Docket No.: 0020-5041PUS2
`(PATENT)
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`In re Patent Application of:
`Mitsutaka NAKAMURA et al.
`
`Application No.: 10/525,021
`
`Confirmation No.: 3141
`
`Filed: February 18, 2007
`
`ArtUnit: 1612
`
`For: AGENT FOR TREATMENT OF
`SCHIZOPHRENIA
`
`Examiner: MAEW ALL, S.
`
`AMENDMENT IN RESPONSE TO FINAL OFFICE ACTION AND RCE
`
`MSAF
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`Madam:
`
`In response to the Office Action issued on September 17, 2008, the following amendments and
`
`remarks are respectfully submitted in connection with the above-identified application:
`
`Amendments to the claims begin on page 2 of this paper;
`
`Remarks begin on page 4 of this paper; and
`
`Birch, Stewart, Kolasch & Birch, LLP
`
`DRN/MHE/cjd
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`App. No.: 10/525,021
`Office Action dated: September 17, 2009
`Reply dated: March 16, 2009
`
`Docket No.: 0020-5041PUS2
`
`AMENDMENTS TO THE CLAIMS
`
`I. (Currently Amended) A method for treating schizophrenia in a patient suffering from
`
`schizophrenia, without said treatment being accompanied by any extrapyramidal symptoms, which
`
`comprises orally administering a once daily dose of 5 mg to I20 mg of the active compound:
`
`(I R,2S,3R,4S)-N-[(I R,2R)-2-[ 4-(1 ,2-benzoisothiazol-3-yl)-I-piperazinylmethyl]-I-(cid:173)
`
`cyclohexylmethyl]-2,3-bicyclo[2.2.I ]heptanedicarboxyimide of the formula ( 1 ):
`
`or a pharmaceutically acceptable salt thereof to a patient suffering from schizophrenia, wherein the
`
`administration of said active compound improves the positive symptoms of schizophrenia and/or the
`
`negative symptoms of schizophrenia and/or the cognitive dysfunction of schizophrenia.
`
`2. (Previously Presented) The method of claim I, wherein the pharmaceutically acceptable salt of
`
`said
`
`active
`
`compound
`
`IS
`
`(IR,2S,3R,4S)-N-[(l R,2R)-2-[ 4-(I ,2-benzoisothiazol-3-yl)-I-
`
`piperazinylmethyl]-I-cyclohexylmethyl]-2,3-bicyclo[2.2.I ]heptanedicarboxyimide hydrochloride.
`
`3.- 4. (Canceled)
`
`5. (Previously Presented) The method of claim I or claim 2, wherein 20 mg to 80 mg of said active
`
`compound is administered to said patient.
`
`6.- 7. (Canceled)
`
`2
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`App. No.: 10/525,021
`Office Action dated: September 17, 2009
`Reply dated: March 16, 2009
`
`Docket No.: 0020-5041 PUS2
`
`8. (Previously Presented) The method of claim 1 or claim 2, wherein said patient is in a chronic
`
`stage of schizophrenia, and wherein 20 mg to 80 mg of said active compound is administered to
`
`said patient.
`
`9. - 10. (Canceled)
`
`11.
`
`(Previously Presented) The method of claim 8, wherein 50 mg to 80 mg of said active
`
`compound is administered to said patient.
`
`12.- 19. (Canceled)
`
`20. (Previously Presented) A method for treating the positive symptoms and the negative symptoms
`
`of schizophrenia in a patient suffering from schizophrenia which comprises orally administering to
`
`said patient a preparation comprising a single active compound or a pharmaceutically acceptable salt
`
`of said active compound, wherein 5 mg to 120 mg of said active compound is administered once a day
`
`to said patient, and wherein said active compound
`
`is
`
`(1R,2S,3R,4S)-N-[(1R,2R)-2-[4-(1,2-
`
`benzoisothiazol-3-yl)-1-piperazinylmethyl]-1-cyclohexylmethyl]-2,3-
`
`bicyclo[2.2.1 ]heptanedicarboxyimide of the formula (I):
`
`~!::!0 Q_
`N NbS
`
`N
`•.
`-.....~'
`.;
`H H
`
`-H
`H o
`
`1 \
`\.__/
`
`N._
`
`-
`~ h
`
`21. (Cancelled)
`
`(I)
`
`3
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`Docket No.: 0020-5041PUS2
`
`App. No.: 10/525,021
`Office Action dated: September 17, 2009
`Reply dated: March 16, 2009
`
`Status of the Claims
`
`REMARKS
`
`Claims I-2, 5 and 8, II, and 20-2I are pending.
`
`Claim I has been amended to incorporate claim 2I.
`
`Claim 2I has been cancelled.
`
`No new matter has been added.
`
`1. Claim Rejections under 35 USC Section 103
`
`On pages 3-5 of the Office Action, the Examiner rejects claims I-I3 as allegedly obvious over
`
`Somerville et a!. (WO 03/066039) in view of Wong et a!. (USPN 6,964,962) and Saji et al., U.S.
`
`Patent 5,532,372). Applicants respectfully traverse.
`
`I.l The references do not make obvious the claimed dose range.
`
`As a preliminary matter, Applicants note that the Examiner has found it necessary to add an
`
`additional reference to the obviousness rejection. The Examiner has already admitted that
`
`Sommerville does not disclose a particular dose of SM-I3496. (Office Action page 3, lines I 0-II ).
`
`The Examiner also admits that Wong et al. "teach [a] wide range of dosage."
`
`(ld. at line I7).
`
`Consequently, Applicants submit that the Examiner has recognized that the previous obviousness
`
`rejection was deficient, at least because it did not disclose the dosage as claimed in the present
`application. 1
`
`1 To ensure the record is complete, Applicants reiterate that Wong, in combination with Sommerville, does not
`render the present invention obvious because Wong teaches a broad dosing of SM-13496 in combination with a
`norepinephrine reuptake inhibitor, and that the dose range for SM-13496 would either not be effective, or would not
`be tolerated by a patient. (See Amendment dated June 17,2008, page 7-9).
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`App. No.: 10/525,021
`Office Action dated: September 17, 2009
`Reply dated: March 16, 2009
`
`Docket No.: 0020-5041 PUS2
`
`The Examiner cites Saji for teaching "oral preparations of the claimed compound containing 10 mg,
`
`20 mg, or 40 mg of a hydrochloride of formula 1." (Office Action, page 3). The Examiner further
`
`argues, "when the difference between the claimed invention and the prior art is the range or value of
`
`a particular variable, then a prima facie rejection is properly established when the difference in the
`
`range or value is minor." In re Geisler, 43 USPQ2d 1362, 1365 (Fed. Cir. 1997), quoting Haynes
`
`Int '1, Inc. v. Jessop Steel Co., 28 USPQ2d 1652, 1655 n.3 (Fed. Cir. 1993).
`
`Applicants submit that Saji does not remedy the deficiencies of the combination of Wong and
`
`Sommerville to establish prima facie obviousness because the difference between the range is not
`
`minor. Saji discloses an extremely broad range of compounds (almost 200 compounds), which it
`
`claims have "significant" anti-psychotic activity (See col. 12, lines 25-28; and col. 2 lines 9-I5 and
`
`64-65). In contrast to the Examiner's assertions, Saji discloses that any one of this broad range of
`
`compounds could be administered in "a dose of from about I to I ,000 mg, preferably from about 5 to
`
`I 00 mg, in case of oral administration and at a daily dose of from about O.I to I 000 mg, preferably
`
`from about 0.3 to 50 mg, in case of intravenous injection." (Saji, col. I2, lines I9-23). Furthermore,
`
`the in vivo methods disclosed in Saji merely disclose "a designated amount of the test compound is
`
`orally administered." (Saji, col. 13, lines 30-3I). Thus, Applicants submit that one of skill would not
`
`be able to determine which particular compound would be effective at any particular dose range from
`
`the disclosure in Saji.
`
`Moreover, Applicants submit that the dosage of Saji does not speak to efficacy against the negative
`
`symptoms of schizophrenia. Saji is directed to a an "anti-psychotic" drug, which may be effective
`
`against "schizophrenia, senile insanity, manic-depressive psychosis, neurosis, etc .. "
`
`(Saji, col. I,
`
`line I O-I2). Saji does not disclose that this compound can be used for treatment of the negative
`
`symptoms of schizophrenia and/or the cognitive dysfunction of schizophrenia. Moreover, at the time
`
`of filing, treatment of the negative symptoms using an atypical neuroleptic for schizophrenia which
`
`did not have adverse side effects was not recognized except by the inventors. (See Amendment dated
`
`July 16,2008, page 10).
`
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`App. No.: 10/525,021
`Office Action dated: September 17, 2009
`Reply dated: March 16,2009
`
`Docket No.: 0020-5041PUS2
`
`The in vivo data in Saji shows that the compound has an ED50 of 10.3 mg/kg in mice in a test directed
`
`to the inhibition of the stimulation of dopamine receptors in the striatum. (Saji, col. 13, line 65).
`
`However, Applicants emphasize that the mouse (or rat) anti-climbing activity test is not specifically
`
`directed to schizophrenia, nor does it relate to efficacy against the negative symptoms of
`
`schizophrenia. See for instance, D. Wang et a!., Neuropharmacology, 52 1179-1187 (2007)
`
`(attached) which discloses that positive symptoms arise from a subcortical hyperstimulation of
`
`dopamine D-2 receptors in striatal areas and negative symptoms are thought to arise from a
`
`doopaminergic hypofunction that results in the hypostimulation of dopamine-01 receptors in
`
`dorsolateral prefrontal cortex (PFC) in schizophrenia patients.
`
`(Wang et a!., page 1179, right
`
`column, bottom of the page and page 1180, left column, line 6-8). Furthermore P. Protais et a!.,
`
`Phychopharmacology 50, 1-6 (1976) (attached) teaches that climbing behavior is useful for screening
`
`the positive symptoms of schizophrenia induced by dopamine. Specifically, Protais at page 3, table 2
`
`disclosed that various neuroleptics inhibited the apomorphine-induced climbing behavior. Similarly,
`
`Protais at page 5, right column, 3 lines from the bottom, states that "this test already appears useful
`
`for the screening of neuroleptics, as well as for the study of the dynamics of cerebral dopamine
`
`receptors."
`
`Thus, Applicants submit that the teachings of Saji are not relevant to efficacy against the negative
`
`symptoms of schizophrenia.
`
`Accordingly, Applicants submit that the Examiner has failed to establish a prima facie case of
`
`obviousness. Applicants request that the Examiner withdraw the rejection.
`
`1.2 The Instantly Claimed Methods for Treating Schizophrenia Provide Surprisingly
`
`Improved Results
`
`1.2 (a) The Unexpected Lack of Negative Side Effects Provided by the Instantly
`
`Claimed Methods for Treating Schizophrenia
`
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`App. No.: 10/525,021
`Office Action dated: September 17, 2009
`Reply dated: March 16, 2009
`
`Docket No.: 0020-5041 PUS2
`
`On page 4 of the Office Action, the Examiner attempts to justify the instant obviousness rejection by
`
`relying on the In re Aller rule that "[W]here the general conditions of a claim are disclosed in the
`
`prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation."
`
`In re Aller, 220 F.2d 454,456, 105 USPQ 223,235 (CCPA 1955).
`
`Applicants submit that any prima facie case of obviousness "can be rebutted if the applicant (1) can
`
`establish the existence of unexpected properties in the range claimed or (2) can show that the art in
`
`any material respect taught away from the claimed invention." In re Geisler, 43 USPQ2d at 1365
`
`(internal quotations omitted).
`
`Because, prior to the instant invention, the dogma in the field of schizophrenia therapy was that
`
`atypical neuroleptics were ineffective at treating the negative symptoms of schizophrenia and
`
`because the instantly claimed schizophrenia treatment provides for the effective treatment of the
`
`negative symptoms of schizophrenia, the instantly claimed treatment methods provide surprisingly
`
`improved results. Applicants submit that the effect of this compound against the negative symptoms
`
`of schizophrenia overcomes any showing of prima facie obviousness the Examiner may have
`
`presented.
`
`1.2 (b) The Declaration is effective to compare the prior art to the present invention.
`
`The Examiner asserts that the Declaration of the study of the maximum tolerated dose of SM-13496
`
`is not sufficient to overcome the rejection based on the prior art since Applicants have not shown
`
`comparative analysis of the prior art versus the claimed invention. Applicants respectfully disagree.
`
`The Ogasa Declaration compares the administration of lurasidone as disclosed in Sommerville and
`
`Wong to the administration of lurasidone as disclosed in the present invention. Sommerville, which
`the Examiner describes as the primary reference, does not teach a dose. 2 Therefore, Applicants used
`
`2 Just because the Declaration does not explicitly state that the Declaration is a comparison of the present invention
`against Sommerville and Wong does not mean that the Declaration does not compare the invention to the teachings
`of the closest prior art, that is either Sommerville or Wong. Moreover, Applicants wonder how they were supposed
`
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`App. No.: 10/525,021
`Office Action dated: September 17, 2009
`Reply dated: March 16, 2009
`
`Docket No.: 0020-5041PUS2
`
`the Declaration to illustrate that lurasidone cannot be administered without some knowledge as to
`
`dose range. The Examiner then pointed out that Wong taught administration of lurasidone (in
`
`combination with a norepinephrin inhibitor) over a given dose range. The Declaration compares
`
`administration of lurasidone over a subset of the range of Wong, and shows that administration of
`
`lurasidone according to Sommerville using the dose range of Wong would either be ineffective or not
`
`be tolerated due to adverse effects. Therefore, Applicants submit that the Declaration directly
`
`compares the teachings of both Sommerville and Wong to the present invention.
`
`The Examiner also indicates that Saji et al. discloses the dose range of the claimed compound, and
`appears to suggest that Saji is the closest prior art. 3 However, Applicants disagree. As discussed
`
`above, the Saji reference does not discuss the negative symptoms of schizophrenia. Moreover,
`
`comparing the Saji reference against the Declaration, the Saji reference teaches that adverse side
`
`effects have an ED50 of at least 747 mg/kg and possibly more than I 000 mg/kg; much higher than
`
`either the Maximum Tolerated Dose (400 mg/kg) or the Minimum Intolerable Dose (520 mg/kg)
`
`disclosed in the Declaration. (Saji, col. 14, lines 26 and 45 and Declaration page 2, respectively).
`
`Applicants therefore submit that the Examiner's dismissal of the Declaration is improper.
`
`For these reasons, and those detailed above, Applicants respectfully request that the Examiner
`
`withdraw the obviousness rejection and allow all claims.
`
`to compare the method of Sommerville alone, which does not teach a dose, to the present invention in any
`meaningful way, since there was not sufficient information to establish an experimental protocol.
`3 Applicants note that the Saji is newly cited prior art. When the Declaration was filed, its experiments compared the
`methods of the references cited against Applicants, i.e., Sommerville and Wong. However, that does not mean that
`the Declaration is not relevant to the Saji reference. But that does mean that the Examiner's cursory dismissal of the
`teachings of the Declaration as lacking "comparative analysis" to Saji is wholly improper.
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`App. No.: 10/525,021
`Office Action dated: September 17, 2009
`Reply dated: March 16, 2009
`
`2. Conclusion
`
`Docket No.: 0020-5041PUS2
`
`Should there be any outstanding matters that need to be resolved in the present application, the
`
`Examiner is respectfully requested to contact Mark J. Nuell, Registration No 36,623 at the telephone
`
`number of the undersigned below, to conduct an interview in an effort to expedite prosecution in
`
`connection with the present application.
`
`Pursuant to 37 C.P.R. §§ 1.17 and 1.136(a), Applicant(s) respectfully petition for a three (3) month
`
`extension of time for filing a reply in connection with the present application, and the required fee of
`
`$I,I 10.00 is attached hereto.
`
`If necessary, the Commissioner is hereby authorized in this, concurrent, and future replies, to charge
`
`payment or credit any overpayment to our Deposit Account No. 02-2448 for any additional fees
`
`required under 37 C.P.R. § 1. I 6 or under§ 1.17; particularly, extension of time fees.
`
`Dated: March I 6, 2009
`
`Respectfully submitted,
`
`By ~~0~­
`Mark J.@Uell
`Registration No.: 36,623
`BIRCH, STEWART, KOLASCH & BIRCH, LLP
`I2770 High Bluff Drive
`Suite 260
`San Diego, California 92130
`(858) 792-8855
`Attorney for Applicant
`
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`Docket No.: 0020-5041PUS2
`
`App. No.: 10/525,021
`Office Action dated: September 17, 2009
`Reply dated: March 16, 2009
`
`Status of the Claims
`
`REMARKS
`
`Claims I-2, 5 and 8, II, and 20-2I are pending.
`
`Claim I has been amended to incorporate claim 2I.
`
`Claim 2I has been cancelled.
`
`No new matter has been added.
`
`1. Claim Rejections under 35 USC Section 103
`
`On pages 3-5 of the Office Action, the Examiner rejects claims I-I3 as allegedly obvious over
`
`Somerville et a!. (WO 03/066039) in view of Wong et a!. (USPN 6,964,962) and Saji et al., U.S.
`
`Patent 5,532,372). Applicants respectfully traverse.
`
`I.l The references do not make obvious the claimed dose range.
`
`As a preliminary matter, Applicants note that the Examiner has found it necessary to add an
`
`additional reference to the obviousness rejection. The Examiner has already admitted that
`
`Sommerville does not disclose a particular dose of SM-I3496. (Office Action page 3, lines I 0-II ).
`
`The Examiner also admits that Wong et al. "teach [a] wide range of dosage."
`
`(ld. at line I7).
`
`Consequently, Applicants submit that the Examiner has recognized that the previous obviousness
`
`rejection was deficient, at least because it did not disclose the dosage as claimed in the present
`application. 1
`
`1 To ensure the record is complete, Applicants reiterate that Wong, in combination with Sommerville, does not
`render the present invention obvious because Wong teaches a broad dosing of SM-13496 in combination with a
`norepinephrine reuptake inhibitor, and that the dose range for SM-13496 would either not be effective, or would not
`be tolerated by a patient. (See Amendment dated June 17,2008, page 7-9).
`
`4
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`Page 10 of 15
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`SLAYBACK EXHIBIT 1016
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`

`

`App. No.: 10/525,021
`Office Action dated: September 17, 2009
`Reply dated: March 16, 2009
`
`Docket No.: 0020-5041 PUS2
`
`The Examiner cites Saji for teaching "oral preparations of the claimed compound containing 10 mg,
`
`20 mg, or 40 mg of a hydrochloride of formula 1." (Office Action, page 3). The Examiner further
`
`argues, "when the difference between the claimed invention and the prior art is the range or value of
`
`a particular variable, then a prima facie rejection is properly established when the difference in the
`
`range or value is minor." In re Geisler, 43 USPQ2d 1362, 1365 (Fed. Cir. 1997), quoting Haynes
`
`Int '1, Inc. v. Jessop Steel Co., 28 USPQ2d 1652, 1655 n.3 (Fed. Cir. 1993).
`
`Applicants submit that Saji does not remedy the deficiencies of the combination of Wong and
`
`Sommerville to establish prima facie obviousness because the difference between the range is not
`
`minor. Saji discloses an extremely broad range of compounds (almost 200 compounds), which it
`
`claims have "significant" anti-psychotic activity (See col. 12, lines 25-28; and col. 2 lines 9-I5 and
`
`64-65). In contrast to the Examiner's assertions, Saji discloses that any one of this broad range of
`
`compounds could be administered in "a dose of from about I to I ,000 mg, preferably from about 5 to
`
`I 00 mg, in case of oral administration and at a daily dose of from about O.I to I 000 mg, preferably
`
`from about 0.3 to 50 mg, in case of intravenous injection." (Saji, col. I2, lines I9-23). Furthermore,
`
`the in vivo methods disclosed in Saji merely disclose "a designated amount of the test compound is
`
`orally administered." (Saji, col. 13, lines 30-3I). Thus, Applicants submit that one of skill would not
`
`be able to determine which particular compound would be effective at any particular dose range from
`
`the disclosure in Saji.
`
`Moreover, Applicants submit that the dosage of Saji does not speak to efficacy against the negative
`
`symptoms of schizophrenia. Saji is directed to a an "anti-psychotic" drug, which may be effective
`
`against "schizophrenia, senile insanity, manic-depressive psychosis, neurosis, etc .. "
`
`(Saji, col. I,
`
`line I O-I2). Saji does not disclose that this compound can be used for treatment of the negative
`
`symptoms of schizophrenia and/or the cognitive dysfunction of schizophrenia. Moreover, at the time
`
`of filing, treatment of the negative symptoms using an atypical neuroleptic for schizophrenia which
`
`did not have adverse side effects was not recognized except by the inventors. (See Amendment dated
`
`July 16,2008, page 10).
`
`5
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`

`App. No.: 10/525,021
`Office Action dated: September 17, 2009
`Reply dated: March 16,2009
`
`Docket No.: 0020-5041PUS2
`
`The in vivo data in Saji shows that the compound has an ED50 of 10.3 mg/kg in mice in a test directed
`
`to the inhibition of the stimulation of dopamine receptors in the striatum. (Saji, col. 13, line 65).
`
`However, Applicants emphasize that the mouse (or rat) anti-climbing activity test is not specifically
`
`directed to schizophrenia, nor does it relate to efficacy against the negative symptoms of
`
`schizophrenia. See for instance, D. Wang et a!., Neuropharmacology, 52 1179-1187 (2007)
`
`(attached) which discloses that positive symptoms arise from a subcortical hyperstimulation of
`
`dopamine D-2 receptors in striatal areas and negative symptoms are thought to arise from a
`
`doopaminergic hypofunction that results in the hypostimulation of dopamine-01 receptors in
`
`dorsolateral prefrontal cortex (PFC) in schizophrenia patients.
`
`(Wang et a!., page 1179, right
`
`column, bottom of the page and page 1180, left column, line 6-8). Furthermore P. Protais et a!.,
`
`Phychopharmacology 50, 1-6 (1976) (attached) teaches that climbing behavior is useful for screening
`
`the positive symptoms of schizophrenia induced by dopamine. Specifically, Protais at page 3, table 2
`
`disclosed that various neuroleptics inhibited the apomorphine-induced climbing behavior. Similarly,
`
`Protais at page 5, right column, 3 lines from the bottom, states that "this test already appears useful
`
`for the screening of neuroleptics, as well as for the study of the dynamics of cerebral dopamine
`
`receptors."
`
`Thus, Applicants submit that the teachings of Saji are not relevant to efficacy against the negative
`
`symptoms of schizophrenia.
`
`Accordingly, Applicants submit that the Examiner has failed to establish a prima facie case of
`
`obviousness. Applicants request that the Examiner withdraw the rejection.
`
`1.2 The Instantly Claimed Methods for Treating Schizophrenia Provide Surprisingly
`
`Improved Results
`
`1.2 (a) The Unexpected Lack of Negative Side Effects Provided by the Instantly
`
`Claimed Methods for Treating Schizophrenia
`
`6
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`App. No.: 10/525,021
`Office Action dated: September 17, 2009
`Reply dated: March 16, 2009
`
`Docket No.: 0020-5041 PUS2
`
`On page 4 of the Office Action, the Examiner attempts to justify the instant obviousness rejection by
`
`relying on the In re Aller rule that "[W]here the general conditions of a claim are disclosed in the
`
`prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation."
`
`In re Aller, 220 F.2d 454,456, 105 USPQ 223,235 (CCPA 1955).
`
`Applicants submit that any prima facie case of obviousness "can be rebutted if the applicant (1) can
`
`establish the existence of unexpected properties in the range claimed or (2) can show that the art in
`
`any material respect taught away from the claimed invention." In re Geisler, 43 USPQ2d at 1365
`
`(internal quotations omitted).
`
`Because, prior to the instant invention, the dogma in the field of schizophrenia therapy was that
`
`atypical neuroleptics were ineffective at treating the negative symptoms of schizophrenia and
`
`because the instantly claimed schizophrenia treatment provides for the effective treatment of the
`
`negative symptoms of schizophrenia, the instantly claimed treatment methods provide surprisingly
`
`improved results. Applicants submit that the effect of this compound against the negative symptoms
`
`of schizophrenia overcomes any showing of prima facie obviousness the Examiner may have
`
`presented.
`
`1.2 (b) The Declaration is effective to compare the prior art to the present invention.
`
`The Examiner asserts that the Declaration of the study of the maximum tolerated dose of SM-13496
`
`is not sufficient to overcome the rejection based on the prior art since Applicants have not shown
`
`comparative analysis of the prior art versus the claimed invention. Applicants respectfully disagree.
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`The Ogasa Declaration compares the administration of lurasidone as disclosed in Sommerville and
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`Wong to the administration of lurasidone as disclosed in the present invention. Sommerville, which
`the Examiner describes as the primary reference, does not teach a dose. 2 Therefore, Applicants used
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`2 Just because the Declaration does not explicitly state that the Declaration is a comparison of the present invention
`against Sommerville and Wong does not mean that the Declaration does not compare the invention to the teachings
`of the closest prior art, that is either Sommerville or Wong. Moreover, Applicants wonder how they were supposed
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`7
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`

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`App. No.: 10/525,021
`Office Action dated: September 17, 2009
`Reply dated: March 16, 2009
`
`Docket No.: 0020-5041PUS2
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`the Declaration to illustrate that lurasidone cannot be administered without some knowledge as to
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`dose range. The Examiner then pointed out that Wong taught administration of lurasidone (in
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`combination with a norepinephrin inhibitor) over a given dose range. The Declaration compares
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`administration of lurasidone over a subset of the range of Wong, and shows that administration of
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`lurasidone according to Sommerville using the dose range of Wong would either be ineffective or not
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`be tolerated due to adverse effects. Therefore, Applicants submit that the Declaration directly
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`compares the teachings of both Sommerville and Wong to the present invention.
`
`The Examiner also indicates that Saji et al. discloses the dose range of the claimed compound, and
`appears to suggest that Saji is the closest prior art. 3 However, Applicants disagree. As discussed
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`above, the Saji reference does not discuss the negative symptoms of schizophrenia. Moreover,
`
`comparing the Saji reference against the Declaration, the Saji reference teaches that adverse side
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`effects have an ED50 of at least 747 mg/kg and possibly more than I 000 mg/kg; much higher than
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`either the Maximum Tolerated Dose (400 mg/kg) or the Minimum Intolerable Dose (520 mg/kg)
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`disclosed in the Declaration. (Saji, col. 14, lines 26 and 45 and Declaration page 2, respectively).
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`Applicants therefore submit that the Examiner's dismissal of the Declaration is improper.
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`For these reasons, and those detailed above, Applicants respectfully request that the Examiner
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`withdraw the obviousness rejection and allow all claims.
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`to compare the method of Sommerville alone, which does not teach a dose, to the present invention in any
`meaningful way, since there was not sufficient information to establish an experimental protocol.
`3 Applicants note that the Saji is newly cited prior art. When the Declaration was filed, its experiments compared the
`methods of the references cited against Applicants, i.e., Sommerville and Wong. However, that does not mean that
`the Declaration is not relevant to the Saji reference. But that does mean that the Examiner's cursory dismissal of the
`teachings of the Declaration as lacking "comparative analysis" to Saji is wholly improper.
`8
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`App. No.: 10/525,021
`Office Action dated: September 17, 2009
`Reply dated: March 16, 2009
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`2. Conclusion
`
`Docket No.: 0020-5041PUS2
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`Should there be any outstanding matters that need to be resolved in the present application, the
`
`Examiner is respectfully requested to contact Mark J. Nuell, Registration No 36,623 at the telephone
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`number of the undersigned below, to conduct an interview in an effort to expedite prosecution in
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`connection with the present application.
`
`Pursuant to 37 C.P.R. §§ 1.17 and 1.136(a), Applicant(s) respectfully petition for a three (3) month
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`extension of time for filing a reply in connection with the present application, and the required fee of
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`$I,I 10.00 is attached hereto.
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`If necessary, the Commissioner is hereby authorized in this, concurrent, and future replies, to charge
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`payment or credit any overpayment to our Deposit Account No. 02-2448 for any additional fees
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`required under 37 C.P.R. § 1. I 6 or under§ 1.17; particularly, extension of time fees.
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`Dated: March I 6, 2009
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`Respectfully submitted,
`
`By ~~0~­
`Mark J.@Uell
`Registration No.: 36,623
`BIRCH, STEWART, KOLASCH & BIRCH, LLP
`I2770 High Bluff Drive
`Suite 260
`San Diego, California 92130
`(858) 792-8855
`Attorney for Applicant
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`9
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