DETAILED ACTION
This office action is in response to applicant’s filing dated March 9, 2026.
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 .
Status of claims
Claims 1 - 9 are pending in the instant application. Acknowledgment is made of Applicant’s amendments filed March 9, 2026. Acknowledgment is made of Applicant’s cancelation of claims 19 – 24 and 28 - 32.
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1 – 9, drawn to a pharmaceutical composition for subcutaneous injection comprising flumazenil and at least one pharmaceutically acceptable excipient in the reply filed on March 9, 2026 is acknowledged. Applicant cancelled claims related to nonelected inventions.
Claims 1 – 9 are presently under examination.
Priority
The present application is a 371 of PCT/US2021/059763, filed November 17, 2021 and claims the benefits of priority of U.S. Provisional Application No. 63/115,485, filed on November 18, 2020.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 11/21/2024 and 03/09/2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Drawings
Acknowledgement is made of the drawings received on May 17, 2023. These drawings are accepted.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1 – 9 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Peled et al (US 2012/0295893 A1, cited in IDS, filed 11/21/2024, hereinafter Peled).
Instant claims are drawn to a pharmaceutical composition, comprising:
(i) flumazenil or a pharmaceutically acceptable salt, solvate or hydrate thereof;
and
(ii) at least one pharmaceutically acceptable excipient, wherein the pharmaceutical composition is in a form for dosing or administration by subcutaneous injection; wherein the concentration of flumazenil in the pharmaceutical composition is greater than 0.7 mg/mL, and where the pharmaceutical composition has a pH of about 5 to about 8.
The pharmaceutically acceptable excipient in said composition comprises a complexing agent, added in a molar ratio from about 1:10 to about 10:1 to flumazenil; wherein complexing agent comprises substituted or unsubstituted cyclodextrin, wherein substituted cyclodextrin is substituted with at least one acidic functional group such as substituted cyclodextrin is sulfobutyl-ether-beta-cyclodextrin (SBEBCD).
Said pharmaceutical composition further comprises an emulsifying agent, a surfactant, a solubilizing agent, a co-solvent or a combination thereof, wherein co-solvent is ethanol, propylene glycol or glycerin.
Peled teaches a pharmaceutical composition comprising flumazenil as an active ingredient, a solubilizing agent selected from an alcohol (e.g. ethanol), a glycol (e.g. propylene glycol) and a combination thereof, a cyclodextrin, a buffering agent, a penetration enhancer and optionally a preservative (page 8, [0116]). The concentration of flumazenil in the pharmaceutical composition taught by Peled is 2 mg/mL or 4 mg/mL and pH of formulations after preparation is e.g.: 5.8, 6.4, 7.03, 7.38 (page 26, [0382], page 32, Table 26). Said pharmaceutical compositions are provided as sublingual dosage form, transdermal dosage form, subdermal dosage form ("subdermal" is synonymous with "subcutaneous"(page 6, [0094])), aerosol form (for inhalation) and transmucosal dosage form. (page 3, [0024]). The cyclodextrin component of the formulations can be present in an amount from about 10% to about 95% w/w, preferably about 60% based on the formulations (page 9, [0137]). According to the flumazenil formulations (e.g. F26) disclosed in Tables 24 - 26 (pages 31 – 32), the molar ratio of cyclodextrin (HPCD) to flumazenil is approximately 10:1 (calculated from molar mass of flumazenil is 303.29 g/mol and molar mass of HPCD is ~1500 g/mol). Under term "cyclodextrin" Peled means α-, β- or γ-cyclodextrin or a derivative thereof. Suitable cyclodextrin derivatives for use in the formulations are e.g. hydroxypropyl derivatives of α-, β- or γ-cyclodextrin or sulfobutylether β-cyclodextrin (SBEBCD). Addition of organic solvents, such as ethanol, to the aqueous complexation media can result in enhanced complexation efficiency (page 9, [0135]).
Thus, Peled teaches pharmaceutical formulations, where all the components are equivalent to those of the instant invention, and all the components are present in the same amounts or ratios as required by instant claims. MPEP 2131.03 states: "[W]hen, as by a recitation of ranges or otherwise, a claim covers several compositions, the claim is ‘anticipated’ if one of them is in the prior art." Titanium Metals Corp. v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985) (citing In re Petering, 301 F.2d 676, 682, 133 USPQ 275, 280 (CCPA 1962)) (emphasis in original) (Claims to titanium (Ti) alloy with 0.6-0.9% nickel (Ni) and 0.2-0.4% molybdenum (Mo) were held anticipated by a graph in a Russian article on Ti-Mo-Ni alloys because the graph contained an actual data point corresponding to a Ti alloy containing 0.25% Mo and 0.75% Ni and this composition was within the claimed range of compositions.). "If the prior art discloses a point within the claimed range, the prior art anticipates the claim." UCB, Inc. v. Actavis Labs. UT, Inc., 65 F.4th 679, 687, 2023 USPQ2d 448 (Fed. Cir. 2023).
Thus, the compositions taught by Peled anticipate instantly claimed compositions.
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 – 6 and 9 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 5 and 7 of U.S. Patent No. US 11,534,454 B2.
Although the claims at issue are not identical, they are not patentably distinct from each other because patented claims are directed to a pharmaceutical composition, comprising:
(i) a pharmaceutical compound, or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof, wherein the pharmaceutical compound comprises a protonated nitrogen atom; and
(ii) a complexing agent, wherein the complexing agent is an acid-substituted cyclodextrin, such as sulfobutylether-β-cyclodextrin, comprising a plurality of acidic functional groups, wherein the plurality of acidic functional groups comprise an acidic group which acts as a counterion for the protonated nitrogen atom of the pharmaceutical compound; wherein the pharmaceutical composition is formulated for subcutaneous or intramuscular administration as an aqueous formulation having a pH of at least about 5.5 to about 8, wherein the osmolality of the pharmaceutical composition is lower than an osmolality of a composition comprising an equivalent amount of a freebase form of the pharmaceutical compound encapsulated within a hydrophobic core of a salt of the complexing agent; wherein the composition has a molar ratio of the pharmaceutical compound to the complexing agent from about 1 :4 to about 1:10.
Instant claims are directed to a pharmaceutical composition, comprising:
(i) flumazenil or a pharmaceutically acceptable salt, solvate or hydrate thereof;
and
(ii) at least one pharmaceutically acceptable excipient, wherein the pharmaceutical composition is in a form for dosing or administration by subcutaneous injection; where the pharmaceutical composition has a pH of about 5 to about 8.
The pharmaceutically acceptable excipient in said composition comprises a complexing agent, added in a molar ratio from about 1:10 to about 10:1 to flumazenil; wherein complexing agent comprises substituted or unsubstituted cyclodextrin, wherein substituted cyclodextrin is substituted with at least one acidic functional group, or excipient is sulfobutyl-ether-beta-cyclodextrin (SBEBCD).
Since flumazenil is the compound having a structure of substituted benzodiazepine:
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, which structure has a basic nitrogen and so, when forming salts, nitrogen atom becomes protonated, flumazenil falls within the scope of definition recited by patented claim 1: “a pharmaceutical compound, […]wherein the pharmaceutical compound comprises a protonated nitrogen atom”. Although instant claims are silent about osmolality of the pharmaceutical composition, this is functional limitation which is an inherent characteristic of the same composition.
Thus, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present invention to take known drug (flumazenil) which has a basic nitrogen atom in the molecular structure and incorporate it into known pharmaceutical composition to arrive at claimed composition. The one of ordinary skills would be motivated to do so in search of a formulation with improved desired properties with the reasonable expectation of success.
Claims 1 – 4 and 6 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 4 of U.S. Patent No. US 12,472,201 B2.
Although the claims at issue are not identical, they are not patentably distinct from each other because patented claims are directed to a pharmaceutical composition, comprising:
(i) a cationic pharmaceutical compound, or an enantiomer, comprising a protonated nitrogen atom; and
(ii) a substituted cyclodextrin comprising a plurality of anionic functional groups, wherein substantially all of the plurality of anionic functional groups of the substituted cyclodextrin are deprotonated, and at least one of the plurality of anionic functional groups acts as a counterion for the protonated nitrogen atom of the cationic pharmaceutical compound, wherein a molar ratio of the cationic pharmaceutical compound to the substituted cyclodextrin from about 1:2 to about 1:10, and wherein the pharmaceutical composition comprising effective amounts of the cationic pharmaceutical compound and the substituted cyclodextrin has an osmolality, when in solution, that is at least about 10% less than a corresponding pharmaceutical composition prepared from a salt of the cationic pharmaceutical compound and a sodium salt of the substituted cyclodextrin.
Instant claims are directed to a pharmaceutical composition, comprising:
(i) flumazenil or a pharmaceutically acceptable salt, solvate or hydrate thereof;
and
(ii) at least one pharmaceutically acceptable excipient, wherein the pharmaceutical composition is in a form for dosing or administration by subcutaneous injection; where the pharmaceutically acceptable excipient comprises a complexing agent, added in a molar ratio from about 1:10 to about 10:1 to flumazenil; wherein complexing agent comprises substituted cyclodextrin.
Since flumazenil is the compound having a structure of substituted benzodiazepine:
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, which structure has a basic nitrogen and so, when forming salts, flumazenil becomes a “cationic pharmaceutical compound comprising a protonated nitrogen atom”, thus flumazenil falls within the scope of definition of the compound recited by patented claim 1. Although instant claims are silent about osmolality of the pharmaceutical composition, this is functional limitation which is an inherent characteristic of the same composition.
Thus, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present invention to take known drug (flumazenil) which has a basic nitrogen atom in the molecular structure and incorporate it into known pharmaceutical composition to arrive at claimed composition. The one of ordinary skills would be motivated to do so in search of a formulation with improved desired properties with the reasonable expectation of success.
Conclusion
Claims 1 – 9 are rejected. No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ELENA V VISHNYAKOVA whose telephone number is (571)272-3781. The examiner can normally be reached 7:30am - 5pm ET.
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/E.V.V./Examiner, Art Unit 1691
/SAVITHA M RAO/Primary Examiner, Art Unit 1691
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