Docket No. 0020-5041PUS2
`(PATENT)
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`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
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`In re Patent Application of:
`Mitsutaka NAKAMURA et al.
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`Application No.: I 0/525,021
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`Confirmation No.: 3141
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`Filed: February 18, 2005
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`For: AGENT FOR TREATMENT OF
`SCHIZOPHRENIA
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`Art Unit: 1612
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`Examiner: S. Maewall
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`AMENDMENT IN RESPONSE TO NON-FINAL OFFICE ACTION
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`MS Amendment
`Commissioner for Patents
`P. 0. Box 1450
`Alexandria, VA 22313-1450
`
`Sir:
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`INTRODUCTORY COMMENTS
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`In response to the Office Action issued on June 12, 2009, the period for response being
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`extended by petition filed herewith, 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 claims begin on page 2 of this paper; and
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`Remarks/Argument begin on page 4 ofthis paper.
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`Birch, Stewart, Kolasch & Birch, LLP
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`Application No. 10/525,021
`Reply to office action issued June 12, 2009
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`Docket No. 0020-5041 PUS2
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`AMENDMENTS TO THE CLAIMS
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`I. (Currently Amended) A method for treating the negative symptoms of schizophrenia and/or
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`the cognitive dysfunction of schizophrenia in a patient suffering from schizophrenia, without said
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`treatment being accompanied by any extrapyramidal symptoms, which comprises orally
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`administering a once daily dose of 5 mg to 120 mg of the active compound: (1R,2S,3R,4S)-N(cid:173)
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`[(1 R,2R)-2-[ 4-(1 ,2-benzoisothiazol-3-yl)-1-piperazinylmethyl]-1-cyclohexylmethyl]-2,3-
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`bicyclo[2.2.1]heptanedicarboxyimide of the formula (I):
`
`~t;J.o R_
`N NOS
`
`.
`
`-H
`.
`H o
`
`.::;';;.
`N..,._'*,..
`H H
`
`I~ N,
`\._/
`
`-
`~ A
`
`(1)
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`or a pharmaceutically acceptable salt thereof to a patient suffering from schizophrenia, wherein
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`the administration of said active compound improves the negative symptoms of schizophrenia
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`and/or the cognitive dysfunction of schizophrenia.
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`2. (Currently amended) The method of claim 1, 22 or 23 wherein the pharmaceutically
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`acceptable
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`salt of
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`said
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`active
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`compound
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`IS
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`(1R,2S,3R,4S)-N-[(1R,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.
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`3.- 4. (Canceled)
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`5. (Currently amended) The method of claim 1 or claim 2 any one of claims I, 2, 22 and 23,
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`wherein 20 mg to 80 mg of said active compound is administered to said patient.
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`6.- 7. (Canceled)
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`2
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`Application No. 10/525,021
`Reply to office action issued June 12, 2009
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`Docket No. 0020-5041 PUS2
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`8. (Currently amended) The method of claim 1 or claim 2 any one of claims 1, 2, 22 and 23,
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`wherein said patient is in a chronic stage of schizophrenia, and wherein 20 mg to 80 mg of said
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`active compound is administered to said patient.
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`9. - 10. (Canceled)
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`11. (Previously Presented) The method of claim 8, wherein 50 mg to 80 mg of said active
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`compound is administered to said patient.
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`12.- 19. (Canceled)
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`20. (Canceled)
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`21. (Cancelled)
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`22. (New) The method of claim 1, which is a method for treating the negative symptoms of
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`schizophrenia in a patient.
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`23. (New) The method of claim 1, which is a method for treating the cognitive dysfunction of
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`schizophrenia in a patient.
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`Application No. 10/525,021
`Reply to office action issued June 12, 2009
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`Docket No. 0020-5041 PUS2
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`REMARKS
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`Status of the Claims
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`Claim 20 is canceled. Claim 1 is amended to clarify the class of symptoms being treated;
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`further amendments to claim 1 are editorial in nature. Dependency is amended in claims 2, 5 and
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`8 to include new claims 22 and 23, which respectively recite each of the individual alternative
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`symptom classes recited in claim 1.
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`No new matter has been added.
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`Anticipation by Saji
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`Claims 1, 2, 5, 8, 11 and 20 are rejected under 35 USC § 1 02(b) as anticipated by Saji et
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`a!. EP '846. This rejection is respectfully traversed. Reconsideration and withdrawal thereof are
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`requested.
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`The Examiner asserts that Saji EP
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`'846
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`teaches treatment of schizophrenia by
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`administration of the claimed compound with a daily dose, for an adult, of from 1 to 1000 mg, or
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`from 0.1 to 100 mg if administered orally.
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`Saji EP '846 does not anticipate the present invention. The present claim 1 recites
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`treatment of two particular classes of symptoms of the particular disease (schizophrenia) by
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`administration of a particular compound (Lurasidone or its salts).
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`On the other hand, as explained in previous responses, Saji EP '846 describes the
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`compound very broadly (see, formula I at p. 4) and names specifically at least 200 compounds
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`that are to be used for "antipsychotic" treatments broadly stated (p. 3, lines 3-4). Nowhere in
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`Saji EP '846 is the particular compound recited in the present claim 1 (Lurasidone) associated
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`with effective treatment of schizophrenia particularly, and especially there is no association of
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`Lurasidone with the treatment of negative symptoms of schizophrenia or with the treatment of
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`cognitive dysfunction arising from schizophrenia.
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`Furthermore, there is no indication in Saji EP '846 that Lurasidone is effective in treating
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`these symptoms without inducing any extrapyramidal symptoms. There is not any recognition
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`by Saji EP '846 that "negative symptoms" are something that should be addressed in an effective
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`treatment of schizophrenia nor that extrapyramidal symptoms are to be avoided.
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`Application No. 10/525,021
`Reply to office action issued June 12, 2009
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`Docket No. 0020-5041 PUS2
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`It is well-established that a broad, generic teaching is not anticipatory of a claim directed
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`to a particular combination of elements in the absence of direction within the reference toward
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`that combination. See, In re Petering 133 USPQ 275 (CCPA 1962). Saji EP '846 does not
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`provide any such direction as explained above, and so does not anticipate the present invention.
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`Anticipation also requires that each and every feature of the claim be described in the
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`reference. As explained above, Saji EP '846 fails to disclose at least one feature in the present
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`claim 1, and so fails to anticipate claim 1 or the claims dependent therefrom. The instant
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`rejection must be withdrawn for this second reason as well.
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`Obviousness
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`Claims 1, 2, 5, 8, 11 and 20 are rejected under 35 USC§ 103(a) as obvious over Saji EP
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`'846. Claims 1, 2, 5, 8, 11 and 20 are also rejected under 35 USC § 1 03(a) as obvious over
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`Sommerville WO '039 in view of Wong '962 alone or in view of Saji EP '846. These rejections
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`are respectfully traversed. Reconsideration and withdrawal thereof are requested.
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`The Examiner asserts that the references teach the treatment of schizophrenia by the
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`claimed compound with the claimed dosage, particularly ...
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`"Sommerville et al. further teaches positive and negative symptoms are often
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`increased during the acute phase, or the florid psychotic phase, of schizophrenia
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`... " (the Office Action, page 5, second paragraph), and
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`"There is nothing in Saji's reference which describes that negative symptoms were
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`still prevailing while treating schizophrenia with the claimed compound." (the
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`Office Action, page 7, third paragraph).
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`It is true that it has been known that negative symptoms are included in the symptoms of
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`schizophrenia. However, it has been considered before filing of the present application that the
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`known drugs for treatment of schizophrenia are effective for the treatment of positive symptoms
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`of schizophrenia but not sufficiently effective for the treatment of negative symptoms of
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`schizophrenia. At the time the present application was filed, there was no drug sufficiently
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`effective for the treatment of negative symptoms of schizophrenia. This long-felt need in the art
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`Application No. 10/525,021
`Reply to office action issued June 12, 2009
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`Docket No. 0020-5041 PUS2
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`IS reflected m many publications. The following five papers are provided attached as
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`exemplary:
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`Reference 1: Stephen M. Erhart et al., "Treatment of Schizophrenia Negative Symptoms:
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`Future Prospects", Schizophrenia Bulletin, vol. 32, no. 2, pp. 234-237, 2006
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`Reference 2: Thomas Laughren et al., "Food and Drug Administration Perspective on
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`Negative Symptoms in Schizophrenia as a Target for a Drug Treatment Claim",
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`Schizophrenia Bulletin, vol. 32, no. 2, pp. 220-222, 2006
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`Reference 3: Larry Alphs, "An Industry Perspective on NIMH Congress Statement on
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`Negative Symptoms", Schizophrenia Bulletin, vol. 32, no. 2, pp. 225-230, 2006
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`Reference 4: John Kane, "Commentary: Consensus Statement on Negative Symptoms",
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`Schizophrenia Bulletin, vol. 32, no. 2, pp. 223-224, 2006
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`Reference 5: Brian Kirkpatrick et al., "The NIMH-MATRICS Consensus Statement on
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`Negative Symptoms", Schizophrenia Bulletin, vol. 32, no. 2, pp. 214-219,2006
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`Although published post-filing of the present application, these papers show that, even a
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`few years after the priority date, the art of treatment of schizophrenia did not include any
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`approved treatment that addressed negative symptoms of the disease. As mentioned in the
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`Abstract and/or introductory passages of these papers, finding an agent effective for the
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`treatment of negative symptoms of schizophrenia has been the object of a great deal of research
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`effort, but the available drugs for schizophrenia do not exhibit sufficient effect upon the
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`treatment of negative symptoms in schizophrenia.
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`The Examiner might note that Laughren et al. suggest that negative symptoms of
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`schizophrenia might represent a completely different target for drug development from the
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`positive symptoms of the disease. Alphs states in his abstract that, "Negative symptoms of
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`schizophrenia remain an area of substantial unmet clinical need." The Examiner should take
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`due note that failure of others to solve a problem and the solving of a long-felt need are two of
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`Application No. I 0/525,021
`Reply to office action issued June 12, 2009
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`Docket No. 0020-5041 PUS2
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`several secondary considerations deemed by the Supreme Court to be strong evidence of
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`unobviousness of an invention.
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`In Graham v. John Deere Co. of Kansas City, 383 U.S. 1 LL:!l .. JJl!.PD __ ~52]
`(1966), the Court set out a framework for applying the statutory language of§ 103,
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`language itself based on the logic of the earlier decision in Hotchkiss v.
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`Greenwood, 11 How. 248 (1851 ), and its progeny. See 383 U.S., at 15-17. The
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`analysis is objective:
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`"Under § 103, the scope and content of the pnor art are to be determined;
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`differences between the prior art and the claims at issue are to be ascertained; and
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`the level of ordinary skill in the pertinent art resolved. Against this background
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`the obviousness or nonobviousness of the subject matter is determined. Such
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`secondary considerations as commercial success, long felt but unsolved needs,
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`failure of others, etc., might be utilized to give light to the circumstances
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`surrounding the origin of the subject matter sought to be patented." !d., at 17-18.
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`KSR v. Teleflex 82 USPQ2d 1385 (2007) at p. 1391.
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`Following intensive study, the present inventors found that lurasidone shows the desired
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`effects on negative symptoms in schizophrenia. The effects of the compound of the present
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`invention have been publicized at a meeting; the poster presenting these results is provided
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`attached:
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`Reference 6: A poster exhibited at the 18111 European College of Neuropsychopharmacology
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`Congress, Amsterdam, Netherlands, October 22-26, 2005.
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`Fig. 2 of the poster shows the PANSS (= positive and negative syndrome scale) scores for the
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`compound of the present invention. Lurasidone showed significantly higher effectiveness on
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`the negative symptoms of schizophrenia in comparison with placebo in a clinical study. The
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`poster further indicates that ...
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`Application No. I 0/525,021
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`A once-a-day dose of 40, 80 or 120 mg Lurasidone achieved clinically
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`meaningful improvements across broad efficacy measures during 6-weeks of
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`treatment, compared with placebo in acutely exacerbated schizophrenic patients.
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`Lurasidone improved positive and negative symptoms of schizophrenia, with
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`significant effects first appearing three days after the initiation of treatment. The
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`improvement in negative symptoms seen in Lurasidone treated patients may be
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`related to the minimal sedative effects and low EPS profile of this drug, as a first
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`demonstration of Lurasidone's possible cognitive benefit there was a significant
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`improvement in the P ANSS-cognitive component, combined with a favorable
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`profile of minimal sedation.
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`The tolerability of Lurasidone appears quite favorable with no notable effects on
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`lipid profile or glucose regulation or weight gain, suggesting Lursidone may have
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`a favorable safety profile regarding cardiovascular events and diabetes. Overall,
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`Lurasidone demonstrated a well-balanced profile of effectiveness and safety in
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`patients with acute schizophrenia.
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`Further study will be needed to confirm this initial favorable profile.
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`Thus, Lurasidone was shown to be the first effective treatment for negative symptoms of
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`schizophrenia and furthermore was also effective in treating the cognitive dysfunction of
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`schizophrenia as well. Given the failure of previous treatments available in the art to address
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`these two classes of symptoms and to do so without also causing undesirable extrapyramidal
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`symptoms (sedation) these results must be considered unexpected by those of ordinary skill in
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`the art (e.g., as established by the five references attached hereto). Furthermore, these results
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`represent a solution to a problem that many others have failed to solve, and furthermore solve a
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`long-felt need in the art of treatment of schizophrenia. As pointed out above, this is substantial,
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`objective evidence of unobviousness of the present invention.
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`Application No. 10/525,021
`Reply to office action issued June 12, 2009
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`Docket No. 0020-5041 PUS2
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`The present inventors have also newly found that Lurasidone is also effective to treat
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`cognitive dysfunction of schizophrenia, as is also proved by the clinical study reported in the
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`poster Reference 6. The Examiner should again note Fig. 2 showing the P ANSS in cognitive
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`function: Lurasidone showed significantly higher effectiveness upon cognitive dysfunction of
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`schizophrenia in comparison with a placebo in the clinical study.
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`As is explained above, at the time of filing of the present application, indeed to date,
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`there are no approved drugs for treating schizophrenia that are effective on the negative
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`symptoms of schizophrenia and upon cognitive dysfunction of schizophrenia, and especially
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`none that also do not cause undesireable extrapyramidal symptoms. On the other hand,
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`according to the intensive studies of the present inventors it has newly been found that the
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`specific compound recited in the present claims, Lurasidone, can show significant effects on the
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`negative symptoms of schizophrenia in addition to effects on the positive symptoms of
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`schizophrenia, and further can also show significant effects on the cognitive dysfunction of
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`schizophrenia. No known treatment for schizophrenia has been effective in treating all three
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`classes of schizophrenia symptoms, and especially not without also causing undesired
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`extrapyramidal symptoms.
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`Accordingly, the present invention as claimed is not disclosed or even suggested by any
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`of Saji EP '846, Sommerville WO '039 or Wong '962, or any combination thereof. Thus, the
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`present claims are not prima facie obvious over these references. Furthermore, the clinical
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`results shown in the attached reference 6, showing that administration of Lurasidone solves a
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`need long-felt in the art and a problem long unsolved, provide objective evidence of
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`unobviousness of the present invention. Thus, the instant rejections of claims 1, 2, 5, 8, 11 and
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`20 (and if applied to 22 and 23) for obviousness must be withdrawn.
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`Applicants submit that the present invention is patentable over the prior art of record.
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`The favorable actions of withdrawal of the standing rejections and allowance of the present
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`claims are requested.
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`Should there be any outstanding matters that need to be resolved in the present
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`application, the Examiner is respectfully requested to contact Mark J. Nuell, Ph.D., Registration
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`Application No. 10/525,021
`Reply to office action issued June 12, 2009
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`Docket No. 0020-5041 PUS2
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`No. 36,623, at the telephone number of the undersigned below, to conduct an interview in an
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`effmi to expedite prosecution in connection with the present application.
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`Pursuant to 37 C.F.R. §§ 1.17 and 1.136(a), Applicants respectfully petition for a three
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`(3) month extension of time for filing a reply in connection with the present application, and the
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`required fee of $1,110.00 is attached hereto.
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`If necessary, the Commissioner is hereby authorized in this, concurrent, and future
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`replies, to charge payment or credit any overpayment to our Deposit Account No. 02-2448 for
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`any additional fees required under 37 C.F.R. § 1.16 or under§ 1.17; particularly, extension of
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`time fees.
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`Dated: December 10, 2009
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`Respectfully submitted,
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`if0~c;;---
`By
`Mark~uell
`Registration No. 36,623
`BIRCH, STEWART, KOLASCH & BIRCH, LLP
`12770 High Bluff Drive, Suite 260
`San Diego, California 92130
`(858) 792-8855
`Attorney for Applicant
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`Attachments: References 1-6
`Stephen M. Erhart et al.
`Thomas Laughren et al.
`Larry Alphs
`John Kane
`Brian Kirkpatrick et al.
`poster exhibited at the 18111 European College ofNeuropsychophannacology Congress
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