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`Ikutaro SAJI et a1.
`
`Serial No.
`
`
`
`
`
`
`
`Filed
`
`For
`
`
`
`:
`
`:
`
`:
`
`-
`
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`
`- August 30, 1993
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`IMIDE DERIVATIVES AND THEIR PRODUCTION HLD U
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`AMENDMENT
`...—_.__.—
`
`Commissioner of Patents
`and Trademarks
`.
`Washington, 'D. C.
`.
`Sir:
`
`20231
`
`December 53:9, 1994
`1r:
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`gm;
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`C;
`1.0
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`In response to the Office Action dated August 30, 1994,
`
`the
`
`due date for
`
`response having been extended one
`
`(1) month to
`
`Recember
`
`3 Q ,
`
`1994 ,
`
`the fol lowing amendments
`
`and remarks are
`
`respectfully submitted in connection with the above application.
`
`In The Claims:
`
`
`
`
`
`Please add new claims 28 and 29 as follows.
`amt-6" 24.
`The imide compound of the formula:
`
`J L
`
`
`
`__130-SC {ii/1.9445 03113320
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`Page 1 of 9
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`SLAYBACK EXHIBIT 1026
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`20-3326P
`
`PATENT
`
`M
`
`
`
`I 08/113,320
`
`Group:
`
`1202
`
`Examiner:
`
`R. Bond
`
`
`
`
`Page 1 of 9
`
`SLAYBACK EXHIBIT 1026
`
`
`1
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`'--?a’-fits
`:
`Ikutaro SAJI et a1.
`
`Serial No.
`
`
`
`
`
`
`
`Filed
`
`For
`
`
`
`:
`
`:
`
`:
`
`-
`
`.
`
`- August 30, 1993
`F/tél
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`IMIDE DERIVATIVES AND THEIR PRODUCTION HLD U
`53
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`
`AMENDMENT
`...—_.__.—
`
`Commissioner of Patents
`and Trademarks
`.
`Washington, 'D. C.
`.
`Sir:
`
`20231
`
`December 53:9, 1994
`1r:
`2,)
`gm;
`.’.
`C;
`1.0
`:9
`
`In response to the Office Action dated August 30, 1994,
`
`the
`
`due date for
`
`response having been extended one
`
`(1) month to
`
`Recember
`
`3 Q ,
`
`1994 ,
`
`the fol lowing amendments
`
`and remarks are
`
`respectfully submitted in connection with the above application.
`
`In The Claims:
`
`
`
`
`
`Please add new claims 28 and 29 as follows.
`amt-6" 24.
`The imide compound of the formula:
`
`J L
`
`
`
`__130-SC {ii/1.9445 03113320
`E : _ 110:50 01x1?(?$ 00113320 __
`{-130 sc_01/10/95 03113320”
`
`152.00 CK
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`"'
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`1—._—-—"-_—-————._.____
`
`Page 1 of 9
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`SLAYBACK EXHIBIT 1026
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`'
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`I
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`I201
`
`20-3326P
`
`PATENT
`
`M
`
`
`
`I 08/113,320
`
`Group:
`
`1202
`
`Examiner:
`
`R. Bond
`
`
`
`
`Page 1 of 9
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`
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`——
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`‘fiém
`
`The imide compound of one of the following formulae:
`
`Serial No. 08/113,320
`
`.HCl
`
`.HCl
`
`Remarks
`
`Claims 11-27 have been rejected under 35 U.S.C. 112, first
`
`paragraph.
`
`This
`
`rejection_ is
`
`respectfully
`
`traversed.
`
`.n
`
`Reconsideration and withdrawal thereof are requested.
`
`t
`
`While the Examiner has urged that the specification fails to
`
`adequately teach "how to use"
`
`the
`
`claimed
`
`subject matter,
`
`applicants submit
`
`that
`
`the specification does
`
`indeed provide a
`
`fully enabling disclosure.
`
`Pages 23 and 24 of the specification
`
`specifically describe pharmaceutical compositions and dosages for
`
`use of the compounds. Numerous examples are then provided for how
`
`2
`
`Page 2 of 9
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`to make various of
`
`the compounds
`
`encompassed by the claims.
`
`Applicants
`
`submit
`
`that
`
`these
`
`and other
`
`teachings
`
`in
`
`the
`
`specification fully enable one skilled in the art how to use the
`
`compounds as presently claimed and in full compliance with 35
`
`U.S.C. 112.
`
`However,
`
`from the Examiner's discussion of the rejection, it
`
`appears that the Examiner's true criticism is an alleged lack of
`
`proof of utility, properly asserted under 35 U.S.C. 101. Assuming
`
`this to be the true basis for the Examiner’s rejection, applicants
`
`submit that the test results in the specification,
`
`taken together
`
`mith the knowledge of one skilled in the art,
`
`sufficiently
`
`establishes the utility of the claimed compounds as required under
`
`35 U.s.c. 101.
`
`The compounds of the present
`
`invention are useful as anti—
`
`psychotic
`
`agents
`
`(neuroleptic
`
`agents,
`
`anti—anxiety
`
`agents)
`
`particularly useful for therapy of schizophrenia, senile insanity,
`
`manic—depressive psychosis,
`
`neurosis,
`
`and
`
`similar disorders.
`
`Various drugs are commercially available for treatment of these
`
`conditions and applicants submit
`
`that
`
`the test results.in the
`
`specification show that the compounds of the present invention have
`
`in vitro and in vivo activities similar to those of
`
`the known
`
`compounds,
`
`such that one skilled in the' art would accept
`
`the
`
`asserted utility for
`
`the
`
`claimed compounds.
`
`The
`
`following
`
`discusses the evidence with respect to four major categories of
`
`therapy.
`
`Page 3 of 9
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`Serial NO. 08/113,320
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`1.
`
`Schizophrenia
`
`It
`
`is well known to those skilled in the art
`
`that anti—
`
`psychotic drugs block the dopamine D2 receptors in the brain,
`
`to
`
`thereby effect improvement
`
`in the symptoms of schizophrenia, such
`
`as improvements in excitation, hallucination and delusions. This
`
`phenomenon is known in the art as the "dopamine hypothesis".
`
`1.1 Philip Seaman: BYNAPSE l:
`
`133—152
`
`(1937)
`
`(Exhibit
`
`1)
`
`discusses this dopamine hvpothesis of schizophrenia and reports the
`
`results of tests to determine the affinity of various known anti-
`
`psychotic drugs to the dopamine D2 receptors.
`
`The authors report
`
`that "the clinical doses of neuroleptics for anti-psychotic action
`
`correlated very well with their ability to block the D2 receptors"
`
`(see the first full paragraph in the right hand column of page 137
`
`and the results reported in Figure 2 of the publication).
`
`The compounds of the present
`
`invention have similarly been
`
`shown to have high affinity to the dopamine Dz receptors.
`
`Pages
`
`24-26 of the specification report the results of the dopamine D2
`
`receptor binding assays for the compounds of the present invention
`
`and show that the compounds are even more active'than the known
`
`compound haloperidol. Applicants submit that these test results
`
`would be sufficient to one skilled in the art to establish that the
`
`claimed compounds have anti—psychotic activity and would be useful
`
`for the treatment of schizophrenia.
`
`1.2 Philip Seaman:
`
`Pharmacological Reviews, g; (3),
`
`229--
`
`230,
`
`232
`
`(1981)
`
`(Exhibit II) also discusses the hypothesis of
`
`4
`
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`neuroleptic blockade of dopamine receptors.
`
`In particular, at page
`
`232,
`
`the left hand column,
`
`line 9
`
`from the bottom,
`
`through the
`
`right hand column, line 5, the publication discusses that compounds
`
`having anti-psychotic activity (i.e. neuroleptics)
`
`inhibit
`
`the
`
`action of animals caused by the administration of dopamine-mimetic
`
`drugs, such as apomorphine.
`
`Similarly, page 26,
`
`line 5
`
`through page 28 of the present
`
`specification reports the results of in vivo tests on the anti-
`
`climbing activity of the claimed compounds,
`
`such climbing action
`
`being typical of the action caused by apomorphine as a dopamine-
`
`mimetic
`
`drug.
`
`Applicants
`
`submit
`
`that
`
`these
`
`test
`
`results
`
`additionally support the utility of the claimed compounds as anti-
`
`psychotic drugs against schizophrenia, establishing the utility
`
`additionally by means of in vivo tests.
`
`2.
`
`Senile Insanity
`
`Senile insanity is a psychotic disorder of aging humans, and
`
`various anti-psychotic agents are frequently used for treatment of
`
`the disorder.
`
`Thomas 3. Ban:
`
`Psycho.Pharmacology for the Aged,
`
`42-43 and 62-73 (1980)
`
`(Exhibit III) states that "it is estimated
`
`that one out of every three individuals over 60 years of age in the
`
`United states is treated with one or more psychotropic drugs"
`
`(of.
`
`Chapter IV, page 42, first paragraph). Thus, many aged people are
`
`treated. with psychotropic drugs
`
`for
`
`‘therapy of
`
`this psychotic
`
`disorder.
`
`Page 62,
`
`line 6 from the bottom to page 73 in the same
`
`5
`
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`Chapter, discusses specific examples of neuroleptics as clinically
`
`used in the treatment of senile insanity.
`
`From the above disclosures,
`
`it is readily understood that
`
`compounds having anti-psychotic activity,
`
`i.e. neuroleptics, are
`
`well
`
`known to those skilled in the _art
`
`to be effective for
`
`treatment of senile insanity. As discussed hereinabove in section
`
`(1),
`
`it is clear that the claimed compounds have anti-psychotic
`
`activity. Accordingly, it should be also clear to those skilled in
`
`the art
`
`that
`
`the claimed compounds would be useful
`
`for
`
`the
`
`treatment of senile insanity.
`I
`
`a. Manic—Depressive Psychosis
`
`It
`
`is well known to those skilled in the art
`
`that anti-
`
`psychotic drugs,
`
`i.e. neuroleptics, are generally effective in
`
`treatment of manic-depressive psychosis. For example, D.L. Dunner
`
`et a1.:
`
`Psycho-pharmacology,
`
`1077-1083
`
`{1987)
`
`(Exhibit
`
`IV)
`
`discloses
`
`that
`
`such
`
`"patients
`
`are
`
`commonly
`
`treated with
`
`neuroleptics alone, with lithium combined with neuroleptics, or
`
`with neuroleptics alone with lithium added later"
`
`(of. Treatment
`
`of Acute Mania on pages 1078-1079).
`
`Likewise, James c. - Y. Chou: Drugs of Today, gg,
`
`(2), 119-
`
`130 (1992)
`
`(Exhibit V) discloses that neuroleptics are used for
`
`treatment of manic patients.
`
`In particular, at page 120,
`
`left
`
`column,
`
`the author states "NeuroleptiCS are the other class of
`
`drugs most commonly prescribed to manic patients,
`
`typically in
`
`6
`
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`"0
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`it .3
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`/
`
`Serial No. 08/113,320
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`.
`
`combination with lithium. Although clearly effective in mania,
`
`their use should be discouraged because other effective treatments
`
`with less problematic side effects can be tried first".
`
`This
`
`publication,
`therefore,
`simultaneously warns of problematic or
`troublesome side effects induced by neuroleptics,
`such as acute
`
`extrapyramidal side effects (cf. page 120, left column, line 2 from
`
`the bottom to right column,
`
`line 2).
`
`As discussed hereinabove in section (1), it is apparent from
`
`the specification that the claimed compounds show significant anti-
`
`psychotic activity. Test results have also shown that the claimed
`
`compounds are quite weak in catalepsy inducing activity (i.e.
`
`extrapyramidal side effect) (cf. Table 5 on page 28). Accordingly,
`
`it would be understood to those skilled in the art that the claimed
`
`compounds would be useful as anti-psychotic agents for therapy of
`
`manic depressive psychosis with minimal side effects.
`
`4.
`
`Neurosis
`
`The conflict test is well known to those skilled in the art as
`
`an animal
`
`test
`
`for evaluation of anti—anxiety agents.
`
`See for
`
`example, 3.6. Berger: Anti-anxiety Agents, John Wiley 5 Sons, 27--
`
`49
`
`(1986), particularly Chapter 2: Pharmacological Evaluation of
`
`Anti-anxiety Agents in Laboratory Animals (Exhibit VI). As noted
`
`in section. "2.2 Anticonflict Activity" on pages 32-33 of- the
`
`reference,
`
`"clinically proven
`
`anxiolytic drugs
`
`significantly
`
`increase responding or reverse suppressed responding during the
`
`conflict period" (cf. page 32,
`
`lines 11 to 8 from the bottom). The
`
`.7
`
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`Serial No. 08/113,320
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`correlation between the anticonflict activity and the utility of
`
`anti-anxiety drugs is thus confirmed.
`
`Further, J. Vogel et a1.: Psychopharmacologia (Ber1.) g;, 1-7
`
`{1971) (Exhibit VII), which is referred to in Exhibit VI, discloses
`
`that
`
`commercial
`
`anti-anxiety drugs
`
`as benzodiazepines
`
`(e.g.
`
`chlordiazepoxide,
`
`diazepam,
`
`oxazepam),
`
`meprobamate
`
`and
`
`pentobarbital show increases in punished responding.
`
`The claimed compounds have similar antianxiety activity as
`
`established by the results of the conflict tests carried out on the
`
`claimed compounds using the same procedures as in Vogel et al. The
`
`results of these studies are submitted herewith in-the form of a
`
`Declaration by Dr. Yukihiro Ohno
`
`(Exhibit VIII).
`
`From this
`
`Declaration,
`
`it
`
`is apparent
`
`that
`
`the claimed compound
`
`(e.g.
`
`Compound No. 101)
`
`increased punished responding significantly at 10
`
`and 30 mg/kg in comparison with the control, and its potency at 10
`
`mg/kg is almost the same level as the commercial antianxiety drug
`
`(e.g. Diazepam).
`
`Applicants
`
`submit
`
`that
`
`the
`
`test
`
`results
`
`reported in the specification and in the attached Declaration of
`
`Dr. Ohno,
`
`taken together with the knowledge of those skilled in the
`
`art as evidenced by the scientific literature, are sufficient to
`
`establish the utility of the claimed compounds as required by 35
`
`U.S.C. 101. Accordingly,
`
`reconsideration and withdrawal of the
`
`rejections and early allowance of all
`
`the claims are,earnestly
`
`solicited.
`
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`Serial NO. 08/113,320
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`Pursuant
`
`to 3?
`
`CFR
`
`1.17
`
`and 1.136(a),
`
`the
`
`applicants
`
`respectfully petition for a one (1) month extension of time for
`
`filing a response in connection with the present application and
`
`the required fee of $110.00 is attached hereto.
`
`Please charge any fees or credit any overpayment pursuant to
`
`37 CFR 1.16 or 1.17 to Deposit Account No. 02~2448.
`
`Respectfully submitted,
`
`BIRCH, ST
`
`LA
`
`H & BIRCH
`
`
`
`Leonard R. Svensson
`
`LRS/pw
`(703) 205-8000
`
`Attachments:
`Exhibits I - VIII
`
`Reg. No. 30,330
`P.0. Box 747
`Falls Church, VA.22040-0747
`
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