Docket No.: 0020-5041 PUS2
`(PATENT)
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`In re Patent Application of:
`Mitsutaka NAKAMURA et al.
`
`Application No.: 10/525,021
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`Confirmation No.: 3141
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`Filed: February 18, 2007
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`Art Unit: 1612
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`For: AGENT FOR TREATMENT OF
`SCHIZOPHRENIA
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`Examiner: KRASS, F. F.
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`AMENDMENT IN RESPONSE TO NON-FINAL OFFICE ACTION
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`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313-1450
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`Sir:
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`In response to the Office Action issued on December 17, 2007, the period for response having
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`been extended by three (3) month, the following amendments and remarks are respectfully
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`submitted in connection with the above-identified application:
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`Amendments to the specification begin on page 2 of this paper;
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`Amendments to the claims begin on page 3 of this paper;
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`Remarks begin on page 6 of this paper; and
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`Copies of the following are attached to this paper:
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`-Erhart et al. (2006),
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`-Laughren and Levin (2005),
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`-Aiphs (2006)
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`-Kane (2005), and
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`-Kirkpatric et al. (2005)
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`Birch, Stewart, Kolasch & Birch, LLP
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`AMENDMENTS TO THE SPECIFICATION
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`Please amend the Abstract as follows:
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`The present invention provides a novel method for treatment of schizophrenia
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`which can improve wide-ranging symptoms of schizophrenia, especially positive
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`symptoms and negative symptoms without being accompanied by extrapyramidal
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`symptoms, which comprises orally administering as an active compound
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`(1 R,2S,3R,4S)-N-[(1 R,2R)-2-[4-(1 ,2-benzoisothiazol-3-yl)-1-piperazinylmethyl]-1-
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`cyclohexylmethyl]-2,3-bicyclo[2.2.1 ]heptanedicarboxyimide or a pharmaceutically
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`acceptable salt thereof (e.g., hydrochloride) at a daily dose of 5 mg to 120 mg
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`once a day to a patient with schizophrenia, and a therapeutic agent to be used in
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`saki-the method.
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`AMENDMENTS TO THE CLAIMS
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`1. (Currently Amended) A method for treatment of treating schizophrenia in a patient suffering
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`from schizophreniaJ. without said treatment being accompanied by any extrapyramidal symptoms,
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`which comprises orally administering a once daily dose of 5 mg to 120 mg of the active
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`compound:
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`(1 R,2S,3R,4S)-N-[(1 R,2R)-2-[4-(1 ,2-benzoisothiazol-3-yl)-1-piperazinylmethyl]-1-(cid:173)
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`cyclohexylmethyl]-2,3-bicyclo[2.2.1]heptanedicarboxyimide of the formula (1 ):
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`or a pharmaceutically acceptable salt thereof to a patient suffering from schizophrenia once a
`aay, 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
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`of schizophrenia.
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`2.
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`(Currently Amended) The method for treatment according to_Qf claim 1, wherein the
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`pharmaceutically acceptable salt of said active compound is (1 R,2S,3R,4S)-N-[(1 R,2R)-2-[4-
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`(1 ,2-benzoisothiazol-3-yl)-1-piperazinylmethyl]-1-cyclohexylmethyl]-2, 3-
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`bicyclo[2.2.1]heptanedicarboxyimide hydrochloride.
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`3. - 4. (Canceled)
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`5. (Currently Amended) The method for treatment according to Qf_claim 1 or claim 2, wRfsh
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`comprises orally administering wherein 20 mg to 80 mg of said the-active compoundj§
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`administered to said patient.
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`(1 R,2S,3R,4S) N [(1 R,2R) 2 [4 (1 ,2 benzoisothiazol 3 yl) 1 piperazinylmethyl] 1
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`cyclohexylmethyl] 2,3 bicyclo[2.2.1]heptanedicarboxyimide hydrochloride at a daily dose of 20
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`mg to 80 mg once a day.
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`6.- 7. (Canceled)
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`8.
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`(Currently Amended) The method for treatment of schizophrenia in the chronic stage
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`according to Qf_claim 1 or claim 2, wherein said patient is in a chronic stage of schizophrenia,
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`and wherein 20 mg to 80 mg of said active compound is administered to said patient.
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`which improves schizophrenia 'Nithout being accompanied by any extrapyramidal symptoms
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`by
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`orally
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`administering
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`the
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`active
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`compound:
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`(1 R,2S,3R,4 S) N [(1 R,2R) 2 [4 (1 ,2
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`benzoisothiazol 3 yl) 1 piperazinylmethyl] 1 cyclohexylmethyl] 2,3
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`bicyclo[2.2.1]heptanedicarboxyimide hydrochloride at a daily dose of 5 mg to 80 mg once a
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`~
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`9. - 10. (Canceled)
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`11. (Currently Amended) The method for treatment according to of claim 8, which comprises
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`orally administering wherein 50 mg to 80 mg of said the-active compound is administered to
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`said patient.
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`(1 R,2S,3R,4 S) N [(1 R,2R) 2[4 (1 ,2 benzoisothiazol 3 yl) 1 piperazinylmethyl] 1
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`cyclohexylmethyl]2,3 bicyclo[2.2.1]heptanedicarboximide hydrochloride at a daily dose of 10 mg
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`to 40 mg once a day.
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`12.-19. (Canceled)
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`20. (New) A method for treating the positive symptoms and the negative symptoms of
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`schizophrenia in a patient suffering from schizophrenia which comprises orally administering to
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`said patient a preparation comprising a single active compound or a pharmaceutically acceptable
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`salt of said active compound, wherein 5 mg to 120 mg of said active compound is administered
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`once a day to said patient, and wherein said active compound is
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`(1 R,2S,3R,4S)-N-[(1 R,2R)-2-
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`[4-(1 ,2-benzoisothiazol-3-yl)-1-piperazinylmethyl]-1-cyclohexylmethyl]-2, 3-
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`bicyclo[2.2.1]heptanedicarboxyimide of the formula (1 ):
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`JJfJ.-N,..,Q__l-'NON,s
`
`-
`~ A
`
`( 1)
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`~r,r H H
`=Ho
`H
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`\_/
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`21. (New) The method of claim 1 wherein the administration of said active compound improves
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`the negative symptoms of schizophrenia and/or the cognitive dysfunction of schizophrenia.
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`App. No.: 10/525,021
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`Docket No. 0020-5041 PUS2
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`REMARKS
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`Status of the Specification
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`The Abstract has been amended so that it does not contain legal phraseology:
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`i.e. the word,
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`"said," has been replaced with the word, "the."
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`No new matter has been added.
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`Status of the Claims
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`Claims 1-2, 5 and 8-13 are pending and amended; and claims 3-4, 6-7, 9-10 and 12-19 are
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`canceled. Claim 20 is added.
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`Claims 1-2, 5 and 8-13 have been amended to improve grammar and to better comply with U.S.
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`formalities.
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`Claim 1 and new claim 21 have been amended/added reciting the cognitive dysfunction of
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`schizophrenia. Support for these amendments is found in the Specification at page 5, lines 1-3.
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`New claim 20 is similar to claim 1, but claim 20 recites that only a single active compound,
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`(1 R,2S,3R,4S)-N-[(1 R,2R)-2-[4-(1 ,2-benzoisothiazol-3-yl)-1-piperazinylmethyl]-1-
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`cyclohexylmethyl]-2,3-bicyclo[2.2.1 ]heptanedicarboxyimide is administered. Support for aspect
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`of claim 20 is found, for instance, in the Examples on pages 7-17 of the instant Specification
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`disclosing the results of phase II clinical trials conducted using the schizophrenia treatment
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`methods of the invention. Support for the reciting a "preparation" is found, for instance, on page
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`6, lines 9-20, of the specification.
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`No new matter has been added.
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`1. The Specification
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`On page 3 of the Office Action, the Examiner requires correction of the abstract: i.e. the removal
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`of the word, "said," as inappropriate legal phraseology.
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`Applicants have, as indicated above, amended the Abstract so that it recites the word, "the,"
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`instead of the word, "said."
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`2. Claim Rejections under 35 USC Section 103
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`On pages 3-5 of the Office Action, the Examiner rejects claims 1-13 as allegedly obvious over
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`Somerville et al. (WO 03/066039) in view of Wong et al. (USPN 6,964,962). Applicants
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`respectfully traverse.
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`2.1 The Factual Foundation of the Obviousness Rejection is Inaccurate
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`As noted by the Examiner, Somerville et al. teaches that the instantly claimed active compound,
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`(1 R,2S,3R,4S)-N-[(1 R,2R)-2-[4-(1 ,2-benzoisothiazol-3-yl)-1-piperazinylmethyl]-1-
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`cyclohexylmethyl]-2,3-bicyclo[2.2.1]heptanedicarboxyimide (a.k.a. SM-13496) may be used to
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`treat schizophrenia. (Office Action, pages 3-4). As admitted by the Examiner, Somerville et al.
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`does not teach any dose of SM-13496 for treating schizophrenia.
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`(Office Action, page 4).
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`Applicants find that the Examiner has accurately described these teachings of Somerville et al.
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`But Applicants respectfully submit that the Examiner has mischaracterized the teachings of
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`Wong et al.
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`In particular, the Examiner states that Wong et al. teaches treating schizophrenia
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`with a dose of 0.05 to 7500 mg/day/patient of SM-13496.
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`(Office Action, page 4). But an
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`accurate reading of Wong et al. reveals that Wong et al. does not actually teach treating any
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`schizophrenic with any particular amount of SM-13496.
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`In addition, a complete reading of
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`Wong et al. reveals that it entirely contemplates treating schizophrenia by administering a
`combination of at least two (2) distinct types of active agents:
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`(i) norepinephrine reuptake
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`inhibitors and (ii) neuroleptic agents. (Wong et al., Column 5, lines 7-12).
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`Wong et al. expressly teaches that the combination of norepinephrine reuptake inhibitors and
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`neuroleptic agents is necessary when treating schizophrenia because the co-administration of a
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`norepinephrine reuptake inhibitor with a neuroleptic agent reduces serious and deleterious side
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`effects caused by the administration of a neuroleptic agent alone.
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`(Column 5, lines 1-4 and
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`Column 10, lines 8-12). In particular, Wong et al. teaches that the side effects caused by typical
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`neuroleptic agents include extrapyramidal symptoms, allergic reactions, weight gain, high body
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`temperature and low blood pressure. (Wong et al., Column 3, lines 1-43). Wong et al. teaches
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`that the side effects caused by atypical neuroleptic agents include agranulocytosis, sleepiness,
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`weight gain, dizziness and increased risk of sudden cardiac death.
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`(Wong et al., Column 4,
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`lines 5-49).
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`2.1 The Examiner Improperly Relies on In re Aller
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`On page 4 of the Office Action, the Examiner attempts to justify the instant obviousness
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`rejection by relying on the In re Aller rule that "[W]here the general conditions of a claim are
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`disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by
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`routine experimentation."
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`In re Aller, 220 F.2d 454,456, 105 USPQ 223, 235 (CCPA 1955).
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`The Examiner asserts that, because "Wong et al. teach 0.05 to 7500 mg/day/patient of [the
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`instantly claimed compound] can be used to treat schizophrenia ... it would be obvious for one
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`skilled in the art that the amount of SM-13496 may be optimized to be administered at [the
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`instantly claimed dose ranges]." (Office Action, page 4).
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`As discussed above in Section 2.1, Wong et al. does not teach treating a schizophrenic with any
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`Instead, Wong et al. speculates that a dose of SM-13496
`particular dose of SM-13496.
`somewhere between 0.05 and 7500 mg/day/patient could be administered in combination with
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`a norepinephrine reuptake inhibitor. But Applicants point out that there is a 150,000 fold
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`difference between the minimum and maximum doses of the alleged "range" of SM-13496
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`doses. Moreover, the minimum intolerable dose of SM-13496 is 520 mg/day (See Declaration
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`of Masaaki Ogasa, attached, a signed copy to be filed in a Supplemental Amendment); so the
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`maximum dose of the alleged "range" taught by Wong et al. is almost 14x higher than the
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`greatest amount of SM-13496 that should be given to a patient. And the minimum dose of SM-
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`13496 required to have any therapeutic effect is 5 mg/day (See Declaration); so the minimum
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`dose of the alleged "range" taught by Wong et al. is 1 OOx below the minimum amount that
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`should be administered to a patient.
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`It follows that the maximum and minimum doses of SM-
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`13496 suggested by Wong et al. for combination schizophrenia therapy cannot be reasonably
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`characterized as teaching a "range" of doses, but rather amounts to an uninformative and
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`inaccurate speculation that covers more than the entire spectrum of amounts of SM-13496 that
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`should be administered.
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`In addition, Applicants point out that, because Wong et al. entirely contemplates treating
`schizophrenia by administering a combination of norepinephrine reuptake inhibitors and
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`neuroleptic agents, its entire disclosure is outside of the general conditions" of the schizophrenia
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`treatment methods of the instant invention.
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`In view of the foregoing points and discussion, Applicants submit that Wong et al. does not
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`teach a "range" of SM-13496 and that Wong et al does not meet the "general conditions" of the
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`schizophrenia treatments of the present invention. Accordingly, the Examiner's reliance on In re
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`Aller is of no avail in attempting to justify the instant obviousness rejection. Moreover, the
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`Examiner has not established prima facie obviousness because neither Sommerville et al. nor
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`Wong et al. teach the administering the 5 - 120 mg of the SM-13496, as recited in the instant
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`claims. The obviousness rejection is therefore improper.
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`2.3 The Instantly Claimed Methods for Treating Schizophrenia Provide Surprisingly
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`Improved Results
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`2.3 (a) The Unexpected Lack of Negative Side Effects Provided by the Instantly
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`Claimed Methods for Treating Schizophrenia
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`In addition to mischaracterizing the teachings of Wong et al., the Examiner mischaracterizes the
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`teachings of the instant specification by alleging that a showing of unexpected results is absent
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`therefrom. (Office Action, page 4). As described above, Wong et al. teaches that weight gain is
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`a side effect of treating schizophrenia with an atypical neuroleptic agent. (Column 4, lines 24-
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`26). Wong et al. further teaches that treating schizophrenia by the co-administration of a
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`norepinephrine reuptake inhibitor together with a neuroleptic agent minimizes the incidence of
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`weight gain. (Column 10, lines 14-18).
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`In contrast, the instant specification discloses that the presently claimed methods for treating
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`schizophrenia by the daily administration of 5 to 120 mg of active compound defined by formula
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`(1) is not only successful for the treatment of schizophrenia, but also provides unexpectedly
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`advantageous results of not being accompanied by the side effects of body weight gain, bulimia,
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`impotence, erectile dysfunction and convulsion. (See, for instance, the instant specification at
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`page 12, lines 14-18). It follows that the instant specification indeed discloses that the presently
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`claimed methods for treating schizophrenia provide surprisingly improved results over the prior
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`art, which further establishes the non-obviousness of the instant claims and the impropriety of
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`the instant obviousness rejection.
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`2.3 (b) The Unexpected Amelioration of the Negative Symptoms of Schizophrenia
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`Provided by the Instantly Claimed Methods for Treating Schizophrenia
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`Applicants point out that, at the time the instant patent application was filed, the dogma in the
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`field of schizophrenia therapy was that atypical neuroleptic drugs, such as SM-13496, were
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`ineffective at treating the negative symptoms of schizophrenia. As evidence of this state of the
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`art, Applicants direct the Examiner's attention to Erhart et al. (2006), Laughren and Levin
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`(2005), Alphs (2006) and Kane (2005) and Kirkpatric et al. (2005) submitted together with this
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`paper. (Exhibits 1-5) These references state that, even three years after the 2002 priority date
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`of the parent application, a treatment for schizophrenia that addresses the negative symptoms
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`of the disease was not available on the market.
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`But the instantly claimed schizophrenia treatment methods effectively ameliorate both the
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`positive and negative symptoms of schizophrenia by administering SM-13496. Here, Applicants
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`direct the Examiner's attention to the disclosure of the phase II clinical trials on pages 7-16 of
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`the specification and the data set forth in the two (2) poster presentations by Ogasa et al.,
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`attached as Exhibit 6 which disclose that the instantly claimed schizophrenia treatment methods
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`provide for the amelioration of the negative affects of schizophrenia.
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`Because, prior to the instant invention, the dogma in the field of schizophrenia therapy was that
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`atypical neuroleptics were ineffective at treating the negative symptoms of schizophrenia and
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`because the instantly claimed schizophrenia treatment provides for the effective treatment of the
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`negative symptoms of schizophrenia,
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`the
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`instantly claimed
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`treatment methods provide
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`surprisingly improved results, which further establishes the non-obviousness of the instant
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`claims and impropriety of the instant obviousness rejection.
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`2.4 Conclusion
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`For at least the foregoing reasons, Applicants submit that the Examiner has failed to establish
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`prima facie obviousness against the presently pending claims over the prior art of record.
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`In
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`addition, Applicants have established that the instant specification discloses evidence of
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`surprisingly
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`improved
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`results provided by
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`the presently claimed methods
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`for
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`treating
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`schizophrenia. Accordingly, Applicants respectfully request reconsideration and withdrawal of
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`the instant obviousness rejection.
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`3. Conclusion
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`Applicants would like to thank the Examiner for granting an interview to be held at 2 pm
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`(Eastern) on Thursday, June 26.
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`In view of the foregoing amendments and remarks, Applicants respectfully request immediate
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`allowance of the claims, which define subject matter that meets all statutory patentability
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`requirements.
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`Pursuant to 37 C.F.R. §§ 1.17 and 1.136(a), Applicants respectfully petitions for a three (3)
`month extension of time for filing a reply in connection with the present application, and the
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`required fee is attached hereto.
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`Should there be any outstanding matters that need to be resolved in the present application, the
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`Examiner is respectfully requested to contact Mark J. Nuell, Registration No 36,623 at the
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`telephone number of the undersigned below, to conduct an interview in an effort to expedite
`prosecution in connection with the present application.
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`If necessary, the Commissioner is hereby authorized in this, concurrent, and future replies, to
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`charge payment or credit any overpayment to our Deposit Account No. 02-2448 for any
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`additional fees required under 37 C.F.R. § 1.16 or under§ 1.17; particularly, extension of time
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`fees.
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`Dated: June 17, 2008
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