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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on December 17, 2025 has been entered.
DETAILED ACTION
3. Claims 1, 4 – 9, 13, 15 – 17, and 19 – 25 are pending in this application. Applicant’s Amendment and Remarks, filed December 17, 2025, is entered, wherein claims 1, 13, and 17 are amended, claims 8 – 9, 13, 15 – 17, and 23 – 24 are withdrawn, claims 2 – 3, 10 – 12, 14, and 18 are canceled, and claim 25 is new.
Priority
4. This is a domestic application filed February 8, 2023.
Withdrawn Rejections
5. The rejection of claims 1, 4 – 7, and 19 – 22 in the previous Office Action, mailed October 20, 2025, under 35 U.S.C. 103 as being unpatentable over Kirsh et al. in view of Price et al. has been considered and is withdrawn in view of the amended claim 1.
The rejection of claims 1, 4 – 7, and 19 – 22 in the previous Office Action, mailed October 20, 2025, on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 2 and 4 – 5 of copending Application No. 18/591,513 in view of Kirsh et al. has been considered and is withdrawn in view of the amended claim 1.
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 1, 4 – 5, 19, 21 – 22, and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Hering et al. (ACS Chemical Biology, 2020, Vol. 15, Issue 11, page 2885 – 2895, Reference included with PTO-892) in view of Jain et al. (International Journal of Pharmaceutics, 2011, Vol. 409, Issue 1 – 2, page 237 – 409, Reference included with PTO-892).
a. Regarding claims 1, 4 – 5, 19, 21 – 22, and 25, Hering et al. teach that the antibiotic compound tunicamycin is a natural product inhibitor of MraY that is also toxic to eukaryotes through the binding to GPT. Therefore, Hering et al. discuss and compare tunicamycin and its modified versions (Abstract). TunR2 is one modified tunicamycin being discussed. Significant reduction in toxicity against eukaryotic cells has been observed in TunR2 compared to native tunicamycin (page 2888, Left Col., para. 1). Hering et al. further observed that TunR2 has a IC50 value about 1.5 times higher than that of native tunicamycin. Upon complete hydrolytic opening of the uracil ring, there is a large drop in potency toward MraY (page 2891. Right Col., para. 3).
However, Hering et al. do not teach an aqueous emulsion containing a complex of at least one antibiotic and sodium deoxycholate, wherein the at least one antibiotic is TunR2.
Jain et al. teach a ciprofloxacin surf-plexes with sodium deoxycholate, which is a hydrophobic ion-pair complexes of ciprofloxacin with sodium deoxycholate, loaded in oil-in-water submicron emulsion (Abstract). Ciprofloxacin is a powerful broad-spectrum antibiotic useful for the treatment of several types of infections (page 237, Left Col., para. 1). However, ciprofloxacin is limited by low encapsulation efficiency, rapid leakage, and poor storage stability, which lead to poor bioavailability through variety of routes (page 237, Right Col., para. 1). The formulation is prepared using equimolar concentration of ciprofloxacin and sodium deoxycholate (page 238, Left Col., para. 5). The surf-plexes can improve loading efficiency into submicron emulsion. Overall, the proposed loading technique increases the drug/lipid ratio due to improvement in lipophilicity, thereby, allowing submicron emulsion to carry and delivery larger amounts of antibiotics to infected cells (page 273, Right Col., para. 2). The technique also minimizes the potential loss of expensive drugs during the formulation process and dramatically improves the retention capacity (page 238, Left Col., para. 1). Therefore, the ciprofloxacin surf-plexes with sodium deoxycholate loaded in oil-in-water submicron emulsion is prepared to improve the loading efficiency of ciprofloxacin within the submicron emulsion and to improve the antimicrobial efficacy of formulations (page 238, Left Col., para. 2). In the study, it is found that the formulation has twice the antimicrobial activity compared to the free ciprofloxacin (page 241, Left Col., para. 2). Furthermore, the mean droplet size does not differ markedly even when the formulation is stored for a period of 3 months at 37 ⁰C (page 242, Left Col., para. 1). Jain et al. conclude that surfactant based ionic complex formation incorporated in surface modified submicron emulsion is a promising approach to improve pay-load efficiency of poorly water soluble drugs with improved antimicrobial efficacy and pharmacokinetic profile (Abstract).
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 TunR2 as taught by Hering et al. into an aqueous emulsion containing a complex of TunR2 and sodium deoxycholate in view of Jain et al. because Hering et al. teach that TunR2 provides reduced toxicity compared to native tunicamycin, but exhibits lower potency, thereby creating a need to improve its antimicrobial performance, and Jain et al. teach that an antibiotic complexed with sodium deoxycholate in an oil-in-water submicron emulsion exhibits improved antimicrobial activity. One would have been motivated to formulate TunR2 as taught by Hering et al. into an aqueous emulsion containing a complex of TunR2 and sodium deoxycholate in view of Jain et al. because Jain et al. explicitly teach that the formulation is able to improve antimicrobial performance of an antibiotic and Jain et al. suggest that such formulation is a promising approach for other antibiotic. The combination of Hering et al. and Jain et al. teaches the claimed invention, therefore, the enhanced functional properties, such as solubility, are necessarily present. One of ordinary skill in the art would have had a reasonable expectation of success to formulate TunR2 as taught by Hering et al. into an aqueous emulsion containing a complex of TunR2 and sodium deoxycholate in view of Jain et al. because Hering et al. teach that TunR2 exhibits lower potency, thereby providing motivation to modification, and Jain et al. teach surfactant based ionic complex formation incorporated in surface modified submicron emulsion that is exemplified by ciprofloxacin to show improvement in antimicrobial efficacy and Jain et al. teach that such formulation is a promising approach for other drugs.
Claims 6 – 7 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Hering et al. (ACS Chemical Biology, 2020, Vol. 15, Issue 11, page 2885 – 2895, Reference included with PTO-892) in view of Jain et al. (International Journal of Pharmaceutics, 2011, Vol. 409, Issue 1 – 2, page 237 – 409, Reference included with PTO-892) as applied to claims 1, 4 – 5, 19, 21 – 22, and 25 above, and further in view of Price et al. (The Journal of Antibiotics, 2019, Vol. 72, Issue 11, page 807 – 815, first cited in the previous Office Action mailed February 11, 2025).
b. Regarding claims 6 – 7 and 20, the references teach the limitations discussed above.
However, these references do not teach the formulation further comprises a β-lactam antibiotic, wherein the β-lactam antibiotic is a penicillin.
Price et al. teaches β-lactams are the most widely used group of antibiotics in human health and agriculture. Several compounds, including tunicamycin, can enhance the antibacterial activity of the β-lactams to the extent of overcoming resistance, but the mammalian toxicity of tunicamycin has precluded its use in this role. Selective hydrogenation of tunicamycin produces modified compounds (TunR2), which retain the enhancement of β-lactams while having much lower mammalian toxicity. Price et al. also discloses that TunR2 enhance the antibacterial activity of multiple β-lactam family members, including penicillins, to a similar extent as does the native tunicamycin. These results support the potential of low toxicity tunicamycin analogs (TunR2) as clinically valid, synergistic enhancers for a broad group of β-lactam antibiotics (Abstract). Furthermore, Price et al. teaches that the TUN-free control wells (columns 1 – 3) received 10 μL of DMSO, the stock solution solvent (page 814, Left Col., para. 2).
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 combine the complex of TunR2 and sodium deoxycholate in submicron emulsion as taught by Hering et al. and Jain et al. with β-lactam antibiotic, such as penicillin, in view of Price et al. because Price et al. teach that the combination of TunR2 and penicillin exhibits synergistic effect. One would have been motivated to combine the complex of TunR2 and sodium deoxycholate in submicron emulsion as taught by Hering et al. and Jain et al. with β-lactam antibiotic, such as penicillin, in view of Price et al. to achieve a formulation with improved antibacterial activity because Price et al. provide evidence that TunR2 is a synergistic enhancer for penicillin. Therefore, one of the skills in the art would have had a reasonable expectation of success to combine the complex of TunR2 and sodium deoxycholate in submicron emulsion as taught by Hering et al. and Jain et al. with β-lactam antibiotic, such as penicillin, in view of Price et al. because Price et al. teach that TunR2 has a lower toxicity and it will exhibit synergistic effects when combined with penicillin, thereby, yielding predictable and improved results.
Responses to Applicant’s Remarks:
Applicant’s Remarks, filed December 17, 2025, have been fully considered and are found to be not persuasive.
Regarding Kirsh et al. and Price et al., Applicant argues that these references do not teach or suggest the pending claims because claim 1 has been amended to recite an aqueous emulsion containing a complex of at least one antibiotic and sodium deoxycholate. Kirsh et al. and Price et al., alone or in combination, do not teach a complex of tunicamycin and sodium deoxycholate, but only tunicamycin derivative incorporated into a deoxycholic acid sodium salt dissolved in DMA. However, the arguments are moot because the new rejection no longer relies on the combination of Kirsh et al. and Price et al. The new rejection is based on the teachings of Hering et al. and Jain et al. Hering et al. teach TunR2 is a promising antibiotic candidate because of the significant reduction in toxicity. However, TunR2 exhibits lower potency and inhibitory properties compared to native tunicamycin, which provides motivation for one of ordinary skill in the art to formulate TunR2. Jain et al. demonstrate the new formulation using ciprofloxacin and show that the formulation improves antimicrobial activity. This formulation is not only limited to ciprofloxacin, but other drugs as well. Therefore, the combination of Hering et al. and Jain et al. renders the claims obvious with a reasonable expectation of success.
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 – 7, and 19 – 22 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 – 2 and 4 – 5 of copending Application No. 18/591,513 in view of Hering et al. (ACS Chemical Biology, 2020, Vol. 15, Issue 11, page 2885 – 2895, Reference included with PTO-892) and Jain et al. (International Journal of Pharmaceutics, 2011, Vol. 409, Issue 1 – 2, page 237 – 409, Reference included with PTO-892).
Regarding claims 1, 4 – 7, and 19 – 22, ‘513 teaches an antibacterial composition comprising at least one polymyxin and at least one modified tunicamycin (claim 1). The modified tunicamycin is
PNG
media_image1.png
210
456
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,
wherein R1 is -CH2-CH2-(CH2)n(CH3)CH-CH2-CH3; R2 is
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194
218
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;
R4 is H; and R5 is H (claim 2). ‘513 teaches that the antibacterial composition further comprising β-lactam antibiotic, wherein the β-lactam antibiotic is penicillin (claims 4 – 5).
However, ‘513 does not teach that the composition is an aqueous emulsion and TunR2 is in a complex with sodium deoxycholate.
Hering et al. teach that the antibiotic compound tunicamycin is a natural product inhibitor of MraY that is also toxic to eukaryotes through the binding to GPT. Therefore, Hering et al. discuss and compare tunicamycin and its modified versions (Abstract). TunR2 is one modified tunicamycin being discussed. Hering et al. observed that TunR2 has a IC50 value about 1.5 times higher than that of native tunicamycin. Upon complete hydrolytic opening of the uracil ring, there is a large drop in potency toward MraY (page 2891. Right Col., para. 3).
Jain et al. teach a ciprofloxacin surf-plexes with sodium deoxycholate, which is a hydrophobic ion-pair complexes of ciprofloxacin with sodium deoxycholate, loaded in oil-in-water submicron emulsion (Abstract). Ciprofloxacin is a powerful broad-spectrum antibiotic useful for the treatment of several types of infections (page 237, Left Col., para. 1). However, ciprofloxacin is limited by low encapsulation efficiency, rapid leakage, and poor storage stability, which lead to poor bioavailability through variety of routes (page 237, Right Col., para. 1). The formulation is prepared using equimolar concentration of ciprofloxacin and sodium deoxycholate (page 238, Left Col., para. 5). The surf-plexes can improve loading efficiency into submicron emulsion. Overall, the proposed loading technique increases the drug/lipid ratio due to improvement in lipophilicity, thereby, allowing submicron emulsion to carry and delivery larger amounts of antibiotics to infected cells (page 273, Right Col., para. 2). The technique also minimizes the potential loss of expensive drugs during the formulation process and dramatically improves the retention capacity (page 238, Left Col., para. 1). Therefore, the ciprofloxacin surf-plexes with sodium deoxycholate loaded in oil-in-water submicron emulsion is prepared to improve the loading efficiency of ciprofloxacin within the submicron emulsion and to improve the antimicrobial efficacy of formulations (page 238, Left Col., para. 2). In the study, it is found that the formulation has twice the antimicrobial activity compared to the free ciprofloxacin (page 241, Left Col., para. 2). Furthermore, the mean droplet size does not differ markedly even when the formulation is stored for a period of 3 months at 37 ⁰C (page 242, Left Col., para. 1). Jain et al. conclude that surfactant based ionic complex formation incorporated in surface modified submicron emulsion is a promising approach to improve pay-load efficiency of poorly water soluble drugs with improved antimicrobial efficacy and pharmacokinetic profile (Abstract).
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 TunR2 in the antibacterial composition comprising at least one polymyxin and TunR2 as taught by ‘513 into an aqueous emulsion containing a complex of TunR2 and sodium deoxycholate in view of Hering et al. and Jain et al. because Hering et al. teach that TunR2 exhibits lower potency, thereby creating a need to improve its antimicrobial performance, and Jain et al. teach that an antibiotic complexed with sodium deoxycholate in an oil-in-water submicron emulsion exhibits improved antimicrobial activity. One would have been motivated to formulate TunR2 in the antibacterial composition comprising at least one polymyxin and TunR2 as taught by ‘513 into an aqueous emulsion containing a complex of TunR2 and sodium deoxycholate in view of Hering et al. and Jain et al. because Jain et al. explicitly teach that the formulation is able to improve antimicrobial performance of an antibiotic and Jain et al. suggest that such formulation is a promising approach for other antibiotic. The combination of Hering et al. and Jain et al. teaches the claimed invention, therefore, the enhanced functional properties, such as solubility, are necessarily present. One of ordinary skill in the art would have had a reasonable expectation of success to formulate TunR2 in the antibacterial composition comprising at least one polymyxin and TunR2 as taught by ‘513 into an aqueous emulsion containing a complex of TunR2 and sodium deoxycholate in view of Hering et al. and Jain et al. because ‘513 teaches the antibacterial composition comprising at least one polymyxin, TunR2, and penicillin , Hering et al. teach that TunR2 exhibits lower potency, thereby providing motivation to modification, and Jain et al. teach surfactant based ionic complex formation incorporated in surface modified submicron emulsion that is exemplified by ciprofloxacin to show improvement in antimicrobial efficacy and Jain et al. teach that such formulation is a promising approach for other drugs.
This is a provisional nonstatutory double patenting rejection.
Responses to Applicant’s Remarks:
Applicant’s Remarks, filed December 17, 2025, have been fully considered and are found to be not persuasive.
Regarding the rejection, Applicant argues that ‘513 and Kirsh et al., alone or in combination, do not teach, suggest, render patently indistinct the pending or amended claims because a person of skill in the art will only arrive at a formulation containing polymyxin, a modified tunicamycin, and may be a β-lactam antibiotic incorporated in sodium deoxycholate dissolved in DMA based on the teachings of ‘513 and Kirsh et al. and not the claimed complex of an antibiotic and sodium deoxycholate. Again, the argument is moot because the new rejection no longer relies on the combination of ‘513 and Kirsh et al. The new rejection is based on the teachings of ‘513. Hering et al., and Jain et al. ‘513 teaches a antibacterial composition comprising polymyxin, a modified tunicamycin, and may be a β-lactam antibiotic. Hering et al. teach TunR2 exhibits lower potency and inhibitory properties compared to native tunicamycin, which provides motivation for one of ordinary skill in the art to formulate TunR2. Jain et al. demonstrate the new formulation using ciprofloxacin and show that the formulation improves antimicrobial activity. This formulation is not only limited to ciprofloxacin, but other drugs as well. Therefore, the combination of ‘513, Hering et al., and Jain et al. renders the claims obvious with a reasonable expectation of success.
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