Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
2. Claims 34 – 51 are pending in this application. Applicant’s preliminary amendment, submitted April 24, 2024, is entered, wherein claims 34 – 51 are new and claims 1 – 33 are canceled.
Claims 34 – 51 are examined on the merits herein.
Priority
3. This application is a divisional application of 14/285,815, filed April 15, 2021, now issued as U.S. Patent No. 12,285,421, which is a national stage application of PCT/IB2019/058853, filed October 17, 2019, that claims benefit of foreign priority document IN201841039516, filed October 18, 2018.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 04/25/2024, 05/22/2024, and 10/31/2024 were filed in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement are being considered by the examiner.
Claim Objections
Claims 45 – 47 are objected to because of the following informalities:
Claims 45 – 47, lines 2, “,” should be inserted immediately after “administering step”. Appropriate correction is required.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 34 – 39 and 41 – 51 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Nirogi et al. (US2015/0283125A1) with evidence provided by Stetka (Scientific American, 2015, Reference included with PTO-892).
a. Nirogi et al. teach the novel compounds of formula (I) and the pharmaceutically acceptable salts thereof. The compounds of formula (I) are useful in the treatment of various disorders that are related to 5-HT4 receptor (Abstract). Nirogi et al. disclose a method of treating cognitive disorders, dementia, attention deficit hyperactivity disorder, schizophrenia, and pain, wherein the method comprising the step of administering to a patient in need thereof an effective amount of a compound of formula (I) or pharmaceutically acceptable salt thereof (claim 10), wherein the compound of formula (I) is 1-Isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate salt (page 10, para. [0224], Example 3). Nirogi et al. specifically disclose the claimed compound as Example 3, namely 1-Isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate salt. Nirogi et al. further disclose that Example 3 is administered to male Wistar rats (225±25 grams) in a brain penetration study at 10 mg/kg by oral gavage using reagent-grade water as vehicle, and at 5 mg/kg intravenously using sterile water for injection as vehicle in example (para. [0269], Example 52):
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Nirogi et al. further evaluate cognitive enhancing properties in Example 53, the object recognition task model, and Example 54, the radial arm maze model. In these assay examples, the “Example Number 3” corresponds to the compound prepared in synthetic Example 3, which is 1-Isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate salt. Nirogi et al. report that Example 3 is active in the object recognition task at 3 mg/kg p.o. and reversed scopolamine-induced amnesia in the radial arm maze at 1 – 3 mg/kg p.o. (para. [0273 – 0279]):
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Therefore, Nirogi et al. teach administration of the claimed compound and improvement of memory and/or cognitive performance after administration.
Regarding claims 38 and 43, Nirogi et al. disclose that Example 3 is administered as a single dose in the rodent brain penetration study. As the compound is administered only once on the day of dosing, Nirogi et al. teach administration of the claimed compound one time per day.
Regarding claims 39 and 44, Nirogi et al. disclose that Example 3 is formulated in a vehicle for administration in the rodent brain penetration study. Specifically, Nirogi et al. disclose that Example 3 is formulated in reagent grade water for oral gavage administration and in sterile water for injection for intravenous bolus administration to male Wistar rats. The reagent grade water and sterile water for injection function as formulation vehicles or excipients for administering the active compound. Thus, Nirogi et al. teach that the claimed compound is present in a composition further comprising an excipient.
Regarding claim 41, Nirogi et al. disclose administration of Example 3 to male Wistar rats having a body weight of 225 g. For the oral dose, 10 mg/kg administered to a 0.225 kg rat corresponds to 2.25 mg of Example 3. For the intravenous dose, 5 mg/kg administered to a 0.225 kg rat corresponds to 1.125 mg of Example 3. Both amounts fall within the claimed range of about 1 mg to about 2000 mg.
Regarding claims 45 – 47, Nirogi et al. further evaluate the cognitive enhancing properties of Example 3, using an object recognition task model and a radial arm maze model in rats. Nirogi et al. report that Example 3 is active in the object recognition task, demonstrating cognition enhancing activity after administration and that Example 3 reverses scopolamine-induced amnesia in the radial arm maze, demonstrating that administration of Example 3 improves memory performance. .
Regarding claim 51, Nirogi et al. teach administering the compound to a “patient in need thereof” for the treatment of cognitive disorders and schizophrenia. Nirogi et al. further teach that the compounds are useful in the treatment of disorders including Alzheimer’s disease, cognitive disorders, dementia, and schizophrenia, and recites treatment of “clinical conditions” including schizophrenia (claim 19). Stetka explains that schizophrenia is common in humans and appears to have spared other animals, and further states that psychosis has not been observed outside human (page 1, para. 2). Because schizophrenia is a human clinical disease and the reference is directed to pharmaceutical therapy in a patient, Nirogi et al. reasonably disclose administration to a human patient. The animal studies in Nirogi et al. are relied upon as supporting pharmacological/biological evidence for the disclosed human therapeutic use, not as the sole disclosure of the patient population. Therefore, the disclosure of Nirogi et al. for treating schizophrenia in a patient in need thereof teaches the human patient limitation.
For these reasons above, Nirogi et al. anticipates the claimed invention.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
i. Determining the scope and contents of the prior art.
ii. Ascertaining the differences between the prior art and the claims at issue.
iii. Resolving the level of ordinary skill in the pertinent art.
iv. Considering objective evidence present in the application indicating obviousness or
nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 34 and 39 – 40 are rejected under 35 U.S.C. 103 as being unpatentable over Nirogi et al. (US2015/0283125A1) in view of Abrantes et al. (Journal of Pharmaceutical Sciences, 2016, Vol. 105, Issue 7, page 2019 – 2026, Reference included with PTO-892).
b. Regarding claims 34 and 39 – 40, Nirogi et al. teach the novel compounds of formula (I) and the pharmaceutically acceptable salts thereof. The compounds of formula (I) are useful in the treatment of various disorders that are related to 5-HT4 receptor (Abstract). Nirogi et al. disclose a method of treating cognitive disorders, dementia, attention deficit hyperactivity disorder, schizophrenia, and pain, wherein the method comprising the step of administering to a patient in need thereof an effective amount of a compound of formula (I) or pharmaceutically acceptable salt thereof (claim 10), wherein the compound of formula (I) is 1-Isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate salt (claim 11). Nirogi et al. disclose a pharmaceutical composition containing a therapeutically effective amount of the compound of formula (I) or the pharmaceutically acceptable salt thereof in admixture with pharmaceutical acceptable excipient (para. [0015]). The pharmaceutical composition may be formulated for oral or parenteral (para. [0077]). Nirogi et al. teach a rodent pharmacokinetic study, wherein male Wister rats of 225 g body weight are dosed with the compound of formula (I) at 10 mg/kg orally one time for one day (para. [0266]).
However, Nirogi et al. do not teach that the 5-HT4 receptor agonist is 1 to 90% by weight of the composition.
Abrantes et al. teaches that a medicine consists of 2 fundamental parts: the active pharmaceutical ingredient and the excipient (Abstract). Excipients constitute about 90% of the total volume of a medicine (page 2020, Left Col., para. 5).
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to formulate the pharmaceutical composition comprising 1-Isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate salt as taught by Nirogi et al. with conventional pharmaceutically acceptable excipients in an amount that provides a workable oral or parenteral pharmaceutical composition, including an API within about 1% to 90% by weight, because the relative amount of API and excipient is a routine formulation parameter selected to provide the desired dosage strength and route of administration and Abrantes et al. teach the conventional pharmaceutical formulation principle that the API is combined with excipients, with excipients commonly making up a substantial portion of the finished medicine. One would have been motivated to consider the conventional pharmaceutical formulation principle disclosed by Abrantes et al. when formulating a pharmaceutical composition because Nirogi et al. already teach that the claimed active compound may be formulated as a pharmaceutical composition in admixture with a pharmaceutically acceptable excipient and Abrantes et al. provides general formulation guidance that medicines ordinarily include both an API and excipients in a certain amount. Based on the conventional pharmaceutical formulation principle, one would have performed routine experimentation to discover the best amount of 5-HT4 receptor agonist and excipient in the composition. One of ordinary skill in the art would have had a reasonable expectation of success to formulate the pharmaceutical composition comprising 1-Isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate salt as taught by Nirogi et al. with conventional pharmaceutically acceptable excipients in an amount that provides a workable oral or parenteral pharmaceutical composition, including an API within about 1% to 90% by weight, because determining the relative amount of API and excipient in a dosage form is a routine formulation parameter selected based on desired dose strength and route of administration. Therefore, selecting an API within the broad claimed range of about 1% to about 90% by weight would have involved no more than routine optimization of a known pharmaceutical composition.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 34 – 36 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, and 10 – 11 of U.S. Patent No. 9363335B2. Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of ‘335B2 anticipates the claimed invention.
a. ‘335B2 claims a method of treating dementia, attention deficit hyperactivity disorder, and schizophrenia, comprising the step of administering to a patient in need thereof an effective amount of a compound of general formula (I) or pharmaceutically acceptable salt thereof, wherein the compound of general formula (I) is Isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate (claims 1, 3, and 10 – 11).
For these reasons above, ‘335B2 anticipates the claimed invention.
Claims 34 – 39 and 41 – 51 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, and 10 – 11 of U.S. Patent No. 9363335B2 in view of Nirogi et al. (US2014/0187581A1; hereinafter ‘581A1) with evidence provided by Stetka (Scientific American, 2015, Reference included with PTO-892).
b. Regarding claims 34 – 39 and 41 – 51, ‘335B2 claims a method of treating dementia, attention deficit hyperactivity disorder, and schizophrenia, comprising the step of administering to a patient in need thereof an effective amount of a compound of general formula (I) or pharmaceutically acceptable salt thereof, wherein the compound of general formula (I) is Isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate (claims 1, 3, and 10 – 11).
However, ‘335B2 does not teach that the claimed compound is administered to the patient by an oral route. ‘335B2 does not teach the claimed compound is administered to the patient one to three times per day. ‘335B2 does not teach that the claimed compound is in a composition further comprising a pharmaceutically acceptable excipient. ‘335B2 does not teach the claimed compound is present in the composition in an amount of about 1 mg to about 2000 mg. ‘335B2 does not explicitly teach the effects of cognitive deficit improvement and memory improvement after administration of the claimed compound. ‘335B2 does not explicitly teach that the patient is a human.
‘581A1 teaches the novel compounds of formula (I) and the pharmaceutically acceptable salts thereof. The compounds of formula (I) are useful in the treatment of various disorders that are related to 5-HT4 receptor (Abstract). ‘581A1 discloses a method of treating cognitive disorders, dementia, attention deficit hyperactivity disorder, schizophrenia, and pain, wherein the method comprising the step of administering to a patient in need thereof an effective amount of a compound of formula (I) or pharmaceutically acceptable salt thereof (claim 7), wherein the compound of formula (I) is 1-Isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate salt (page 10, para. [0223], Example 3). ‘581A1 specifically disclose the claimed compound as Example 3, namely 1-Isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate salt. ‘581A1 further disclose that Example 3 is administered to male Wistar rats (225±25 grams) in a brain penetration study at 10 mg/kg by oral gavage using reagent-grade water as vehicle, and at 5 mg/kg intravenously using sterile water for injection as vehicle in example (para. [0266], Example 52):
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‘581A1 further evaluates cognitive enhancing properties in Example 53, the object recognition task model, and Example 54, the radial arm maze model. In these assay examples, the “Example Number 3” corresponds to the compound prepared in synthetic Example 3, which is 1-Isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate salt. ‘581A1 reports that Example 3 is active in the object recognition task at 3 mg/kg p.o. and reverses scopolamine-induced amnesia in the radial arm maze at 1 – 3 mg/kg p.o. (para. [0270 – 0276]):
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Therefore, ‘581A1 teaches administration of the claimed compound and improvement of memory and/or cognitive performance after administration.
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the method claimed in ‘335B2 by administering the claimed compound according to the administration, formulation, dosing , and cognitive or memory teachings in view of ‘581A1. ‘335B2 claims treating schizophrenia by administering to a patient in need thereof an effective amount of the same oxalate compound. ‘581A1 further discloses that this same compound, identified as Example 3, is actually administered orally at 10 mg/kg using reagent grade water as vehicle and intravenously at 5 mg/kg using sterile water for injection as vehicle. ‘581A1 also discloses that Example 3 is active in the object recognition task and reverses scopolamine-induced amnesia in the radial arm maze model. Thus, the claimed administration route, formulation, dosage amount, and cognitive/memory improvement limitations are known properties and uses of the same compound and do not render the pending claims patentably distinct from the patented claims.
Regarding claims 38 and 43, ‘581A1 discloses that Example 3 is administered as a single dose in the rodent brain penetration study. As the compound is administered only once on the day of dosing, ‘581A1 teaches administration of the claimed compound one time per day.
Regarding claims 39 and 44, ‘581A1 discloses that Example 3 is formulated in a vehicle for administration in the rodent brain penetration study. Specifically, ‘581A1 discloses that Example 3 is formulated in reagent grade water for oral gavage administration and in sterile water for injection for intravenous bolus administration to male Wistar rats. The reagent grade water and sterile water for injection function as formulation vehicles or excipients for administering the active compound. Thus, ‘581A1 teaches that the claimed compound is present in a composition further comprising an excipient.
Regarding claim 41, ‘581A1 discloses administration of Example 3 to male Wistar rats having a body weight of 225 g. For the oral dose, 10 mg/kg administered to a 0.225 kg rat corresponds to 2.25 mg of Example 3. For the intravenous dose, 5 mg/kg administered to a 0.225 kg rat corresponds to 1.125 mg of Example 3. Both amounts fall within the claimed range of about 1 mg to about 2000 mg.
Regarding claims 45 – 47, ‘581A1 further evaluates the cognitive enhancing properties of Example 3, using an object recognition task model and a radial arm maze model in rats. ‘581A1 reports that Example 3 is active in the object recognition task, demonstrating cognition enhancing activity after administration and that Example 3 reverses scopolamine-induced amnesia in the radial arm maze, demonstrating that administration of Example 3 improves memory performance. .
Regarding claim 51, ‘581A1 teaches administering the compound to a “patient in need thereof” for the treatment of cognitive disorders and schizophrenia. ‘581A1 further teaches that the compounds are useful in the treatment of disorders including Alzheimer’s disease, cognitive disorders, dementia, and schizophrenia, and recites treatment of “clinical conditions” including schizophrenia (claim 19). Stetka explains that schizophrenia is common in humans and appears to have spared other animals, and further states that psychosis has not been observed outside human (page 1, para. 2). Because schizophrenia is a human clinical disease and the reference is directed to pharmaceutical therapy in a patient, ‘581A1. reasonably discloses administration to a human patient. The animal studies in ‘581A1 are relied upon as supporting pharmacological/biological evidence for the disclosed human therapeutic use, not as the sole disclosure of the patient population. Therefore, the disclosure of ‘581A1 for treating schizophrenia in a patient in need thereof teaches the human patient limitation.
Accordingly, the pending claims are not patentably distinct from claims 1, 3, and 10 – 11 of ‘335B2 because they recite the same active compound for the same schizophrenia therapeutic use, with only routine for disclosed administration route, formulation, dosage, and cognitive or memory result limitations taught by ‘581A1.
Claim 40 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, and 10 – 11 of U.S. Patent No. 9363335B2 in view of Nirogi et al. (US2014/0187581A1; hereinafter ‘581A1) with evidence provided by Stetka (Scientific American, 2015, Reference included with PTO-892) as applied to claims 34 – 39 and 41 – 51 above, and further in view of Abrantes et al. (Journal of Pharmaceutical Sciences, 2016, Vol. 105, Issue 7, page 2019 – 2026, Reference included with PTO-892).
c. Regarding claim 40, the references teach the limitations discussed above.
However, ‘335B2 do not teach that the 5-HT4 receptor agonist is 1 to 90% by weight of the composition.
Abrantes et al. teaches that a medicine consists of 2 fundamental parts: the active pharmaceutical ingredient and the excipient (Abstract). Excipients constitute about 90% of the total volume of a medicine (page 2020, Left Col., para. 5).
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to formulate the pharmaceutical composition comprising 1-Isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate salt as taught by ‘335B2 with conventional pharmaceutically acceptable excipients in an amount that provides a workable oral or parenteral pharmaceutical composition, including an API within about 1% to 90% by weight, in view of Abrantes et al. because the relative amount of API and excipient is a routine formulation parameter selected to provide the desired dosage strength and route of administration and Abrantes et al. teach the conventional pharmaceutical formulation principle that the API is combined with excipients, with excipients commonly making up a substantial portion of the finished medicine. One would have been motivated to consider the conventional pharmaceutical formulation principle disclosed by Abrantes et al. when formulating a pharmaceutical composition because ‘581A1 already teaches that the claimed active compound may be formulated as a pharmaceutical composition in admixture with a pharmaceutically acceptable excipient and Abrantes et al. provides general formulation guidance that medicines ordinarily include both an API and excipients in a certain amount. Based on the conventional pharmaceutical formulation principle, one would have performed routine experimentation to discover the best amount of 5-HT4 receptor agonist and excipient in the composition. One of ordinary skill in the art would have had a reasonable expectation of success to formulate the pharmaceutical composition comprising 1-Isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate salt as taught by ‘335B2 and ‘581A1 with conventional pharmaceutically acceptable excipients in an amount that provides a workable oral or parenteral pharmaceutical composition, including an API within about 1% to 90% by weight, because determining the relative amount of API and excipient in a dosage form is a routine formulation parameter selected based on desired dose strength and route of administration. Therefore, selecting an API within the broad claimed range of about 1% to about 90% by weight would have involved no more than routine optimization of a known pharmaceutical composition.
Claims 34 – 36, 39, and 44 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 2, 5 – 10, and 13 of U.S. Patent No. 9079894B2.Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of ‘894B2 anticipates the claimed invention.
d. ‘894B2 teaches a compound of general formula (I) or a pharmaceutically acceptable salt thereof (claim 1), wherein the a compound of general formula (I) is Isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate (claims 2, 7 – 9, and 13). ‘894B2 teaches a pharmaceutical composition comprising said compound and pharmaceutically acceptable excipients (claims 5 and 10). The pharmaceutical composition is used for the treatment of clinical condition, such as schizophrenia (claim 6).
For these reasons above, ‘894B2 anticipates the claimed invention.
Claims 34 – 39 and 41 – 51 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 2, 5 – 10, and 13 of U.S. Patent No. 9079894B2 in view of Nirogi et al. (US2015/0283125A1) with evidence provided by Stetka (Scientific American, 2015, Reference included with PTO-892).
e. Regarding claims 34 – 39 and 41 – 51, ‘894B2 teaches a compound of general formula (I) or a pharmaceutically acceptable salt thereof (claim 1), wherein the a compound of general formula (I) is Isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate (claims 2, 7 – 9, and 13). ‘894B2 teaches a pharmaceutical composition comprising said compound and pharmaceutically acceptable excipients (claims 5 and 10). The pharmaceutical composition is used for the treatment of clinical condition, such as schizophrenia (claim 6).
However, ‘894B2 does not teach that the claimed compound is administered to the patient by an oral route. ‘894B2 does not teach the claimed compound is administered to the patient one to three times per day. ‘894B2 does not teach the claimed compound is present in the composition in an amount of about 1 mg to about 2000 mg. ‘894B2 does not explicitly teach the effects of cognitive deficit improvement and memory improvement after administration of the claimed compound. ‘894B2 does not explicitly teach that the patient is a human.
Nirogi et al. teach the novel compounds of formula (I) and the pharmaceutically acceptable salts thereof. The compounds of formula (I) are useful in the treatment of various disorders that are related to 5-HT4 receptor (Abstract). Nirogi et al. disclose a method of treating cognitive disorders, dementia, attention deficit hyperactivity disorder, schizophrenia, and pain, wherein the method comprising the step of administering to a patient in need thereof an effective amount of a compound of formula (I) or pharmaceutically acceptable salt thereof (claim 10), wherein the compound of formula (I) is 1-Isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate salt (page 10, para. [0224], Example 3). Nirogi et al. specifically disclose the claimed compound as Example 3, namely 1-Isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate salt. Nirogi et al. further disclose that Example 3 is administered to male Wistar rats (225±25 grams) in a brain penetration study at 10 mg/kg by oral gavage using reagent-grade water as vehicle, and at 5 mg/kg intravenously using sterile water for injection as vehicle in example:
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Nirogi et al. further evaluate cognitive enhancing properties in Example 53, the object recognition task model, and Example 54, the radial arm maze model. In these assay examples, the “Example Number 3” corresponds to the compound prepared in synthetic Example 3, which is 1-Isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate salt. Nirogi et al. report that Example 3 is active in the object recognition task at 3 mg/kg p.o. and reversed scopolamine-induced amnesia in the radial arm maze at 1 – 3 mg/kg p.o. (para. [0273 – 0279]):
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,
Therefore, Nirogi et al. teach administration of the claimed compound and improvement of memory and/or cognitive performance after administration.
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the method claimed in ‘894B2 by administering the claimed compound according to the administration, formulation, dosing , and cognitive or memory teachings in view of Nirogi et al. ‘894B2 claims treating schizophrenia by administering to a patient in need thereof an effective amount of the same oxalate compound. Nirogi et al. further disclose that this same compound, identified as Example 3, is actually administered orally at 10 mg/kg using reagent grade water as vehicle and intravenously at 5 mg/kg using sterile water for injection as vehicle. Nirogi et al. also disclose that Example 3 is active in the object recognition task and reverses scopolamine-induced amnesia in the radial arm maze model. Thus, the claimed administration route, formulation, dosage amount, and cognitive/memory improvement limitations are known properties and uses of the same compound and do not render the pending claims patentably distinct from the patented claims.
Regarding claims 38 and 43, Nirogi et al. disclose that Example 3 is administered as a single dose in the rodent brain penetration study. As the compound is administered only once on the day of dosing, Nirogi et al. teach administration of the claimed compound one time per day.
Regarding claim 41, Nirogi et al. disclose administration of Example 3 to male Wistar rats having a body weight of 225 g. For the oral dose, 10 mg/kg administered to a 0.225 kg rat corresponds to 2.25 mg of Example 3. For the intravenous dose, 5 mg/kg administered to a 0.225 kg rat corresponds to 1.125 mg of Example 3. Both amounts fall within the claimed range of about 1 mg to about 2000 mg.
Regarding claims 45 – 47, Nirogi et al. further evaluate the cognitive enhancing properties of Example 3, using an object recognition task model and a radial arm maze model in rats. Nirogi et al. report that Example 3 is active in the object recognition task, demonstrating cognition enhancing activity after administration and that Example 3 reverses scopolamine-induced amnesia in the radial arm maze, demonstrating that administration of Example 3 improves memory performance. .
Regarding claim 51, Nirogi et al. teach administering the compound to a “patient in need thereof” for the treatment of cognitive disorders and schizophrenia. Nirogi et al. further teach that the compounds are useful in the treatment of disorders including Alzheimer’s disease, cognitive disorders, dementia, and schizophrenia, and recites treatment of “clinical conditions” including schizophrenia (claim 19). Stetka explains that schizophrenia is common in humans and appears to have spared other animals, and further states that psychosis has not been observed outside human (page 1, para. 2). Because schizophrenia is a human clinical disease and the reference is directed to pharmaceutical therapy in a patient, Nirogi et al. reasonably disclose administration to a human patient. The animal studies in Nirogi et al. are relied upon as supporting pharmacological/biological evidence for the disclosed human therapeutic use, not as the sole disclosure of the patient population. Therefore, the disclosure of Nirogi et al. for treating schizophrenia in a patient in need thereof teaches the human patient limitation.
Accordingly, the pending claims are not patentably distinct from claims 1, 3, and 10 – 11 of ‘894B2 because they recite the same active compound for the same schizophrenia therapeutic use, with only routine for disclosed administration route, formulation, dosage, and cognitive or memory result limitations taught by Nirogi et al.
Claim 40 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 2, 5 – 10, and 13 of U.S. Patent No. 9079894B2 in view of Nirogi et al. (US2015/0283125A1) with evidence provided by Stetka (Scientific American, 2015, Reference included with PTO-892) as applied to claims 34 – 39 and 41 – 51 above, and further in view of Abrantes et al. (Journal of Pharmaceutical Sciences, 2016, Vol. 105, Issue 7, page 2019 – 2026, Reference included with PTO-892).
f. Regarding claim 40, the references teach the limitations discussed above.
However, ‘894B2 do not teach that the 5-HT4 receptor agonist is 1 to 90% by weight of the composition.
Abrantes et al. teaches that a medicine consists of 2 fundamental parts: the active pharmaceutical ingredient and the excipient (Abstract). Excipients constitute about 90% of the total volume of a medicine (page 2020, Left Col., para. 5).
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to formulate the pharmaceutical composition comprising 1-Isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate salt as taught by ‘894B2 with conventional pharmaceutically acceptable excipients in an amount that provides a workable oral or parenteral pharmaceutical composition, including an API within about 1% to 90% by weight, in view of Abrantes et al. because the relative amount of API and excipient is a routine formulation parameter selected to provide the desired dosage strength and route of administration and Abrantes et al. teach the conventional pharmaceutical formulation principle that the API is combined with excipients, with excipients commonly making up a substantial portion of the finished medicine. One would have been motivated to consider the conventional pharmaceutical formulation principle disclosed by Abrantes et al. when formulating a pharmaceutical composition because both ‘894B2 and Nirogi et al. already teach that the claimed active compound may be formulated as a pharmaceutical composition in admixture with a pharmaceutically acceptable excipient and Abrantes et al. provides general formulation guidance that medicines ordinarily include both an API and excipients in a certain amount. Based on the conventional pharmaceutical formulation principle, one would have performed routine experimentation to discover the best amount of 5-HT4 receptor agonist and excipient in the composition. One of ordinary skill in the art would have had a reasonable expectation of success to formulate the pharmaceutical composition comprising 1-Isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate salt as taught by ‘894B2 and Nirogi et al. with conventional pharmaceutically acceptable excipients in an amount that provides a workable oral or parenteral pharmaceutical composition, including an API within about 1% to 90% by weight, because determining the relative amount of API and excipient in a dosage form is a routine formulation parameter selected based on desired dose strength and route of administration. Therefore, selecting an API within the broad claimed range of about 1% to about 90% by weight would have involved no more than routine optimization of a known pharmaceutical composition.
Claims 34 – 51 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 34 – 44 and 50 – 53 of copending Application No. 18/645,140 in view of Nirogi et al. (US2015/0283125A1) with evidence provided by Stetka (Scientific American, 2015, Reference included with PTO-892).
g. Regarding claims 34 – 51, ‘140 teaches a method of treating behavioral and psychological symptoms of dementia comprising the step of administering to a patient in need thereof, a therapeutically effective amount of a 5-HT4 receptor agonist, wherein the 5-HT4 receptor agonist is Isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole or a pharmaceutically acceptable salt thereof (claim 34). ‘140 teaches that the pharmaceutically acceptable salt is Isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate (claims 35 – 36). The 5-HT4 receptor agonist is administered to the patient by an oral route one to three times per day (claims 37 – 38 and 42 – 43)). ‘140 teaches that the 5-HT4 receptor agonist is in a composition further comprising a pharmaceutically acceptable excipient (claims 39 and 44), wherein the 5-HT4 receptor agonist is 1 to 90% by weight of the composition (claim 40). The 5-HT4 receptor agonist is present in the composition in an amount of about 1 mg to about 2000 mg (claim 41). The patient to be treated is an animal, wherein the animal is a mammal, wherein the mammal is a human (claims 50 – 53).
However, ‘140 does not teach a method of treating a cognitive deficit associated with schizophrenia.
Nirogi et al. teach the novel compounds of formula (I) and the pharmaceutically acceptable salts thereof. The compounds of formula (I) are useful in the treatment of various disorders that are related to 5-HT4 receptor (Abstract). Nirogi et al. disclose a method of treating cognitive disorders, dementia, attention deficit hyperactivity disorder, schizophrenia, and pain, wherein the method comprising the step of administering to a patient in need thereof an effective amount of a compound of formula (I) or pharmaceutically acceptable salt thereof (claim 10), wherein the compound of formula (I) is 1-Isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate salt (claim 11). Nirogi et al. disclose a pharmaceutical composition containing a therapeutically effective amount of the compound of formula (I) or the pharmaceutically acceptable salt thereof in admixture with pharmaceutical acceptable excipient (para. [0015]). The pharmaceutical composition may be formulated for oral or parenteral (para. [0077]). Nirogi et al. teach a rodent pharmacokinetic study, wherein male Wister rats of 225 g body weight are dosed with the compound of formula (I) at 10 mg/kg orally one time for one day (para. [0266]).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of treating behavioral and psychological symptoms of dementia as taught by ‘140 to a method of treating cognitive disorders, dementia, attention deficit hyperactivity disorder, schizophrenia, and pain in view of Nirogi et al. because Nirogi et al. teach the claimed 1-Isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate salt and teach that the claimed compound may be used to treat schizophrenia. One would have been motivated to modify the method of treating behavioral and psychological symptoms of dementia as taught by ‘140 to a method of treating cognitive disorders, dementia, attention deficit hyperactivity disorder, schizophrenia, and pain in view of Nirogi et al. because Nirogi et al. teach the same claimed compound and disclose that the claimed compound may be used to treat schizophrenia. One of ordinary skill in the art would have had a reasonable expectation of success to modify the method of treating behavioral and psychological symptoms of dementia as taught by ‘140 to a method of treating cognitive disorders, dementia, attention deficit hyperactivity disorder, schizophrenia, and pain in view of Nirogi et al. because it is known in the art that the claimed compound may be used to treat schizophrenia.
Regarding claim 41, Nirogi et al. disclose administration of Example 3 to male Wistar rats having a body weight of 225 g. For the oral dose, 10 mg/kg administered to a 0.225 kg rat corresponds to 2.25 mg of Example 3. For the intravenous dose, 5 mg/kg administered to a 0.225 kg rat corresponds to 1.125 mg of Example 3. Both amounts fall within the claimed range of about 1 mg to about 2000 mg.
Regarding claims 45 – 47, Nirogi et al. teach that cognitive enhancing properties of the compound of formula (I) are evaluated in object recognition task model and radial arm maze model:
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Nirogi et al. disclose that the object recognition task included a long-term memory test and reports that Example 3, corresponding to the claimed 1-Isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate salt, is active in the object recognition model. Nirogi et al. further disclose that Example 3 reversed scopolamine-induced amnesia at 1 – 3 mg/kg p.o. in the radial arm maze (para. [0273 – 0279]). Therefore, Nirogi et al. teach that administration of the claimed compound improves cognitive function and memory, thereby anticipating claims 45 – 47.
Regarding claim 51, Nirogi et al. teach administering the compound to a “patient in need thereof” for the treatment of cognitive disorders and schizophrenia. Nirogi et al. further teach that the compounds are useful in the treatment of disorders including Alzheimer’s disease, cognitive disorders, dementia, and schizophrenia, and recites treatment of “clinical conditions” including schizophrenia (claim 19). Stetka explains that schizophrenia is common in humans and appears to have spared other animals, and further states that psychosis has not been observed outside human (page 1, para. 2). Because schizophrenia is a human clinical disease and the reference is directed to pharmaceutical therapy in a patient, Nirogi et al. reasonably disclose administration to a human patient. The animal studies in Nirogi et al. are relied upon as supporting pharmacological/biological evidence for the disclosed human therapeutic use, not as the sole disclosure of the patient population. Therefore, the disclosure of Nirogi et al. for treating schizophrenia in a patient in need thereof teaches the human patient limitation.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claim is found to be allowable.
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/H.Y.L./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner, Art Unit 1693
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