IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Application No.:
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`l 1/285,905
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`Customer No.:
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`72664
`
`Applicant:
`
`Gregory T. Went et al.
`
`Docket No.:
`
`.
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`522 US
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`Filed:
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`November 22, 2005
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`Group Art Unit:
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`4161
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`Confirmation No.:
`Title:
`
`‘
`
`9709
`.
`Examiner:
`Carter, Kendra D.
`Method and Composition for Administering an NMDA Receptor
`Antagonist to a Subject
`
`Commissioner for Patents
`PO. Box 1450
`
`Alexandria, VA 22313-1450
`
`DECLARATION OF GAYATRI SATHYAN, Ph.D. UNDER 37 C.F.R. §1.l32
`
`I, Gayatri Sathyan, declare and state as follows:
`
`I am a Senior Director of Clinical Pharmacology at Adamas India Pharmaceuticals, Pvt.
`1.
`Ltd, a wholly-owned subsidiary of Adamas Pharmaceuticals, assignee of the subject patent
`application. As part of my employment compensation, I have received stock options in Adamas
`Pharmaceuticals.
`
`I have a Ph.D. from the University of Cincinnati’s College of Pharmacy, Division of
`2.
`Pharmaceutics and Drug Delivery Systems.
`I have over 15 years ofpharmaceutical industry
`experience. Prior to my employment with Adamas India I was employed for over 10 years by
`ALZA Corporation, a recognized leader in controlled-release drug delivery systems. While at
`ALZA, I was involved in the development of oral controlled-release products and was lead
`clinical phannacologist responsible for NDAs and EX—US/Worldwide submissions for 5
`products.
`I am an author of over 30 publications in the fields of pharmacology and
`pharmacokinetics. My publication list is attached as Appendix A.
`
`I have read the subject patent application, the pending claims, the Patent Office Action
`3.
`dated 03/23/2009 and the cited references (Le. US Patent No. 6,194,000 to Smith et al., and
`'l‘immermans ct al., Drug Dev Ind Pharm. (1998) 6:517-25). For reasons explained below, it is
`my opinion that the cited references do not suggest or make obvious to a person of ordinary skill
`in the art a method of avoiding side-effects in a patient initiating memantine therapy by
`administering to the patient a therapeutically effective dose of memantine from initiation of
`therapy without dose escalation, or reaching a therapeutically effective steady state plasma
`concentration of memantine within fifteen days from initiating therapy. It is my expert Opinion
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`that the person of ordinary skill in the field would not have found it obvious and be motivated to
`use extended release as a substitute for dose escalation in view of the following facts.
`
`A person having ordinary skill in the field of developing improved formulations and
`4.
`dosing regimens for existing drugs will be familiar with the clinical studies published for the
`drug they are developing. The skilled person will know the drug’s pharmacokinetic properties
`(e.g. rate of absorption, time to maximum plasma concentration, elimination half-life, etc.), prior
`dosage forms and methods of administration, indications, and side-effect profiles. With respect
`to memantine, the skilled person in 2005 would have known from the relevant literature that
`memantine is escalated at initiation of therapy to avoid psychotomimetic side-effects:
`
`In contrast with some other NMDA-receptor antagonists (e.g. PCP, MK-801), memantine
`is associated with minimal psychotomimetic side-effects (e.g. delusions, hallucinations
`and depersonalization), ataxia and motor incoordination, providing that the dose is
`properly titrated over a period of3-4 weeks. (Eleanor Bull, Drug review — Memantine,
`Drugs in Context (2005) I(I):I-40; emphasis added; article attached as Appendix B).
`
`S.
`
`The Office Action dated Mar. 23, 2009, in the paragraph bridging pages 4-5, alleges:
`
`To one of ordinary skill in the art at the time of the invention would have found it
`obvious and motivated to combine the method of Smith et al. and a method to avoid side-
`effects because Smith et al. teaches a sustained release form of memantine and
`Timmermans et al. teach that sustained release dosage forms are effective in reducing the
`incidence of concentrationjrelated side effects, e.g., emesis, and of behavioral symptoms,
`restlessness, discomfort and indisposition (see abstract, lines 6-9).
`
`2005. In fact, the person of ordinary skill would not have found Timmerrnans et al. useful with
`respect to how to improve the dosing schedule of memantine.
`
`It is well-known in the field of pharmacokinetics that sustaining release of a drug with a
`6.
`m time to maximum plasma concentration (’l‘max) and a sing elimination half-life will
`prolong the duration of action of the drug, allowing for'less frequent dosing.
`It is also known
`that sustaining release of such a drug may also reduce drug concentration-related side effects
`because, typically, the sustained release (SR) formulation achieves a maximum plasma
`concentration (Cmax) that is 1_o_w_e_r than that of the immediate release (IR) formulation of the
`drug at the same dose level.
`> This is .illustrated in Fig. 1 of the article by Lloyd N. Sansom
`entitled “Oral extended-release products”, attached as Appendix C, in which the curve with the
`three peaks depicts a theoretical drug concentration profile of an IR form of a drug administered
`three times daily and the dotted line curve depicts an SR form of the same drug administered
`once daily at the same daily dose as the IR form. The IR form’s Cmax materially exceeds the
`necessary therapeutic concentration, and may result in plasma concentrations at which side
`effects occur, whereas the SR form has a substantially reduced Cmax while maintaining drug
`concentration at therapeutic levels.
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`Timmermans et al demonstrated that short Tmax and half-life are the case with ucb
`7.
`11056 (see Abstract: All SR [sustained release] dosageforms were seen to be ejfictive in
`prolonging the relatively short biological half-life ofthe compound and in reducing the
`incidence ofconcentration—related side-efiects. . .). Timmermans et al. do not disclose the precise
`half-life of an IR formulation of ucb 11056, but from the graph on p. 520, the terminal half-life
`appears to be in the range of about 1.5-2.5 hours. Table 1 shows that the Tmax of an immediate
`release (IR) formulation of the drug is 1.1 i 0.5 hrs. Assuming once or twice per daydosing, all
`or most of ucb 11056 would be metabolized or eliminated prior to a subsequent dose given this
`short half—life. This is in contrast to memantine which accumulates to a level significantly higher
`than the concentrations observed after a single dose, due to a much longer half-life! Table 1 in
`Timmermans also shows the reductions in maximum concentration (Cmax) of the drug that were
`achieved by sustaining release of ucb 11056. In each case, the Cmax of the SR formulation was
`less than half that of the IR formulation at the same dose. Timmermans clearly appreciated” the
`relationship between Cmax and the side effects (emesis) as noted at the top of page 523 in the
`second column: “The IR capsule study group showing the highest ucb l 1056 peak plasma
`concentration is most frequently affected by emesis... whereas no emesis is observed following
`the SR pellets batch ll dosing that produces a comparatively 10-times lower Cmax value.”
`Indeed, the authors state on p. 523 column 2, paragraph 4, that “Emesis can thus be defined as a
`dose-dependent effect or perhaps more rigorously speaking in the case of SR forms, as a
`concentration-dependent effect.”
`
`There is nothing in Timmermans that would lead one skilled in the art to consider this
`8.
`reference when making improvements to a memantine formulation because it is well~kn0wu in
`the art that memantine’s side effects occur upon initiation of therapy with the IR formulation
`when plasma concentrations of the drug are well below therapeutically-effective levels. Further,
`the pharmacoldnetic properties of memantine are very different from that of Timmermans’ drug.
`Referring to the Table 1 on p. 20 of the article attached as Appendix B, in contrast to the very
`short 1.1 hour Tmax of Timmermans’ drug, memantine has a Tmax of 3-8 hours; and, in contrast
`to the 1.5-2.5 hour half-life of Timmermans drug, memantine has a half-life of about 60-100
`hours. Because of memantine’s relatively long Tmax and elimination half-life, the Cmax of a
`single dose of an SR. formulation of memantine will be very close to the Cmax of a single dose
`of an IR formulation of the same strength at equivalent exposure. This is because very little drug
`is eliminated from a patient before the Cmax of an SR formulation is reached. Thus the
`substantial reduction in Cmax that was achieved by sustaining release of Timmermans’ drug will
`not happen when release of memantine is sustained. This point is illustrated in the attached
`Appendix D, which is an annotated version of FIGS 1A and 1B from the application. Referring
`to FIG 1A, pharmacokinetic modeling (SoftwarezGastroPlusTM) shows that administering a
`
`
`' This is illustratedin the attached Appendix D, which is an annotated version of FIGS 1A and 18 from the
`application. Referring to Fig. 13, pharmacokinetic modeling software (GastroPlusTM) shows that at 24 hours afler
`administration of a 22.5 mg dose of an SR memantine formulation (5001-6701 , a patient will have a memantine
`plasma concentration ofjust above 0.02 ug/ml. After administration of the 2" dose, the patient will achieve a
`memantine plasma concentration of about 0.04 nyml, and so on, until a steady state plasma concentration is
`reached.
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`22.5mg dose of an SR memantine formulation (5001-6701) to a patient initiating memantine
`therapy will achieve a maximum plasma concentration that is approximately 95% that of a 20 mg
`dose of an IR memantine formulation (Namenda). Thus, One of ordinary skill in the art would
`not consider Timmerrnans et a1. relevant to memantine as 1) there is no apparent need to prolong
`the duration of action of memantine, 2) one would not expect an SR formulation of memantine to
`substantially reduce Cmax, and consequently concentration-related side effects, and 3) unlike
`Timmermans’ drug, the Cmax of memantine increases with each day of dosing until a steady~
`state plasma concentration is reached.
`
`To the extent one of ordinary skill in the art would have considered the Timmemrans et
`9.
`a1. relevant to memantine therapy, the reference would have taught away from administering a
`therapeutically effective dose of Smith’s SR memantine formulation to a patient initiating
`memantine therapy because: 1) it was known in the art, as evidenced by the Appendix B review
`article, that memantine should be titrated over 3 to 4 weeks to avoid side-effects; and 2)
`Timmerrnans teaches to reduce maximum plasma concentration in order to reduce side—effects.
`One of ordinary skill in the art would have been able to determine that by eliminating the dose
`escalation of memantine, even if formulated for sustained release, initial maximum plasma
`concentrations would significantly increase compared to the Cmax values initially achieved by
`following the medically-accepted practice of initiating memantine therapy at a sub-therapeutic
`dose of 5mg. The principle applied by Timmerrnans, that side effects of a drug can be
`eliminated in some cases using sustained release formulations, when applied to memantine
`actually suggests to the person of ordinary skill to avoid substituting a “full-strength” ER
`formulation for the state of the art IR dose escalation. The initiation of therapy with the ER
`memantine of the subject patent application results in a significantly higher Cmax than the
`standard dose escalation. This point is also illustrated in FIG 1A ofAppendix D, which,
`compared to the figure in the application, adds a 3rd curve simulating a single-dose plasma
`concentration curve for 5 mg Namenda. The graph illustrates that by administering a therapeutic
`dose (eg. 22.5mg) of an SR memantine formulation (5001-6701) to a patient initiating
`memantine therapy, a maximum plasma concentration will be achieved that isapproximately
`four times greater than that achieved by a 5 mg dose of IR memantine. This point is further
`illustrated by the attached Appendix E, which shows the modeled profile (Software:
`GastroPlusTM) of a 22.5 mg strength of an SR memantine formulation, ADS-5002, administered
`without dose escalation once daily for four days compared to once daily dosing with 5mg
`Namenda in accordance with the recommended initial dosing schedule. On day four, the Cmax
`achieved by ADS-5002 is approximately 0.060 ug/ml, whereas the Cmax achieved by 5mg
`NAMENDA is about 0.018 ug/ml. Thus, the person of ordinary skill trying to apply
`Timmermans to memantine side effect control would not start the therapy at the much higher
`memantine concentrations even if they were in ER form.
`~
`
`The Office Action dated Mar. 23, 2009, made the remark on p. 5, line I 1, that “because
`10.
`the overlap in administration the dosage is naturally escalated.” While daily administration of a
`sustained release oral dosage form comprising memantine will naturally result in increasing
`plasma concentration of memantine each day (due to its long half-life) until a steady-state plasma
`concentration is reached, one skilled in the art would not consider this to be “dose escalation”.
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`Dose escalation is when the daily dose administered to a patient is higher than a previously
`administered daily dose. Fig 18 in the attached Appendix D compares the pharmacokinetic
`profile of memantine when administered in accordance with standard dose-escalation with the
`profile of a sustained release oral dosage form administered at a therapeutically effective daily
`dose from initiation of therapy (Namenda Ramp profile vs. 5001-6701 profile, respectively), and
`shows that the two dosing regimens yield very different results. With the 5001-6701 dosing
`regimen, a therapeutically effective steady state plasma concentration is reached about 15 days
`after initiating therapy.
`in comparison, using the standard dose-escalation regimen provided in
`the approved Namenda product label, a therapeutically effective steady state plasma
`concentration is reached about 37 days after initiating therapy. This illustrates that a non dose-
`escalating regimen using a sustained release dosage form is not pharmacokinetically or
`f
`therapeutically equivalent to a dose-escalation regimen, and one of ordinary skill in the art would
`not consider the two regimens to be generally substitutable for each other.
`
`The Office Action dated Mar. 23, 2009, further remarked on p. 6, line 17, that “regardless
`11.
`if the patient is administered the drug in dose escalation or all at once in a sustained release form,
`it is obvious that both will reduce side effects compared to offering the drug at the therapeutic
`amount in a non-sustained release form.” However, this statement is inaccurate. Ifa drug’s
`side-effect is purely concentration-dependent then sustaining release of the drug will not
`necessarily reduce the side effects, but may just delay the occurrence of the side effects until the
`concentration at which the side effects occur is reached. This is evident from Timmermans et a]:
`
`The IR capsule-dosed animals are seen to vomit soon after drug administration (44+/— 15
`min). . ,. For the SR matrix and SR pellets batch 15, the animals having vomited are
`among the more exposed ones, which conforms to expectation because this side effect is
`known to be concentration dependent. ..
`.In addition, the shorter the Tmax value, the
`sooner the onset time of vomiting. The SR dosageforms therefore exhibit a delayed
`pattern ofside effects in comparison with the IRformulation. (Timmermans et al., p.
`523, col 1, line 3 to col 2, line 16; emphasis added).
`'
`
`Thus, Timmermans’ SR formulation does not appear to reduce the side effects at a given
`concentration.
`In other words, the Timmermans SR formulation did not reduce side effects by
`slowing uptake of the drug — the same side effects that were seen with the IR formulation of the
`drug were also seen with some of the SR formulations, albeit delayed, provided a high enough
`concentration of the drug was achieved.
`
`12.
`Further, it is well-known in the art that SR formulations are often dose—escalated.
`RAZADYNE, COREG CR, and WELLBUTRIN SR, are all examples of SR formulations that
`require dose escalation at initiation of therapy to avoid side effects . Another example is
`REQUIP XL. Obviously, sustained release technology does not necessarily eliminate the need to
`dose escalate drugs to avoid side effects.
`
`2 The response filed Dec. 23, 2008, also listed Dl'l‘ROPAN XL® as a drug that is titrated at initiation of therapy.
`However, with some patients the 5mg starting dose may be therapeutically effective such that they are not
`subsequently titrated to higher levels of the drug.
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`I am aware of only two examples of sustained release formulations of drugs that
`13.
`eliminated the need to dose escalate the drug to avoid side effects. In both cases, however,
`initiating therapy with a starting therapeutic dose of an SR form of the drug achieved a Cmax
`that was comparable to that achieved by the starting sub-therapeutic dose of an IR form of the
`drug.
`In effect, the SR formulations allowed a therapeutic dose to be given without reaching the
`Cmax at which unacceptable side effects occur. This is quite different from the present invention
`where the starting therapeutic dose of SR memantine achieves a Cmax that is approximately 3-4
`times greater during the first week of dosing than that achieved by the recommended 5mg/day
`starting dose ofthe IR formulation. The Cmax of the starting SR memantine, therefore, is not
`comparable to the Cmax of the starting IR dose, and SR memantine reaches a Cmax that is
`known to have unacceptable side effects when an [R drug is initiated without dose escalation.
`Thus, one of ordinary skill in the art would not find these two isolated examples relevant to
`memantine, and if considered, would likely be discouraging with respect to SR formulations as a
`solution to the lengthy dose escalation problem. For completeness, I will discuss below each of
`the examples of which I am aware.
`
`One of the examples is doxazosin mesylate, in which the Cmax achieved following a
`14.
`single 8 mg dose of an SR form of the drug (doxazosin GITS) was similar to that of a 2 mg dose
`of an IR fomrulation of the drug (referred to as “doxazosin standard"; see p. 683, col. 1, line 1 of
`Chung et al. (J. Clin. Pharmacol (1999) 48:678-687), attached as Appendix F)). The other
`example is formulations of the benzisoxazole derivatives, risperidone and paliperidone,
`described in US patent publication no. 2005/0208132 to Sathyan et al., which I developed while
`employed at ALZA Corporation. The studies described in that patent application demonstrate
`that, on the first day of dosing, patients administered a 3-4 mg (therapeutically effective) dose of
`the drug in an SR form will have side-effect profiles comparable to patients administered a 2 mg,
`sub-therapeutic dose of an IR form of the drug, with comparable Cmax values between the IR
`forms and the higher strength SR forms. These examples, as explained above, are not relevant
`to a therapeutic dose (~20 mg/day) of an SR formulation of memantine that achieves a Cmax that
`is approximately 3-4 times greater during the first week of dosing than that achieved by the
`recommended 5mg/day starting dose of the IR formulation. In view of the Chung et al. and
`Sathyan et al. publications, memantine would not be a suitable candidate for elimination of dose
`escalation.
`
`The non-obviousness of sustaining memantine release to obviate initial dose escalation,
`15.
`while still avoiding side effects, is evident from more recent publications and events.
`In
`particular, attached as Appendix G is an article by Andrew N. Wilner, MD, reporting on clinical
`study results of an SR formulation of memantine that were presented at the American
`Neurological Association (ANA) 133rd Annual Meeting in 2008. The study was sponsored by
`Forest Laboratories, the maker of the NAMENDA, the memantine product currently marketed in
`the US. The article reports that “over the course of 4 weeks, extended-release memantine was
`titrated by 7 mg each week to a final dose of 28 mg/day.” Thus, to date, the literature suggests
`that even when formulated for extended release, it was not obvious to the company with the most
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`memantine experience in the US. that dose escalation could be eliminated with an SR
`formulation.
`
`Additionally, in connection with an IND Adamas Phannaceutieal’s submitted for its
`16.
`sustained-release memantine product, I participated in a meeting with the FDA to discuss the
`design of a Phase 3 study. Initially, representatives of the FDA, including a Ph.D.-level clinical
`pharmacology reviewer and an M.D.-level clinical review, among others, did not agree with our
`proposal to conduct our trial without an initial dose escalation of the product. Specifically, as
`part of their pre-meeting comments the FDA remarked that our proposal to administer our
`product without titration would appear to be “a significant departure from what this Agency
`currently recommends”, and instead recommended that we use titration “using the current
`approved labeling for Namenda® as a guide.” At the meeting, Adamas representatives explained
`the rationale behind eliminating the dose escalation, specifically, that the product slows the rate
`of rise of plasma memantine concentrations within a dosing interval (see annotated FIG 1A in
`Appendix D which shows the reduced rate of rise in comparison to the rate of rise with 20 mg of
`an IR form, and even compared to 5mg of the IR form). The FDA representatives became
`receptive to our proposal, however they made some recommendations with respect to the study
`design to include additional safety-directed provisions, and further recommended that once our
`protocol is finalized, that we submit it to them with a request for a Special Protocol Assessment.
`This further indicates that memantine was known to be dose-escalated at initiation of therapy,
`and it would not have been obvious to the person of ordinary skill in the art to extend release of
`memantine to obviate the need to ,use dose escalation to avoid side effects.
`
`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 these
`statements were made with the knowledge that willful false statements and the like so made are
`punishable by a fine or imprisonment, or both, under Section 1001 of Title 18 of the United
`States Code, and that such willful false statements may jeopardize the validity of the application
`or any patent issued thereon.
`
`. Date: lilac. K4333?
`
`By: m:
`
`Gayatri Sathyan
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