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 .
Summary
Receipt of Applicants Reply and Remarks filed on 06/19/2026 is acknowledged. Claims 8, 10, 11 and 15 are pending. Claims 1-7, 9, and 12-14 remain cancelled. Claims 16-20 remain withdrawn from further consideration Claim 8 is amended.
Claims 8, 10, 11 and 15 are pending and under examination in this application.
New Rejection Necessitated by Amendment
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:
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) 8, 10, 11 and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Xu (Zwitterionic Chitosan Derivatives for pH-sensitive Stealth Coating) in view of Ejima (One-Step Assembly of Coordination complexes for Versatile Film and Particle Engineering), Tang (Polymer Directed Self-Assembly of pH-Responsive Antioxidant Nanoparticles), Park (Antimicrobial activity and cellular toxicity of nanoparticle-polymyxin B conjugates), and further in view of Tsubery (The Functional Association of Polymyxin B with Bacterial Lipopolysaccharide Is Stereospecific: Studies on Polymyxin B Nonapeptide).
Xu teaches preparation of zwitterionic chitosan (ZWC) by reaction of chitosan primary amine groups with succinic anhydride (i.e., succinylation) to produce a pH-sensitive polymer with both cationic and anionic character. Xu demonstrates that the resulting succinic anhydride-conjugated chitosan (SALM-CS) exhibits an isoelectric point tunable between pH 4.9 and 7.1, inhibits protein adsorption to cationic nanoparticle surfaces at physiological pH, is blood-compatible, and is well tolerated upon intraperitoneal (IP) injection in vivo. Xu further teaches coating cationic drug carrier NP surfaces with this ZWC material to attenuate undesirable interactions between the positively charged drug carrier and biological membranes, thereby serving as a biocompatible stealth coating for systemic drug delivery applications (abstract; ¶ Introduction).
Ejima teaches self-assembly of tannic acid (TA) with Fe³⁺ ions through coordination complex formation to produce versatile films and nanoparticles/capsules in a one-step process. Ejima demonstrates that mixing an ethanolic or aqueous solution of tannic acid with an aqueous ferric chloride (FeCl₃) solution at an interface instantly generates a blue-black TA–Fe coordination complex network that self-assembles into capsules or particles with pH-responsive properties, wherein the tris-complex dominates at pH > 6 (page 155-156). Ejima teaches encapsulation of diverse materials within the TA–Fe particle core and in (Applicant’s specification, ¶ 0096, expressly cites Ejima as the foundational reference for core NP synthesis in the claimed invention), further confirming the state of the art.
Tang teaches pH-responsive, multifunctional nanoparticles based on encapsulation of an antioxidant, tannic acid (TA), using flash nanoprecipitation, a polymer directed self-assembly method. Formation of insoluble coordination complexes of tannic acid and iron during mixing drives nanoparticle assembly. Tuning the core material to polymer ratio, the size of the nanoparticles can be readily tuned between 50 and 265 nm. The resulting nanoparticle is pH-responsive, i.e., stable at pH 7.4 and soluble under acidic conditions due to the nature of the coordination complex. Further, the coordination complex can be coprecipitated with other hydrophobic materials such as therapeutics or imaging agents. For example, coprecipitation with a hydrophobic fluorescent dye creates fluorescent nanoparticles. In vitro, the nanoparticles have low cytotoxicity and show antioxidant activity. Therefore, these particles may facilitate intracellular delivery of antioxidants (abstract). Tang further teaches forming tannic acid–Fe nanoparticles using flash nanoprecipitation by mixing an ethanolic solution of tannic acid with an aqueous FeCl₃ solution, which causes formation of hydrophobic tannic acid–Fe³⁺ coordination complexes at the ethanol/water interface that self-assemble into spherical nanoparticles of controlled size. Tang teaches that the resulting NPs can encapsulate hydrophobic cargo (e.g., a hydrophobic drug) during the ethanol-injection step and that NP surface coating with a stabilizing polymer provides colloidal stability and biocompatibility for drug delivery purposes. Tang further discloses pH-responsive properties suitable for parenteral drug delivery (pages 3613-3616).
Park teaches the antimicrobial activity and cytotoxicity to mammalian cells of conjugates of the peptide antibiotic polymyxin B (PMB) to Au nanoparticles and CdTe quantum dots. Au nanoparticles fully covered with PMB are identical in antimicrobial activity to the free drug alone, whereas partially-conjugated Au particles show decreased effectiveness in proportion to the concentration of Au. CdTe–PMB conjugates are more toxic to Escherichia coli than PMB alone, resulting in a flattening of the steep PMB dose–response curve. The effect is most pronounced at low concentrations of PMB, with a greater effect on the concentration required to reduce growth by half (IC50) than on the concentration needed to inhibit all growth (minimum inhibitory concentration, MIC). The Gram positive organism Staphylococcus aureus is resistant to both PMB and CdTe, showing minimal increased sensitivity when the two are conjugated (abstract).
Tsubery discloses that the Gram-negative bacterial endotoxin lipopolysaccharide (LPS) is a major inducer of sepsis, and that the natural cyclic peptide polymyxin B (PMB) is a potent antimicrobial agent by virtue of its capacity to bind lipid A, the conserved hydrophobic domain of LPS, and neutralize the devastating effects of LPS. Tsubery further teaches that PMB inhibits the biological effects of LPS, including inflammatory cytokine release (e.g., TNF, IL-1), the mechanism by which circulating LPS drives Gram-negative sepsis (abstract; Introduction).
Regarding claim 8 (amended), the claim recites a pharmaceutical composition for the treatment of sepsis comprising nanoparticles (NPs) manufactured according to steps (a)–(d), together with diluents/excipients/carriers, wherein the API is polymyxin B (PMB), surface-bound to the zwitterionic chitosan coating and configured to neutralize circulating lipopolysaccharide (LPS).
Step (a) — Core Nanoparticle Formation: Ejima and Tang teach the preparation of tannic acid–Fe (T) core nanoparticles by mixing tannic acid with aqueous FeCl₃. Tang specifically teaches interfacial self-assembly of tannic acid–Fe³⁺ coordination complexes using a water-miscible organic solvent phase, and specifically discloses forming such complexes using THF, acetone, or DMSO as the water-miscible organic solvent for the tannic acid phase (Tang at pages 3612–3613). Ethanol was well known in the art, independent of these references, as another pharmaceutically acceptable, low-toxicity, water-miscible organic solvent suitable for the same interfacial nanoprecipitation chemistry prior to the effective filing date. Selecting ethanol from this finite, known set of suitable solvents for the tannic acid phase—in order to achieve the same interfacial coordination-complex formation taught generically by Tang—is a routine substitution of one known element for another with predictable results, and does not itself confer patentability absent some unexpected property tied specifically to ethanol. See KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007).
Steps (b) & (c) — ZWC Coating: as noted above, Xu teaches the preparation of zwitterionic chitosan (ZWC) via succinylation of chitosan primary amines (SALM-CS) and the application of ZWC as a pH-sensitive stealth coating onto nanoparticle surfaces to reduce protein adsorption and biological membrane toxicity.
Step (d) & Surface-Bound PMB Clause: Xu teaches that the ZWC coating exhibits an isoelectric point (IEP) between pH 4.9 and 7.1, carrying a net negative charge at elevated pH above its IEP, which electrostatically attracts positively charged compounds. Park teaches nanoparticle-polymyxin B (PMB) conjugates wherein PMB (a positively charged polypeptide antibiotic) is surface-loaded onto nanoparticle carriers, and that such surface-bound PMB retains antibacterial activity while reducing toxicity to mammalian cells. Tsubery further establishes that PMB is known in the art to bind with high affinity to lipid A, the conserved hydrophobic domain of bacterial lipopolysaccharide (LPS), and to inhibit the biological effects of LPS, including inflammatory cytokine release (e.g., TNF, IL-1), the mechanism by which circulating LPS drives Gram-negative sepsis. Tsubery additionally confirms that LPS is a major inducer of sepsis. Accordingly, a person having ordinary skill in the art (PHOSITA) would have recognized that PMB, as surface-loaded onto the ZWC-coated nanoparticle taught by the Xu/Ejima/Tang/Park combination, would retain its art-recognized capacity to bind and neutralize circulating LPS when presented on the particle surface for contact with circulating endotoxin, as recited in the amended clause of Claim 8.
A person having ordinary skill in the art (PHOSITA) would have been motivated to combine the teachings of Ejima, Tang, Xu, Park, and Tsubery to apply Xu's ZWC coating to Ejima/Tang's tannic acid–Fe core nanoparticles and surface-load PMB at an elevated pH. A PHOSITA would have expected that electrostatically binding PMB to the negatively charged ZWC surface would yield a stable nanoparticle formulation capable of neutralizing circulating LPS in sepsis while reducing systemic PMB toxicity, consistent with PMB's known LPS-binding and LPS-neutralizing mechanism as established in Tsubery.
Regarding claim 10, as noted above, Tang teaches the co-encapsulation of hydrophobic compounds (e.g., therapeutics or dyes) into the tannic acid–Fe core during the interfacial mixing step. A PHOSITA would have found it obvious to include vitamin D3 (a well-known hydrophobic anti-inflammatory compound soluble in ethanol) in the ethanolic tannic acid solution of step (a) to co-encapsulate it within the core for its known immunomodulatory benefits in sepsis.
Regarding claim 11, as noted above, Xu teaches that ZWC carries a negative charge above its IEP that electrostatically attracts positively charged therapeutic compounds generally. The use of positively charged therapeutic APIs for surface loading onto anionic nanoparticle coatings was routine and predictable in the art.
Regarding claim 15, Tsubery establishes that LPS is a major inducer of sepsis and that PMB’s art-recognized mechanism of binding and neutralizing LPS is directly relevant to the treatment of Gram-negative sepsis and endotoxemia. Park demonstrates that nanoparticle-bound PMB retains antibacterial activity while substantially reducing toxicity to mammalian cells relative to free PMB. A PHOSITA would have been motivated to apply Park’s reduced-toxicity, nanoparticle-bound PMB construct systemically for the treatment of sepsis, since Park’s demonstrated reduction in mammalian toxicity directly addresses the principal barrier—systemic PMB toxicity—to using PMB systemically, consistent with Tsubery’s teaching of PMB’s LPS-neutralizing mechanism in sepsis.
Response to Arguments
Applicant's Remarks filed June 19, 2026, have been fully considered. Applicant respectfully traverses the rejection on several grounds. The Examiner responds as follows:
1. Regarding the Integrated TZP/D-TZP Architecture, Sequential Preparation, and “Elevated pH” Loading (Sections III, V, & VI of Remarks)
Applicant argues that the cited art does not teach or suggest the integrated nanoparticle architecture, the specific sequential preparation steps, or loading PMB at an elevated pH.
Examiner respectfully disagrees: The combination of teachings in Xu, Ejima, Tang, Park, and Tsubery expressly suggests every structural element and manufacturing step recited in Claim 8.
Ejima and Tang teach step (a) (forming tannic acid–Fe core nanoparticles).
Xu teaches steps (b) and (c) (succinylating chitosan to form ZWC and applying it as a surface coating to nanoparticles).
Xu further teaches that ZWC is negatively charged at elevated pH (above its IEP), which inherently dictates incubating or adding positively charged molecules at an elevated pH to facilitate electrostatic surface attraction.
Park teaches step (d) and Tsubery corroborates the amended clause (surface-loaded PMB retaining its art-recognized capacity to bind and neutralize LPS).
Combining these known steps in sequence represents the straightforward assembly of known functional elements according to established surface-chemistry principles (MPEP § 2143, Exemplar 1).
Moreover, Applicant's argument is not commensurate with the scope of Claim 8. Claim 8 recites only “adding one or more active pharmaceutical ingredients at an elevated pH”—it does not recite the specific pH 6.0-to-8.5 incubation sequence disclosed as a preferred embodiment in the specification. Applicant's remarks repeatedly characterize this specific disclosed sequence as if it were required by the claim language, but limitations from the specification not recited in the claims cannot be relied upon to distinguish over the prior art. Xu's teaching that ZWC carries a net negative charge above its IEP of pH 4.9–7.1 fully meets the broader “elevated pH” limitation as actually claimed.
Applicant further argues in Section VI of the Remarks that the ethanol limitation is tied to interfacial assembly and, for claim 10, to co-processing of vitamin D3, and is therefore not a mere routine solvent substitution. This argument has been fully addressed in the rejection of claim 8, Step (a), above: ethanol is one of a finite, known set of water-miscible organic solvents suitable for interfacial tannic acid–Fe coordination-complex formation, and its selection for this purpose, including for co-processing hydrophobic cargo such as vitamin D3, constitutes the routine selection of a known solvent for its known function, yielding predictable results. See KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007). Applicant has not identified any unexpected property specifically attributable to ethanol itself, as opposed to the general class of water-miscible organic solvents, that would distinguish the claimed process from this routine substitution.
2. Regarding the Technical Role of ZWC in Preventing Aggregation (Section IV of Remarks)
Applicant argues that ZWC is not merely a generic stealth coating, but solves a specific problem of uncontrolled particle aggregation (from 247 nm to 986 nm) when PMB is added to uncoated cores.
Examiner respectfully disagrees: Xu explicitly teaches that succinylated zwitterionic chitosan (SALM-CS) acts as a biocompatible stealth coating that prevents non-specific surface interactions, suppresses protein adsorption, and stabilizes nanoparticle suspensions. Suppressing unwanted non-specific surface interactions and preventing particle aggregation during subsequent processing is the precise, expected functional outcome of applying a ZWC stealth coating as taught by Xu. A PHOSITA applying Xu's coating to the nanoparticles of Ejima/Tang would reasonably expect the ZWC layer to maintain colloidal stability during PMB surface loading.
Additionally, Applicant's aggregation data (247 nm vs. 986 nm) is not commensurate in scope with Claim 8, which recites no particle size, diameter, or aggregation-state limitation whatsoever. Evidence directed to a specific numerical outcome in an optimized embodiment cannot support patentability of a claim broad enough to encompass compositions and processes falling outside that specific data set. See MPEP § 716.02(d).
3. Regarding Secondary Considerations / Unexpected Results (Section VII of Remarks)
Applicant argues that the specification demonstrates unexpected results, citing experimental data showing reduced cytotoxicity in THP-1/J774A.1 cells, preserved LPS neutralization, and enhanced survival in mouse sepsis models (CLP and LPS-induced) compared to free PMB and vehicle controls.
Examiner respectfully disagrees: Applicant's showing of unexpected results under 37 CFR 1.132 / MPEP § 716 is persuasive of patentability only if the evidence complies with established statutory standards. Here, the evidence fails to establish non-obviousness for two primary reasons:
1. Failure to Compare with the Closest Prior Art (MPEP § 716.02(e)): To demonstrate unexpected results, Applicant's comparative evidence must compare the claimed invention with the closest prior art. Here, the closest prior art is Park, which already teaches nanoparticle-bound PMB conjugates that retain antibacterial activity while substantially reducing mammalian cellular toxicity compared to free PMB. Applicant's specification compares the claimed D-TZP/TZP particles against free PMB and vehicle controls. Showing that nanoparticle-bound PMB is less toxic and more effective than free PMB merely confirms what Park already established in the art. Because Applicant failed to compare the claimed composition against the nanoparticle-PMB conjugates of Park, the evidence fails to demonstrate an unexpected superiority over the prior art.
2. Evidence Is Not Commensurate in Scope with the Claims (MPEP § 716.02(d)): Under MPEP § 716.02(d), evidence of non-obviousness must be commensurate in scope with the broad coverage sought by the claims.
Claim 8 broadly encompasses any pharmaceutical composition manufactured according to broad ranges of steps (a)–(d), regardless of specific component ratios, particle dimensions, or concentration limits.
Claim 11 broadly recites any “positively charged therapeutic compound.”
Applicant's experimental data in the specification are limited to highly specific, optimized formulation ratios (D-TZP and TZP). Testing a narrow embodiment does not provide a reasonable basis to infer that unexpected results would be obtained across the entire scope of broad claims 8, 11, and 15.
4. Regarding Hindsight Reconstruction (Section VIII of Remarks)
Applicant contends that the Examiner relied on hindsight reconstruction to combine Xu, Ejima, Tang, and Park.
Examiner respectfully disagrees: The motivation to combine the references originates entirely from clear teachings within the prior art itself, not from Applicant's disclosure:
1. Ejima and Tang provide the core tannic acid–Fe nanoparticle platform for systemic drug delivery.
2. Xu explicitly provides the motivation to coat nanoparticle carriers with zwitterionic succinylated chitosan to improve blood compatibility and attenuate membrane interactions during parenteral administration.
3. Park explicitly provides the motivation to surface-bind PMB to nanoparticle carriers to mitigate systemic PMB toxicity while preserving its therapeutic activity, and Tsubery independently confirms, as established background art, that PMB's mechanism of action includes binding to and neutralizing LPS, the causative agent of Gram-negative sepsis.
Combining a known nanoparticle carrier (Ejima/Tang) with a known biocompatible surface coating (Xu) and a known nanoparticle-bound therapeutic agent with an independently documented LPS-neutralizing mechanism (Park, Tsubery) represents a combination of prior art elements according to known methods with a reasonable expectation of success.
5. Regarding Claim-Specific Remarks for Claims 11 and 15 (Section IX of Remarks)
Applicant argues that claim 11 is patentable because the rejection relies on generic electrostatic attraction rather than the specific tannic acid–Fe/ZWC nanoparticle system of claim 8, and that claim 15 is patentable because the specification demonstrates systemic sepsis treatment activity arising from the claimed nanoparticle architecture rather than from free PMB or a generic PMB conjugate.
Examiner respectfully disagrees: Claims 11 and 15 depend from claim 8 and recite no additional structural or functional limitations beyond those addressed above. As claim 8 remains unpatentable over the Xu/Ejima/Tang/Park/Tsubery combination for the reasons set forth above, and as Applicant’s asserted unexpected results have been shown not to be commensurate in scope with, or properly compared against, the closest prior art (see the response to Section VII, above), claims 11 and 15 remain unpatentable for the same reasons, without need for further independent analysis.
Conclusion
No Claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
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 ANDRE MACH whose telephone number is (571)272-2755. The examiner can normally be reached 0800 - 1700 M-F.
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/ANDRE MACH/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615
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