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`UNITED STATES PATENT AND TRADEMARK OFFIGE
`
`UNITED STATES DEPARTMENT OF COMMERCE
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`!
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`
`APPLICATION
`NUMBER
`
`FILING or
`371(c) DATE
`
`GRP ART
`UNIT
`
`
`
`
`
`FIL
`
`61/487,789
`
`05/19/2011
`
`FEE REC'D
`
`220
`
`ATTY.DOCKET.NO
`
`3988 US Pr
`
`ITOT CLAIMSJIND CLAIMS
`
`CONFIRMATION NO. 4778
`
`FILING RECEIPT
`
`26356
`ALCON
`
`6201 SOUTH FREEWAY
`FORT WORTH, TX 76134
`
`IP LEGAL, TB4-8 A00000004850995
`
`Date Mailed: 06/30/2011
`
`It will not be examined for patentability and will
`Receipt is acknowledged of this provisional patent application.
`become abandonednotlater than twelve monthsafter its filing date. Any correspondence concerning the application
`mustinclude the following identification information: the U.S. APPLICATION NUMBER, FILING DATE, NAME OF
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`any corrections to this Filing Receipt with your reply to the Notice. When the USPTO processesthe reply
`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;
`Powerof Attorney:
`Scott Chapple--46287
`
`If Required, Foreign Filing License Granted: 06/29/2011
`The country code and number of your priority application, to be usedfor 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
`
`Since the rights granted by a U.S. patent extend only throughoutthe territory of the United States and have no
`effect in a foreign country, an inventor who wishes patent protection in another country must apply for a patent
`in a specific country or in regional patent offices. Applicants may wish to consider the filing of an international
`application under the Patent Cooperation Treaty (PCT). An international (PCT) application generally has the same
`effect as a regular national patent application in each PCT-member country. The PCT process simplifies the filing
`page 1 of 3
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`IPR2018-01020 and IPR2018-01021, Exhibit 1009, Page 1
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`of patent applications on the same invention in member countries, but does notresult in a grantof "an international
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`The applicant has been granted a license under 35 U.S.C. 184,
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`IPR2018-01020 and IPR2018-01021, Exhibit 1009, Page 2
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`IPR2018-01020 and IPR2018-01021, Exhibit 1009, Page 2
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`State (with respect to Arms, Munitions and Implements of War (22 CFR 121-128)); the Bureau of Industry and
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`page 3 of 3
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`IPR2018-01020 and IPR2018-01021, Exhibit 1009, Page 3
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`IPR2018-01020 and IPR2018-01021, Exhibit 1009, Page 3
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`Doc Code: TR.PROV
`Document Description: Provisional Cover Sheet (SB16)
`
`PTO/SB/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 cf information unlessit displays a valid OMB control number
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`Provisional Application for Patent Cover Sheet
`This is a requestforfiling a PROVISIONAL APPLICATION FOR PATENTunder 37 CFR 1.53(c)
`
`Inventor(s)
`
`Inventor 1
`
`Given Name
`Middle Name
`Family Name
`City
`
`Laman
`Alani
`Fort Worth
`US
`
`Inventor 2
`
`Inventor 3
`
`Family Name
`Middle Name
`Given Name
`
`Francisco
`Javier
`Galan
`
`Inventor 4
`
`
`
`[Add|generated within this form by selecting the Add button.All Inventors Must Be Listed — Additional Inventor Information blocks may be [Add]
`
`©) Yes, the name of the U.S. Government agency and the Government contract numberare:
`
`
`
`High Concentration Clopatadine Ophthalmic Composition
`Title of Invention
`
`Attorney Docket Number (if applicable}
`3988 US Pr
`
`Correspondence Address
`
`Direct all correspondenceto (select one):
`
`(@) The address corresponding to Customer Number
`
`C) Firm orIndividual Name
`
`Customer Number
`
`26356
`
`The invention was made by an agency of the United States Government or under a contract with an agency of the United
`States Government.
`
`() No.
`
`EFS - Web 1.0.1
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`IPR2018-01020 and IPR2018-01021, Exhibit 1009, Page 4
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`IPR2018-01020 and IPR2018-01021, Exhibit 1009, Page 4
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`

`

`Doc Code: TR.PROV
`Document Description: Provisional Cover Sheet (SB16)
`
`PTO/SB/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 cf information unlessit displays a valid OMB control number
`
`Entity Status
`Applicant claims small entity status under 37 CFR 1.27
`
`C) 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.
`
`‘Scott A. Chapple, Reg. #46,287/
`
`Date (YYYY-MM-DD}
`
`9011-05-19
`
`First Name
`
`Scott
`
`Last Name
`
`Chapple
`
`Registration Number
`(lf appropriate}
`
`46287
`
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`EFS - Web 1.0.1
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`IPR2018-01020 and IPR2018-01021, Exhibit 1009, Page 6
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`Atty. Docket No.: 3988 US Pr
`
`HIGH CONCENTRATION OLOPATADINE
`
`OPHTHALMIC COMPOSITION
`
`Technical Field of the Invention
`
`invention relates to an ophthalmic composition containing a
`The present
`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
`
`experience
`conjunctivitis
`allergic
`suffering from ocular
`Individuals
`It has been
`symptoms such as ocularirritation, itchiness, redness and the like.
`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.
`
`it has been discovered that
`Recently, and as discussed further below,
`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. Avoiding 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 developmentof a multi-
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`Atty. Docket No.: 3988 US Pr
`
`includes high concentrations of olopatadine
`dose ophthalmic solution that
`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.
`
`is has been discovered that higher
`In the process of such innovation,
`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-B-
`cyclodextrin and sulfoalkyl ether-B-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 olopatadineis 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
`
`Summaryof 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 B-cyclodextrin derivative to
`aid in the solubility of the olopatadine. The B-cyclodextrin derivative is preferably
`hydroxypropyl- B-cyclodextrin (HP- B-CD), sulfoalkyl ether B-cyclodextrin (SAE-
`B-CD)(e.g., sulfobutyl ether B-cyclodextrin (SBE- B-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 benzalkoniumchloride.
`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 includesa 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
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`In a preferred embodiment, the ophthalmic composition is a multi-
`conjunctivitis.
`dose ophthalmic composition that also exhibits a required degree of preservation
`efficacy.
`
`Unless indicated otherwise, all component amounts are presented on a %
`(w/v) basis andall 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
`symptomsat 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-(-
`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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`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.
`
`invention also preferably includes
`the present
`The composition of
`cyclodextrin derivative and more preferably B-cyclodextrin derivative to aid in
`solubilizing the olopatadine(1.e., as a solubilizer). The B-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 B-cyclodextrin derivative in a particular composition
`will depend upon the type or combination of types of derivatives used. One
`particularly desirable B-cyclodextrin derivative is hydroxypropyl-B-cyclodextrin
`(HP-B-CD). Another particularly desirable B-cyclodextrin derivative is sulfoalkyl
`ether-B-cyclodextrin (SAE-B-CD), particularly sulfobutyl
`ether-B-cyclodextrin
`(SBE-B-CD).
`It
`is contemplated that a combination of hydroxypropyl-B-
`cyclodextrin and sulfoalkyl ether-B-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) B-cyclodextrin derivative.
`
`When HP-B-CD is employed as the sole or substantially sole B-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-B-CD is employed as
`the sole or substantially sole B-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 andis typically no greater than 1.1%
`wiv.
`
`HP-B-CD is a commodity product and pharmaceutical grades of HP-B-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
`SPECIALTY PRODUCTS, headquartered in Wayne, New Jersey. SAE-B-CD can
`
`20
`
`25
`
`30
`
`35
`
`-5-
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1009, Page 11
`
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1009, Page 11
`
`

`

`Atty. Docket No.: 3988 US Pr
`
`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-B-CD. Purified SAE-B-CD is preferably
`formed in accordance with the teachings of U.S. Patent Nos. 6,153,746 and
`7,635,773. Purified SAE-B-CD is commercially available under the tradename
`CAPTISOL® from CyDex Pharmaceuticals, Inc., Lenexa, KS.
`
`With regard to B-cyclodextrin derivative in the composition of the present
`invention, it has been found that undesirably high concentrations of B-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 B-
`cyclodextrin derivative are typically preferred. Advantageously, it has also been
`found, however, that the ability of the B-cyclodextrin derivatives in solubilizing
`olopatadine is very strong and relatively low concentrations of B-cyclodextrin
`derivative can solubilize significant concentrations of olopatadine in aqueous
`solution. As such, a relatively low concentration of additional solubilizing agentis
`needed to solubilize the desired amounts of olopatadine.
`
`20
`
`25
`
`30
`
`35
`
`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 B-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 f-
`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
`
`-6-
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1009, Page 12
`
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1009, Page 12
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`

`Atty. Docket No.: 3988 US Pr
`
`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 moretypically 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