DETAILED ACTION
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 .
Withdrawn Objections/Rejections
The objections to claim 1 are withdrawn in view of the claim amendments.
The rejections of claim 17 and 20 are withdrawn in view of the cancellation of the claim.
The provisional rejection of claims 1-4, 18-19, 21-22, and 32 on the ground of nonstatutory double patenting over claims 1, 9-22, and 25-26 of copending Application No. 18/129,538 in view of Mannion is withdrawn in view of the cancellation of the copending claims.
Claim Status
Applicant’s amendments and arguments filed 03/02/2026 have been fully considered.
Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Claims 5-17, 20, 23-31, and 33-44 are cancelled.
Claims 1-4, 18-19, 21-22, and 32 are under current examination. In the reply filed 01/17/2024, the species of a compound of Formula (I) of N-(4,6-Bis-n-propylamino-[1,3,5] triazin-2-yl)-O,N-dimethyl-hydroxylamine hydrogen sulfate was elected. This compound is consistent with the hydrogen sulfate salt of the structure recited in amended instant claim 1.
Information Disclosure Statement
The information disclosure statement (IDS) filed 12/04/2025 has been consider by the Examiner.
Rejections Maintained, Slightly Modified to Address Claim Amendments
Claim Rejections - 35 USC § 103
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:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. 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 1-4, 18-19, 21-22, and 32 are rejected under 35 U.S.C. 103 as being unpatentable over Mannion et al. (US 2012/0295911 A1, published November 22, 2012; of record), hereafter “Mannion”.
Mannion teaches a composition useful in the treatment of breathing control diseases or disorders (abstract). The composition comprises N-(4,6-bis-n-propylamino-[1,3,5] triazin-2-yl)-N-O-dimethyl-hydroxylamine (XXXV) or a salt thereof (paragraph [0015], claim 22); in one embodiment, the salt is the hydrogen sulfate salt (XXXVI) (paragraph [0018], claim 30). The composition further comprises a buffer and a liquid carrier (claim 29). Compositions can be those suitably developed for parenteral administration (paragraphs [0283], [0289], and [0321]-[0323]). The formulation of Mannion is taught to be administered by intramuscular route (claims 12 and 21).
Mannion teaches that XXXVI in a liquid carrier can be admixed with agents to adjust pH to optimize solubility and minimize degradation; suitable organic cosolvents include propylene glycol, polyethylene glycol 400, and ethanol (paragraph [0228]). Mannion teaches the preparation and evaluation of nine prototypes of XXXVI formulations, including those formulated with polyethylene glycol (a polyalkylene glycol) and propylene glycol (an alkylene glycol) (see paragraphs [0705]-[0707]). Mannion teaches that low pH contributes to instability and that good stability is seen in buffered PEG and propylene glycol formulations as well as simple solutions of the salt in PEG or propylene glycol (paragraph [0707]); such formulations result in only small amounts of impurities after storage at 60 °C for up to 4 weeks (see tables at paragraph [0707]).
Mannion further teaches that a formulation of XXXVI can be developed which, under formal GMP stability tests (25 °C/60% relative humidity for 9 months, see Table 12I.1), indicate that a single degradant was formed and can be expected to remain below 0.5% for at least two years (paragraph [0225]).
The composition of Mannion has a pH from about 2.5 to about 6 (claim 35), more specifically from about 3 to about 4 (claim 37), overlapping the ranges of instant claim 1 and 18-19. From MPEP 2144.05: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).” Mannion further teaches that low pH contributes to instability of the formulation (paragraph [0707]), providing motivation to the ordinary skill artisan to optimize the pH within the claimed range of Mannion to optimize the formulation stability. Per MPEP 2144.05: “"[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)”.
Mannion teaches a composition with a concentration of XXXV, or salt thereof, of about 10 mg/mL (claim 40). Mannion further teaches that formulation prototypes were prepared at 25 mg/mL XXXV as free base, which corresponds to 35 mg/mL XXXVI (paragraph [0223]). Mannion teaches that reducing the concentration by about half allows for an increase in pH, which can result in improved stability of the formulation (paragraph [0224]). Mannion further teaches that the amount of the active ingredient can range from 0.1-100% w/w (equivalent to about 1 mg/mL to 1,000 mg/mL) (see paragraph [0282]). It would have been prima facie obvious to one of ordinary skill in the art before the time of filing the instant invention to adjust the concentration of XXXVI taught by Mannion to achieve the desired stability. Mannion suggests that lower concentrations would predictably result in formulations with a higher pH and improved stability. From MPEP 2144.05: "’[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.’ In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)”.
Mannion does not specifically exemplify a parenteral formulation with a pH from about 3.5 to about 5.5 comprising N-(4,6-bis-n-propylamino-[1,3,5] triazin-2-yl)-N-O-dimethyl-hydroxylamine hydrogen sulfate at a concentration of from about 10 mg/mL to about 30 mg/mL and a pharmaceutically acceptable excipient selected from ethanol, polyalkylene glycol, alkylene glycol, cyclodextrin, dextrose, polyethylene glycol-hydroxystearate that maintains at least 90% of the compound after the recited accelerated storage conditions for 2 weeks, 1 month, 2 month, and 3 months, as recited in instant claims 1-4. However, the teachings of Mannion render obvious such formulations.
As discussed above, the teachings of Mannion arrive at a composition comprising N-(4,6-bis-n-propylamino-[1,3,5] triazin-2-yl)-N-O-dimethyl-hydroxylamine hydrogen sulfate and pharmaceutically acceptable excipients including polyethylene glycol, propylene glycol, and ethanol, consistent with the formulation recited in instant claim 1. Mannion teaches that the composition can be for parenteral administration. Mannion teaches factors that contribute to the stability of the composition, including pH and concentration of active ingredients, and teaches pH ranges and concentrations consistent with those instantly claimed. They further teach that “good stability” is seen in compositions with polyethylene glycol or propylene glycol upon extended storage at elevated temperatures. Mannion teaches that a composition comprising N-(4,6-bis-n-propylamino-[1,3,5] triazin-2-yl)-N-O-dimethyl-hydroxylamine hydrogen sulfate which results in minimal degradation (below 0.5%) of the compound on prolonged storage at 25°C at 60% relative humidity is achievable.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to follow the suggestions of Mannion to combine the prior art elements of N-(4,6-bis-n-propylamino-[1,3,5] triazin-2-yl)-N-O-dimethyl-hydroxylamine hydrogen sulfate, and pharmaceutically acceptable excipients of polyethylene glycol and/or propylene glycol, and adjust the concentration and pH of the composition to achieve a composition that maintains at least 90% of the compound after the recited accelerated storage conditions for 2 weeks, 1 month, 2 month, and 3 months. As set forth above, Mannion teaches strategies for achieving stable N-(4,6-bis-n-propylamino-[1,3,5] triazin-2-yl)-N-O-dimethyl-hydroxylamine hydrogen sulfate compositions; following these methods known in the prior art, one of ordinary skill in the art would predictably achieve the recited stability.
Further, as Mannion teaches the structural components of the formulation of instant claim 1 (i.e., N-(4,6-bis-n-propylamino-[1,3,5] triazin-2-yl)-N-O-dimethyl-hydroxylamine hydrogen sulfate and pharmaceutically acceptable excipients of propylene glycol, polyethylene glycol, or ethanol, and overlapping pH and concentrations), absent evidence to the contrary, the claimed stability properties will be present. See MPEP 2112.01 I., “[w]here the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). "When the PTO shows a sound basis for believing that the products of the applicant and the prior art are the same, the applicant has the burden of showing that they are not." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). Therefore, the prima facie case can be rebutted by evidence showing that the prior art products do not necessarily possess the characteristics of the claimed product. In re Best, 562 F.2d at 1255, 195 USPQ at 433. See also Titanium Metals Corp. v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985)”. See also MPEP 2112.01 II, “A chemical composition and its properties are inseparable”. There is currently no evidence of record demonstrating that the compositions of Mannion do not possess the claimed stability characteristics.
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 1-4, 18-19, 21-22, and 32 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 36-37 of copending Application No. 18/213,451 in view of Mannion et al. (US 2012/0295911 A1, published November 22, 2012; of record), hereafter “Mannion”.
Claims 1-4, 18-19, 21-22, and 32 are directed to an invention not patentably distinct from claims 36-37 of commonly assigned Application No. 18/213,451.
Both the instant claims and the claims of ‘451 are directed to a composition/formulation comprising a salt of N-(4,6-Bis-n-propylamino-[1,3,5] triazin-2-yl)-O,N-dimethyl-hydroxylamine and a pharmaceutically acceptable excipient.
The claims of ‘451 differ from the instant claims in that they do not recite that the formulation is parenteral, that the salt is hydrogen sulfate, or that the formulation maintains at least 90% of the compound after accelerated storage conditions. They further do not recite the pH, concentration of compound, identity of the excipient, or that the formulation is suitable for intramuscular administration.
Mannion teaches a composition useful in the treatment of breathing control diseases or disorders (abstract) which can be administered parenterally (paragraphs [0321]-[0323]). The composition comprises N-(4,6-bis-n-propylamino-[1,3,5] triazin-2-yl)-N-O-dimethyl-hydroxylamine (XXXV) or a salt thereof (paragraph [0015], claim 22); in one embodiment, the salt is the hydrogen sulfate salt (XXXVI) (paragraph [0018], claim 30). The composition further comprises a buffer and a liquid carrier (claim 29). Compositions can be those suitably developed for parenteral administration (paragraphs [0283], [0289], and [0321]-[0323]). The formulation of Mannion is taught to be administered by intramuscular route (claims 12 and 21).
Mannion teaches that XXXVI in a liquid carrier can be admixed with agents to adjust pH to optimize solubility and minimize degradation; suitable organic cosolvents include propylene glycol, polyethylene glycol 400, and ethanol (paragraph [0228]). Mannion teaches the preparation and evaluation of nine prototypes of XXXVI formulations, including those formulated with polyethylene glycol and propylene glycol (see paragraphs [0705]-[0707]). Mannion teaches that low pH contributes to instability and that good stability is seen in buffered PEG and propylene glycol formulations as well as simple solutions of the salt in PEG or propylene glycol (paragraph [0707]); such formulations result in only small amounts of impurities after storage at 60 °C for 4 weeks (see tables at paragraph [0707]). Mannion further teaches that a formulation of XXXVI can be developed which, under formal GMP stability tests (25 °C/60% relative humidity for 9 months, see Table 12I.1), indicate that a single degradant was formed and can be expected to remain below 0.5% for at least two years (paragraph [0225]).
The composition of Mannion has a pH from about 2.5 to about 6 (claim 35). It would have been prima facie obvious to provide the claims of copending Application ‘451 with a pH of about 2.5-6 because Mannion teaches that the pH of the composition can be adjusted in order to substantially improve stability of the composition (paragraphs [0224] and [0227]).
The composition of Mannion has a concentration of XXXV, or salt thereof, of about 10 mg/mL (claim 40). Formulation prototypes of Mannion were prepared at 25 mg/mL XXXV as free base, which corresponds to 35 mg/mL XXXVI (paragraph [0223]). They further teach that reducing the concentration by about half allows for an increase in pH, which can result in improved stability of the formulation (paragraph [0224]). It would have been prima facie obvious to provide the claims of copending Application ‘451 with the concentration of XXXVI taught by Mannion to result in formulations with improved stability as described above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the composition claimed by ‘451 with the hydrogen sulfate salt, pH, concentration of compound, and identity of the excipient to make a parenteral formulation suitable for intramuscular administration that maintains at least 90% of the compound after accelerated storage conditions of 25°C at 60% relative humidity for 2 weeks, 1 month, 2 months, and 3 months as suggested by Mannion.
One of ordinary skill would have been motivated to do so because Mannion teaches that such compositions are useful in the treatment of breathing control diseases or disorders (abstract) and optimization of factors such as concentration, pH, and excipients can result in stable formulations with minimal compound degradation after accelerated storage conditions, as described above.
Given the subject matter of the instant claims is obvious and the structural components of the instant claims overlaps those of the claims of ‘451, the instant claims are rejected on the ground of nonstatutory double patenting. This is a provisional nonstatutory double patenting rejection.
The U.S. Patent and Trademark Office may not institute a derivation proceeding in the absence of a timely filed petition. The USPTO normally will not institute a derivation proceeding between applications or a patent and an application having common ownership (see 37 CFR 42.411). Commonly assigned Application No. 18/213,451, discussed above, may form the basis for a rejection of the noted claims under 35 U.S.C. 102 or 103 if the commonly assigned case qualifies as prior art under 35 U.S.C. 102(a)(2) and the patentably indistinct inventions were not commonly owned or deemed to be commonly owned not later than the effective filing date under 35 U.S.C. 100(i) of the claimed invention.
In order for the examiner to resolve this issue the applicant or patent owner can provide a statement under 35 U.S.C. 102(b)(2)(C) and 37 CFR 1.104(c)(4)(i) to the effect that the subject matter and the claimed invention, not later than the effective filing date of the claimed invention, were owned by the same person or subject to an obligation of assignment to the same person. Alternatively, the applicant or patent owner can provide a statement under 35 U.S.C. 102(c) and 37 CFR 1.104(c)(4)(ii) to the effect that the subject matter was developed and the claimed invention was made by or on behalf of one or more parties to a joint research agreement that was in effect on or before the effective filing date of the claimed invention, and the claimed invention was made as a result of activities undertaken within the scope of the joint research agreement; the application must also be amended to disclose the
names of the parties to the joint research agreement.
A showing that the inventions were commonly owned or deemed to be commonly owned not later than the effective filing date under 35 U.S.C. 100(i) of the claimed invention will preclude a rejection under 35 U.S.C. 102 or 103 based upon the commonly assigned case. Alternatively, applicant may take action to amend or cancel claims such that the applications, or the patent and the application, no longer contain claims directed to patentably indistinct inventions.
Claims 1-4, 18-19, 21-22, and 32 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 19 of copending Application No. 18/289,288 in view of Mannion et al. (US 2012/0295911 A1, published November 22, 2012; of record), hereafter “Mannion”.
Claims 1-4, 17-22, and 32 are directed to an invention not patentably distinct from claim 19 of commonly assigned Application No. 18/289,288.
The claims of ‘288 are directed to a composition comprising a compound of Formula I or a salt thereof and a pharmaceutically acceptable excipient, where the compound of Formula I or salt thereof is inclusive of the instantly claimed salt of N-(4,6-Bis-n-propylamino-[1,3,5] triazin-2-yl)-O,N-dimethyl-hydroxylamine.
The claims of ‘288 differ from the instant claims in that they do not recite that the formulation is parenteral, that the salt is hydrogen sulfate, or that the formulation maintains at least 90% of the compound after accelerated storage conditions. They further do not recite the pH, concentration of compound, identity of the excipient, or that the formulation is suitable for intramuscular administration.
Mannion teaches a composition useful in the treatment of breathing control diseases or disorders (abstract) which can be administered parenterally (paragraphs [0321]-[0323]). The composition comprises N-(4,6-bis-n-propylamino-[1,3,5] triazin-2-yl)-N-O-dimethyl-hydroxylamine (XXXV) or a salt thereof (paragraph [0015], claim 22); in one embodiment, the salt is the hydrogen sulfate salt (XXXVI) (paragraph [0018], claim 30). The composition further comprises a buffer and a liquid carrier (claim 29). Compositions can be those suitably developed for parenteral administration (paragraphs [0283], [0289], and [0321]-[0323]). The formulation of Mannion is taught to be administered by intramuscular route (claims 12 and 21).
Mannion teaches that XXXVI in a liquid carrier can be admixed with agents to adjust pH to optimize solubility and minimize degradation; suitable organic cosolvents include propylene glycol, polyethylene glycol 400, and ethanol (paragraph [0228]). Mannion teaches the preparation and evaluation of nine prototypes of XXXVI formulations, including those formulated with polyethylene glycol and propylene glycol (see paragraphs [0705]-[0707]). Mannion teaches that low pH contributes to instability and that good stability is seen in buffered PEG and propylene glycol formulations as well as simple solutions of the salt in PEG or propylene glycol (paragraph [0707]); such formulations result in only small amounts of impurities after storage at 60 °C for 4 weeks (see tables at paragraph [0707]). Mannion further teaches that a formulation of XXXVI can be developed which, under formal GMP stability tests (25 °C/60% relative humidity for 9 months, see Table 12I.1), indicate that a single degradant was formed and can be expected to remain below 0.5% for at least two years (paragraph [0225]).
The composition of Mannion has a pH from about 2.5 to about 6 (claim 35). It would have been prima facie obvious to provide the claims of copending Application ‘288 with a pH of about 2.5-6 because Mannion teaches that the pH of the composition can be adjusted in order to substantially improve stability of the composition (paragraphs [0224] and [0227]).
The composition of Mannion has a concentration of XXXV, or salt thereof, of about 10 mg/mL (claim 40). Formulation prototypes of Mannion were prepared at 25 mg/mL XXXV as free base, which corresponds to 35 mg/mL XXXVI (paragraph [0223]). They further teach that reducing the concentration by about half allows for an increase in pH, which can result in improved stability of the formulation (paragraph [0224]). It would have been prima facie obvious to provide the claims of copending Application ‘288 with the concentration of XXXVI taught by Mannion to result in formulations with improved stability as described above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the composition claimed by ‘288 with the hydrogen sulfate salt, pH, concentration of compound, and identity of the excipient to make a parenteral formulation suitable for intramuscular administration that maintains at least 90% of the compound after accelerated storage conditions of 25°C at 60% relative humidity for 2 weeks, 1 month, 2 months, and 3 months as suggested by Mannion.
One of ordinary skill would have been motivated to do so because Mannion teaches that such compositions are useful in the treatment of breathing control diseases or disorders (abstract) and optimization of factors such as concentration, pH, and excipients can result in stable formulations with minimal compound degradation after accelerated storage conditions, as described above.
Given the subject matter of the instant claims is obvious and the structural components of the instant claims overlaps those of the claims of ‘288, the instant claims are rejected on the ground of nonstatutory double patenting. This is a provisional nonstatutory double patenting rejection.
The U.S. Patent and Trademark Office may not institute a derivation proceeding in the absence of a timely filed petition. The USPTO normally will not institute a derivation proceeding between applications or a patent and an application having common ownership (see 37 CFR 42.411). Commonly assigned Application No. 18/289,288, discussed above, may form the basis for a rejection of the noted claims under 35 U.S.C. 102 or 103 if the commonly assigned case qualifies as prior art under 35 U.S.C. 102(a)(2) and the patentably indistinct inventions were not commonly owned or deemed to be commonly owned not later than the effective filing date under 35 U.S.C. 100(i) of the claimed invention.
In order for the examiner to resolve this issue the applicant or patent owner can provide a statement under 35 U.S.C. 102(b)(2)(C) and 37 CFR 1.104(c)(4)(i) to the effect that the subject matter and the claimed invention, not later than the effective filing date of the claimed invention, were owned by the same person or subject to an obligation of assignment to the same person. Alternatively, the applicant or patent owner can provide a statement under 35 U.S.C. 102(c) and 37 CFR 1.104(c)(4)(ii) to the effect that the subject matter was developed and the claimed invention was made by or on behalf of one or more parties to a joint research agreement that was in effect on or before the effective filing date of the claimed invention, and the claimed invention was made as a result of activities undertaken within the scope of the joint research agreement; the application must also be amended to disclose the
names of the parties to the joint research agreement.
A showing that the inventions were commonly owned or deemed to be commonly owned not later than the effective filing date under 35 U.S.C. 100(i) of the claimed invention will preclude a rejection under 35 U.S.C. 102 or 103 based upon the commonly assigned case. Alternatively, applicant may take action to amend or cancel claims such that the applications, or the patent and the application, no longer contain claims directed to patentably indistinct inventions.
Claims 1-4, 18-19, 21-22, and 32 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 69 of copending Application No. 18/795,777 in view of Mannion et al. (US 2012/0295911 A1, published November 22, 2012; of record), hereafter “Mannion”.
Claims 1-4, 18-19, 21-22, and 32 are directed to an invention not patentably distinct from claim 69 of commonly assigned Application No. 18/795,777.
The claims of ‘777 are directed to a composition comprising a compound of Formula I or a salt thereof and a pharmaceutically acceptable excipient, where Formula I or a salt thereof is inclusive of the instantly claimed salt of N-(4,6-Bis-n-propylamino-[1,3,5] triazin-2-yl)-O,N-dimethyl-hydroxylamine.
The claims of ‘777 differ from the instant claims in that they do not recite that the formulation is parenteral, that the salt is hydrogen sulfate, or that the formulation maintains at least 90% of the compound after accelerated storage conditions. They further do not recite the pH, concentration of compound, identity of the excipient, or that the formulation is suitable for intramuscular administration.
Mannion teaches a composition useful in the treatment of breathing control diseases or disorders (abstract) which can be administered parenterally (paragraphs [0321]-[0323]). The composition comprises N-(4,6-bis-n-propylamino-[1,3,5] triazin-2-yl)-N-O-dimethyl-hydroxylamine (XXXV) or a salt thereof (paragraph [0015], claim 22); in one embodiment, the salt is the hydrogen sulfate salt (XXXVI) (paragraph [0018], claim 30). The composition further comprises a buffer and a liquid carrier (claim 29). Compositions can be those suitably developed for parenteral administration (paragraphs [0283], [0289], and [0321]-[0323]). The formulation of Mannion is taught to be administered by intramuscular route (claims 12 and 21).
Mannion teaches that XXXVI in a liquid carrier can be admixed with agents to adjust pH to optimize solubility and minimize degradation; suitable organic cosolvents include propylene glycol, polyethylene glycol 400, and ethanol (paragraph [0228]). Mannion teaches the preparation and evaluation of nine prototypes of XXXVI formulations, including those formulated with polyethylene glycol and propylene glycol (see paragraphs [0705]-[0707]). Mannion teaches that low pH contributes to instability and that good stability is seen in buffered PEG and propylene glycol formulations as well as simple solutions of the salt in PEG or propylene glycol (paragraph [0707]); such formulations result in only small amounts of impurities after storage at 60 °C for 4 weeks (see tables at paragraph [0707]). Mannion further teaches that a formulation of XXXVI can be developed which, under formal GMP stability tests (25 °C/60% relative humidity for 9 months, see Table 12I.1), indicate that a single degradant was formed and can be expected to remain below 0.5% for at least two years (paragraph [0225]).
The composition of Mannion has a pH from about 2.5 to about 6 (claim 35). It would have been prima facie obvious to provide the claims of copending Application ‘777 with a pH of about 2.5-6 because Mannion teaches that the pH of the composition can be adjusted in order to substantially improve stability of the composition (paragraphs [0224] and [0227]).
The composition of Mannion has a concentration of XXXV, or salt thereof, of about 10 mg/mL (claim 40). Formulation prototypes of Mannion were prepared at 25 mg/mL XXXV as free base, which corresponds to 35 mg/mL XXXVI (paragraph [0223]). They further teach that reducing the concentration by about half allows for an increase in pH, which can result in improved stability of the formulation (paragraph [0224]). It would have been prima facie obvious to provide the claims of copending Application ‘777 with the concentration of XXXVI taught by Mannion to result in formulations with improved stability as described above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the composition claimed by ‘777 with the hydrogen sulfate salt, pH, concentration of compound, and identity of the excipient to make a parenteral formulation suitable for intramuscular administration that maintains at least 90% of the compound after accelerated storage conditions of 25°C at 60% relative humidity for 2 weeks, 1 month, 2 months, and 3 months as suggested by Mannion.
One of ordinary skill would have been motivated to do so because Mannion teaches that such compositions are useful in the treatment of breathing control diseases or disorders (abstract) and optimization of factors such as concentration, pH, and excipients can result in stable formulations with minimal compound degradation after accelerated storage conditions, as described above.
Given the subject matter of the instant claims is obvious and the structural components of the instant claims overlaps those of the claims of ‘777, the instant claims are rejected on the ground of nonstatutory double patenting. This is a provisional nonstatutory double patenting rejection.
The U.S. Patent and Trademark Office may not institute a derivation proceeding in the absence of a timely filed petition. The USPTO normally will not institute a derivation proceeding between applications or a patent and an application having common ownership (see 37 CFR 42.411). Commonly assigned Application No. 18/795,777, discussed above, may form the basis for a rejection of the noted claims under 35 U.S.C. 102 or 103 if the commonly assigned case qualifies as prior art under 35 U.S.C. 102(a)(2) and the patentably indistinct inventions were not commonly owned or deemed to be commonly owned not later than the effective filing date under 35 U.S.C. 100(i) of the claimed invention.
In order for the examiner to resolve this issue the applicant or patent owner can provide a statement under 35 U.S.C. 102(b)(2)(C) and 37 CFR 1.104(c)(4)(i) to the effect that the subject matter and the claimed invention, not later than the effective filing date of the claimed invention, were owned by the same person or subject to an obligation of assignment to the same person. Alternatively, the applicant or patent owner can provide a statement under 35 U.S.C. 102(c) and 37 CFR 1.104(c)(4)(ii) to the effect that the subject matter was developed and the claimed invention was made by or on behalf of one or more parties to a joint research agreement that was in effect on or before the effective filing date of the claimed invention, and the claimed invention was made as a result of activities undertaken within the scope of the joint research agreement; the application must also be amended to disclose the
names of the parties to the joint research agreement.
A showing that the inventions were commonly owned or deemed to be commonly owned not later than the effective filing date under 35 U.S.C. 100(i) of the claimed invention will preclude a rejection under 35 U.S.C. 102 or 103 based upon the commonly assigned case. Alternatively, applicant may take action to amend or cancel claims such that the applications, or the patent and the application, no longer contain claims directed to patentably indistinct inventions.
Response to Arguments
Applicants’ arguments filed 03/02/2026 have been fully considered.
Regarding the claim rejections under 35 USC § 103, Applicant argues that amended claim 1 recites a specific species of formula (I), a specific salt, specific excipients, a specific concentration, and a specific pH range, wherein the composition provides a specific stability profile, and that when the cited art is properly considered in its entirety, there is no reasonable expectation that one of ordinary skill in the art would have successfully arrived at the presently amended claim. Applicant argue that, similarly to Coalition to Affordable Drugs, Mannion included a very broad teaching of components of a formulation, and submits that Mannion does not teach or suggest the particular selection as recited in the present claims.
These arguments are unpersuasive. As set forth in the above rejections, Mannion specifically claims compositions comprising the hydrogen sulfate salt of N-(4,6-bis-n-propylamino-[1,3,5] triazin-2-yl)-N-O-dimethyl-hydroxylamine (claim 30), and exemplifies the preparation and evaluation of nine prototypes of XXXVI formulations, including those formulated with polyethylene glycol (a polyalkylene glycol) and propylene glycol (an alkylene glycol) (see paragraphs [0705]-[0707]). Mannion further claims a pH range consistent with that instantly claimed (claims 35 and 37). Mannion further claims a composition with a concentration of XXXV, or salt thereof, of about 10 mg/mL (claim 40), consistent with the concentration of claim 1; Mannion further teaches formulation prototypes were prepared at 25 mg/mL XXXV as free base, which corresponds to 35 mg/mL XXXVI (paragraph [0223]) and that reducing the concentration by about half allows for an increase in pH, which can result in improved stability of the formulation (paragraph [0224]).
In specifically claiming and exemplifying the structural components of the claimed formulation, the Examiner respectfully maintains that Mannion provides sufficient guidance to one of ordinary skill in the art to arrive at the structural components of the formulation of the instant claims, as detailed in the above rejections. Absent evidence to the contrary, the claimed stability properties will be present in such formulations; per MPEP 2112.01 II, “A chemical composition and its properties are inseparable”.
Nevertheless, Mannion further demonstrates that a formulation of XXXVI can be developed which, under formal GMP stability tests (25 °C/60% relative humidity for 9 months, see Table 12I.1), indicate that a single degradant was formed and can be expected to remain below 0.5% for at least two years (paragraph [0225]). Mannion teaches that “good stability” is seen in buffered PEG and propylene glycol formulations as well as simple solutions of the salt in PEG or propylene glycol (paragraph [0707]). Mannion further teaches that a both pH and concentration, contribute to the stability of such formulations (see for example paragraphs [0024] and [0707]).
Thus, Mannion provides motivation to the skilled artisan to adjust pH and concentration conditions as a strategy for achieving stable N-(4,6-bis-n-propylamino-[1,3,5] triazin-2-yl)-N-O-dimethyl-hydroxylamine hydrogen sulfate compositions; following these methods known in the prior art, one of ordinary skill in the art would predictably achieve the recited stability. While Mannion does not explicitly exemplify the claimed formulation with the claimed stability conditions, the Examiner respectfully maintains that combining the teachings of Mannion to reach the instantly claimed formulation is well within the capabilities of one of ordinary skill; per MPEP 2141 II. C., "A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton." KSR, 550 U.S. at 421, 82 USPQ2d at 1397. "[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle." Id. at 420, 82 USPQ2d at 1397.
Regarding the non-statutory double patenting rejections, Applicant requests that the present rejection be held in abeyance until allowable subject matter is identified.
In response, the Examiner notes that a request to hold a rejection in abeyance is not a proper response to a rejection. Rather, a request to hold a matter in abeyance may only be made in response to an OBJECTION or REQUIREMENTS AS TO FORM (see MPEP 37 CFR 1.111(b) and 714.02). Thus, the double patenting rejections set forth above have been maintained as no action regarding these rejections has been taken by Applicant at this time.
Conclusion
Applicant’s arguments are considered unpersuasive. Accordingly, THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JUDITH M KAMM whose telephone number is (703)756-4575. The examiner can normally be reached M-F 8:00 am-4:30 pm EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Bethany Barham can be reached at (571)272-6175. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/BETHANY P BARHAM/Supervisory Patent Examiner, Art Unit 1611
/J.M.K./Examiner, Art Unit 1611
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