IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Application No.:
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`11/399,879
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`Customer No.:
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`94584
`
`Applicant:
`
`Went et al.
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`New Docket No.:
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`34550—705501
`
`Filed:
`
`April 6, 2006
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`Group Art Unit:
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`1627
`
`Confirmation No.:
`
`3491
`
`Examiner:
`
`Carter, Kendra D.
`
`Title:
`
`Methods and Compositions for the Treatment of CNS—Related Conditions
`
`Commissioner for Patents
`
`P .O. Box 1450
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`Alexandria, VA 22313 -1450
`
`AMENDMENT AND RESPONSE TO AN OFFICE ACTION
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`This is an Amendment and Response to the Office Action dated February 8, 2011 (Office
`
`Action). Because this response is being filed with a petition for a one (1) month extension of time,
`
`Applicants believe that this application is timely filed. Applicants authorize the Commissioner to
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`charge any additional fees that may be required, including petition fees and/or extension of time fees,
`
`to Deposit Account No. 23-2415 (Docket No. 34550-705501).
`
`Authorization for payment of the Fee for a one (1) month Extension of Time is filed
`
`herewith.
`
`Amendments to the Claims begin on page 2 of this paper.
`
`Remarks begin on page 9 of this paper.
`
`A Declaration by Sid Gilman, MD. is enclosed herewith as a separate paper.
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`Application No. 11/399,879 (34550-705501)
`Response to 8 February 2011 Office Action
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`AMENDMENTS TO THE CLAIMS:
`
`1-1 1.
`
`(Canceled)
`
`12.
`
`(Currently Amended) A method of treating a CNS-related condition comprising orally
`
`administering once a day to a Msubject in need thereof a—tlaerapeutieallfyLeffeetwe—ame’cmt—ef:
`
`(a) 5-40 mg memantine or a pharmaceutically acceptable salt thereof provided in an extended
`
`release dosage form, wherein said extended release memantine or pharmaceutically acceptable salt
`
`thereof provides a rate—of change in plasma concentration as a function of time (dC/dT) that is less
`
`than about 50% of the dC/dT of the same quantity of an immediate release form of memantine,
`
`wherein the dC/dT is measured in a single dose human PK study between the time period of 0 to
`
`Tmax of the immediate release form of memantine; and
`
`(b) a therapeutically effective amount of donepezil or a pharmaceutically acceptable salt
`
`thereof, wherein the CNS-related condition is selected from the group consisting of Alzheimer’s
`
`disease and dementia.
`
`13—22. (Canceled)
`
`23.
`
`(Currently Amended) The method of claim 12, wherein the amount of memantine or
`
`pharmaceutically acceptable salt thereof ranges between 20 Lgto 40 mg per dose.
`
`24.
`
`(Currently Amended) The method of claim 23, wherein the amount of memantine or
`
`pharmaceutically acceptable salt thereof ranges between 2—2—é @to 40 mg per dose.
`
`25-27. (Canceled)
`
`28.
`
`(Previously Presented) The method of claim 12, wherein said memantine or a
`
`pharmaceutically acceptable salt thereof and said donepezil or a pharmaceutically acceptable salt
`
`thereof are administered simultaneously.
`
`29.
`
`(Previously Presented) The method of claim 12, wherein said memantine or a
`
`pharmaceutically acceptable salt thereof and said donepezil or a pharmaceutically acceptable salt
`
`thereof are administered as a single composition.
`
`30-49. (Canceled)
`
`50.
`
`(Currently Amended) A method of reducing the potential for an adverse effect in a
`
`human subject being treated for a CNS-related condition comprising orally administering once a day
`
`to a human subject in need thereof a pharmaceutical composition comprising:
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`2 0f 20
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`Application No. 11/399,879 (34550-705501)
`Response to 8 February 2011 Office Action
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`(a) 5-40 mg memantine or a pharmaceutically acceptable salt thereof in an extended release
`
`form, wherein said extended release memantine or pharmaceutically acceptable salt thereof provides a
`
`rateef change in plasma concentration as a function of time (dC/dT) that is less than about 50% of the
`
`dC/dT of the same quantity of an immediate release form of memantine, wherein the dC/dT is
`
`measured in a single dose human PK study between the time period of 0 to Tmax of the immediate
`
`release form of memantine; and
`
`(b) donepezil or a pharmaceutically acceptable salts thereof, and wherein the CNS-related
`
`condition is selected from the group consisting of Alzheimer’s disease and dementia;
`
`and further wherein said adverse effect is related to memantine.
`
`51.
`
`(Currently Amended) The method of claim 50, wherein the composition is in a unit
`
`dosage form comprising Q—Qé L0_to 40 mg of the memantine or pharmaceutically acceptable salt
`
`thereof.
`
`52.
`
`53.
`
`(Canceled)
`
`(Previously Presented) The method of claim 50, wherein the donepezil or
`
`pharmaceutically acceptable salt thereof is in an immediate release form.
`
`54.
`
`55.
`
`(Canceled)
`
`(Previously Presented) The method of claim 50, wherein the memantine or
`
`pharmaceutically acceptable salt thereof is formulated as beads and/or pellets.
`
`56.
`
`(Previously Presented) The method of claim 55, wherein the beads and/or pellets
`
`comprise an extended release coating.
`
`57.
`
`(Previously Presented) The method of claim 56, wherein the extended release coating
`
`comprises an insoluble matrix polymer and a water soluble material.
`
`58.
`
`(Previously Presented) The method of claim 5 7, wherein the insoluble matrix polymer
`
`is ethyl cellulose.
`
`59.
`
`(Previously Presented) The method of claim 57, wherein the insoluble matrix polymer
`
`is ethyl cellulose, and the water soluble material is selected from the group consisting of
`
`hydroxypropyl methyl cellulose and polyvinylpyrrolidone.
`60.
`(Previously Presented) The method of claim 51, wherein the dosage form is in a
`
`capsule.
`
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`Application No. 11/399,879 (34550-705501)
`Response to 8 February 2011 Office Action
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`6 l .
`
`62.
`
`(Canceled)
`
`(Currently Amended) The method of claim 6—1_5_Q, wherein the composition comprises
`
`1 to 20 mg donepezil hydrochloride.
`
`63-65. (Canceled)
`
`66.
`
`(Previously Presented) The method of claim 50, wherein administration of the
`
`composition to a human subject provides a shift in memantine Tmax of at least 8 hours relative to an
`
`immediate release form of memantine.
`
`67.
`
`(Previously Presented) The method of claim 50, wherein administration of the
`
`composition to a human subject provides a memantine Tmax of at least 19 hours.
`
`68.
`
`69.
`
`(Canceled)
`
`(Previously Presented) The method of claim 50, wherein administration of the
`
`composition to a human subject provides a plasma memantine concentration profile characterized by
`
`a maximum memantine plasma concentration to mean memantine plasma concentration ratio
`
`(Cmax/Cmean) of about 2.5 to 2 at 1 hour to at least 6 hours after administration.
`
`70.
`
`(Previously Presented) The method of claim 50, wherein said memantine or a
`
`pharmaceutically acceptable salt thereof and said donepezil or a pharmaceutically acceptable salt
`
`thereof are provided in a unit dosage form.
`
`71.
`
`(Currently Amended) The method of claim 50, wherein the composition comprises at
`
`least 22.5 12.5 mg to 40 mg memantine hydrochloride.
`
`72.
`
`(Previously Presented) The method of claim 50, wherein the composition comprises at
`
`least 22.5 mg memantine hydrochloride and 1 to 20 mg of donepezil hydrochloride.
`
`73 .
`
`74.
`
`(Canceled)
`
`(Previously Presented) The method of claim 12, wherein said extended release
`
`memantine or a pharmaceutically acceptable salt thereof has an in vitro dissolution profile less than
`
`30% in one hour, less than 40% in two hours, greater than 40% in six hours as measured using a USP
`
`type 2 (paddle) dissolution system at 50 rpm, at a temperature of 37i0.5° with water as a dissolution
`
`medium.
`
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`Application No. 11/399,879 (34550—705501)
`Response to 8 February 2011 Office Action
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`75.
`
`(Previously Presented) The method of claim 12, wherein at least 80% of the
`
`memantine or pharmaceutically acceptable salt thereof in the composition is provided in an extended
`
`release form, with the remainder in an immediate release form.
`
`76.
`
`(Previously Presented) The method of claim 12, wherein at least 95% of the
`
`memantine or pharmaceutically acceptable salt thereof in the composition is provided in an extended
`
`release forms, with the remainder in an immediate release form.
`
`77.
`
`(Previously Presented) The method of claim 12, wherein the release of the memantine
`
`or pharmaceutically acceptable salt thereof is monophasic.
`
`78.
`
`(Previously Presented) The method of claim 12, wherein the release of the memantine
`
`or pharmaceutically acceptable salt thereof is biphasic.
`79.
`(Previously Presented)~ The method of claim 12, wherein the memantine further
`
`comprises one or more extended release excipients selected from the group consisting of ethyl
`
`cellulose, hydroxypropyl methyl cellulose and polyvinylpyrrolidone.
`
`80.
`
`(Previously Presented) The method of claim 50, wherein the composition comprises
`
`20 mg to 40 mg of memantine.
`
`81.
`
`(Previously Presented) The method of claim 50, wherein at least 80% of the
`
`memantine or pharmaceutically acceptable salt thereof in the composition is provided in an extended
`
`release form, with the remainder in an immediate release form.
`
`82.
`(Previously Presented) The method of claim 50, wherein at least 95% of the
`memantine or pharmaceutically acceptable salt thereof in the composition is provided in an extended
`
`release forms, with the remainder in an immediate release form.
`
`83.
`
`(Previously Presented) The method of claim 50, wherein the release of the memantine
`
`or pharmaceutically acceptable salt thereof is monophasic.
`
`84.
`
`(Previously Presented) The method of claim 50, wherein the release of the memantine
`
`or pharmaceutically acceptable salt thereof is biphasic.
`
`85.
`
`(Previously Presented) The method of claim 50, wherein the memantine fiirther
`
`comprises one or more extended release excipients selected from the group consisting of ethyl
`
`cellulose, hydroxypropyl methyl cellulose and polyvinylpyrrolidone.
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`Application No. 11/399,879 (34550—705501)
`Response to 8 February 2011 Office Action
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`86.
`
`(New) In a method of treating a subject for a CNS-related condition comprising
`
`administering to said subject a memantine drug selected from the group consisting of memantine and
`
`a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of a donepezil drug
`
`selected from the group consisting of donepezil and a pharmaceutically acceptable salt thereof, the
`
`improvement comprising:
`
`(a) said memantine drug is administered in an extended release dosage form, wherein said
`
`extended release memantine provides a change in plasma concentration as a function of time (dC/dT)
`
`in a defined time period of O to Tmax of an immediate release form of memantine after
`
`administration, as measured in a human single dose PK study, that is less than about 50% of the
`
`change in plasma concentration (dC/dT) of the same quantity of said immediate release form of said
`
`memantine drug during said defined time period; and
`
`(b) said memantine drug is administered once daily in a dose range of 5 mg to 40 mg; wherein
`
`said CNS-related condition is selected from the group consisting of Alzheimer’s disease and
`
`Parkinson’s disease.
`
`87.
`
`(New) The method of claim 86, wherein said memantine drug daily dose range is 10
`
`mg to 40 mg.
`
`88.
`
`(New) The method of claim 86, wherein said memantine drug and said donepezil drug
`
`are administered as a composition.
`
`89.
`
`(New) The method of claim 87, wherein said memantine drug and said donepezil drug
`
`are administered in a unit dosage form.
`
`90.
`
`(New) The method of claim 88, wherein said donepezil drug is administered in an
`
`immediate release form.
`
`91.
`
`(New) The method of claim 89, wherein said donepezil drug is administered in an
`
`immediate release form.
`
`92.
`
`(New) The method of claim 12, wherein the amount of said memantine or
`
`pharmaceutically acceptable salt thereof ranges between 20 to 40 mg per dose.
`
`93.
`
`(New) The method of claim 29, wherein the amount of said memantine or
`
`pharmaceutically acceptable salt thereof ranges between 12.5 to 40 mg per dose.
`
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`Application No. 11/399,879 (34550-705501)
`Response to 8 February 2011 Office Action
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`94.
`
`(New) The method of claim 50, wherein the amount of said memantine or
`
`pharmaceutically acceptable salt thereof ranges between 10 to 40 mg per dose.
`
`95.
`
`(New) The method of claim 92, wherein said memantine or pharmaceutically
`
`acceptable salt thereof and said donepezil or a pharmaceutically acceptable salt thereof are
`
`administered in a unit dosage form.
`
`96.
`
`(New) The method of claim 94, wherein said memantine or pharmaceutically
`
`acceptable salt thereof and said donepezil or a pharmaceutically acceptable salt thereof are
`
`administered in a unit dosage form.
`
`97.
`
`(New) The method of claim 93, wherein said donepezil or a pharmaceutically
`
`acceptable salt thereof is administered in an immediate release form.
`
`98.
`
`(New) The method of claim 95, wherein said donepezil or a pharmaceutically
`
`acceptable salt thereof is administered in an immediate release form.
`
`99.
`
`(New) The method of claim 93, wherein said donepezil or a pharmaceutically
`
`acceptable salt thereof is administered in an immediate release form.
`
`100.
`
`(New) The method of claim 12, wherein the amount of said memantine or
`
`pharmaceutically acceptable salt thereof ranges between 22.5 mg to 40 mg per dose.
`
`101.
`
`(New) The method of claim 50, wherein the amount of said memantine or
`
`pharmaceutically acceptable salt thereof ranges between 22.5 mg to 40 mg per dose.
`
`102.
`(New) The method of claim 86, wherein the amount of said memantine or
`pharmaceutically acceptable salt thereof ranges between 12.5 mg to 40 mg per dose.
`
`103.
`
`(New) The method of claim 86, wherein the amount of said memantine or
`
`pharmaceutically acceptable salt thereof ranges between 20 mg to 40 mg per dose.
`
`104.
`
`(New) The method of claim 86, wherein the amount of said memantine or
`
`pharmaceutically acceptable salt thereof ranges between 22.5 mg to 40 mg per dose.
`
`105.
`
`(New) The method of claim 12, wherein the defined time period of 0 to Tmax of an
`
`immediate release form of memantine is the first 6 hours after administration.
`
`106.
`
`(New) The method of claim 50, wherein the defined time period of 0 to Tmax of an
`
`immediate release form of memantine is the first 6 hours after administration.
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`Application No. 11/399,879 (34550—705501)
`Response to 8 February 2011 Office Action
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`107.
`
`(New) The method of claim 86, wherein the defined time period of O to Tmax of an
`
`immediate release form of memantine is the first 6 hours after administration.
`
`108.
`
`(New) The method of claim 100, wherein the defined time period of 0 to Tmax of an
`
`immediate release form of memantine is the first 6 hours after administration.
`
`109.
`
`(New) The method of claim 101 , wherein the defined time period of 0 to Tmax of an
`
`immediate release form of memantine is the first 6 hours after administration.
`
`110.
`
`(New) The method of claim 104, wherein the defined time period of 0 to Tmax of an
`
`immediate release form of memantine is the first 6 hours after administration.
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`8 0f20
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`Application No. 11/399,879 (34550-705501)
`Response to 8 February 201 1 Office Action
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`REMARKS
`
`The foregoing listing of the claims reflects the current status of the claims. Claims 12, 23-24,
`28—29, 50—51, 53, 55—60, 62, 66-67, 69-72 and 74-110 are pending. Claims 12, 23, 24 50, 51, 62 and
`
`71 are amended; claims 23, 24, 28, 29, 51, 53, 55-60, 66, 67, 69—72 and 74-85 were previously
`
`presented; and claims 86-110 are new. Claims 1—1 1, 13-22, 25—27, 30—49, 52, 54, 61, 63—65 and 73
`
`are canceled. No new matter has been added.
`
`I
`
`Support for the amendments to the claims can be found through the specification as filed,
`
`including, but not limited to:
`
`0
`
`0
`
`0
`
`0
`
`0
`
`claims 12, 86: p. 3, l. 2; p. 11, l. 24;
`
`claim 50: p. 3, l. 2; p. 7, 1. 14-15, 30; p. 8,1. 1-2; p. 11,1. 24; p. 12, Table 1;p. 16,1. 18-20, 26-
`
`28; and pp. 38-41;
`
`claims 23, 24, 51, 71, 87, 92—96, 100-104: p. 11,1. 24;p. 31, Table 7;
`
`claims 88, 89, 95, 96: p. 8, 1. 26—27; p. 20, 1. 21—22
`
`claims 90, 91, 97-99: p. 10, 1. 24—25; p. 19,1. 23—24;p. 21, 1. 6-7
`
`0'
`
`claims 105—110: p. 6, 1. 17
`
`Response to Examiner Interview on April 19, 2011
`
`Applicants wish to thank Examiner Carter for the courtesy extended to their representatives
`
`during an Examiner Interview on April 19, 2011. Applicants’ representatives included Esther
`
`Kepplinger, who met with Examiner Carter in person, as well as two others, who joined the
`
`discussion by telephone conference: Dr. Greg Went (one of the instant inventors) and Peter Munson
`
`(the undersigned attorney). During the interview, Applicants’ representatives discussed with
`
`Examiner Carter the scope and construction of the claims, the scope of the cited prior art, evidence of
`
`non-obviousness that is already of record (e.g., Dr. Went’s declaration and Applicants’ November 5,
`
`2010 response) and additional evidence of non-obviousness that Applicants proposed to make of
`
`record (e. g., a declaration by Dr. Gilman). A copy of the Gilman declaration is submitted herewith as
`
`a separate paper. Particular points raised by the Examiner and Applicants during the Interview are
`
`addressed where appropriate herein.
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`Application No. 11/399,879 (34550—705501)
`Response to 8 February 2011 Office Action
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`Withdrawal of Rejections
`
`Applicants gratefully acknowledge the explicit withdrawal of the rejection under § 102 based
`
`upon Moebius alone, and the implicit withdrawal of the rejection under § 103 based upon Moebius
`
`and Laurin.
`
`Obviousness-Type Double Patenting
`
`Claims 12, 23-25, 28, 29 and 50 were provisionally rejected on the ground of nonstatutory
`
`double patenting over claims 12-14 and 21-29 of copending Application No. 12/753,769.
`
`Additionally, claims 12, 23—25, 28, 29 and 50 were provisionally rejected on the ground of
`
`nonstatutory double patenting over claims 12-14 and 21—29 of copending Application No. 12/757,795.
`Applicants note that these are provisional double patenting rejections over copending patent
`
`applications that have not yet been patented. Applicants note that a restriction requirement has been
`
`made in the instant application and the possibility exists that the claims of the instant application
`
`and/or the copending applications may eventually be so limited as to conform to the restriction
`
`requirement and/or avoid overlap betweenthe claims of the copending applications. Should overlap
`
`remain at the time that allowable subject matter is identified in this application, Applicants understand
`
`that they may overcome the double patenting (ODP) rejections by terminal disclaimer. Additionally,
`
`when the ODP rejections are the only remaining rejections, it is proper to drop those ODP rejections
`
`made over later-filed applications, and pursue the GDP in the later-filed applications. As this
`
`application is much farther along in prosecution than the other copending applications at this time,
`
`Applicants believe this would be the appropriate course of action in this case. Applicants therefore
`
`request that these ODP rejections be held in abeyance until such time as patentable subject matter is
`
`identified in the instant application.
`
`Claim Rejections — 35 USC § 103
`
`The pending claims are not rendered obvious by Moebius, Ditzler and/0r Numberg
`
`Claims 12, 23, 24, 28, 29, 50, 51, 60, 62, 66, 67, 69, 70—72, 74, 77, 79, 80, 83 and 85 stand
`
`rejected under 35 USC. § 103(a) as being unpatentable over Moebius (US 2004/0087658 A1), in
`
`combination with Ditzler and Numberg (US 5,382,601). Applicants respectfully traverse this
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`rejection as it may be applied against any of the pending claims, at least on the grounds that the
`
`references fail to establish a primafacie case of obviousness and that the claimed invention
`
`demonstrates unexpected results that were not predictable from the cited references.
`
`The law ofobviousness under 35 US. C. § 1503
`
`Applicants hereby incorporate by reference all citations to, and recitation of, case law relevant
`
`to § 103 jurisprudence in their response, dated November 5, 2010. (“Last Response,” pp. 14-15.)
`
`Moebius, Ditzler and Nurnberg fail to teach or suggest methods of administering an
`extended release memantine formulation that exhibits a dC/dT less than 50% of the
`dC/dT of an immediate release memantine formulation
`
`Introduction
`
`The cited prior art fails to teach an extended release memantine having an initial dC/dT that is
`
`less than about 50% of the dC/dT of the same quantity of an immediate release form of memantine.
`
`The person having ordinary skill in the art would not have been motivated to prepare an extended
`
`release formulation of memantine in any case, as memantine is a long half—life drug with a T1 /2 of 60-
`
`80 hours and no meaningful advantage would have been expected from extending residence of
`
`memantine in the gastrointestinal (GI) system for 12-24 hours at the most.
`
`In particular, Ditzler et a1. alone or in combination with any of the other cited references fails
`
`to teach extended release (ER) memantine having the recited initial dC/dT parameter. Applicants
`
`were the first to describe dC/dT as a distinct and unique design parameter in the context of extended
`
`release memantine. Importantly, it is this design parameter that Applicants were the first to identify
`
`as being responsible for the reported CNS adverse effects of memantine. None of the cited references
`
`suggest that use of an extended release memantine exhibiting the specific dC/dT values recited in the
`
`instant claims would result in reduced CNS side effects (in particular dizziness) compared to
`
`immediate release (IR) or extended release memantine formulations that do not meet these particular
`
`initial dC/dT values.
`
`This is a clear distinction from the prior art understanding and approach to theCNS side
`
`effects of memantine. As evidenced by the approval history of IR memantine (Namenda®) and the
`
`therapeutic approach suggested by Ditzler et al., CNS side effects were managed by administering IR
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`Application No. 11/399,879 (34550-705501)
`Response to 8 February 2011 Office Action
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`memantine on a stepped increasing dose schedule of more than a week and according to the FDA
`
`approved label, stopping at 10 mg twice a day (20 mg per day) after 3 weeks. Applicants’ invention
`
`surprisingly achieves reduced CNS side effects over a range of memantine doses, permits once daily
`
`dosing, and permits higher doses than was heretofore possible with the IR memantine formulations.
`
`Detailed Discussion
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`The Office Action fails to establish that the prior art teaches or fairly suggests the claimed
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`method, which requires use of “an extended release memantine having a dC/dT that is less than about
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`50% of the dC/dT of the same quantity of an immediate release form of memantine.” Apparently the
`Office Action points to Ditzler et al. in an effort to assert that it suggests some modification to the
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`dose increase taught therein, that this would motivate one of skill in the art to consider developing
`extended release memantine and is somehow relevant to the reduction in the dC/dT in plasma
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`concentration required by the instant invention.
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`However, the Office Action does not take into account that Ditzler et al. fails to disclose or
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`even suggest the use of any ER formulation whatsoever, let alone one meeting the dC/dT
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`requirements of the instant claims.
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`In fact, Ditzler et a1. teaches that the side effects that were noted
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`with IR memantine on day 14 of IR memantine therapy could potentially be addressed by increasing
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`the dose “distinctly more slowly” (i.e., over a course of greater than 8 days) and adjusting the dose “to
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`the individual situation until the optimal effect has been reached.” The Office likewise ignores what
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`the experts in the field actually did following Ditzler et a1. Rather than adopting an ER approach,
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`others in the art(the developers of Namenda together with the FDA), took an approach that included
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`more frequent administration and lower start and final dose (and associated reduced pharmacologic
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`activity) than is possible with Applicants’ ER formulation approach with reduced dC/dT. Applicants
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`submit that it is only by the improper use of hindsight that one could imagine any similarity between
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`the Ditzler et a1. reference’s suggested approach and the approach embodied in the instant claims.
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`While not explicitly stated in the Office Action, one obvious shortcoming of Moebius, the
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`primary reference, is the failure to disclose or suggest Applicants’ initial dC/dT parameter; and the
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`Office thus relies on Ditzler et al. to provide this missing teaching. However, one of skill in the art
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`would not have made the leap from Ditzler et al. to the instant claims; and the Office Action offers no
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`clear explanation how this could happen. Indeed, it is not clear from the Office Action that the Office
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`Application No. 11/399,879 (34550-705501)
`Response to 8 February 2011 Office Action
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`even recognizes the missing dC/dT parameter as a failing of Moebius, the primary reference. (See,
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`Office Action, page 7.) During the April 19, 2011 Interview, the Examiner seemed to acknowledge
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`that the dC/dT parameter recited in the instant claims is novel, but offered the following explanation
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`why the claims are obvious nonetheless:
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`o memantine was known;
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`0 Ditzler mentions memantine CNS side effects;
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`0
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`o
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`extended release formulations were known; and
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`the idea of increasing the dosing schedule of memantine was taught in Ditzler et a1.
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`Applicants understand the Examiner to have thus concluded that Ditzler et a1. somehow:
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`0
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`0
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`suggests teaching of increasing the memantine dosing schedule is somehow equivalent to (or
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`suggestive of) formulating an extended release memantine,
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`further suggests extended release formulations with specific variations in dC/dT as an
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`alternative means of achieving the same pharmacological result as would have been achieVed
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`by increasing the dose of memantine more slowly, and that
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`0
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`varying dC/dT was an obvious design choice, and that one of ordinary skill would vary dC/dT
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`as a matter of routine optimization of an ER memantine formulation.
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`Applicants completely disagree with this logic — there is nothing in the art that suggests initial
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`dC/dT of memantine is relevant to memantine’s CNS side effects, and thus subject to routine
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`‘
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`optimization.
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`Ditzler et a1. does not suggest varying initial dC/dT as a means of increasing the dose of
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`memantine mOre slowly. The dC/dT parameter specified in the instant invention is measured on the
`order of hours, whereas the daily dose changes of Ditzler are on the order of weeks. Indeed, these two
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`parameters are completely independent of one another. That is to say, initial dC/dT as specified in the
`instant invention is a parameter that may have no direct relationship with the daily dose of
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`memantine: one may “increase the daily dose more slowly”, per Ditzler’s teaching, and still have a
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`dC/dT that is outside the critical value stated in the claims; and conversely, one may achieve an initial
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`dC/dT within the critical values without increasing the daily dose more slowly, per Ditzler.
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`In contrast, Applicants were the first to identify the dC/dT of memantine as an independent
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`design parameter and identify this parameter as a source of memantine CNS side effects.
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`Application No. 11/399,879 (34550-705501)
`Response to 8 February 2011 Office Action
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`Applicants were also the first to identify particular values of initial dC/dT which are critical to
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`preparing a memantine formulation that can be given once daily, which may be combined with
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`donepezil, and which demonstrates reduced'CNS side effects. There is nothing in Ditzler et al. or any
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`of the other cited art that would suggest Applicants’ invention and the signifiCant advantages it has
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`over the prior art.
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`The position of the Office seems to be that it would have been obvious to optimize the ER
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`formulation and find the claimed dC/dT. However, nothing in the prior art points to this feature of the
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`ER formulation as being effective to provide the benefits of reducing side effects, permitting once
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`daily dosing, or dosing at higher doses than were previously possible. Ditzler does not teach an ER
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`formulation; and no reference teaches the claimed dC/dT. It is not obvious to optimize “where the
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`parameter optimized was not recognized in the prior art as one that would affect results.” Ex parte
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`Whalen II, 89 USPQ2d 1078 (B.P.A.I. 2008).
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`I
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`The proposition that varying memantine dC/dT is an obvious design choice is further rebutted
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`by the attached declaration under 37 CPR. § 1.132 of Sid Gilman, M.D., F.R.C.P. (The “Gilman
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`declaration”) Dr. Gilman is an expert in the field of neurology who has authored approximately 500
`scientific papers in the fields of neurology and neuroscience. Having reviewed Ditzler et a1., Dr.
`V
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`Gilman found that a person of ordinary skill in the art at the time the present application was filed
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`would not have expected that extending the release of memantine, and in particular slowing the rate of
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`rise in memantine plasma concentration (dC/dT) in the first few hours after administration, would
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`have any impact at all on tolerability. (Gilman Decl. paras. 6-11.) According to Dr. Gilman, Ditzler
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`suggested spacing out dose increases of IR memantine over a period of weeks.
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`(Id. para. 9). Dr.
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`Gilman directly rejects the Office Action's interpretation of Ditzler, stating at para. 11:
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`It does not follow logically that slowing the dose increase of memantine by weeks would
`ever lead one to the use of the claimed extended release formulations of memantine (as
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`described by Went et al.).
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`Dr. Gilman further illuminates the misreading of Ditzler et al. in the Office Action by pointing out
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`that following Ditzler et al. the standard clinical practice (that is the state of the art) was to commence
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`memantine therapy at a lower dose than Ditzler, dose memantine twice daily, increase memantine
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`Application No. 11/399,879 (34550-705501)
`Response to 8 February 2011 Office Action
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`dose on a weekly basis over a three-week period (versus a one—week period), up to a maximum
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`recommended dose of 20 mg per day administered 10 mg twice daily. Dr. Gilman further points out
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`that Namenda®, the currently approved brand of IR memantine, is so labeled. (Id. para. 9.) Applicants
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`submit that, given Dr. Gilman’s expert testimony of the state of the art and of the understanding of the
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`person of ordinary skill in the art (and in the absence of any evidence of record to the contrary)
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`Ditzler et a1. fails to supply the missing teaching of dC/dT values recited in the instant claims.
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`Dr. Gilman further states that the present inventors’ discovery— that memantine’s adverse
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`effects were related to the rate of rise in plasma concentration in the first few hours after the drug is
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`administered (i. e., dC/dT) — were surprising and contrary to the teachings of Ditzler et a1., as were the
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`inventors’ discoveries that the use of an ER memantine formulation having a dC/dT less than 50% of
`an IR memantine formulation would reduce side effects, and that one could thus give once-daily doses
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`of memantine, including, above 20 mg.
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`(161., para. 12.) Dr. Gilman further confirms that nothing in
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`the other references relied upon in the Office Action remedy the deficiency in the teaching of Ditzler.
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`(Id. paras. 13—14.) Dr. Gilman’s declaration thus establishes the level of skill in th