IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
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`Application No.:
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`I l/399,879
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`Customer No.:
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`94584
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`Applicant:
`Filed:
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`Went et al.
`April 6, 2006
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`New Docket No.:
`Group Art Unit:
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`34550-705.5(_)l
`1627
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`Confirmation No.:
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`3491
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`Examiner:
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`Carter, Kendra D.
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`Title:
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`Methods and Compositions for the Treatment of CNS~Related Conditions
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`Commissioner for Patents
`P.O. Box 1450
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`Alexandria, VA 22313-1450
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`' DECLARATION OF SID GILMAN M.D. F.R.C.P. UNDER 37 C.F.R. 1.132
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`1, Sid Gilman, deciare and state as follows.
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`1.
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`'
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`i am the William J. Herdman Distinguished University Professor ofNeurology at the
`University of Michigan, and Director oftiie Michigan Alzheimer’s Disease Research
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`Center.
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`I am an attending neurologist in the University of Michigan Hospitals.
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`I am
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`certified by the American Board of Psychiatry and Neurology.
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`l have authored
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`approximately 500 scientific papers, book chapters and abstracts in the fields of
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`neurology and neuroscience. My curriculum vitae is attached.
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`2.
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`i am a paid consultant as a member of the Clinical Advisory Board of Adamas
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`Pharmaceuticals, Inc, the assignee of this patent application, but i have not received
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`stock options in the company.
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`3.
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`I have been asked by Adamas Pharmaceuticals to read and review Ditzler, Arrizneinz.-
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`Forsch./Drug Res, 1991, no. 8, pp. 773-780 and provide my opinion on how a person of
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`ordinary skill in the art at the time of the invention claimed in US, Patent Application
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`Serial No.
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`i l/399,879 would understand the meaning of the Ditzler article, in particular
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`the following disclosure:
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`Adverse drug effects recorded by DOTES for memantine were
`agitation/excitation, increased motor activity, sleeplessness which, however,
`receded in the course of treatment. These adverse effects repre.s'em an excessive
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`I
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`pharmacoclynarnic effect resultingflom a too rapid dose increase. (Abstract,
`emphasis added)
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`However, the adverse reactions recorded in DOTES/TWIS were not serious and
`were transient, and very probably the result of a too rapid dose increase at the
`beginning of treatment. The dose should therefore be increased distinctly more
`slowly and aayusted to the individual situation until the optimal effect has been
`reached. (p. 778, emphasis added)
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`To avoid adverse reactions such as restlessness, excitation and insomnia, the dose
`must be increased at a rate adjusted to the individual patient. (p. 780)
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`_l have read and understood the cited portion and entire Ditzler article, the subject patent
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`application, the pending claims, as well as the office action dated Feb. 8, 2011 and other
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`cited references: Moebius (US 2004/0087658 A 1) and Nurnberg et al., (US 5,382,601).
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`To arrive at my opinion, I rely on the plain language and disclosure of Ditzler, the general
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`knowledge in the art and my own experience.
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`i am and have been familiar since the
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`19905 with the therapeutic use of memantine, ‘a NMDA receptor antagonist, and of
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`donepezil, an acetyl cholinesterase inhibitor.
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`l have prescribed each of these drugs, alone
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`and in combination, to my patients to treat the symptoms oi'Alzheimer’s Disease.
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`l have
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`served as a member of the Peripheral and Central Nervous System Drugs Advisory
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`Committee (from 1983 until 2000), and l chaired the Committee from i996 until 2000.
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`l
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`have been retained as a special consultant to the FDA in 5 year terms beginning in 2000.
`My current term runs from 2010 until 2015.
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`Ditzler describes side effects associated with the administration of memantine to
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`Alzheimer’s Disease patients in a study wherein memantine dose was increased over an
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`eight day period (about 1 week), from a starting dose of IO mg/day to a final dose 01°30
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`mg/day. Ditzler reports that these side effects “represent an excessive pharmacodynamic
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`effect rcszzltingfrom a too rapid dose increase" and “the dose should therefore be
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`increased distincrtlv more slowly.” He further adds that “this dose must be increased at a
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`rate aaj'u.s'ted to the individual patient. "
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`The Examiner states that based on the above observations of Ditzler in light of Moebius
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`“one would have been motivated to provide memanllne in an extended re/eascform to
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`avoid adverse effects” (for example, page 8-9 of Office Action). She bases this upon
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`Ditzler’s statement that, for memantine, “the dose shozild therefore be increased
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`distinctly more slowly”, and, I presume, Moebius’ statement that memantine can be
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`“suitablyformulated to give a controlled orposiponed release. " (fl [Ol 94].) The
`Examiner believes that these statements logically lead to the development of an extended
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`release drug fitting the limitations of the claims of the Went et al. application. This
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`belief, however, does not follow logically from the Facts. The Examiners conclusion is
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`inconsistent with what one of skill in the art would have understood from the Ditzler
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`article in light of Moebius and from the known pharmacokinetic properties of memantine.
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`A person of ordinary skill in the art at the time the invention was made would have
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`understood that Ditzler taught only that the period of 1 week between initiating therapy
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`and arriving at the final dose was too short in his study, and that Ditzler’s only guidance
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`was “to increase the dose distinctly more slowly” beyond 1 week.
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`Ditzler’s reference to a “too rapid dose increase” and “to increase the dose distinctly
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`more slowly” does not refer to or suggest the use of any type of extended release
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`formulation such as those described by Went et al., nor does he even reference the
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`pharmacokinetics of memantine. Rather, Ditzler was referring to the 1 week time period
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`between initiating therapy and arriving at the final dose. Thus, Ditzler may have
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`suggested to one of skill in the art that the tolerability of immediate release memantine
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`could be improved by implementing a more gradual schedule for increasing the dose of
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`memantine, that is, by having a dose increase period longer than the 1 week used in the
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`Ditzler study. Even on this point, Ditzler does not suggest how long the period in weeks
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`needs to be, other than to say that it should be tailored to each individual patient. A plain
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`reading of Ditzler supports my opinion. Moreover, a more gradual schedule for
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`increasing memantine dose — over a period of 3 weeks versus the 1 week period used by
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`Ditzler — became standard medical practice. Hence, the approved labeled dosing for
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`FDA-approved immediate release memantine (Namenda) in the U.S. is 5 mg for the first
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`week, 5 mg twice daily for the second week, '10 mg morning and 5 mg evening for the
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`third week, and [0 mg twice daily thereafter.
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`l0.
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`Ditzler does not disclose nor suggest to one ofskill in the art the method of the present
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`invention. This invention provides an extended release rnemantine formulation with a
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`ll.
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`l2.
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`change in plasma concentration ofmemantine as a function of time (dC/dT) that is less
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`than about 50% of the dC/dT of the same quantity of an immediate release form of
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`memantine between the time period of O to Tmax of the immediate release form.
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`l)itzler’s reference to a “too rapid dose increase” would not suggest or motivate the use
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`of any type of extended release formulation. Ditzler makes no reference to the
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`pharmacokinetics ofmemantine nor does he in any manner suggest that there might be
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`any connection between the adverse drug eflects ([tl1at] represent an excessive
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`pharmacodynamic effect) and the pharmacokinetics of memantine (i.e. the plasma
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`concentration versus time).
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`it does not follow logically that slowing the dose increase of memantine by weeks, (i.e.,
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`increasing the period between the initiation and final dose administered as proposed by
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`Ditzler) would ever lead one to the use of extended release formulations of memantine
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`(as described by Went et al.).
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`In sharp difference to the teachings of Ditzler, Went et al. made the surprising
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`observation that the side effects of mcmantine were related to the _i_n_i_t_ia_1_l_ rate of rise in
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`memantine plasma concentration over the first several l1_o;I_l;§ after dosing. Went et al.
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`discovered that by modifying the release of memantine in a manner that slowed the initial
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`rate of rise in plasma concentration over about 4-7 hours to a level that is less than about
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`50% of that of immediate release lR memantine, the side effects of memantine could be
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`in addition to providing benefit over a range of doses such as 5-40 mgs/clay,
`reduced.
`Went further teaches that this can lead to a once«dailv administration of me-mantine at
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`doses above 20 mg using the specified ER formulations developed by Went et al. The
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`claimed benefits of Went et al. are contrary to the teachings of Ditzler, whose suggestion
`of a dose that sliould be increased dt'stt'nct1y more slowly led to the labeled dose titration
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`over 3 weeks and a final daily dosing of memantine of 20 mg, given as 10 mg twice
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`daily. Thus, Went et al.’s findings are entirely unanticipated from clinical practice at the
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`time or indeed any prior art that I am aware of.
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`0
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`13.
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`Thus, based on the plain meaning of Ditzler and my own clinical experience, it is my
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`opinion that a person of ordinary skill in the art at the time the Went application was filed
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`would have properly understood Ditzler as recommending an increase in the period
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`between initiation to final dose from ~ 1 week to the order of 3 weeks to alleviate the side
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`effects. Given what was known about the pharmacokinetic and pharmacodynamic
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`characteristics of memantine at the time ofthe invention, one would not have expected
`that extending the release of memantine, and in particular, slowing the rate of rise in
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`memantine plasma concentration in the first few l_1_o_t_i__1_'_§ after administration would have
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`any impact at all on tolerability. This could not have been inferred from Ditzler alone or
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`in combination with Nurnberg and Moebius.
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`I4.
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`With respect to Nurnberg, who teaches a two—phase formulation of memantine, this
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`reference does not contribute alone or in combination with Moebius and Ditzler to
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`suggest or lead to the novel teaching of Went et al. The Nurnberg reference does not
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`contain or suggest any ER formuiation approximating the Went formulation, nor does he
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`refer to any relationship between the pharmacokinetics of memantine and its side effects.
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`Summarv
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`15.
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`This invention provides a method of alleviating the well known side effects of memantine
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`in an unanticipated way. Went et al. demonstrated that memantine formulations with a
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`dC/dT of less than about 50% of IR memantine are well tolerated. They have thereby
`enabled a formulation of memantine that can be taken once daily without the previously
`problematic side effects. There is nothing in Ditzler, Moebius or Nurnberg, singly or in
`combination, that would motivate or teach the above.
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`I6.
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`I hereby declare that all statements made herein of my own knowledge are true and that
`all statements made on. information and belief are believed to be true; and further that
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`these statements were made with the knowledge that willful false statements and the like
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`so made are punishable by line or imprisonment, or both, under Section i001 of Title I8
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`of the United States Code, and that such willful false statements mayjeopardize the
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`validity of the application or any patent issued thereon.
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`Date: (W 1 JON
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