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 Applicant’s Remarks, Arguments and Amendments filed 5/18/2026 is acknowledged. Claims 1-8 are pending. Claims 1 and 5 are amended. Claims 9-21 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention. In view of Applicant’s arguments and the amendment incorporating dependent claim 5 into claim 1, this Office action is non-final.
Claims 1-8 are pending and under examination in this application.
Response to Arguments
Applicant’s arguments filed on May 18, 2026 have been fully considered by the Examiner and are found to be persuasive, see new grounds of rejection below.
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.
Claims 1–8 are rejected under 35 U.S.C. § 103 as being unpatentable over Nukolova in view of Kreuter, further in view of Ishihara, and now further in view of Xu et al. (Advanced Materials, 2019, 31, 1807557; hereinafter referred to as Xu).
Nukolova teaches surface-functionalized crosslinked nanogels were developed as a platform to allow conjugation of monoclonal antibodies (mAb) for targeted drug delivery, and well-defined diblock copolymers of poly(ethylene glycol)-b-poly(methacrylic acid) (PEG-b-PMA) with PEG terminal aldehyde functionality were synthesized by atom transfer radical polymerization (ATRP) and characterized by GPC and 1H NMR. These copolymers were used to prepare nanogels via condensation of PEG-b-PMA with Ca2+ ions into micelle-like aggregates, crosslinking of the PMA/Ca2+ cores and removal of Ca2+ ions. The resulting nanogels represent highly swollen spherical polyelectrolyte particles with free terminal aldehyde functionalities at the nonionic PEG chains, and the mAb retained the binding affinity to bovine submaxillary mucin after conjugation as shown by surface plasmon resonance (SPR). Therefore, aldehyde functionalized nanogels can be linked to mAb using a simple, one-step approach. They may have potential for targeted delivery of diagnostic and therapeutic agents to tumors (abstract). Nukolova fails to specifically teach strategies to cross BBB and phosphorylcholine.
Kreuter teaches strategies to cross BBB using brain blood vessel endothelial cells and possible mechanism of the nanoparticle-mediated transport of drugs into the brain (page 70-73, ¶ 3. In vitro experiments with brain blood vessel endothelial cells).
Ishihara teaches 2-methacryloyloxyethyl phosphorylcholine (MPC) copolymers show excellent blood compatibility, and suppression of clot formation following platelet adhesion and activation was observed even when the MPC polymer came in contact with human whole blood without anticoagulants. This is due to the reduced protein adsorption on the MPC polymer surfaces even from human plasma, and other research groups also have observed the protein adsorption-resistant properties of MPC copolymers (abstract).
Xu teaches Central nervous system (CNS) diseases are the leading cause of morbidity and mortality; their treatment, however, remains constrained by the blood–brain barrier (BBB) that impedes the access of most therapeutics to the brain. A CNS delivery platform for protein therapeutics, which is achieved by encapsulating the proteins within nano-capsules that contain choline and acetylcholine analogues, is reported herein. Mediated by nicotinic acetylcholine receptors and choline transporters, such nano-capsules can effectively penetrate the BBB and deliver the therapeutics to the CNS, as demonstrated in mice and non-human primates. This universal platform, in general, enables the delivery of any protein therapeutics of interest to the brain, opening a new avenue for the treatment of CNS diseases (abstract).
Regarding claims 1 and 8, Nukolova teaches a method of delivering a therapeutic composition comprising systemically administering nanogels composed of crosslinked polymer networks (Pages 1–2), and further teaches that the nanogels include polymer backbones with poly(ethylene glycol) segments and are decorated with monoclonal antibodies conjugated to the polymer networks (Pages 2–4, Sections 2.2, 2.2.2, 2.2.3, 2.3, 2.4, & 3.1–3.3). Nukolova discloses that the antibody-decorated nanogels are suitable for systemic administration, such as parenteral injection, and for targeted therapeutic delivery (Page 5, Section 2.6 and Pages 10–11, Conclusion). Furthermore, Nukolova discloses that the pH-responsive swelling and condensation of such nanogels is essential for controlled loading and release characteristics, noting that crosslinked ionic cores can serve as a reservoir to modulate the release of drug molecules in a pH-dependent fashion due to the protonation of carboxylic groups in the cores of the nanogels (Pages 9, 13). Therefore, the baseline limitations of systemic delivery via parenteral injection, nanogel crosslinking polymers, mAb/protein conjugation, PEG pendant groups, PEGylated backbones, and controlled degradation/release of payloads represent known and predictable features of polymeric drug-delivery systems as taught by Nukolova.
Regarding claim 2, the recitation of wherein the antibody comprises anti-polypyrimidine tract binding protein 1, anti-Amyloid-β, anti-tau, anti-α-synuclein, or anti-C-C Motif Chemokine Receptor 5 is a selection of a known therapeutic antibody from a finite and predictable group of antibodies known to target CNS-related antigens and represents an obvious choice. General knowledge of a PHOSITA would have established that anti-amyloid-β and anti-tau are directly involved in Alzheimer's, and anti-α-synuclein is directly involved in Parkinson's. Thus, claim 2 recites these known specific antibodies, and because Nukolova teaches antibody-based nanogel delivery, the selection of a particular antibody from among known therapeutic antibodies targeting CNS-related antigens represents an obvious choice from a finite and predictable group and does not impart patentable weight.
Nukolova fails to specifically teach strategies to cross the blood-brain barrier (BBB) using surface-bound ligands or the incorporation of a second copolymer comprising a phosphorylcholine targeting ligand directed to nicotinic acetylcholine receptors. Kreuter cures the deficiency regarding BBB crossing. Kreuter teaches strategies to cross the BBB using brain blood vessel endothelial cells and possible mechanisms of nanoparticle-mediated transport of drugs into the brain (Pages 70–73, Section 13).
Regarding claim 1, Kreuter teaches hexapeptide dalargin delivered to the brain via ligand-decorated nanoparticles (Pages 66–67, Section 2). Furthermore, Kreuter discloses receptor-mediated transcytosis following intravenous administration (Pages 73–78), which corresponds to the limitations of a ligand for a blood-brain barrier receptor at a surface of the nanogel as recited in claim 1.
Regarding claim 3, Kreuter discloses the challenges posed by the blood-brain barrier, noting it represents an insurmountable obstacle for many central nervous system (CNS)-active drugs, and that nanoparticles are especially helpful for the treatment of disseminated and aggressive brain tumors (Abstract and Page 65, Introduction). While Kreuter does not enumerate all neurodegenerative disorders, it reasonably implies that nanoparticles are used to deliver therapeutic agents against CNS-related indications that otherwise could not cross the BBB. Thus, Kreuter's nanoparticulate systems for brain delivery are directed to treating CNS pathology, and the recitation of specific neurodegenerative or retinal disorders comprises intended uses of the claimed delivery method and does not further limit the operational steps of the method.
Ishihara teaches 2-methacryloyloxyethyl phosphorylcholine (MPC) copolymers showing excellent blood compatibility and reduced protein adsorption on MPC polymer surfaces even from human plasma (Abstract). Regarding claims 1 and 4, Ishihara teaches MPC copolymers, polymerization schemes, and reaction products forming phosphorylcholine-containing polymers incorporated into polymer backbones for biomedical applications (Pages 324–328, Materials and Discussion, and Figure 1). Claim 4 recites a phosphorylcholine group having a specified chemical structure, and Ishihara expressly teaches phosphorylcholine monomers and matching reaction products incorporated into polymer backbones (Pages 324–325, and Figure 1).
The combined teachings of Nukolova, Kreuter, and Ishihara fail to explicitly teach that the phosphorylcholine group functions as an active targeting ligand for a nicotinic acetylcholine receptor expressed on an endothelial cell or a glial cell to drive active internalization. Xu cures this technical deficiency. Regarding claims 1 and 5, Xu explicitly teaches that phosphorylcholine groups act as structural mimics of native acetylcholine due to their quaternary ammonium head group configuration. Xu teaches that these phosphorylcholine groups function as active targeting ligands for nicotinic acetylcholine receptors (nAChRs) expressed on blood-brain barrier endothelial cells and glial cells, thereby triggering receptor-mediated internalization, intracellular entry, and subsequent cargo release within the cells. Because Ishihara teaches the identical incorporation of phosphorylcholine groups into polymer backbones, the resulting polymer network inherently possesses the capability to target and bind nAChRs as taught by Xu.
Regarding claims 1, 5 and 6, as noted above, Ishihara and Xu teach phosphorylcholine-containing polymers and copolymers interacting with nAChRs. Kreuter teaches that the endothelial cells of the cerebral capillaries comprise the major interface between the blood and the brain (Pages 65–66). Therefore, the recitation of specific glial cell types (microglia, astrocytes, oligodendrocytes) represents representative CNS cell populations that are encountered upon crossing the BBB, and exposure to such cells is a reasonable consequence of CNS delivery as taught in Kreuter.
Regarding claim 7, the recitation of "the antibody induces the degradation of polypyrimidine tract binding protein 1 (PTBP1) and induces conversion of the glial cell to a neuron" represents a functional biological therapeutic outcome of treatment and does not add additional manipulative method steps or structural limitations. The Examiner interprets this as a downstream biological effect of antibody activity without an additional delivery step, providing no structural limitation upon the method itself.
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 modify the nanogel delivery system of Nukolova to include surface ligands for BBB receptors as taught by Kreuter in order to facilitate delivery of therapeutic antibodies to the brain, because the blood-brain barrier is a well-known obstacle to CNS therapy and ligand-mediated transcytosis was a known and predictable solution. Furthermore, it would have been obvious to a PHOSITA to incorporate a second copolymer containing phosphorylcholine groups into the polymeric nanogel system as taught by Ishihara to improve circulation stability and biocompatibility of the delivery vehicle. This structural modification is heavily motivated by the teachings of Xu, which demonstrate that the selection of phosphorylcholine provides a dual-functional mechanism, acting simultaneously as a biocompatible anti-fouling layer (Ishihara) and as an active structural mimic targeting nAChRs to drive active brain delivery and cellular internalization. The claimed features therefore represent the combination of known elements performing their expected functions to achieve a predictable result under KSR.
Conclusion
No claims are allowed.
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.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Robert A Wax can be reached at 571-272-0323. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ANDRE MACH/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615
Prosecution Insights