DETAILED ACTION
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 18 December 2025 has been entered, and the arguments presented therein 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 Rejections and/or objections not reiterated from previous office actions are hereby withdrawn.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.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Interpretation
The instant claims recite the term “antibiotic.” The skilled artisan would have understood an antitumor antibiotic to have been within the scope of the claimed term “antibiotic.” The skilled artisan would have understood doxorubicin to have been an antitumor antibiotic; see e.g. Fenical et al. (US 2004/0266701 A1), paragraph 0069.
Claim Rejections - 35 USC § 103 – Obviousness
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.
Claim(s) 1, 3, 7-9, 11, and 15 is/are rejected under 35 U.S.C. 103 as being unpatentable over Shen et al. (CN 110170057 A) in view of Xie et al. (International Journal of Nanomedicine, Vol. 7, 2012, pages 163-175).
As an initial matter, Shen et al. (CN 110170057 A) was published in Chinese. The examiner has provided an English language translation. All page and paragraph citations are to the English translation; however, the material cited therein is assumed by the examiner to have been present in the original Chinese document.
Shen et al. (hereafter referred to as Shen) is drawn to a PEG-PLGA nanoparticle modified by transferrin (abbreviated as “Tf”), as of Shen, page 1, title and abstract. The purpose of the transferrin appears to access the blood brain barrier, as of Shen, page 3, relevant paragraph reproduced below with various terms highlighted by the examiner.
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Shen teaches delivery of an antibiotic, as of Shen, page 2, second paragraph, which appears to teach the delivery of minocycline, which is a tetracycline antibiotic.
Shen does not teach that the PEG-PLGA is bound to glucose. Also, the examiner admits that given the translation, it is unclear if the transferrin in the teachings of Shen is covalently bound to PEG-PLGA.
Xie et al. (hereafter referred to as Xie) is drawn to glucose modified liposomes for brain targeting, as of Xie, page 163, title and abstract. The liposomes of Xie are made with cholesterol-PEG-glucose, as of Xie, page 165, left column, top paragraph and scheme 1, relevant portion of the figure reproduced below.
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The purpose of the glucose in Xie appears to be target the blood brain barrier, as of Xie, page 171, left column, relevant text reproduced below.
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As such, Xie teaches glucose as a targeting ligand to target the blood brain barrier.
Xie differs from the claimed invention because the liposome lipids of Xie differ from the required PLGA. Also, Xie does not teach an antibiotic.
It would have been prima facie obvious for one of ordinary skill in the art to have substituted the glucose of Xie in place of the transferrin in Shen to have been used in the particle of Shen. Shen is drawn to a PLGA nanoparticle intended to target the brain via the blood brain barrier, and teaches the use of transferrin as a ligand for the blood brain barrier. Xie teaches that glucose can also be used as a targeting ligand for the blood brain barrier. As such, the skilled artisan would have been motivated to have substituted the glucose of Xie in place of the transferrin of Shen to have predictably targeted the particle of Shen to the blood brain barrier with a reasonable expectation of success. See MPEP 2143, Exemplary Rationale B. The skilled artisan would have expected that the result of this substitution would have had glucose covalently bound to PEG as this appears to have been taught by Xie.
In the alternative, the skilled artisan would have been motivated to have modified the particle of Shen to have covalently bound glucose to the PEG in the PEG-PLGA of Shen. Shen is drawn to targeting the blood brain barrier, and Xie teaches that glucose covalently bound to PEG in a particle helps for targeting the blood brain barrier. As such, the skilled artisan would have been motivated to have modified the particle of Shen to have covalently bound glucose to the PEG in the particle of Xie to have predictably targeted the blood brain barrier with a reasonable expectation of success.
As to claim 1, the claim requires a nanoparticle encapsulated antibiotic. Shen teaches this, as minocycline reads on the required antibiotic and shen teaches a PLGA-PEG nanoparticle.
As to claim 1, the claim requires glucose-PEG-PLGA. Shen teaches PEG-PLGA and Xie teaches glucose-PEG.
As to claim 3, Shen appears to teach a mass ratio of amphiphilic polymer to hydrophilic drug of 10-500:1-50, as of Shen, second to last page, claim 3. This would appear to overlap with the claimed invention in the case wherein the hydrophilic drug is present at an amount of e.g. 50 and the amphiphilic polymer present at an amount of e.g. 100. While the prior art does not disclose the exact claimed values, but does overlap: in such instances even a slight overlap in range establishes a prima facie case of obviousness. See MPEP 2144.05(I). In the alternative, generally, differences in concentration between the prior art and claimed invention will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical. See MPEP 2144.05(II)(A). In this case, no evidence of the criticality of the concentration of the antibiotic has been provided. Additionally, where 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. See MPEP 2144.05(II)(A). In this case, the general conditions of a PLGA-PEG-ligand containing nanoparticle encapsulating an antibiotic has been provided by the prior art. As such, it would not have been inventive for the skilled artisan to have discovered the optimum or workable ranges of these ingredients via routine experimentation.
As to claim 7, the minocycline of Shen is a tetracycline antibiotic, as required by the claimed method.
As to claim 8, the method of Shen, page 4, Example 1 would appear to read on either the single emulsion or double emulsion method.
As to claim 9, Shen teaches the following method, as of page 2 of the translation, relevant text reproduced below.
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This would appear to read on the required double emulsion because Shen teaches a first and second emulsion.
As to claim 11, Shen teaches that minocycline can inhibit intestinal tract bacteria, as of Shen, page 2, second paragraph.
As to claim 15, the overlap and optimization rationale applied to claim 3 also applies to claim 15.
Note Regarding Reference Date: The instant application has an effective filing date of 13 November 2020 based upon the filing date of PCT/CN2020/128693, which was filed on 13 November 2020. Shen was published on 27 August 2019. As such, Shen was published over a year earlier than the effective filing date of the instant application. Shen is therefore prior art under AIA 35 U.S.C. 102(a)(1).
Claim(s) 10 is/are rejected under 35 U.S.C. 103 as being unpatentable over Shen et al. (CN 110170057 A) in view of Xie et al. (International Journal of Nanomedicine, Vol. 7, 2012, pages 163-175), the combination further in view of Suthar et al. (Indian Journal of Pediatrics, Vol. 86(1), January 2019, pages 60-69).
Shen is drawn to a PLGA-PEG containing nanoparticle for delivering minocycline to the brain. Xie is drawn to the use of glucose as a targeting ligand for delivering a payload across the blood brain barrier.
Shen differs from the claimed invention because, although Shen teaches the antibiotic minocycline, Shen appears to intend minocycline for treating ischemic stroke rather than for treating a bacterial infection.
Suthar is drawn to bacterial infections of the central nervous system, including the brain, as of Suthar, page 60, title and abstract. Suthar teaches the use of antibiotics to treat brain infections, as of at least Suthar, page 63, right column and page 67, section entitled “Treatment.”
Suthar does not teach a PLGA-PEG particle.
It would have been prima facie obvious for one of ordinary skill in the art to have used the composition of Shen, by itself or as modified by Xie, to have treated a bacterial infection in the brain. Shen is drawn to administration of an antibiotic minocycline which is a tetracycline antibiotic, as of Shen, page 2, second paragraph. Although Shen appears to intend this composition for treatment of ischemic stroke, the skilled artisan would have understood that the brain can suffer bacterial infections and that the skilled artisan would have been motivated to have administered an antibiotic to have treated brain infections, as of Suthar. The composition of Shen in view of Xie would have been able to have crossed the blood-brain-barrier; as such, the skilled artisan would have been motivated to have used this composition to have predictably treated a brain infection with a reasonable expectation of success.
Claim(s) 4-6, 13-14, and 16-17 is/are rejected under 35 U.S.C. 103 as being unpatentable over Shen et al. (CN 110170057 A) in view of Xie et al. (International Journal of Nanomedicine, Vol. 7, 2012, pages 163-175) and Suthar et al. (Indian Journal of Pediatrics, Vol. 86(1), January 2019, pages 60-69), the combination further in view of Loo et al. (WO 2019/135715 A1).
Shen is drawn to a PLGA-PEG containing nanoparticle for delivering minocycline to the brain. Xie is drawn to the use of glucose as a targeting ligand for delivering a payload across the blood brain barrier. Suthar is drawn to treating a bacterial infection in the brain with an antibiotic.
None of the above references teach a cationic lipid.
Loo et al. (hereafter referred to as Loo) is drawn to a lipid-polymer hybrid nanoparticle comprising PLGA and DOTAP, as of Loo, title, abstract, and figure in abstract, reproduced below.
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Loo teaches that addition of DOTAP as a coating increase the potency of the antibiotics by two to sixteen fold, as of Loo, page 39, relevant text reproduced below.
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As such, Loo teaches that inclusion of DOTAP results in greater antibiotic effectiveness.
Loo differs from the claimed invention because (a) Loo does not teach glucose attached to PEG, and (b) while Loo teaches PEG, the PEG of Loo is attached to a lipid rather than to PLGA.
It would have been prima facie obvious for one of ordinary skill in the art to have modified the particle of Shen when used for treatment of bacterial infection as of Suthar, whether by itself or as modified by Xie, with DOTAP, as taught by Loo. Shen is drawn to a PLGA containing nanoparticle for delivery of an antibiotic, and Suthar teaches treating a bacterial infection. Loo teaches that inclusion of DOTAP as a coating results in increased potency of an antibiotic encapsulated in a nanoparticle. As such, the skilled artisan would have been motivated to have coated the particle of Shen with DOTAP, as taught by Loo, in order to have predictably improved antibiotic effectiveness with a reasonable expectation of success.
As to claim 4, the claim requires a cationic lipid. The DOTAP of Loo reads on this requirement.
As to claim 5, the DOTAP of Loo reads on the additional requirement of this claim.
As to claim 6, Loo teaches the ratio of DOTAP to PLGA as of page 32, as well as the ratio of active agent to the remainder of the particle, as of pages 32-33, wherein this ratio can be calculated by the encapsulation efficiency. As such, the general conditions of a particle comprising a PLGA containing polymer, DOTAP, and an antibiotic have been taught by the prior art. Where 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. See MPEP 2144.05(II)(A). In this case, the general conditions of a nanoparticle comprising a PLGA containing polymer, DOTAP, and an antibiotic have been taught by the prior art. As such, it would not have been inventive for the skilled artisan to have discovered the ratio of these ingredients via routine experimentation.
As to claim 13, the rationale provided above in regard to the rejection of claim 6 regarding optimization of ranges is also applicable to claim 13.
As to claim 14, the skilled artisan would have been motivated to have included the step of adding DOTAP, in view of the teachings of Loo.
As to claim 16, the rationale provided above in regard to the rejection of claim 6 regarding optimization of ranges is also applicable to claim 13.
As to claim 17, the rationale provided above in regard to the rejection of claim 6 regarding optimization of ranges is also applicable to claim 13.
Claim(s) 1, 3, and 15 is/are rejected under 35 U.S.C. 103 as being unpatentable over Farokhzad et al. (US 2010/0266491 A1) in view of Lu et al. (Macromolecules, Vol. 52, 2019, pages 477-486).
Farokzhad et al. (hereafter referred to as Farokhzad) is drawn to a drug delivery system comprising a nanoparticle, as of Farokhzad, title and abstract and figure in abstract, which is reproduced below.
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As such, Farokhzad teaches a nanoparticle made from PLGA-PEG-ligand, wherein the term “Apt” in the above-reproduced figure refers to an aptamer and is a targeting ligand, as of paragraph 0020 of Farokhzad. Farokhzad teaches doxorubicin in paragraph 0214, which is understood to read on the required antibiotic.
Farokhzad does not teach fructose-PEG-PLGA. While Farokhzad does teach fructose (e.g. as of paragraph 0249), the fructose taught in this paragraph is not covalently bound to PEG which is ultimately covalently bound to PLGA.
Lu et al. (hereafter referred to as Stenzel after the last-named inventor) is drawn to “fructose-based” polymer micelles, as of Stenzel, page 477, title and abstract. Fructose appears to be covalently bound to PEG, as of Stenzel, page 478, Scheme 1, reproduced below.
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Fructose also appears to be on the exterior of the particle, as of Stenzel, page 481, figure 2, reproduced below.
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The purpose of fructose appears to deliver active agent to certain cell types, as of Stenzel, page 477, abstract.
Stenzel is not anticipatory because Stenzel does not teach PLGA, and does appear to teach an antibiotic.
It would have been prima facie obvious for one of ordinary skill in the art to have substituted the fructose of Stenzel in place of the targeting ligand of Farokhzad to have been used in the particle of Farokhzad. While Farokhzad teaches particles made from ligand-PEG-PLGA, Farokhzad does not teach that fructose can be used as such a ligand. However, Stenzel teaches that fructose can be used as a targeting ligand. As such, the skilled artisan would have been motivated to have substituted the fructose of Stenzel in place of the ligand of Farokhzad to have been covalently bound to PEG-PLGA in order to have predictably targeted a desired cell type with a reasonable expectation of success. The simple substitution of one known element (e.g. the fructose of Stenzel) in place of another (e.g. the aptamer of Farokhzad) in order to have achieved predictable results (e.g. targeting of a particular cell type) is prima facie obvious. See MPEP 2143, Exemplary Rationale B.
As to claim 3, Farokhzad teaches 10% loading of active agent in paragraph 0413. This would appear to be a 1:9 ratio of active agent to polymer, which is less than what is required by the instant claims, because there would have been 10% active agent and 90% polymer. Nevertheless, generally, differences in concentration between the claimed invention and prior art will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical. See MPEP 2144.05(II)(A). In this case, there appears to be no evidence of criticality. Additionally, where 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. See MPEP 2144.05(II)(A). In this case, the general conditions of a PLGA-PEG-ligand particle encapsulating an antibiotic have been taught by the prior art. As such, it would not have been inventive for the skilled artisan to have determined the optimum ratio of active agent to polymer via routine experimentation.
As to claim 15, this claim is rejected for essentially the same reason that claim 3 is rejected.
Claim 4 and other claims requiring a cationic lipid are not rejected on this ground of rejection. This is because cationic lipids are used most often to deliver genetic material, though can also be used to increase the potency of antibacterial antibiotics, as of Loo et al. (WO 2019/135715 A1). The anticancer antibiotic doxorubicin is neither genetic material nor an antibacterial antibiotic. As such, there would have been no motivation for the skilled artisan to have added a cationic lipid to the composition of Farokhzad in view of Stenzel because there would have been no reasonable expectation that doing so would have successfully improved drug delivery of doxorubicin. A statement that modifications of the prior art to meet the claimed invention would have been "‘well within the ordinary skill of the art at the time the claimed invention was made’" because the references relied upon teach that all aspects of the claimed invention were individually known in the art is not sufficient to establish a prima facie case of obviousness without some objective reason to combine the teachings of the references. In this case, there is no objective reason to combine the teachings of the references to achieve the combination required by claim 4. See MPEP 2143.01(IV) as well as MPEP 2143.01(III).
Claim(s) 11 is/are rejected under 35 U.S.C. 103 as being unpatentable over Farokhzad et al. (US 2010/0266491 A1) in view of Lu et al. (Macromolecules, Vol. 52, 2019, pages 477-486), further as evidenced by Blaustein et al. (US 2022/0184147 A1).
Farokhzad is drawn to a PLGA-PEG-targeting ligand containing particle comprising doxorubicin, which reads on the required antibiotic. Stenzel is drawn to using fructose as a targeting ligand. See the rejection above over Farokhzad in view of Stenzel.
Neither Farokhzad nor Stenzel teach that the doxorubicin affects the intestinal flora. However, Blaustein, paragraph 0064, appears to teach that doxorubicin causes intestinal microbiota dysbiosis. As such, the skilled artisan would have understood that the doxorubicin of Farokhzad would have inherently affected the intestinal flora even if this was not explicitly taught by Farokhzad. When the structure recited in the reference (in this case, the relevant structure referred to here is that of doxorubicin itself, not the structure of the whole composition) is substantially identical to that of the claims, the claimed properties or functions are presumed to be inherent. See MPEP 2112.01(I). As such, the skilled artisan would have expected that the fact that doxorubicin affects the intestinal flora would have been inherent in the doxorubicin taught by Farokhzad.
Note Regarding Reference Date: The instant application appears to have an earliest effective filing date of 13 November 2020. Blaustein was effectively filed as early as 4 March 2019 and has a PCT filing date of 4 March 2020. As such, Blaustein appears to be prior art under AIA 35 U.S.C. 102(a)(2).
Response to Arguments
Applicant has provided arguments in applicant’s response on 18 December 2025. These arguments appear to relate to a rejection that was previously applied in the office action mailed on 22 September 2025 and has since been withdrawn. As such, applicant’s arguments have not been addressed substantively as they appear to relate to a rejection which has been withdrawn.
Conclusion
No claim is allowed.
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ISAAC . SHOMER
Primary Examiner
Art Unit 1612
/ISAAC SHOMER/ Primary Examiner, Art Unit 1612