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`11/399,879
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`PATENT
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`In re Application
`
`Inventor: Gregory T. Went, et a1.
`
`Application No.: 11/399,879
`
`Filed: April 6, 2006
`
`Title: Methods and Compositions for the
`Treatment of CNS-Related Conditions
`
`Confirmation No.2 3491
`
`Art Unit: 1627
`
`Examiner: CARTER, Kendra D.
`
`Attorney Docket No. 34550-705501
`
`VVVVVVVVVV
`
`Declaration Under 37 C.F.R. § 1.132
`
`1, Gregory T. Went, Ph.D., declare as follows:
`
`1.
`I am an inventor of the patent application identified above (“Application”), and
`the subject matter described and claimed therein.
`I
`
`2.
`
`I am currently Co-founder and Chief Executive Officer, of Adamas
`
`Pharmaceuticals, Inc., the assignee of the Application.
`
`3.
`
`4.
`
`My curriculum vitae is attached as Appendix A.
`
`'
`
`I-have reviewed the Office Action mailed June 21, 2010 (“Office Action”) and the
`
`references cited therein, in particular the Moebius (US 2004/0087658 A1) and Laurin (US
`
`' 2006/0079578) references.
`
`I understand that, in part, the Examiner has rejected previous claims
`
`in the Application, citing to Moebius at paragraphs 192 and 194.
`
`I have also reviewed the claims
`
`of the Application, as amended and filed concurrently with this Declaration, and am familiar
`
`with methods and compositions using the technology described in the Application comprising
`
`donepezil and extended-release memantine.
`
`Memantine Property Background —- Half Life, Cmax and Side Effects
`
`5.
`
`Extended-release products are designed to prolong the absorption of drugs with
`
`short half-lives, thereby allowing longer dosing intervals while minimizing fluctuations in serum
`
`drug levels.
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`Memantine is a long half-life drug (about 60 hours) which is nearly completely
`
`bioavailable when given in immediate release form (Namenda package insert) that is approved
`
`for dosing twice daily. This means that once immediate release memantine is given, its blood
`
`plasma concentration rises over a period of about 0-7 hours and then starts to slowly decrease.
`
`The blood plasma concentration has generally not decreased significantly before the next dose of
`
`memantine is given after 12 hours.
`
`A person having ordinary skill in the art at the time of filing of the Application would
`
`have lacked any motivation to prepare an extended release form of memantine, as duration of
`
`activity is not really an issue with memantine. Nor would that person have been motivated to
`
`develop and administer specific memantine formulations with a reduced initial rate of change in
`
`plasma concentration (i.e., dC/dT) with an expectation of success in significantly reducing
`
`memantine’s CNS side effects to the point where it could be administered once per day, alone or
`
`with donepezil.
`
`6.
`
`Extended-release formulations are also useful in the case of drugs for which high
`
`peak plasma concentrations are associated with significant adverse effects. However, the most
`
`significant side effects of memantine are actually observed early in memantine dosing (Ambrozi,
`
`1988; Ditzler, 1991) when plasma concentrations are a fraction of steady state peak plasma
`
`concentration .
`
`7.
`
`On the other hand, immediate release memantine is not reported to be very well
`
`tolerated at doses higher than the labeled dose (i.e. 20 mg/day) (Maier, 2002; Swerdlow, 2009).
`
`Given the relatively low fluctuation of immediate release memantine at steady state owing to the
`
`significant accumulation of the drug at steady state, extending the release of memantine would
`
`not have been expected to reduce the Cmax at steady state. Therefore on this basis, a person
`
`having ordinary skill in the art at the time of the filing of the Application would not have been
`
`motivated to formulate an extended release formulation of memantine dosed once daily at
`
`strengths greater than 20 mg/day, and expect such a formulation to necessarily be‘well tolerated
`
`at steady state.
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`Experiments Conducted
`
`ADS-DEM-C106: Pharmacokinetic Characterization of Memantine Immediate Release IR
`
`
`
`and Memantine Extended Release gER) Forms A, B and C:
`
`8.
`
`A cohort of 64 subjects was randomized to one of four treatment arms of 16
`
`subjects each ~ IR, A, B and C. Group IR received a single dose of 20 mg of a commercially
`
`available immediate release memantine (Namenda®). Treatment arm A received 22.5 mg of a
`
`first extended release memantine formulation. Treatment arms B and C received 22.5 mg of
`
`memantine in second and third ER formulations of memantine, respectively. Blood was drawn
`
`at T=0 and at 1,2, 3,4, 5, 6, 7, 8, 10, 12, 14, 16, 18, 20, 22, 24, 36, 48, 96, 144, and 192 hours
`
`after oral administration of memantine for each treatment arm, for the determination of
`
`memantine blood plasma level at each time point.
`
`Figure 1. Results from ADS-DEM-C 106
`
`Plasma Memantine Concentration Profile per Mg of Memantine
`
`msxwlR (20 mg)
`
`-~§-~A(22.5 mg)
`
`--\\\-..B(22.5 mg)
`
`a-3<~wC (22.5 mg) w
`
`dC/dT of 50% of IR
`
`Tmax of IR
`
`1.40 '1‘
` \
`\\\\\\\\\m\\\
`\\ ‘
`\ “A“““N‘“‘\\~\l\\\\\\\\\\\x\m\\\\\“\\\\\\\\\“\\w\\“\\“‘\\
`~
`'
`:
`.0"
`1 20 .‘x..........................................................................................g“sf..................i.............................................................................“‘fi‘
`:
`\
`.~
`.
`V“‘°
`““\\¢v-\‘\
`I
`““m‘“m“wnm\xww§
`go
`‘o\‘\\\“\\\\\\\“§§\“‘«‘
`
`1
`5
`
`
`.
`i
`
`0‘ \x.‘..............................................................................
`
`1_oo
`
`0.80
`
`
`
`
`‘ ...................................................................................
`
`N
`,. dC/dT of
`5
`s
`-
`.
`50% °!l3.\
`050 \W...“ *.1».....‘ _..._....._.......,..,~11
`_
`\rfi‘flf‘..._u.m_.,.".,.w..._.‘......m .W,
`
`
`s
`
`0.20
`
`‘
`
` 0.40
`
`9. Results of ADS-DEM-C106: As can be seen in Figure 1, above:
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`I The IR memantine formulation achieved maximum blood plasma concentration in about
`
`7 hours, in agreement with the literature (Namenda Package Insert) corresponding to a
`
`rate of change of memantine blood plasma concentration (i.e., dC/dT) of about 4
`
`ng/ml/hr;
`
`I ER memantine formulation A achieved a dC/dT as measured between the period of 0-
`
`Tmax of the IR formulation of about 80% of the IR formulation (adjusted proportionally
`
`for strength); and
`
`I ER memantine formulation B achieved a dC/dT as measured between the period of 0-
`
`Tmax of the IR formulation of about 40% of the IR formulation (adjusted proportionally
`
`for strength); and
`
`I ER memantine formulation C achieved a dC/dT as measured between the period of 0-
`
`Tmax of the IR formulation of about 30% of the IR formulation (adjusted proportionally
`
`for strength).
`
`I
`
`Thus, two of the tested. ER formulations (B and C) fall within the initial dC/dT requirement
`
`specified in the application and the subject of the pending claims, whereas the IR and Form A
`
`ER memantine formulations do not.
`
`10.
`
`Reduction in CNS Side Effects: The subjects in the study were evaluated for side
`
`effects, especially those side effects related to the central nervous system (CNS), associated with
`
`memantine administration. The outcomes of these evaluations are summarized in Table 1,
`
`below.
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`Table 1: CNS Side Effects
`
`Number of Subjects with CNS Side Effects, Listed by Side Effect
`
`i
`i
`
`
`
`1
`l
`
`Treatment A
`Treatment B
`i
`
`(Fm
`
`Treatment C
`
`A _ ._...
`
`444444
`4
`444444
`444444
`, m.” _____._____.T__,_n______
`2(130)
`0(0%)
`3
`0(0%)
`1
`
`1
`
`s
`
`!
`
`3
`
`2 ( l3 %)
`
`0 ( 0 %)
`
`l ( 6 %)
`
`0(0%)
`
`l ( 6 %)
`
`0(0%)
`
`0 ( 0 %)
`
`0 ( 0 %)
`
`0(0%)
`
`4
`
`0 (0 %)
`
`1
`
`4!
`
`1(6%)
`
`0 ( o no)
`
`0 ( 0 %)
`
`0(0%)
`
`0 (0 %)
`
`II“III
`!III“4‘
`
`
`‘
`
`
`
`
`
`i l
`
`
`
`
`‘
`
`
`
`1
`
`4
`
`444444
`
`l(6%)
`
`1(6%)
`
`1 (6 %)
`
`0(0%)
`
`l(6%)
`
`0 ( 0 %)
`
`______._
`Dizziness*
`
`Fatigue“
`
`Somnolence*
`
`Cognitive disorder*
`
`Confusion“
`
`Disturbance in attention*
`
`Aggression“
`
`Anxiety*
`
`Migraine
`
`
`
`
`
`
`
`i
`
`1
`
`3
`
`I
`l (6 %)
`
`0(0%)
`
`0(0%)
`
`l l
`
`Is i Ii
`
`0(0%)
`
`
`
`
`
`
`
`l(6%)
`
`3
`
`0(0%)
`
`
`0(0%)
`0(0%)
`
`ll
`0(0%) 1(6%) ill 1 0(0%)
`
`0(0%)
`
`
`«44444
`44444
`44444
`;
`1
`l
`0(0%)
`0(0%)
`0(0%)
`3
`
`
`
`l_l 4444
`lParaesthesia
`4
`1(6%)
`
`*Known side effects of memantine
`
`11.
`
`Evaluation of Memantine-Related CNS Side Effects. The treatment emergent
`
`incidence of memantine related CNS side effects were examined. Headache was excluded from
`
`this analysis since it is a common adverse event observed in phase I studies and the reasons for it
`
`can be many including restriction of caffeine intake, confinement, lack of sleep or disturbed
`
`sleep due to many blood samples during the night.
`
`12.
`
`Surprisingly, fewer subjects receiving Treatments B and C had incidences of
`
`memantine-related CNS side effects than those administered Treatment A or IR. As can be seen
`
`in Table 1, five of 16 (31%) of patients in the IR memantine arm, and 4 of 16 (25%) of subjects
`
`who were administered formulation A had at least one known CNS side effect of memantine
`
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`other than headache. . In contrast, zero of 16 (0%) subjects administered Form B and one of 16
`
`(6%) of subjects administered Form C respectively, experienced any memantine-related side
`
`effect other than headache. Thus, the clearly discernable trend is for there to be a decrease in
`
`memantine-related side effects in the ER memantine study arms in which the patients were
`
`administered ER memantine having dC/dT values less than 50% of the memantine dC/dT of IR
`
`memantine.1
`
`13.
`
`Also notable in Table 1 is that two of 16 (or 13%) of subjects administered ER
`
`formulation A and one of 16 (or 6%) of subjects administered IR memantine experienced
`
`dizziness. In contrast, subjects treated with either the B or C ER form of memantine experienced
`
`zero occurrences of dizziness each, for a rate of 0%. Thus there is a discernible trend that
`
`subjects treated with formulations having a memantine dC/dT greater than 50% of an IR
`
`formulation (IR and Form A ER) experienced a higher rate of occurrence of dizziness than
`
`patients treated with formulations having a memantine dC/dT less than 50% of an IR formulation
`
`(Form B ER and Form C ER). 2 Or, stated another way, there is a discernable trend for there to
`
`be a decrease in dizziness in the ER memantine study arms in which the patients were
`
`administered ER memantine having dC/dT values less than 50% of the memantine dC/dT of IR
`
`memantine. 3
`
`ME-110: Steady State Administration of 20 mg memantine immediate release (10 mg IR
`memantine administered twice a day) and 25 mg extended release memantine Form B
`administered once daily 19D)
`
`14.
`
`ME] 10 was a two period two treatment crossover study without a washout
`
`between treatments in 24 healthy subjects. In period 1, half the subjects were randomized to
`
`receive 10 mg twice—a—day IR treatment and the other half was randomized to receive the 25 mg
`
`1 In fact, there is a clearly discernable trend for there to be a decrease in memantine-related
`side effects in the ER memantine study arms in which the patients were administered ER
`memantine dC/dT values less than 80% of the memantine dC/dT of IR memantine.
`
`2 In fact, the trend holds for formulations having memantine dC/dT greater than 80% of the
`1R formulation.
`
`3 Again, the trend holds for formulations having memantine dC/dT less than 80% of the IR
`formulation.
`
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`once—daily ER treatment for 14 days (since IR memantine is typically dose-titrated a one week
`
`run in period of 5 mg twice-a—day IR preceded the IR treatment and one week run in period with
`
`placebo preceded the ER treatment). In period 2, which began immediately after end of closing
`
`in period 1 without a washout, the subjects were crossed over to receive the alternate treatment
`
`for 14 days. Blood samples to measure memantine concentration were taken on the 14th day of
`
`treatment in both periods at predose and l, 2, 4, 6, 7, 8, 10, 12, 13, 14, 16, 18, 19, 20, 22, 24
`
`hours post close on the 14111 day. The immediate release (IR) formulation was the commercially
`
`available immediate release memantine marketed under the trade name Namenda® dosed at the
`
`maximum recommended dose of 20 mg/day (administered 10 mg twice daily). The extended
`
`release memantine was 25 mg of the previously-described Form B, which has a dC/dT of about
`
`40% of IR, as described above, administered once daily. Results of the study are summarized in
`
`Figure 2, below.
`
`Figure 2.
`
`
`
`MamantinePlasmaConcentration(fig/mu,
`
`
`
`
`
`ME110 Steady State Plasma Concentration Profiles
`
`141:: {.0 .. ..........................................................................................................................................................................
`
`
`
`:.......
`
`-®~IR(1O mg BID)
`............................................................................................................................................................................
`
`u ER (25 mg)
`..........................................................................................................................................................................
`
`am c-o.
`
`
`
`15.
`
`In Figure 2, above, the stead state blood plasma concentration of memantine for
`
`25 mg/day extended release (ER) memantine is represented by the upper curve (boxes) and the
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