Express Mail Label No.: EV464271789US
`Date of Deposit: November 23, 2004
`
`Attorney Docket No. 22531-522
`
`PROVISIONAL APPLICATION FOR PATENT COVER SHEET
`This is a request for filing a PROVISIONAL APPLICATION FOR PATENT under 37 CFR § l.S3(c)
`
`INVENTORS I APPLICANTS
`
`0
`·~
`
`·
`
`Given Name (last name, first name, and middle initial [if any])
`Gregory
`Tim
`Seth
`Laurence
`
`Went
`Fultz
`Porter
`Meyerson
`
`Residence (City and State or Foreign Country)
`Mill Valley, CA
`Pleasant Hill, CA
`S:1n Carlos, CA
`San Raf:1el, CA
`
`0
`
`Additio031 inventors are being named on page 2 attached hereto
`
`TITLE OF THE INVENTION
`
`METHOD AND COMPOSITION FOR ADMINISTERING AN NMDA RECEPTOR ANT AGONIST TO A
`SUBJECT
`
`Attorney Name:
`Firm Name :1nd Address:
`
`CORRESPONDENCE ADDRESS
`
`lvor R. Elrifi, Ph.D.
`MINTZ, LEVIN, COHN, FERJUS, GLOVSKV AND POPEO, P.C.
`One Financial Center
`Boston, MA 0211 1
`
`Telephone:
`F:1x:
`
`(617} 542-6000
`
`(617) 542-2241
`
`ENCLOSED APPLICATION PARTS
`
`~ Specification
`0
`Sequence Listing
`
`Number of Pages: 20
`Number of Pages:
`Number of Sheets:
`
`0 Other documents (specify):
`1l1c invention was made by an agency of the United States Government or under a contract with an agency of the United States Government:
`l?Sl
`No.
`0
`Yes. the name of the U.S. Government :1gency and the Government contract number are:
`
`A check in the amount of $160.00 is enclosed to cover the fitc(g fees of the Provisional application.
`
`METHOD,.OF.PAYMENT
`
`50.{)3\ I, R<f"<ott No.
`, ,
`The Commissioner is hereby authorized to charge additio at fees or credit a y overpaYT!l(:n o ~posit Account No. 50-0311, ibference No.
`[client 22531-522]
`1
`/
`/'\
`
`l?Sl
`0
`
`l?Sl
`
`Tho Comm\"1"'" ;, ho~by '"'"'""" <o '""•' $00.00 Z"" '"' fiUog f«o of<h< Pro•i<loool •ppU<,.Ioo <o ll<J'O'I< A=o" No
`f
`.
`if 't !\/
`\:)pec~ll L~t·
`'lA / 1
`lvor'R. ~iWRe~. No. '39,
`David E. Jolmson, Reg. Nq.
`c/o MINTZ, LEVIN
`One Financial Center
`Boston, Massachusetts 02111
`Tel: (617) 542-6000
`Fax: (617) 542-2241
`Customer No. 30623
`
`!~.874 v
`
`November 23, 2004
`
`USE ONLY FOR FILING A PROVISIONAL APPLICATION FOR PATENT
`SEND TO: Commissioner for Patents
`P. 0. Box 1450 Alexandria, VA 22313-1450
`
`TRA 1981049vl
`
`. . .•
`
`IPR2015-00410
`Petitioners' Ex. 1005
`Page 1
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`

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`Express Mail Label No. EV 464271789US
`Date of Deposit: November 23, 2004
`
`Attorney Docket No. 22531-522
`
`METHOD AND COMPOSITION FOR ADMINISTERING AN NMDA
`RECEPTOR ANTAGONIST TO A SUBJECT
`
`FIELD OF THE INVENTION
`
`The invention relates to compositions containing N-methyl-D- Aspartate (NMDA)
`
`receptor antagonists and methods for using such compositions.
`
`BACKGROUND OF THE INVENTION
`
`5
`
`10
`
`Acute and chronic neurological and neuropsychiatric diseases are among the leading
`
`causes of death, disability, and economic expense in the world. One of the key challenges in
`
`treating these disorders is the high degree of interplay amongst the pathways that control both
`
`normal and abnormal neuronal function.
`
`15
`
`Excitatory amino acid receptors, including the N-Methyl-D-Aspartate (NMDA) receptor,
`
`are important mediators of excitatory synaptic transmissions (i.e., stimulation of neurons) in the
`
`brain, participating in wide-ranging aspects of both normal and abnormal central nervous system
`
`(CNS) function. The NMDA receptor and its associated calcium (Ca2+) permeable ion channel
`
`are activated by glutamate, a common excitatory neurotransmitter in the brain and the spinal
`
`20
`
`cord, and the co-agonist glycine. NMDA receptor activity and consequent Ca2+ influx are
`
`necessary for long-term potentiation (a correlate of learning and memory).
`
`Aberrant glutamate receptor activitY has been implicated in a large number of
`
`neurodegenerative conditions including, for example, Alzheimer's disease, depression,
`
`neuropathic pain, multiple sclerosis, epilepsy, ALS (amyotrophic lateral sclerosis or Lou
`
`25 Gehrig's disease), and Huntington's disease. ln this regard, the abnormal activation of the
`
`NMDA receptor resulting from elevated levels of glutamate, for example, may lead to sustained
`
`activity of the receptor's ion channel (often lasting for minutes rather than milliseconds), thereby
`
`allowing Ca2+ to build-up. The excessive influx of Ca2+ eventually leads to the generation of
`
`damaging free radicals, extended release of excitatory amino acids, and inappropriate stimulation
`
`30
`
`of adjacent neurons. Thus, strategies that reduce glutamate-mediated excitotoxicity are needed,
`
`particularly those that inhibit the consequences of over-stimulation while preserving normal
`
`glutamate activity.
`
`1
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`IPR2015-00410
`Petitioners' Ex. 1005
`Page 2
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`

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`Express Mail Label No. EV464271789US
`Date of Deposit: November 23, 2004
`
`Attorney Docket No. 22531-522
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`Certain NMDA receptor antagonists, such as memantine, readily cross the blood-brain
`
`barrier, achieving nearly identical concentrations in the extra cellular fluid surrounding brain
`
`tissue and systemic serum. Ideally, the NMDA receptor antagonist should be present at a
`
`concentration sufficient to reduce the symptoms of the disease in the absence of debilitating side
`
`5
`
`effects.
`
`In the present dosage forms however, these drugs, which have a relatively long half(cid:173)
`
`life, need to be administered frequently and require an initial dose escalation to avoid side effects
`
`associated with initial exposure. This leads to difficulty in achieving adequate patient
`
`compliance, which is further exacerbated by the complicated dosing schedules of therapeutic
`
`modalities used for neurological or neuropyschiatric disorders.
`
`10
`
`Thus, better methods are needed to treat and prevent neurological disorders.
`
`SUMMARY OF THE INVENTION
`
`In general, the present invention provides pharmaceutical compositions that are
`
`administered so as to deliver to a subject in a single administration, an amount of an NMDA
`
`15
`
`receptor antagonist (e.g., an aminoadamantine derivative such as memantine) that is high enough
`
`to treat symptoms of an underlying disease but is low enough to avoid undesirable side effects.
`
`Also provided are methods for using such compositions.
`
`According to this invention, at least 95%, 97%, 98%, 99% or even 100% of the NMDA
`
`receptor antagonist is provided in an extended release dosage form and upon the administration
`
`20
`
`of this composition to a subject (e.g., a mammal such as a human), the NMDA receptor
`
`antagonist has a Cmax /C mean of approximately 2.5, 2, 1.5, or 1.0, approximately 1, 1.5, 2 hours to
`
`at least 6, 9, 12, 18, 21, 24 hours following such administration. When referring to an agent, the
`
`term "C" designates the blood or serum levels of such agent at any point in time. Thus, the
`
`"Cmean" of an agent refers to the mean concentration of such agent in the blood or plasma as
`
`25 measured by any standard method known in the art over a set period of time. The "Cmax" of an
`
`agent refers to the maximum concentration that such an agent can reach at any point in time. If
`
`desired, the release of the NMDA receptor antagonist may be monophasic or multiphasic (e.g.,
`
`biphasic). Desirably, 99%,98%, 95%,90%,85%,80%,70%, 50%, or 30% of the NMDA
`
`receptor antagonist remains in an extended release dosage form within one hour of such
`
`30
`
`administration. The pharmaceutical composition may be formulated for oral, topical
`
`2
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`Petitioners' Ex. 1005
`Page 3
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`

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`Express Mail Label No. EV464271789US
`Date of Deposit: November 23, 2004
`
`Attorney Docket No. 22531-522
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`transepithelial, subdermal, or inhalation delivery. Optionally, the phannaceutical composition
`
`may be formulated as a lotion, patch, or device (e.g., a subdermally implantable delivery device
`
`or an inhalation pump).
`
`Upon contact with a cell, the pharmaceutical compositions described herein reduce the
`
`5
`
`activity of an NMDA receptor. Accordingly, such compositions may be employed to treat,
`
`prevent, or reduce conditions associated with deregulation in NMDA receptor activity or
`
`conditions that would benefit from a reduction in such activity. Exemplary conditions include
`
`Parkinson's disease, multiple sclerosis, neuropathic pain, depression, Alzheimer's disease,
`
`amyotrophic lateral sclerosis, and neuropathic pain. Accordingly, a subject (e.g., human) having
`
`10
`
`or at risk of having such conditions is administered the composition described herein (e.g., once a
`
`day, every 2 days, every 3 days, every week, or every month).
`
`Unless otherwise defined, all technical and scientific terms used herein have the same
`
`meaning as commonly understood by one of ordinary skill in the art to which this invention
`
`belongs. Although methods and materials similar or equivalent to those described herein can be
`
`15
`
`used in the practice or testing of the invention, suitable methods and materials are described
`
`below. All publications, patent applications, patents, and other references mentioned herein are
`
`incorporated by reference in their entirety. In the case of conflict, the present Specification,
`
`including definitions, will control. In addition, the materials, methods, and examples are
`
`illustrative only and not intended to be limiting. All parts and percentages are by weight unless
`
`20
`
`otherwise specified.
`
`Other features and advantages of the invention will be apparent from the following
`
`detailed description and claims.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`25
`
`In general, the present invention features pharmaceutical compositions that contain an
`
`NMDA receptor antagonist formulated for extended release to provide a concentration over a
`
`desired time period that is high enough to be therapeutically effective but low enough so as to
`
`avoid adverse events associated with excessive levels ofthe NMDA receptor antagonist in the
`
`subject. Control of drug release is particularly desirable for reducing and delaying the peak
`
`30
`
`plasma level without affecting the extent of drug availability. Therapeutic levels are therefore
`
`3
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`Petitioners' Ex. 1005
`Page 4
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`

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`Express Mail Label No. EV46427 1789US
`Date of Deposit: November 23, 2004
`
`Attorney Docket No. 2253 1-522
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`achieved whi le minimizing debilitating side-effects that are usually associated with immediate
`
`release formulations. Furthermore, as a result of the delay in the time to obtain peak plasma level
`
`and the extended period of time at the therapeutically effective plasma level, the dosage
`
`frequency is reduced to, for example, once or twice dai ly dosage, thereby improving patient
`
`5
`
`compliance.
`
`Ma king NMDA R eceptor Antagonist Controlled Release Formulations
`
`A pharmaceutical composition according to the invention is prepared by combining a
`
`desired NMDA receptor antagonist or antagonists with one or more additional ingredients that,
`
`10 when administered to a subject, causes the NMDA receptor antagonist to be released at a
`
`targeted concentration range for a specified period of time. A release profile, i.e., the extent of
`
`release of the NMDA receptor antagonist over a desired time, can be conveniently determined for
`
`a given time by calculating the Cmax /C mean for a desired time range. For example, the NMDA
`
`receptor antagonist can be provided so that it is released at Cmax /C me:~n of approximately 2 or less
`
`15
`
`for approximately 2 hours to at least 6 hours after the NMDA receptor antagonist is introduced
`
`into a subject. One of ordinary skill in the art can prepare combinations with a desired release
`
`profile using the NMDA receptor antagonists and formulation methods described below.
`
`Selecting an NMDA Receptor Antagonist
`
`20
`
`In general, any non-toxic NMDA receptor antagonist can be used so long as it is non(cid:173)
`
`toxic when used in the composition. The term "nontoxic" is used in a relative sense and is
`
`intended to designate any substance that has been approved by the United States Food and Drug
`
`Admirtistration ("FDA") for administration to humans or, in keeping with established regulatory
`
`criteria and practice, is susceptible to approval by the FDA for administration to humans.
`
`25
`
`Many suitable NMDA receptor antagonists are known in the art. Desirably, the NMDA
`
`receptor antagonist is an aminodamantane. Suitable aminoadamantane compounds are known in
`
`the art and include, e.g., memantine (1-amino-3,5-dimethyladamantane), rimantadine (1-(1 -
`
`aminoethyl)adamantane), amantadine (1-amino-adamantane), as well as pharmaceutically
`
`acceptable salts thereof. Additional aminoadamantane compounds are described in. e.g .• U.S.
`
`4
`
`IPR2015-00410
`Petitioners' Ex. 1005
`Page 5
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`

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`Express Mail Label No. EY464271789US
`Date of Deposit: November 23, 2004
`
`Attorney Docket No. 22531-522
`
`Patent Nos. 4,346, 112, 5,061, 703, 5,334,618, 6,444, 702, 6,620,845, and 6,662,845, all of which
`
`are incorporated by reference.
`
`Further NMDA receptors include, for example, ketamine, eliprodil, ifenprodil,
`
`dizoci lpine, remacemide, iamotrigine, riluzole, aptiganel, phencyclidine, flupirtine, celfotel,
`
`5
`
`felbamate, spermine, spermidine, levemopamil, dextromethorphan ((+)-3-hydroxy-N(cid:173)
`
`methylmorphinan) and its metabolite, dextrorphan ((+)-3-hydroxy-N-methylmorphinan), a
`
`pharmaceutically acceptable salt or ester thereof, or a metabolic precursor of any of the
`
`foregoing.
`
`10 Making Controlled Release Formulations with a Selected NMDA Receptor Antagonist
`
`Extended drug release is generally controlled either by diffusion through a coating or by
`
`erosion of a coating by a process dependent on, for example, enzymes or pH. The NMDA
`
`receptor antagonist may be formulated for extended release as described herein or using standard
`
`techniques in the art.
`
`15
`
`The artisan can adapt methods known in the art for preparing formulations with the
`
`desired release profile. One such method is described in U.S. Patent No. 4,606,909 (hereby
`
`incorporated by reference). This reference describes a controlled release multiple unit
`
`formulation in which a multiplicity of individually coated or microencapsulated units are made
`
`available upon disintegration of the formulation (e.g., pill or tablet) in the stomach of the animal
`
`20
`
`(see, for example, column 3, line 26 through column 5, line 10 and column 6, line 29 through
`
`column 9, line 16). Each of these individually coated or microencapsulated units contains cross(cid:173)
`
`sectionally substantially homogenous cores containing particles of a sparingly soluble active
`
`substance, the cores being coated with a coating that is substantially resistant to gastric
`
`conditions but which is erodable under the conditions prevailing in the small intestine.
`
`25
`
`The compositions described herein may alternatively be formulated using the methods
`
`disclosed in U.S. Patent No. 4,769,027, for example. Accordingly, extended release formulations
`
`involve priUs of pharmaceutically acceptable material (e.g., sugar/starch, salts, and waxes) may
`
`be coated with a water permeable polymeric matrix containing an NMDA receptor antagonist
`
`and next overcoated with a water permeable film containing dispersed within it a water soluble
`
`30
`
`particulate pore forming material.
`
`5
`
`IPR2015-00410
`Petitioners' Ex. 1005
`Page 6
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`

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`Express Mail Label No. EV464271789US
`Date of Deposit: November 23, 2004
`
`Attorney Docket No. 22531-522
`
`As another example, the NMDA receptor antagonist-containing compositions may be
`
`prepared as described in U.S. Patent No. 4,897,268, involving a biocompatible, biodegradable
`
`microcapsule delivery system. Thus, the NMDA receptor antagonist may be formulated as a
`
`composition containing a blend of free-flowing spherical particle obtained by individually
`
`5 microencapsulating quantities of memantine, for example, in different copolymer excipients
`
`which biodegrade at different rate, therefore releasing memantine into the circulation at a
`
`constant rate and varying rates. A quantity of these particles are of such a copolymer excipient
`
`that the core active ingredient is released quickly after injection, and thereby delivers the
`
`ingredient for an initial period. A second quantity of the particles are of such type excipient that
`
`10
`
`delivery of the encapsulated ingredient begins as the first quantity's delivery begins to decline. A
`
`third quantity of ingredient may be encapsulated with a still different excipient which results in
`
`delivery beginning as the delivery of the second quantity beings to decline. The rate of delivery
`
`may be altered, for example, by varying the lactide/glycolide ratio in a poly(D,L-lactide-co(cid:173)
`
`glycolide) encapsulation. Other polymers that may be used include polyacetal polymers,
`
`15
`
`polyorthoesters, polyesteramides, polycaprolactone and copolymers thereof, polycarbonates,
`
`polyhydroxybuterate and copolymers thereof, polymaleamides, copolyaxalates and
`
`polysaccharides.
`
`U.S. Patent No. 5,395,626 features a multilayered controlled release pharmaceutical
`
`dosage form. The dosage form contains a plurality of coated particles wherein each has multiple
`
`20
`
`layers about a core containing an NMDA receptor antagonist whereby the drug containing core
`
`and at least one other layer of drug active is overcoated with a controlled release barrier layer
`
`therefore providing at least two controlled releasing layers of a water soluble drug from the
`
`multilayered coated particle.
`
`Preparation of a pharmaceutical composition for delivery in a subdermally implantable
`
`25
`
`device can be performed using methods known in the art, such as those described in, e.g., US
`
`Patent Nos. 3,992,518; 5,660,848; and 5,756,115. Preparation for delivery in a patch can be
`
`performed using methods also known in the art, including those described generally in, e.g., US
`
`Patent Nos. 5,186,938 and 6, 183,770.
`
`6
`
`IPR2015-00410
`Petitioners' Ex. 1005
`Page 7
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`

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`Express Mail Label No. EV464271789US
`Date of Deposit: November 23, 2004
`
`Attorney Docket No. 2253 1-522
`
`Additional methods for making controlled release formulations are described in, e.g.,
`
`U.S. Patent Nos. 5,422, 123, 5,601,845, 5,912,013, and 6,194,000, all of which are hereby
`
`incorporated by reference.
`
`The artisan wi ll additionally recognize that extended release formulation can be prepared
`
`5
`
`using additional methods known in the art. For example, a suitable extended release form of the
`
`NMDA receptor antagonist may be a matrix tablet composition. Suitable matrix forming
`
`materials include, for example, waxes (e.g., carnauba, bees wax, paraffin wax, ceresine, shellac
`
`wax, fatty acids, and fatty alcohols), oils, hardened oils or fats (e.g., hardened rapeseed oil, castor
`
`oil, beef tallow, palm dil, and soya bean oil), and polymers (e.g., hydroxypropyl cellulose,
`
`l 0
`
`polyvinylpyrrolidone, hydroxypropyl methyl cellulose, and polyethylene glycol). Other suitable
`
`matrix tabletting materials are microcrystalline cellulose, powdered cellulose, hydroxypropyl
`
`cellulose, ethyl cellulose, with other carriers, and fillers. Tablets may also contain granulates,
`
`coated powders, or pellets. Tablets may also be multi-layered. Optionally, the finished tablet
`
`may be coated or uncoated.
`
`15
`
`The coating composition typically contains an insoluble matrix polymer (approximately
`
`15-85% by weight of the coating composition) and a water soluble material (e.g., approximately
`
`15-85% by weight of the coating composition). Optionally an enteric polymer (approximately 1
`
`to 99% by weight of the coating composition) may be used or included. Suitable insoluble
`
`matrix polymers include ethyl cellulose, cellulose acetate butyrate, cellulose acetates,
`
`20
`
`polymetbacrylates containing quaternary ammonium groups or other pharmaceutically acceptable
`
`polymers. Suitable water soluble materials include polymers such as polyethylene glycol,
`
`hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, polyvinyl
`
`alcohol, and monomeric materials such as sugars (e.g., lactose, sucrose, fructose, mannitol and
`
`the like}, salts (e.g., sodium chloride, potassium chloride and the like), organic acids (e.g.,
`
`25
`
`fumaric acid, succinic acid, lactic acid, and tartaric acid), and mixtures thereof. Suitable enteric
`
`polymers include acetate succinate, hydroxypropyl methyl cellulose, phthalate, polyvinyl acetate
`
`phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, shellac, zein, and
`
`polymethacrylates containing carboxyl groups.
`
`The coating composition may be plasticised according to the properties of the coating
`
`30
`
`blend such as the glass transition temperature of the main component or mixture of components
`
`7
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`Page 8
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`

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`Express Mail Label No. EV46427 1789US
`Date of Deposit: November 23, 2004
`
`Attorney Docket No. 22531-522
`
`or the solvent used for applying the coating compositions. Suitable plasticisers may be added
`
`from 0 to 50% by weight of the coating composition and include, for example, diethyl phthalate,
`
`citrate esters, polyethylene glycol, glycerol, acetylated glycerides, acetylated citrate esters,
`
`dibutylsebacate, and castor oil. If desired, the coating composition may include a filler. The
`
`5
`
`amount of the filler may be 1% to approximately 99% by weight based on the total weight of the
`
`coating composition and may be an insoluble material such as silicon dioxide, titanium dioxide,
`
`talc, kaolin, alumina, starch, powdered cellulose, MCC, or polacrilin potassium.
`
`The coating composition may be applied as a solution or latex in organic solvents or
`
`aqueous solvents or mixtures thereof. If solutions are applied, the solvent may be present in
`
`1 0
`
`amounts from approximate by 25-99% by weight based on the total weight of dissolved solids.
`
`Suitable solvents are water, lower alcohol, lower chlorinated hydrocarbons, ketones, or mixtures
`
`thereof. If latexes are applied, the solvent is present in amounts from approximately 25-97% by
`
`weight based on the quantity of polymeric material in the latex. The solvent may be
`
`predominantly water.
`
`15
`
`The pharmaceutical composition described herein may also include a carrier such as a
`
`solvent, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption
`
`delaying agents. The use of such media and agents for pharmaceutically active substances is well
`
`known in the art. Pharmaceutically acceptable salts can also be used in the composition, for
`
`example, mineral salts such as hydrochlorides, hydrobromides, phosphates, or sulfates, as well as
`
`20
`
`the salts of organic acids such as acetates, proprionates, malonates, or benzoates. The
`
`composition may also contain liquids, such as water, saline, glycerol, and ethanol, as well as
`
`substances such as wetting agents, emulsifying agents, or pH buffering agents. Liposomes, such
`
`as those described in U.S. Pat. No. 5,422,1 20, WO 95/13796, WO 91 /1 4445, or EP 524,968 Bl,
`
`may also be used as a carrier.
`The pharmaceutical composition may be formulated to provide memantine in an amount
`
`25
`
`ranging between 1 and 200 mg/day, 2 and 80 mg/day, 5 and 40 mg/day, or 10 and 20 mg/day;
`
`amantadine in an amount ranging between 25 and 500 mg/day, 15 and 400 mg/day, or 100 and
`
`200 mg/day; dextromethorphan in an amount ranging between 1-5000 mg/day, 1-1000 mg/day,
`
`and 100-800 mg/day, or 200-500 mg/day. The pharmaceutical composition may be in a form
`
`30
`
`suitable for oral or rectal administration or for administration by transdennal, intravenous,
`
`8
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`Page 9
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`Express Mail Label No. EV464271789US
`Date ofDeposit: November 23, 2004
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`Attorney Docket No. 22531-522
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`intramuscular, subcutaneous, intrathecal, epidural or intracerebroventricular means. The
`
`pham1aceutical composition may be formulated as an oral dosage form (e.g., a tablet, capsule, a
`
`liquid, powder, granule or suspension), injectable solution, suppository, device (e.g., inhalation
`
`pump or implant), or transdermal patch.
`
`5
`
`Using the NMDA Receptor Antagonist Controlled Release Formulations
`
`The pharmaceutical composition providing an NMDA receptor antagonist in extended
`
`release form are in general useful for treating over a defined period any condition which responds
`
`to antagonism ofNMDA receptors. Neurological disorders (e.g., neurological diseases,
`
`10
`
`conditions, or syndromes) including, for example, a stroke or other forms of hypoxic injury,
`
`haemorrhagic brain injury, traumatic brain injury, spinal cord injury, familial Alzheimer's disease
`
`(FAD), Parkinson's disease, amyotrophic lateral sclerosis (ALS), neuroprotection in epilepsy, a
`
`metabolic disorder, hypoglycemia, encephalopathy, tumors and malignancies (e.g., brain, spinal
`
`cord, and systemic), cerebellar degenerations, and ataxias, migraine, vertigo, tinnitus and
`
`15
`
`cochlear disorders, bowel syndromes, peripheral neuropathy, metabolic bone disease and
`
`osteoporosis, obesity, and diabetes and pre-diabetic syndromes, glaucoma, HIV associated
`
`dementia neuropathic pain, Huntington's disease or other dementing disease, anxiety, depression
`
`or withdrawal from drug (or opiate) addiction or drug (or opiate) dependency, minimal cognitive
`
`impairment (MCI), Down's syndrome, normal cognitive senescence, meningitis, sepsis and septic
`
`20
`
`encephalopathy, CNS vasculitis, schizophrenia, alcoholic diseases, multiple sclerosis or other
`
`demyelinating disease, leukodystrophies and X-ADL, childbirth and surgical anesthesia.
`
`Treatment also provides neuroprotection from cerebrovascular risk factors and post-ischemic
`
`neurovascular syndromes.
`
`The compositions may also be used for treating hyperhomocysteinemia contributing to
`
`25
`
`atherosclerotic and other degenerative disease processes, head trauma, spinal cord injury, and
`
`demyelinating disease (e.g., multiple sclerosis).
`
`The invention will be illustrated in the following non-limiting examples.
`
`9
`
`IPR2015-00410
`Petitioners' Ex. 1005
`Page 10
`
`

`
`Express Mail Label No. EV464271789US
`Date of Deposit: November 23, 2004
`
`Attorney Docket No. 22531-522
`
`Example 1: Preparation of Memantine-Containing Cores to be Coated with an Enteric
`
`Coating
`
`Memantine-containing cores is prepared as follows and as described, for example, in U.S.
`
`patent No. 4,606,909. Cores (containing 24% talc) are prepared using 0.97 kg memantine, 0.2 kg
`
`5
`
`sodium laurylsulphate, 0.5 kg microcrystalline cellulose, 5.93 kg saccharose powder, and 2.4 kg
`
`talc. Memantine and sodium laurylsulphate are co-comminuted by passage through a grinder
`
`using a 0.5 mm sieve. The ground mixture is mixed with microcrystalline cellulose, saccharose,
`
`and talc in a planet mixer. 10 kg ofthe resulting mixture is moistened with 0.8 kg purified water
`
`and mixed in a planet mixer until the mixture is slightly lumpy. The moist mixture is extruded
`
`10
`
`through a 0.5 mm sieve. The first kilograms of extrudate passing the sieve is powdery and re(cid:173)
`
`extruded. The resulting extrudates form strings, breaking off in lengths of 10-30 em. 2 kg of the
`
`extruded strings is formed into compact-shaped cores in a marumerizer™ and the resulting
`
`compact-shaped cores are dried in a fluidized bed dryer and sieved through a separator (the upper
`
`sieve (0.71 mm) and the bottom sieve (0.46 mm). Using the same technique, cores (containing
`
`15
`
`10% talc) are prepared using 0.97 kg memantine, 0.2 kg sodium laurylsulphate, 1.0 kg
`
`microcrystalline cellulose, 6.83 kg saccharose powder, and 1.0 kg talc.
`
`The release ofmemantine is measured, at a pH 7.5 for the cores containing 24% talc and
`
`10% talc, respectively. The reduction in the talc content from 24% to 10% decreases the release
`
`weight of memantine from the core.
`
`20
`
`An enteric coating suspension, which further delays the release of memantine, is prepared
`by homogenizing 9.0 kg Eudragit ™ S 12,5 together with 0.135 kg acetyltributylcitrate, 0.9 kg
`talc, and 7.965 kg isopropanol. 10 kg of the above-described cores containing 10% talc are
`
`coated with 4.167 kg of this coating suspension in a fluidized bed and the resulting pellets are
`
`covered with talcum. For the preparation of a pharmaceutical dosage form, 1000 of these pellets
`
`25
`
`are filled in a capsule No. 1, such that each of the capsule contains 25 mg memantine.
`
`Example 2: Preparation of Amantadine extended release capsules
`
`Amantadine extended release capsules may be formulated as follows or as described, for
`
`example, in U.S. Patent No. 5,395,626.
`
`30
`
`10
`
`IPR2015-00410
`Petitioners' Ex. 1005
`Page 11
`
`

`
`Express Mail Label No. EV464271789US
`Date of Deposit: November 23, 2004
`
`A. Composition: Unit Dose
`
`Attorney Docket No. 22531-522
`
`The theoretical quantitative composition (per unit dose) for amantadine extended release
`
`capsules is provided below.
`
`5
`
`Components
`
`% weight/weight
`
`mg/Capsule
`
`Amantadine
`
`10
`
`(OP ADRY ®Clear
`YS-3-7011) I
`(Colorcon, Westpoint PA)
`
`Purified Water, USP2
`
`15
`
`Sugar Spheres, NF
`
`OPADRY ®Clear
`YS-1-70063
`(Colorcon, Westpoint PA)
`
`SURELEASE ® E-7-7050 4
`(ColorCon, Westpoint PA)
`
`Capsules 5
`
`Total
`
`68.34
`
`1.14
`
`12.5
`
`4.48
`
`200
`
`5.01
`
`54.87
`
`19.66
`
`13.54
`
`59.44
`
`100.00%
`
`338.98 mg6
`
`20
`
`25
`
`30
`
`3 5
`
`40
`
`1 A mixture ofhydroxypropyl methylcellulose, polyethylene glycol, propylene glycol.
`2 Purified Water, USP is evaporated during processing.
`3 A mixture ofhydroxypropyl methylcellulose and polyethylene glycol
`4 Solid content only of a 25% aqueous dispersion of a mixture of ethyl cellulose, dibutyl sebacate, oleic acid,
`ammoniated water and fumed silica. The water in the dispersion is evaporated during processing.
`s White, opaque, hard gelatin capsule, size 00.
`6 Each batch is assayed prior to filling and the capsule weight is adjusted as required to attain 200 mg amantadine
`per capsule.
`
`The quantitative batch composition for amantadine extended release capsule is shown below.
`(Theoretical batch quantity 25,741 capsules):
`
`11
`
`IPR2015-00410
`Petitioners' Ex. 1005
`Page 12
`
`

`
`Express Mail Label No. EV464271789US
`Date ofDeposit: November 23, 2004
`
`Attorney Docket No. 22531-522
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`Components
`
`Weight
`
`Step 1: Preparation of memantine
`Hydrochloride Beads (bead Build-up #1)
`Amantadine
`Opadry ®Clear YS-3-7011
`Purified Water, USP
`Sugar Spheres, NF
`Total Weight Amantadine
`Beads (Bead Build-up #1)
`
`12.000
`0.200
`5.454
`4.000
`16.200 kg
`
`The amantadine beads obtained from step 1 are used as follows.
`
`Step 2: Clear & Sustained Release
`Bead Coating #1
`Amantadine Beads
`Opadry ® Clear YS-1-7006
`Purified Water, USP
`Surelease ®E-7-7050
`Total Weight Clear Coated Sustained
`Release Beads
`
`8.000
`0.360
`5.928
`0.672
`9.032 kg
`
`The sustained release beads obtained from step 2 are used as follows.
`
`Step 3: Amantadine Hydrochloride Beads
`(Build-up #2)
`Sustained Release Beads
`Amantadine
`Opadry ® Clear YS-3-7011
`Purified Water, USP
`Total Weight Amantadine
`Beads (Build-up #2)
`
`8.000
`4.320
`0.072
`1.964
`12.392 kg
`
`35
`
`The amantadine beads obtained from step 3 are formulated as follows.
`
`12
`
`IPR2015-00410
`Petitioners' Ex. 1005
`Page 13
`
`

`
`Express Mail Label No. EV464271789US
`Date of Deposit: November 23, 2004
`
`Step 4: Clear & Sustained Release Bead
`Coating #2
`Amantadine Beads
`Opadry ® Clear YS- 1-700
`Purified Water, USP
`Surelease ® E-7-7050
`Total Weight Amantadine
`Extended Release Beads
`
`5
`
`10
`
`Step 5: Capsule Filling --
`
`Attorney Docket No. 2253 1-522
`
`10.000
`0.250
`6.450
`1.050
`11.300 kg
`
`Examples 3-10: Extended release formulation of Rimantidine
`
`The NMDA receptor antagonist, rimantidine, is formulated for extended release as
`
`15
`
`follows (see, for example, U.S. Patent No. 5,912,013).
`
`20
`
`25
`
`30
`
`35
`
`40
`
`Example 3:
`Core Pellet
`MCC
`Hydroxypropylmethylcellulose
`Phthalate (HPMCP)
`Tartaric Acid
`Sodium Monoglycerate
`DSS
`Rimantidine
`Total
`
`25.0
`10.0
`
`10.0
`7.5
`0.5
`47.0
`100.0
`
`Coating:
`Cellulose Acetate Phthalate (CAP)
`Ethylcellulose
`PEG400
`Total
`
`60.0
`25.0
`15.0
`100.0
`
`Example 4:
`Core pellet from example 3
`Coating:
`Ethacrylic/Methacrylic Acid Esters
`(Eudragit line of enteric polymers)
`Propylene Glycol
`Talc
`Total
`
`85.0
`
`14.0
`1.0
`100.0
`Percent
`
`13
`
`Kilograms
`
`0.25
`0.10
`
`0.10
`0.075
`0.005
`0.470
`1.000
`
`0.60
`0.25
`0. 15
`1.00
`
`0.85
`
`0.14
`0.01
`1.00
`Kilograms
`
`IPR2015-00410
`Petitioners' Ex. 1005
`Page 14
`
`

`
`Express Mail Label No. EV464271789US
`Date of Deposit: November 23, 2004
`
`Attorney Docket No. 22531-522
`
`Example 5:
`Core pellet from example 3
`Coating:
`CAP
`HPMCP
`PEG 400
`PEG 8000
`Total
`
`Example 6:
`Core Pellet:
`MCC
`Mono/Di/Tri-