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 Remarks and Restriction/Elections filed on 01/30/2026 is acknowledged. Claims 8, 10, 11 and 15 are pending.
Election/Restrictions
Applicant elects Group II with traverse, claims 6-15 drawn to a pharmaceutical composition. Group III, claims 16-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. The election is made FINAL.
Claims 1-7, 9, and 12-14 have been have been cancelled.
Claims 8, 10, 11, 15, and (16-20 – withdrawn) have been amended.
Claims 8, 10, 11 and 15 are pending and under examination in this application.
Response to Traverse
Applicant’s election of claims 8, 10, 11, 15 in the reply filed on 01/30/2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Priority
The current application is a continuation of U.S. Patent Application 17/636,453 filed 02/18/2022, which is a 371 U.S. National Phase of International Application PCT/US2020/047289 filed 08/21/2020, which in turn claims priority to U.S. Provisional patent application 62/890,304 filed on 08/22/2019.
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) and further in view of Park (Antimicrobial activity and cellular toxicity of nanoparticle-polymyxin B conjugates).
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 parenteral administration. 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. Xu discloses using low-molecular-weight chitosan produced by hydrogen peroxide digestion as the starting material.
Regarding claim 8 step (b), Xu discloses succinylation of chitosan (amidation with succinic anhydride) to produce SALM-CS, the zwitterionic chitosan derivative (pages 2353-2357), in precisely the manner described in Applicant’s specification at (¶ 0095).
Regarding claim 8 step (c), Xu discloses expressly teaches coating cationic NPs with ZWC to provide a pH-sensitive stealth layer that reduces protein adsorption and membrane toxicity (pages 2352-2355), which is the same functional purpose as set forth in Applicant’s specification (¶ 0079).
Regarding claim 8 step (d), Xu discloses and specifically explains that the ZWC coating is negative above its isoelectric points (IEP) and positive below it (page 2355-2357). A PHOSITA would immediately recognize that a cationic compound like PMB (positively charged at physiological pH) would be attracted to and bind the negatively charged ZWC surface at elevated pH, providing surface loading of PMB. Moreover, loading PMB in an elevated pH environment follows directly from the standard understanding of electrostatic interaction between the cationic PMB and the anionic ZWC above its IEP.
Regarding claim 11, the claim recites that the API is a positively charged therapeutic compound. PMB is explicitly a positively charged compound at physiological pH, as acknowledged throughout the specification (i.e., ¶ 0042). A PHOSITA would have recognized that any cationic therapeutic compound would electrostatically interact with the anionic ZWC surface above its isoelectric points (IEP, per Xu’s disclosure, page 2552 right column, last ¶). The use of positively charged therapeutic compounds for loading onto negatively charged nanoparticle surfaces was routine and predictable.
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).
Regarding claim 8 step (a), Ejima teaches one-step assembly of TA/Fe³⁺ coordination complexes to form nanoparticles and capsules (pages 154-156).
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).
Regarding claim 8 step (a), Tang specifically discloses mixing tannic acid with aqueous FeCl₃ to form tannic acid-Fe NPs complexes (pages 3612-3618), which is precisely the process recited in step (a). However, Tang flash nanoprecipitation (FNP), which involves dissolving tannic acid (TA) and a block copolymer (polystyrene-b-PEG) in an organic solvent that is rapidly mixed with an aqueous steam containing FeCl, and the organic solvent in the FNP method is typically THF or acetonitrile, where Tang encapsulates tannic acid using flash nanoprecipitation by forming coordination complexes with iron during the mixing and assembly process. Tang describes the concept and use of organic phase generically and the specific solvent is a block copolymer compatible solvent, not specifically ethanol.
Regarding claim 10, Tang teaches encapsulation of hydrophobic materials during the ethanolic mixing step for NP formation. Vitamin D3 is well-known as a hydrophobic compound soluble in ethanol. A PHOSITA would have recognized that vitamin D3 could be dissolved in the ethanolic tannic acid solution and co-encapsulated into the TA-Fe NP core during the interfacial self-assembly step taught by Tang, since Tang expressly teaches co-encapsulation of hydrophobic drugs during NP formation (page 3618, ¶ 3.2-3.3 and ¶ Conclusion). The inclusion of an additional hydrophobic anti-inflammatory agent in a sepsis NP formulation would have been predictable and desirable given the well-known immunomodulatory effects of vitamin D3.
Park 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).
Regarding claims 8 step (d) and 15, Park disclose polymyxin B (PMB) (abstract). Therefore, the limitation wherein active pharmaceutical ingredient is polymyxin B (PMB) is taught. Polymyxin B (PMB) as a cationic polypeptide antibiotic with potent anti-LPS activity useful for treating Gram-negative sepsis (page 2, left column, ¶ 2) was well-known in the art well before the earliest effective filing date. It was also well understood in the art that immobilizing or attaching cationic antimicrobials, including PMB, to a nanoparticle surface was a known strategy for retaining antibacterial activity while mitigating the toxic membrane interactions with mammalian cells as taught by Park. Moreover, Park discloses the use of PMB for sepsis treatment via systemic lipopolysaccharide (LPS) neutralization was recognized long before the effective filing date of this application. The prior art explicitly recognized the challenge of systemic PMB toxicity and the need for a NP-based delivery strategy to enable safe systemic administration. This combination of providing PMB in a nanoparticle carrier to enable its systemic use was a recognized goal in the field, providing further motivation to make the combination of claims 8 and 15 obvious.
It would have been prima facie obvious to a person having ordinary skill in the art (PHOSITA) before the effective filing date of the claimed invention to arrive at the pharmaceutical composition for the treatment of sepsis comprising ethanol solution of tannic acid to an aqueous solution of FeCl3, resulting in tannic acid-Fe NPs, preparing succinylated chitosan to afford ZWC -coated tannic acid-Fe NPs, and with API polymyxin B (PMB). The combination of Xu, Ejima, Tang and Park teaches every element of the claimed limitations. Regarding claim 8 step (a), and the resulting tannic acid-Fe core NPs are taught by Ejima and Tang. The resulting NPs have identical structural character and concept: tannic acid coordinated to Fe³⁺ forming a hydrophobic coordination network that self-assembles at the organic solvent-water interface. Regarding step (c), coating the tannic acid-Fe NPs with ZWC, represents an obvious combination of Xu’s ZWC coating method with the tannic acid-Fe NP platform of Ejima/Tang. A person having of ordinary skill in the art (PHOSITA) would have been motivated to apply Xu’s disclosed ZWC coating to tannic acid-Fe NPs prepared by the Ejima/Tang method, since both Xu and Tang are directed to systemic nanoparticle drug delivery applications requiring blood compatibility and reduced immune clearance, and the surface of tannic acid-Fe NPs (negatively charged, as shown in the specification at (¶ 0072) would readily accept the ZWC coating through electrostatic interaction, consistent with Xu’s teaching that SALM-CS coats cationic surfaces. Regarding step (d), loading PMB at elevated pH onto TZ NPs, is the obvious next step from Xu’s teaching that the ZWC surface provides a negatively charged environment at physiological pH that attracts cationic molecules via electrostatic interaction, combined with the art-recognized use of PMB as a cationic LPS-binding agent for sepsis therapy. The remainder of claim 8, recitation of “together with one or more diluents, excipients, or carriers”, is routine formulation practice universally recognized in the pharmaceutical arts. Use of PMB as the active pharmaceutical ingredient for the treatment of sepsis via LPS neutralization was well known in the art prior to the effective filing date.
The claimed combination would have been obvious to a PHOSITA because: (1) each individual component (TA-Fe NPs, ZWC coating, PMB loading for sepsis) was known in the prior art; (2) the combination represents the straightforward application of a known NP platform (TA-Fe) with a known surface coating method (ZWC succinylation from Xu) and a known therapeutic agent (PMB) for a known therapeutic target (LPS neutralization in sepsis); and (3) the combination would have been expected to yield predictable results, where a biocompatible NP carrier with surface-loaded PMB that retains LPS-binding activity while reducing direct membrane contact by the PMB. A PHOSITA would have been motivated to combine these references with a reasonable expectation of success because all elements were well-characterized in their respective fields, the surface chemistry was straightforward and predictable, and there was recognized clinical need for a less toxic systemic PMB formulation.
The use of an ethanol solution of tannic acid in step (a) would have been obvious to a person having ordinary skill in the art (PHOSITA). While Ejima teaches dissolving tannic acid in an aqueous solution for coordination complex formation with Fe3+, and Tang teaches dissolving tannic acid in an organic solvent (acetone or THF) for interfacial nanoprecipitation with aqueous FeCl3, neither reference is limited to a specific solvent identity. The underlying chemistry of interfacial self-assembly of a tannic acid-Fe3+ coordination complex at the boundary between an organic phase and an aqueous FeCl, phase is driven by the coordination affinity between the galloyl groups of tannic acid and Fe3+ ions, and is not dependent on the identity of the organic solvent. A PHOSITA would have recognized that the critical requirement for the organic phase is that it (1) dissolves tannic acid at sufficient concentration; (2) is miscible with water to enable interfacial mixing; and (3) is pharmaceutically acceptable for parenteral drug delivery applications. Therefore, ethanol satisfies all three criteria and would have been an immediately obvious solvent choice for a PHOSITA for the following reasons:
First, ethanol is the most common water-miscible organic solvent used in pharmaceutical nanoprecipitation and is universally recognized as a standard solvent for this purpose. The substitution of ethanol for acetone or THF in a nanoprecipitation based NP synthesis represents nothing more than the routine selection among a finite number of well-known art recognized alternatives. Second, ethanol is specifically preferred over acetone or THF in parenteral pharmaceutical formulations because of its superior biocompatibility. A PHOSITA developing a nanoparticle formulation intended for intravenous administration for sepsis treatment, as claimed, would have been motivated to select ethanol over less biocompatible organic solvents as a matter of routine pharmaceutical development practice, with a clear and predictable expectation of success. Third, tannic acid is well known in the art to be freely soluble in ethanol, making ethanol an obvious and immediately apparent solvent choice for preparing a tannic acid solution for subsequent mixing with aqueous FeCl. Accordingly, the specific recitation of “an ethanol solution of tannic acid” in step (a) of claim 8 does not patentably distinguish the claimed composition form the prior art. A PHOSITA would have arrived at the use of ethanol through routine solvent selection guided by well-established pharmaceutical formulation principles, with a reasonable expectation that the interfacial TA-Fe3+ coordination complex assembly taught by Ejima and Tang would proceed in the same manner regardless of whether the organic phase comprised of ethanol, acetone, or THF.
The combination of known elements using known methods to yield predictable results renders a claim obvious. Here, all claim elements are present in the prior art: (1) tannic acid-Fe NP synthesis by ethanol-injection (Ejima; Tang); (2) succinylated and zwitterionic chitosan surface coating (Xu); (3) PMB as a cationic, LPS-neutralizing drug for sepsis (art-recognized); (4) surface loading of cationic drugs onto anionic NPs via electrostatic interaction at elevated pH (follows directly from Xu’s pH-dependent ZWC charge behavior). A PHOSITA seeking to develop a systemic PMB formulation with reduced toxicity would have had clear reason to combine these known elements in the manner claimed with a reasonable expectation of success.
Conclusion
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