DOCKET NO: 4 72340US
`
`IN THE UNITED STATES PATENT & TRADEMARK OFFICE
`
`IN REAPPLICATION OF
`
`MITSUT AKA NAKAMURA, ET AL.
`
`EXAMINER: MAEWALL, SNIGDHA
`
`SERIAL NO: 14/471,919
`
`FILED: AUGUST 28, 2014
`
`GROUP ART UNIT: 1612
`
`FOR: AGENT FOR TREATMENT OF
`SCHIZOPHRENIA
`
`AMENDMENT
`
`COMMISSIONER FOR PATENTS
`ALEXANDRIA, VIRGINIA 22313
`
`Commissioner:
`
`In response to the Office Action dated October 19, 2016, please amend the above(cid:173)
`
`identified application as follows:
`
`Amendments to the Claims are reflected in the listing of claims which begins on
`
`page 2 of this paper.
`
`Remarks/Arguments begin on page 14 of this paper.
`
`Page 1 of 21
`
`SLAYBACK EXHIBIT 1034
`
`

`

`Application No. 14/471,919
`Reply to Office Action of October 19, 2016
`
`IN THE CLAIMS
`
`Please amend the claims as follows:
`
`Claims 1-19 (Canceled).
`
`Claim 20 (Currently Amended): A method for treating schizophrenia in a patient
`
`without a clinically significant weight gain, or manie depressive psyehoses in a patient,
`
`without eausing clinically significant body Vleight gain in the patient, the method comprising_;_
`
`administering orally to the patient a dose of 5 mg to 120 mg of the active eompound:
`
`(1 R,2S,3R,4S)-N-[(1 R,2R)-2-[ 4-(1,2-benzoisothiazol-3-yl)-1-piperazinylmethyl]-1-
`
`cyclohexylmethyl]-2,3-bicyclo[2.2.1 ]heptanedicarboximide or a pharmaceutically acceptable
`
`salt thereof at a dose of from 20 to 120 mg/day such that the patient does not experience a
`
`clinically significant weight gain.
`
`Claim 21 (Currently Amended): The method of claim 20, wherein said active
`
`compound is (I R,2S,3R,4S)-N-[(1 R,2R)-2-[ 4-(1,2-benzoisothiazol-3-yl)-l(cid:173)
`
`piperazinylmethyl]-1-cyclohexy lmethyl]-2,3-bicyclo[2.2. I ]heptanedicarboximide
`
`hydrochloride is administered.
`
`Claim 22 (Canceled).
`
`Claim 23 (Currently Amended): The method of claim [[20]] 21, wherein said active
`
`compound is administered to said patient orally the administering is conducted such that the
`
`patient does not experience a clinically significant weight gain after six weeks of
`
`administration.
`
`2
`
`Page 2 of 21
`
`SLAYBACK EXHIBIT 1034
`
`

`

`Application No. 14/4 71,919
`Reply to Office Action of October 19, 2016
`
`Claim 24 (Currently Amended): The method of claim [[20]] 23, wherein said aetive
`
`eompound is administered to said patient the administering is conducted without concurrently
`
`administering another antipsychotic medication.
`
`Claim 25 (Currently Amended): The method of claim [[20]] Zl_, wherein said aetive
`
`eompound is administered to said patient for a period of at least six 'Weeks further
`
`comprising:
`
`detecting a weight gain after six weeks of administration.
`
`Claim 26 (Currently Amended): The method of claim 20, wherein said patient has a
`
`BPRS score of at least 42 and wherein the patient's BPRS score is significantly reduced from
`
`a baseline measurement prior to the administering of said aetive eompound.
`
`Claim 27 (Currently Amended): The method of claim [[20]] 23, wherein said aetive
`
`eempound is administered the dose is from 40 to 120 mg once daily.
`
`Claim 28 (Currently Amended): The method of elaim 20, wherein [[the]] A method
`
`[[is]] for treating manic depressive psyehoses psychosis in a patient without a clinically
`
`significant weight gain, comprising:
`
`administering orally to the patient (1 R,2S,3 R,4S)-N-[(1 R,2R)-2-[ 4-( 1,2-
`
`benzoisothiazol-3-yl)-1-piperazinylmethyll- l-cyclohexylmethyl]-2,3-
`
`bicyclo[2.2. l ]heptanedicarboximide or a pharmaceutically acceptable salt thereof at a dose of
`
`from 20 to 120 mg/day such that the patient does not experience a clinically significant
`
`weight gain.
`
`3
`
`Page 3 of 21
`
`SLAYBACK EXHIBIT 1034
`
`

`

`Application No. 14/471,919
`Reply to Office Action of October 19, 2016
`
`Claim 29 (New): The method of claim 28, wherein (1R,2S,3R,4S)-N-[(1R,2R)-2-[4-
`
`(1,2-benzoisothiazol-3-yl)-1-piperazinylmethyl]-1-cyclohexylmethyl]-2,3-
`
`bicyclo[2.2. l ]heptanedicarboximide hydrochloride is administered.
`
`Claim 30 (New): The method of claim 29, wherein the administering is conducted
`
`such that the patient does not experience a clinically significant weight gain after six weeks
`
`of administration.
`
`Claim 31 (New): The method of claim 29, further comprising:
`
`detecting a weight gain after six weeks of administration.
`
`Claim 32 (New): The method of claim 30, wherein the administering is conducted
`
`without concurrently administering another antipsychotic medication.
`
`Claim 33 (New): The method of claim 30, wherein the dose is 20 mg once daily.
`
`Claim 34 (New): The method of claim 30, wherein the dose is 40 mg once daily.
`
`Claim 35 (New): The method of claim 30, wherein the dose is 60 mg once daily.
`
`Claim 36 (New): The method of claim 30, wherein the dose is 80 mg once daily.
`
`Claim 37 (New): The method of claim 30, wherein the dose is 120 mg once daily.
`
`4
`
`Page 4 of 21
`
`SLAYBACK EXHIBIT 1034
`
`

`

`Application No. 14/4 71,919
`Reply to Office Action of October 19, 2016
`
`Claim 38 (New): The method of claim 29, wherein the dose is 20 mg, 40 mg, 60 mg,
`
`80 mg or 120 mg once daily.
`
`Claim 39 (New): The method of claim 23, wherein the dose is 20 mg once daily.
`
`Claim 40 (New): The method of claim 23, wherein the dose is 40 mg once daily.
`
`Claim 41 (New): The method of claim 23, wherein the dose is 60 mg once daily.
`
`Claim 42 (New): The method of claim 23, wherein the dose is 80 mg once daily.
`
`Claim 43 (New): The method of claim 23, wherein the dose is 120 mg once daily.
`
`Claim 44 (New): The method of claim 21, wherein the dose is 20 mg, 40 mg, 60 mg,
`
`80 mg or 120 mg once daily.
`
`Claim 45 (New): A method of treating a patient with an anti psychotic without a
`
`clinically significant weight gain in the patient, comprising:
`
`orally administering the anti psychotic to the patient once daily at a dose of from 20 to
`
`120 mg such that the patient does not experience a clinically significant weight gain,
`
`wherein the anti psychotic is ( 1 R,2S,3 R,4S)-N-[(1 R,2R)-2-[ 4-( l ,2-benzoisothiazol-3-
`
`yl)- l -piperazinylmethyl]-1-cyclohexylmethyl]-2,3-bicyclo(2.2.1 ]heptanedicarboximide or a
`
`pharmaceutically acceptable salt thereof.
`
`5
`
`Page 5 of 21
`
`SLAYBACK EXHIBIT 1034
`
`

`

`Application No. 14/471,919
`Reply to Office Action of October 19, 2016
`
`Claim 46 (New): The method of claim 45, wherein the antipsychotic is
`
`(I R,2S,3R,4S)-N-[(1 R,2R)-2-[4-(1,2-benzoisothiazol-3-yl)-l-piperazinylmethyl]-l(cid:173)
`
`cyclohexylmethyl]-2,3-bicyclo[2.2. l ]heptanedicarboximide hydrochloride.
`
`Claim 47 (New): The method of claim 46, wherein the administering is conducted
`
`such that the patient does not experience a clinically significant weight gain after six weeks
`
`of administration.
`
`Claim 48 (New): The method of Claim 46, further comprising:
`
`detecting a weight gain after six weeks of administration.
`
`Claim 49 (New): The method of claim 47, wherein the method treats schizophrenia
`
`in the patient.
`
`Claim 50 (New): The method of claim 47, wherein the method treats manic
`
`depressive psychosis in the patient.
`
`Claim 51 (New): The method of claim 45, wherein the method treats the patient
`
`without the patient experiencing a weight gain.
`
`Claim 52 (New): The method of claim 49, wherein the administering is conducted
`
`without concurrently administering another antipsychotic medication.
`
`6
`
`Page 6 of 21
`
`SLAYBACK EXHIBIT 1034
`
`

`

`Application No. 14/471,919
`Reply to Office Action of October 19, 2016
`
`Claim 53 (New): The method of claim 50, wherein the administering is conducted
`
`without concurrently administering another antipsychotic medication.
`
`Claim 54 (New): The method of claim 47, wherein the dose is 20 mg.
`
`Claim 55 (New): The method of claim 47, wherein the dose is 40 mg.
`
`Claim 56 (New): The method of claim 47, wherein the dose is 60 mg.
`
`Claim 57 (New): The method of claim 47, wherein the dose is 80 mg.
`
`Claim 58 (New): The method of claim 47, wherein the dose is 120 mg.
`
`Claim 59 (New): The method of claim 46, wherein the dose is 20 mg, 40 mg, 60 mg,
`
`80 mg or 120 mg.
`
`Claim 60 (New): A method of treating a patient with an anti psychotic without a
`
`clinically significant weight gain, comprising:
`
`orally administering once daily to the patient a pharmaceutical composition
`
`comprising 20 to 120 mg of (1 R,2S,3R,4S)-N-[( I R,2R)-2-[ 4-(1,2-benzoisothiazol-3-yl)-1-
`
`piperazinylmethyl]-1-cyclohexylmethyl]-2,3-bicyclo[2.2. l ]heptanedicarboximide or a
`
`pharmaceutically acceptable salt thereof as a sole active ingredient such that the patient does
`
`not experience a clinically significant weight gain.
`
`7
`
`Page 7 of 21
`
`SLAYBACK EXHIBIT 1034
`
`

`

`Application No. 14/471,919
`Reply to Office Action of October 19, 2016
`
`Claim 61 (New): The method of claim 60, wherein the sole active ingredient is
`
`(1 R,2S,3R,4S)-N-[(1R,2R)-2-[4-(1,2-benzoisothiazol-3-yl)-l-piperazinylmethyl]-l(cid:173)
`
`cyclohexylmethyl]-2,3-bicyclo[2.2.1 ]heptanedicarboximide hydrochloride.
`
`Claim 62 (New): The method of Claim 61, wherein the pharmaceutical composition
`
`is a tablet.
`
`Claim 63 (New): The method of Claim 61, wherein the administering is conducted
`
`such that the patient does not experience a clinically significant weight gain after six weeks
`
`of administration.
`
`Claim 64 (New): The method of Claim 61, further comprising:
`
`detecting a weight gain after six weeks of administration.
`
`Claim 65 (New): The method of claim 63, wherein the method treats schizophrenia in
`
`the patient.
`
`Claim 66 (New): The method of claim 63, wherein the method treats manic
`
`depressive psychosis in the patient.
`
`Claim 67 (New): The method of claim 65, wherein the administering is conducted
`
`without concurrently administering another antipsychotic medication.
`
`Claim 68 (New): The method of claim 66, wherein the administering is conducted
`
`without concurrently administering another antipsychotic medication.
`
`8
`
`Page 8 of 21
`
`SLAYBACK EXHIBIT 1034
`
`

`

`Application No. 14/471,919
`Reply to Office Action of October 19, 2016
`
`Claim 69 (New): The method of claim 61, wherein the pharmaceutical composition
`
`includes 40 to 120 mg of (1 R,2S,3R,4S)-N-[(l R,2R)-2-[ 4-(l ,2-benzoisothiazol-3-yl)-l(cid:173)
`
`piperazinylmethyl]-1-cyclohexylmethyl]-2,3-bicyclo[2.2. l ]heptanedicarboximide
`
`hydrochloride.
`
`Claim 70 (New): The method of claim 61, wherein the pharmaceutical composition
`
`includes 20 mg, 40 mg, 60 mg, 80 mg or 120 mg of (1 R,2S,3R,4S)-N-[(1 R,2R)-2-[ 4-(1,2-
`
`benzoisothiazol-3-yl)-l-piperazinylmethyl]-l-cyclohexylmethyl]-2,3-
`
`bicyclo[2.2. l )heptanedicarboximide hydrochloride.
`
`Claim 71 (New): The method of claim 61, wherein the pharmaceutical composition
`
`includes 20 mg of (1R,2S,3R,4S)-N-[(l R,2R)-2-[4-(l ,2-benzoisothiazol-3-yl)-l(cid:173)
`
`piperazinylmethyl]-1-cyclohexylmethyl)-2,3-bicyclo[2.2.1 )heptanedicarboximide
`
`hydrochloride.
`
`Claim 72 (New): The method of claim 61, wherein the pharmaceutical composition
`
`includes 40 mg of (1 R,2S,3R,4S)-N-[(l R,2R)-2-[4-(l ,2-benzoisothiazol-3-yl)-l(cid:173)
`
`piperazinylmethyl]-1-cyclohexylmethyl)-2,3-bicyclo[2.2.1 ]heptanedicarboximide
`
`hydrochloride.
`
`Claim 73 (New): The method of claim 61, wherein the pharmaceutical composition
`
`includes 60 mg of (1R,2S,3R,4S)-N-[(1R,2R)-2-[4-(1,2-benzoisothiazol-3-yl)-1-
`
`piperazinylmethyl]-1-cyclohexylmethyl]-2,3-bicyclo[2.2. l ]heptanedicarboximide
`
`hydrochloride.
`
`9
`
`Page 9 of 21
`
`SLAYBACK EXHIBIT 1034
`
`

`

`Application No. 14/471,919
`Reply to Office Action of October 19, 2016
`
`Claim 74 (New): The method of claim 61, wherein the pharmaceutical composition
`
`includes 80 mg of (I R,2S,3R,4S)-N-[(l R,2R)-2-[ 4-(l ,2-benzoisothiazol-3-yl)- l -
`
`piperazinylmethyl]- l-cyclohexylmethyl]-2,3-bicyclo[2.2. l ]heptanedicarboximide
`
`hydrochloride.
`
`Claim 75 (New): The method of claim 61, wherein the pharmaceutical composition
`
`includes 120 mg of (I R,2S,3R,4S)-N-[(l R,2R)-2-[4-(1,2-benzoisothiazol-3-yl)-l(cid:173)
`
`piperazinylmethy l]-1-cyclohexylmethy l]-2,3-bicyclo[2.2.1 ]heptanedicarboximide
`
`hydrochloride.
`
`Claim 76 (New): A method of treating a patient with an anti psychotic without a
`
`weight gain, comprising:
`
`orally administering once daily to the patient a pharmaceutical composition
`
`comprising 20 to 120 mg of (1 R,2S,3R,4S)-N-[(1 R,2R)-2-[ 4-( l ,2-benzoisothiazol-3-yl)-l(cid:173)
`
`piperazinylmethyl]- l-cyclohexylmethyl]-2,3-bicyclo[2.2. l ]heptanedicarboximide or a
`
`pharmaceutically acceptable salt thereof as a sole active ingredient such that the patient does
`
`not experience a weight gain.
`
`Claim 77 (New): The method of claim 76, wherein the sole active ingredient is
`
`(1 R,2S,3R,4S)-N-[(1 R,2R)-2-[ 4-(1,2-benzoisothiazol-3-yl)-1-piperazinylmethyl]-1-
`
`cyclohexylmethyl]-2,3-bicyclo[2.2.1 )heptanedicarboximide hydrochloride.
`
`Claim 78 (New): The method of claim 77, wherein the pharmaceutical composition is
`
`a tablet.
`
`10
`
`Page 10 of 21
`
`SLAYBACK EXHIBIT 1034
`
`

`

`Application No. 14/471,919
`Reply to Office Action of October 19, 2016
`
`Claim 79 (New): The method of claim 77, wherein the administering is conducted
`
`such that the patient does not experience a weight gain after six weeks of administration.
`
`Claim 80 (New): The method of claim 77, further comprising:
`
`detecting a weight gain after six weeks of administration.
`
`Claim 81 (New): The method of claim 77, wherein the method treats schizophrenia in
`
`the patient.
`
`Claim 82 (New): The method of claim 77, wherein the method treats manic
`
`depressive psychosis in the patient.
`
`Claim 83 (New): The method of claim 81, wherein the administering is conducted
`
`without concurrently administering another antipsychotic medication.
`
`Claim 84 (New): The method of claim 82, wherein the administering is conducted
`
`without concurrently administering another antipsychotic medication.
`
`Claim 85 (New): The method of claim 81, wherein the pharmaceutical composition
`
`includes 40 to 120 mg of (lR,2S,3R,4S)-N-[(lR,2R)-2-[4-(1,2-benzoisothiazol-3-yl)-l(cid:173)
`
`piperazinylmethyl]-l-cyclohexylmethyl]-2,3-bicyclo[2.2.l ]heptanedicarboximide
`
`hydrochloride.
`
`1 1
`
`Page 11 of 21
`
`SLAYBACK EXHIBIT 1034
`
`

`

`Application No. 14/471,919
`Reply to Office Action of October 19, 2016
`
`Claim 86 (New): The method of claim 77, wherein the pharmaceutical composition
`
`includes 20 mg, 40 mg, 60 mg, 80 mg or 120 mg of ( 1 R,2S,3R,4S)-N-[( 1 R,2R)-2-[ 4-( l ,2-
`
`benzoisothiazol-3-yl)-1-piperazinylmethyl]-1-cyclohexylmethyl]-2,3-
`
`bicyclo[2.2.1 ]heptanedicarboximide hydrochloride.
`
`Claim 87 (New): The method of claim 82, wherein the pharmaceutical composition
`
`includes 20 mg of (1 R,2S,3R,4S)-N-[(1 R,2R)-2-[ 4-(1,2-benzoisothiazol-3-yl)-1-
`
`piperazinylmethyl]-1-cyclohexylmethyl]-2,3-bicyclo[2.2.1 ]heptanedicarboximide
`
`hydrochloride.
`
`Claim 88 (New): The method of claim 81, wherein the pharmaceutical composition
`
`includes 40 mg of (1 R,2S,3R,4S)-N-[(1 R,2R)-2-[4-(l ,2-benzoisothiazol-3-yl)-l(cid:173)
`
`piperazinylmethyl]-l-cyclohexylmethy l]-2,3-bicyclo[2.2. l ]heptanedicarboximide
`
`hydrochloride.
`
`Claim 89 (New): The method of claim 82, wherein the pharmaceutical composition
`
`includes 40 mg of (1 R,2S,3R,4S)-N-[(1R,2R)-2-[4-(l ,2-benzoisothiazol-3-yl)-l(cid:173)
`
`pi peraziny lmethy l]-1-cyclohexy lmethy l]-2,3-bicyclo [2 .2 .1 ]heptanedicarboximide
`
`hydrochloride.
`
`Claim 90 (New): The method of claim 81 wherein the pharmaceutical composition
`
`includes 60 mg of (1 R,2S,3R,4S)-N-[(l R,2R)-2-[ 4-(l ,2-benzoisothiazol-3-yl)-1-
`
`piperazinylmethyl]-1-cyclohexylmethyl]-2,3-bicyclo[2.2.1 ]heptanedicarboximide
`
`hydrochloride.
`
`12
`
`Page 12 of 21
`
`SLAYBACK EXHIBIT 1034
`
`

`

`Application No. 14/471,919
`Reply to Office Action of October 19, 2016
`
`Claim 91 (New): The method of claim 82 wherein the pharmaceutical composition
`
`includes 60 mg of (I R,2S,3R,4S)-N-[(l R,2R)-2-[ 4-(l ,2-benzoisothiazol-3-yl)-l(cid:173)
`
`piperaziny lmethy I]- l-cyclohexylmethyl]-2,3-bicyclo[2.2. l ]heptanedicarboximide
`
`hydrochloride.
`
`Claim 92 (New): The method of claim 81, wherein the pharmaceutical composition
`
`includes 80 mg of (I R,2S,3R,4S)-N-[(l R,2R)-2-[ 4-( l ,2-benzoisothiazol-3-yl)-1-
`
`piperazinylmethyl]-l-cyclohexylmethyl]-2,3-bicyclo[2.2. l ]heptanedicarboximide
`
`hydrochloride.
`
`Claim 93 (New): The method of claim 82, wherein the pharmaceutical composition
`
`includes 80 mg of (1 R,2S,3R,4S)-N-[(1 R,2R)-2-[ 4-(1,2-benzoisothiazol-3-yl)-1-
`
`piperaziny lmethyl]-1-cyclohexy lmethy l]-2,3-bicyclo[2.2. l ]heptanedicarboximide
`
`hydrochloride.
`
`Claim 94 (New): The method of claim 81, wherein the pharmaceutical composition
`
`includes 120 mg of ( 1 R,2S,3R,4S)-N-[( 1 R,2R)-2-[ 4-( l ,2-benzoisothiazol-3-yl)- l -
`
`piperazinylmethyl]-1-cyclohexylmethyl]-2,3-bicyclo[2.2.1 ]heptanedicarboximide
`
`hydrochloride.
`
`Claim 95 (New): The method of claim 82, wherein the pharmaceutical composition
`
`includes 120 mg of ( 1 R,2S,3 R,4S)-N-[ (1 R,2R)-2-[ 4-( l ,2-benzoisothiazol-3-yl)-1-
`
`piperazinylmethyl]-1-cyclohexylmethyl]-2,3-bicyclo[2.2. l ]heptanedicarboximide
`
`hydroch Io ride.
`
`13
`
`Page 13 of 21
`
`SLAYBACK EXHIBIT 1034
`
`

`

`Application No. 14/471,919
`Reply to Office Action of October 19, 2016
`
`REMARKS/ ARGUMENTS
`
`Favorable consideration of this application, as presently amended and in light of the
`
`following discussion, is respectfully requested.
`
`Claims 20, 21 and 23-95 are presently pending in this application, Claims 20, 21, and
`
`23-28 having been amended, Claim 22 having been canceled, and Claims 29-95 having been
`
`newly added based on the original claims and disclosure, for example, page 5, line 29 to page
`
`6, line 17, and Experiment 1, page 11, line 5 to page 12, line 20. No new matter is added.
`
`Applicant respectfully traverses the obviousness rejection of Claims 20-28 over Wong
`
`(US 6,964,962) and Pozuelo (US 2001/0047010).
`
`The present application relates to a method of treating a patient with schizophrenia or
`
`manic depressive psychosis (bipolar disorder) without inducing a clinically significant weight
`
`gain. A problem with many antipsychotics used to treat these conditions is an undesirable
`
`weight gain. The present invention is based on the discovery that a clinically significant
`
`weight gain can be avoided by the use of the active compound:
`
`( 1 R,2S,3R,4S)-N-[ (1 R,2R)-2-[ 4-(1,2-benzoisothiazol-3-yl)-l-piperaziny lmethyl]-1-
`
`cyclohexylmethyl]-2,3-bicyclo[2.2.l]heptanedicarboximide or its pharmaceutical1y acceptable
`
`salt, such as hydrochloride (= SM-13496), at the dosage specified in the claims. As stated
`
`above, many antipsychotics were conventionally considered to cause serious side effects, and
`
`Wong lists such antipsychotics including SM-13496 as those with side effects. However, the
`
`inventors have found through clinical studies that the active compound can be effectively
`
`used in the treatment while minimizing such side effects, in particular, a weight gain.
`
`The original specification describes relevant clinical studies. For example, the
`
`specification states on page 8, lines 1-3, that "[t]he efficacy and safeness were studied when
`
`SM-13496 at a dose of 40 mg or 120 mg, or a placebo was orally administered once a day for
`
`6 weeks after placebo washout." Table 5 on page 11 shows "[a]dverse events observed in 10
`
`14
`
`Page 14 of 21
`
`SLAYBACK EXHIBIT 1034
`
`

`

`Application No. 14/471,919
`Reply to Office Action of October 19, 2016
`
`% or more of the patients," and Applicant reports on page 12 that "[e]ither body weight gain,
`
`bulimia, impotence, erectile dysfunction or convulsion was not observed." Therefore, the
`
`ratio of patients who experienced a weight gain after 6 weeks of administration was less than
`
`10%. These results are significant and unexpected because conventional anti psychotic drugs
`
`caused serious side effects such as undesired metabolic changes (e.g., hyperglycemia and
`
`dyslipidemia) and cardiovascular adverse reaction, which were considered as closely linked
`
`with a weight gain.
`
`The present method can safely treat patients with schizophrenia or manic depressive
`
`psychosis (bipolar disorder), and the treatment can be continued even for an extended period
`
`of time such as six weeks or longer. Applicant's original specification describes the
`
`advantageous effects on page 5, lines 23-28 as follows:
`
`... in the therapeutic method of the present invention, side
`effects such as extrapyramidal symptoms ... , abnormal
`electrocardiogram, hepatic dysfunction are hardly observed,
`and hence, the present method may be quite safely used and
`suitable for a prolonged medication.
`
`Wong fails to teach treating schizophrenia in a patient without a clinically significant
`
`weight gain by administering the active compound of Claim 20 "at a dose of from 20 to 120
`
`mg/day such that the patient does not experience a clinically significant weight gain."
`
`Applicant respectfully submits that Wong rather discourages one from using the active
`
`compound of Claim 20 because the reference recognizes that anti psychotic drugs such as the
`
`claimed active compound cause side effects, in particular, a significant weight gain.
`
`In the "BACKGROUND OF THE INVENTION" section, Wong lists many
`
`typical/atypical neuroleptic/antipsychotic agents including the hydrochloride compound (SM-
`
`13496) encompassed by Claim 20. Wong repeatedly states that these antipsychotic drugs
`
`cause weight gain as side effects:
`
`i) Column 3, lines 31-35 (regarding typical neuroleptic agents):
`
`15
`
`Page 15 of 21
`
`SLAYBACK EXHIBIT 1034
`
`

`

`Application No. 14/471,919
`Reply to Office Action of October 19, 2016
`
`These medications can have adverse side effects on many
`organs and systems in the body. Sleepiness and lethargy
`commonly occur in the beginning of therapy, but usually
`decrease over time. Other side effects include dry mouth, eye
`problems, allergic reactions, temporary weight gain, and
`
`ii) Column 4, lines 2-6, 26-27 & 39-40 (regarding atypical neuroleptic/antipsychotic
`
`agents, in particular, Clozapine, Risperidone and Olanzapine) (emphasis added):
`
`Although the drug [Clozapine] does not appear to cause tardive
`dyskinesia, it does have other side effects including nasal
`congestion, drooling, low blood pressure, headache, sleeplessness,
`and significant weight gain.
`
`Common side effects [ of Risperidone] include sleepiness, weight
`gain, and dizziness.
`
`Like risperidone, olanzapine can cause sleepiness, weight gain, and
`dizziness.
`
`Wong appears to focus on clozapine, olanzapine and risperidone because Wong specifically
`
`names them in Abstract and describes them in Examples 1-3 as well.
`
`On the other hand, SM-13496 covered by Applicant's Claim 20 is simply named in
`
`the long list of various typical/atypical neuroleptic agents (see col. 3, line 44 to col. 4, last
`
`line). Wong neither specifically discusses SM-13496 nor reports favorable experimental
`
`results on SM-13496. As such, according to Wong, SM-13496 is one of the typical/atypical
`
`neuroleptic agents that cause various side effects, and there is nothing in Wong that would
`
`have provided reasons to specifically select SM-13496 in treating schizophrenia or manic
`
`depressive psychosis.
`
`Moreover, in order to reduce the side effects caused by typical/atypical neuroleptic
`
`agents, Wong utilizes norepinephrine reuptake inhibitor (NRI) together with the typical or
`
`atypical neuroleptic agents. Indeed, Wong requires NRI to reduce the side effects caused by
`
`16
`
`Page 16 of 21
`
`SLAYBACK EXHIBIT 1034
`
`

`

`Application No. 14/471,919
`Reply to Office Action of October 19, 2016
`
`the neuroleptic agents. Wong's composition contains NRI as the first, essential component
`
`and a neuroleptic agent as the second component (see col. 5, lines 8-12 and 57-61 ):
`
`More specifically, the composition combines one or more
`norepinephrine reuptake inhibitors, more preferably one or
`more selective norepinephrine reuptake inhibitors with one
`or more neuroleptic agents (typical or atypical
`antipsychotic agents) ....
`
`The present invention provides a novel composition which
`is a combination of different chemical entities, more
`specifically, the first entity being a norepinephrine reuptake
`inhibitor, particularly a selective norepinephrine reuptake
`inhibitor and the second being a neuroleptic agent.
`
`Wong specifically attributes the reduction in weight gain to the use ofNRI. See col. 10, lines
`
`15- I 8:
`
`the incidence of weight gain typically associated with the administration of
`atypical neuroleptic agents is minimized by the administration of the
`norepinephrine reuptake inhibitor.
`
`With regard to dosage, Wong provides a list of various neuroleptic agents and their
`
`average daily dosage in cols. 7-8:
`
`17
`
`Page 17 of 21
`
`SLAYBACK EXHIBIT 1034
`
`

`

`Application No. 14/471,919
`Reply to Office Action of October 19, 2016
`
`Component
`
`Average Daily Dosage (mg/day/J)lltient)
`
`Chlorpronmzine
`Haloperidol
`Mesoridazine
`Perphenazine
`Thioridazi ne
`Tritluopemzine
`rluphenazine
`Clozapine
`
`!Oto 150
`.5 to 100
`75 to 400
`5 to 100
`30 to 800
`I lo 50
`2.5 to 100
`25 to 500
`
`-continued
`
`Component
`
`Average Daily Dosage (mg/day/patient)
`
`01iln7,.'1.pinc
`Rispcridone
`Zipmsidone
`Quetiapinc
`ScrlindQle
`Aripipmzolc
`Soncplprazole
`Blonanserin
`ilopcridonc
`Perospi,onc
`·zotepinc
`Dll-127090
`ORG~5222
`SM-13496
`AmisuJpridc
`Raclopri<le
`CP-361428
`Lu J5-J38
`Balapcddone
`S·l8327
`WAY-135452
`Epliv;:mserin
`E-5842
`SR-3!742
`:SE-JOO
`o~anelanl
`SR-141711>
`SR-48692
`BSF-101640
`BSF-190555
`LAX-Wla
`Sarizotr1n
`CX-1,91
`SB-'.!7J04o
`
`0.05 to 3,0
`.25 to ~5
`5 to 500
`25 to 800
`l to 500
`7.5 to 750
`.75 lo 3750
`.75 to 3750
`.75 lo 75!)0
`.5 to HJOO
`30 to lrnlO
`.05 to 7500
`.75 to 750
`.05 to 7500
`50 tu 750
`I to 500
`J)5 lo 7500
`.05 to 7500
`.75 to 7500
`.5 to JOO
`.05 to 7500
`.I to 2000
`l to 2000
`.5 to 4000
`.I lo 100
`.5 to 4000
`.5 to 4000
`I to ](~10
`l to 1000
`l to 500
`.05 to 7500
`0.2 to 2lX)O
`l to 4()0
`0.05 to HXlO
`
`SM-13496 is listed with the dose range of 0.05-7500 mg/day/patient, which is extremely
`
`broad and hardly provides any meaningful guidance or suggestions for the actual effective
`
`dosage. The list simply gives general information, and nothing points to SM-13496 or the
`
`specific dose range of 20-120 mg recited in Claim 20 of the present application. There is no
`
`description in Wong on any specific factors to consider in finding a more realistic, effective
`
`dose range specifically for SM-13496. The reference does not identify any relationship
`
`between the dosage of SM-13496 and its side effects. As such, one would not have arrived at
`
`administering the active compound of Claim 20 "at a dose of from 20 to 120 mg/day such
`
`that the patient does not experience a clinically significant weight gain." Furthermore, Wong
`
`18
`
`Page 18 of 21
`
`SLAYBACK EXHIBIT 1034
`
`

`

`Application No. 14/471,919
`Reply to Office Action of October 19, 2016
`
`does not address administration of SM-13496 for a prolonged time such as six weeks and
`
`detecting whether the patient experiences a weight gain after six weeks (see Claim 25).
`
`Wong simply acknowledges weight gain as the undesired side effect typically caused by
`
`various neuroleptic agents, and does not provide any clues in finding actual effective ways to
`
`administer the specific active compound without serious side effects.
`
`Instead of directing one to screen many neuroleptic agents in the long list and find
`
`effective dosage, Wong proposes co-administering NRis with neuroleptic agents in order to
`
`reduce side effects. As stated above, Wong specifically attributes the reduction in side effects
`
`to the NRis. One would neither ignore such Wong's proposal nor expect that an effective
`
`dosage for SM-13496 without the problem of side effects could be readily found somewhere
`
`in the broad range of 0.05-7500 mg.
`
`Regarding this range of 0.05-7500 mg in Wong, the lower limit of 0.05 mg is l/400 of
`
`20 mg in Claim 20, and the upper limit of 7500 mg in Wong is 60 times greater than 120 mg
`
`in the claim. In the field of pharmaceuticals, such an extremely broad dose range would not
`
`be sufficient for one to have reasonable expectation that a specific dose range would provide
`
`desired effects, particularly when various side effects are known. In this regard, the Office
`
`Action asserts "the predictable use of prior art elements" (see OA, p. 3), but the reality is one
`
`could hardly predict efficacy and the extent of side effects. If there were any in this case,
`
`Wong would have provided negative expectation that the listed neuroleptic agents including
`
`SM-13496 would have "known" side effects and require addition ofNRis to minimize them.
`
`Applicant has found that the active compound of Claim 20 is unexpectedly effective
`
`for treating schizophrenia at the dose of 20-120 mg, despite the conventionally "known" side
`
`effects. The finding is based on Applicant's various studies on pharmacokinetics and safety
`
`as well as clinical studies of pharmaceutical activities. In addition to the clinical data in the
`
`original specification, the results are rep011ed in the attached research poster (published after
`
`19
`
`Page 19 of 21
`
`SLAYBACK EXHIBIT 1034
`
`

`

`Application No. 14/471,919
`Reply to Office Action of October 19, 2016
`
`the filing date of the present application) by J. W. Newcomer et al. MD15, "EFFECT OF
`
`LONG-TERM TREATMENT WITH LURASIDONE OR RISPERIDONE ON
`
`METABOLIC SYNDROME STATUS INPATIENTS WITH SCHIZOPHRENIA," British
`
`Association for Psychopharmacology (BAP) Annual Summer Meeting, July 20-23, 2014,
`
`Cambridge, UK.
`
`The poster reports 12-month double-blind safety studies comparing the effects of
`
`lurasidone (37-111 mg/day in free base conversion; 40-120 mg in hydrochloride conversion)
`
`with a reference drug, risperidone (at a much lower dose of 2-6 mg/day), on metabolic
`
`syndrome prevalence in schizophrenic patients (see left column, METHODS section). The
`
`clinical studies showed that after the 12-month administration (much longer than 6 weeks in
`
`Experiment I in the present application), the conventional antipsychotic drug, risperidone,
`
`caused undesired weight gain (mean change of +2.6 kg), whereas lurasidone showed weight
`
`loss (mean change of -0.9 kg) (see Table 3, top data). Moreover, the studies found that
`
`lurasidone provides significantly lower metabolic syndrome risk than risperidone. The
`
`authors state that "[t]he prevalence of metabolic syndrome remained stable over 12 months of
`
`treatment with lurasidone, in contrast to the increase in metabolic syndrome prevalence over
`
`12 months in patients treated with risperidone" (CONCLUSIONS section, first paragraph).
`
`One would not have expected that lurasidone would provide both of such therapeutic effects
`
`and additional significant benefits over the conventional antipsychotic drug. The authors
`
`also mention that "[t]he incidence of metabolic-related adverse events during the double-
`
`blind phase was 11.7% in the lurasidone group compared with 20.8% in the risperidone group,
`
`and appeared to be driven primarily by weight gain (9.3% with lurasidone vs 19.8% with
`
`risperidone)" (RES UL TS section, below Figure 3). The result that the incidence of weight
`
`gain with lurasidone is less than 10% even after the 12-month administration corroborates its
`
`significant effect.
`
`20
`
`Page 20 of 21
`
`SLAYBACK EXHIBIT 1034
`
`

`

`Application No. 14/4 71,919
`Reply to Office Action of October 19, 2016
`
`For the foregoing reasons, Applicant respectfully submits that the method of Claim 20
`
`is distinguishable from Wong. Pozuelo is simply cited with regard to manic depressive
`
`psychosis, and does not cure the deficiencies of Wong in regards to the treatment without a
`
`clinically significant weight gain. Therefore, Claim 20 and its dependent claims are
`
`unobvious over Wong and Pozuelo.
`
`Similarly, independent Claims 28, 45, 60 and 76 as well as their dependent claims are
`
`unobvious over the cited references because the references do not teach or suggest treating a
`
`patient specifically with the claimed active ingredient for the claimed methods.
`
`With regard to the rejection of Claims 20-28 under nonstatutory double patenting
`
`rejection over Claims 1-11 of Nakamura (US 9,174,975) in view of Wong and Pozuelo,
`
`Applicant submits herewith a terminal disclaimer against Nakamura. Withdrawal of the
`
`rejection is respectfully requested.
`
`In view of the amendments and discussions presented above, Applicant respectfully
`
`submits that the present application is in condition for allowance, and an early action
`
`favorable to that effect is earnestly solicited.
`
`Customer Number
`22850
`
`Tel (703) 413-3000
`Fax. (703) 413-2220
`(OMMN 07/09)
`
`Respectfully Submitted,
`
`OBLON, McCLE