadine in a stable manner has
`proven difficult by itself. Olopatadine, by itself, is only soluble up to a
`concentration of about 0.18 w/v% in water at a pH of about 7.0 and at about room
`temperature. However, it is desirable to achieve solubilization of much higher
`concentrations of olopatadine in an effort to treat late phase ocular allergic
`conjunctivitis.
`
`Solubilizing such higher concentrations of olopatadine has proven difficult.
`As one example, excipients such as polyethylene glycol (PEG) 400 and
`polyvinylpyrrolidone (PVP), when used at reasonably desirable concentrations,
`have proven to be insufficient, alone or in combination, to solubilize sufficient
`concentrations of olopatadine. Thus, innovation is required to solubilize a
`sufficient concentration of olopatadine.
`
`In the process of such innovation, is has been discovered that higher
`molecular weight PEGs such as PEG 6000 can significantly enhance solubility of
`olopatadine. However, such PEGs cause risk of discomfort when administered to
`humans. It has also been discovered that cyclodextrins such as hydroxypropyl-~­
`cyclodextrin and sulfoalkyl ether-~-cyclodextrin have the ability to solubilize
`significantly higher concentrations of olopatadine, however, use of undesirably
`high concentrations of these cyclodextrins has been found to reduce olopatadine
`efficacy and/or preservation efficacy of solutions. As such, still further innovation
`was needed to create a desirable olopatadine formulation that not only solubilized
`sufficient amounts of olopatadine, but also allowed the formulation to achieve other
`desired criteria.
`
`Thus, the present invention is directed at an ophthalmic composition that can
`provide high concentrations olopatadine topically to the eye. Further, the present
`invention is directed at such a composition wherein the olopatadine is solubilized in
`solution in a stable manner, the composition exhibits consistent efficacy against late
`phase symptoms of ocular allergic conjunctivitis,
`the composition exhibits
`sufficient antimicrobial activity to provide desired levels of preservation efficacy or
`any combination thereof.
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`Atty. Docket No.: 3988 US Pr
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`Summary of the Invention
`
`The present invention is directed to an ophthalmic composition for treatment
`of ocular allergic conjunctivitis. The composition will include a relatively high
`concentration of olopatadine, preferably at least 0.67 w/v % olopatadine, dissolved
`in solution. The composition will typically include a f3-cyclodextrin derivative to
`aid in the solubility of the olopatadine. The P-cyclodextrin derivative is preferably
`hydroxypropyl- f3-cyclodextrin (HP- f3-CD), sulfoalkyl ether f3-cyclodextrin (SAE(cid:173)
`P-CD)(e.g., sulfobutyl ether f3-cyclodextrin (SBE- f3-CD)). The composition will
`typically include a lactam polymer (e.g., polyvinylpyrrolidone (PVP)) to aid in the
`solubility of the olopatadine. The composition will also typically include a
`polyether (e.g., polyethylene glycol (PEG)) for enhancing solubility and/or aiding
`in achieving the desired tonicity. It is generally desirably for the composition to
`isotonic, be disposed in an eyedropper, have a pH of 5.5 to 8.0, to have an
`osmolality of 200 to 450 or any combination thereof. The composition will also
`typically includes a preservative to allow the composition to achieve United State
`and/or European Pharmacopeia preservation standards. Preferred preservatives
`include a polymeric quaternary ammonium compound and benzalkonium chloride.
`The composition also typically includes borate and/or polyol to aid in achieving
`preservation standard.
`
`The present invention also contemplates a method of treating ocular allergy
`symptoms. The method will include topically applying a composition having a
`defined combination of the characteristics described above to an eye of a human.
`This step of topically applying the composition preferably includes dispensing an
`eyedrop from an eyedropper.
`
`Detailed Description of the Invention
`
`The present invention is predicated upon the provision of an ophthalmic
`composition for treatment of allergic conjunctivitis. The ophthalmic composition is
`preferably an aqueous solution. The ophthalmic composition includes a relatively
`high concentration of olopatadine solubilized in aqueous solution. The ophthalmic
`composition also includes a unique set of excipients for solubilizing the olopatadine
`while maintaining comfort of the composition and/or efficacy of the composition in
`treating ocular allergic conjunctivitis, particularly late phase ocular allergic
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`Atty. Docket No.: 3988 US Pr
`
`conjunctivitis. In a preferred embodiment, the ophthalmic composition is a multi(cid:173)
`dose ophthalmic composition that also exhibits a required degree of preservation
`efficacy.
`
`5
`
`Unless indicated otherwise, all component amounts are presented on a %
`(w/v) basis and all references to olopatadine are to olopatadine free base.
`
`Olopatadine is a known compound that 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 for all purposes. The solution
`formulation of the present invention contain at least 0.55%, more typically at least
`0.6% or 0.65%, even more typically at least 0.68%, still more typically at least
`0.7%, possibly at least 0.75% and even possibly at least 0.85% but typically no
`greater than 1.5% more typically no greater than 1.0%, still more typically no
`greater than 0.8%, possibly no greater than 0.75% and even possibly no greater
`than 0.72%. These lower limits of concentrations of olopatadine are particularly
`important since it has been found that efficacy of olopatadine in aqueous
`ophthalmic solutions in reducing late phase allergy symptoms begins to show
`improvement at concentrations greater than 0.5 w/v% of olopatadine and begins to
`show statistically significant
`improvements
`in reducing
`late phase allergy
`symptoms at concentrations of about 0.7 w/v% olopatadine and above (e.g., at least
`0.65 w/v% or at least 0.68 w/v%).
`
`Generally, olopatadine will be added in the form of a pharmaceutically
`acceptable salt. Examples of the pharmaceutically acceptable salts of olopatadine
`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 triethylamine addition salt (also
`known as tromethamine ), morpholine addition salt and piperidine addition salt.
`The most preferred form of olopatadine for use in the solution compositions of the
`present
`invention
`is
`the
`hydrochloride
`salt
`of
`(Z)-11-(3-
`dimethylaminopropylidene )-6, 11-dihydro-dibenz-[b,e ]oxepin-2-acetic acid. When
`olopatadine is added to the compositions of the present invention in this salt form,
`0.77% olopatadine hydrochloride is equivalent to 0.7% olopatadine free base,
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`Page 10
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`
`Atty. Docket No.: 3988 US Pr
`
`0.88% olopatadine hydrochloride is equivalent to 0.8% olopatadine free base, and
`0.99% olopatadine hydrochloride is equivalent to 0.9% olopatadine free base.
`
`includes
`invention also preferably
`The composition of the present
`cyclodextrin derivative and more preferably f3-cyclodextrin derivative to aid in
`solubilizing the olopatadine (i.e., as a solubilizer). The f3-cyclodextrin derivative is
`typically present in the composition at a concentration that is at least 0.5% w/v,
`more typically at least 1.0% w/v and even possibly at least 1.3% w/v, but is
`typically no greater than 4.0% w/v, typically no greater than 3.2% w/v and even
`possibly no greater than 2.8% w/v.
`
`The specific amount of f3-cyclodextrin derivative in a particular composition
`will depend upon the type or combination of types of derivatives used. One
`particularly desirable f3-cyclodextrin derivative is hydroxypropyl-f3-cyclodextrin
`(HP-f3-CD). Another particularly desirable f3-cyclodextrin derivative is sulfoalkyl
`ether-f3-cyclodextrin (SAE-f3-CD), particularly sulfobutyl ether-f3-cyclodextrin
`(SBE-f3-CD).
`It is contemplated that a combination of hydroxypropyl-f3-
`cyclodextrin and sulfoalkyl ether-f3-cyclodextrin derivative may be employed in a
`single composition, but it is typically desirable to use only one or the other as the
`sole or substantially the sole (i.e., at least 90% by weight of the cyclodextrin
`component) f3-cyclodextrin derivative.
`
`When HP-f3-CD is employed as the sole or substantially sole f3-cyclodextrin
`derivative, it is typically present in the composition at a concentration that is at
`least 0.5% w/v, more typically at least 1.0% w/v and even more typically at least
`1.3% w/v, but is typically no greater than 3.0% w/v, typically no greater than 2.2%
`w/v and is typically no greater than 1.7% w/v. When SAE-f3-CD is employed as
`the sole or substantially sole f3-cyclodextrin derivative, it is typically present in the
`composition at a concentration that is at least 0.3% w/v, more typically at least
`0.7% w/v and even more typically at least 0.9% w/v, but is typically no greater than
`2.4% w/v, typically no greater than 1.5% w/v and is typically no greater than 1.1 %
`w/v.
`
`HP-f3-CD is a commodity product and pharmaceutical grades of HP-f3-CD
`can be purchased from a variety of sources, for example, from SIGMA ALDRICH,
`which has its corporate headquarters in St. Louis, Missouri or INTERNATIONAL
`SPECIAL TY PRODUCTS, headquartered in Wayne, New Jersey. SAE-f3-CD can
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`Atty. Docket No.: 3988 US Pr
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`be formed based upon the teachings of U.S. Patent Nos. 5,134,127 and 5,376,645,
`which are incorporated herein by reference for all purposes.
`It is generally
`preferred, however, to use purified SAE-J3-CD. Purified SAE-J3-CD is preferably
`formed in accordance with the teachings of U.S. Patent Nos. 6,153,746 and
`7,635,773. Purified SAE-J3-CD is commercially available under the tradename
`CAPTISOL® from CyDex Pharmaceuticals, Inc., Lenexa, KS.
`
`With regard to J3-cyclodextrin derivative in the composition of the present
`invention, it has been found that undesirably high concentrations of J3-cyclodextrin
`derivative can significantly interfere with preservation efficacy of the compositions,
`particularly when benzalkonium chloride and/or polymeric quaternary ammonium
`compound are employed as preservation agents. Thus, lower concentrations of J3-
`cyclodextrin derivative are typically preferred. Advantageously, it has also been
`found, however, that the ability of the J3-cyclodextrin derivatives in solubilizing
`olopatadine is very strong and relatively low concentrations of 13-cyclodextrin
`derivative can solubilize significant concentrations of olopatadine in aqueous
`solution. As such, a relatively low concentration of additional solubilizing agent is
`needed to solubilize the desired amounts of olopatadine.
`
`Further, it has been found that a composition formed using a combination of
`solubilizing agents such as polyvinylpyrrolidone, tyloxapol, polyethylene glycol
`and others to solubilize relatively high concentrations of olopatadine in the absence
`of J3-cyclodextrin derivative will typically lack long term stability or shelf life. It
`has been found that such a composition will typically begin to precipitate after
`undesirably short periods of time. Thus, it is important to employ the J3-
`cyclodextrin derivative in combination with one or more additional solubilizers.
`
`As such, the ophthalmic composition of the present invention includes at
`least one solubilizing agent (i.e., solubilizer), but possibly two or more solubilizing
`agents in addition to cyclodextrin. The solubilizing agents can include surfactants
`such as castor oil, polysorbate or others. Preferably, the solubilizing agent[ s]
`includes one or more polymers. One highly preferred polymer for aiding in
`solubilizing the olopatadine is lactam polymer. Another highly preferred polymer
`for aiding in solubilizing the olopatadine is polyether.
`
`As used herein, the phrase "lactam polymer" refers to any polymer formed
`from more than one lactam monomer. The lactam polymer is typically present in
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`the composition at a concentration that is at least 1.0% w/v, more typically at least
`3.0% w/v and even more typically at least 3.7 % w/v, but is typically no greater
`than 8.0% w/v, typically no greater than 5.0% w/v and is typically no greater than
`4.3% w/v. Polyvinylpyrrolidone (PVP) is the most preferred lactam polymer and
`can be the only or substantially the only lactam polymer. Thus, in a preferred
`embodiment, the lactam polymer consists or consists essentially of PVP. The
`average molecular weight of the lactam polymer, particularly when it is PVP, is at
`least 20,000, more typically at least 46,000 and even more typically at least 54,000
`but is typically no greater than 90,000, more typically no greater than 70,000 and
`still more typically no greater than 62,000. One preferred PVP is sold under the
`tradename PLASDONE® K29/32, which has an average molecular weight of
`approximately 50,000 and is commercially available from International Specialty
`Products, headquartered in Wayne, NJ, USA.
`
`The polyether can aid in the solubility of olopatadine in the composition
`and/or can provide tonicity to the composition (i.e., act as a tonicity agent). The
`polyether is typically present in the composition at a concentration that is at least
`1.0% w/v, more typically at least 3.0% w/v and even more typically at least 3.7 %
`w/v, but is typically no greater th