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 .
Election/Restrictions
Applicant elects Group I without traverse, claims 1-8, drawn to method of treatment for a neurodegenerative or retinal disorder.
Claims 9-21 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claims 1-8 are pending and under examination in this application.
The election is made FINAL.
Priority
The current application filed on 11/05/2023 is a 371 of PCT/US2022/018696 filed 03/03/2022, which in turn has a provisional patent application 63/230,965 filed 08/08/2021, which in turn claims priority to provisional patent application 63/185,157 filed on 05/06/2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 11/06/2023, are in compliance with the provisions of 37 CFR 1.98. Accordingly, the information disclosure statements has been considered by the examiner. Signed copies have been attached to this office action.
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 Polyelectrolyte Nanogels Decorated with Monoclonal Antibody for Targeted Drug Delivery (hereinafter the reference is referred as Nukolova) in view of Nanoparticulate systems for brain delivery of drugs (hereinafter the reference is referred as Kreuter) and further in view of Why do phospholipid polymers reduce protein adsorption? (hereinafter the reference is referred as Ishihara).
Nukolova teaches surface-functionalized cross-linked 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, cross-linking 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).
Regarding claims1 and 8, Nukolova teaches a method of delivering a therapeutic composition comprising systemically administering nanogels composed of crosslinked polymer networks (page 1-2), and further teach the nanogels include polymer backbones with poly (ethylene glycol) segments and are decorated with (monoclonal antibodies (mAb) conjugated to the polymer networks (page 2-4, ¶ 2.2; ¶ 2.2.2.; ¶ 2.2.3; ¶ 2.3, ¶ 2.4 & ¶ 3.1-¶ 3.3). Furthermore, Nukolova discloses mAb or their fragments possess exquisite specificity and high affinity for the target, well-defined block ionomers containing PEG with terminal acetal groups, and subsequent cross-linking of the cores to produce nanogels with aldehyde groups, and the surfaced-functionalized nanogels were conjugated using simple one-step reaction with mAb CC49 against a tumor-associated glycoprotein 72 (TAG-72) for example (page 2, ¶ 2), and that the antibody-decorated nanogels are suitable for systemic administration and for targeted therapeutic delivery (page 5, ¶ 2.6 and page 10-11, ¶ conclusion). Moreover, Nukolova discloses the pH-responsive swelling and condensation of such nanogels is essential for the design of drug carriers with controlled loading and release characteristics, In particular, the cross-linked ionic cores of nanogels can serve as a reservoir that accommodates charged drug molecules through a combination of hydrophobic, electrostatic interactions, hydrogen bonding. For instance, anticancer drugs such as cis-di-chloro-diammino-platinum (II) (CDDP) or doxorubicin can be incorporated into ionic cores
of nanogel through metal complexation or electrostatic interactions, and Notably,
cross-linked cores of nanogels allowed for higher loading capacity of charged drug
molecules as well as higher micellar stability. It was shown that such nanogels can modulate release of drug molecules in a pH-dependent fashion due to protonation of carboxylic groups in the cores of the nanogels. Therefore, pH-sensitivity of nanogels can provide a unique opportunity to control the loading and triggered release of the active therapeutic agent (page 9, ¶ 3). Therefore, the limitation of systemic delivery comprises parenteral injection, nanogel cross-linking polymers, mAb or protein conjugation, PEG pendant groups, PEGylated backbones, controlled degradation and release of conjugated therapeutic agents (linker groups) to release antibodies represents a known and predictable feature 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-C-C Motif Chemokine Receptor 5, or a combination thereof is a selection of a known therapeutic antibody from a finite and predictable group of antibodies known to target CNS-related antigens represents an obvious choice. For example, general knowledge of a PHOSITA would have known that anti-amyloid-β and anti-tau is directly involved in Alzheimer’s, and anti-α-synuclein is directly involved in Parkinson’s. Thus, claim 2 recites these known specific antibodies
and Nukolova teaches antibody based nanogel delivery, and the selection of a particular antibody from among known therapeutic antibodies targeting CNS-related antigens represent an obvious choice from a finite and predictable group and is not a structural limitation on the delivery method, it is a selection of known therapeutic antibodies and does not impart patentable weight.
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).
Regarding claim 1, Kreuter teaches hexapeptide dalargin (Tyr-D-Ala-Gly-Phe-Leu-Arg), a Leu-enkephalin analogue with opioid activity, delivered to the brain (page 66-67, ¶ 2 In vivo brain drug delivery with nanoparticles), and this suggests ligand-decorated nanoparticles. Furthermore, Kreuter discloses receptor-mediated transcytosis following intravenous administration (page 73-78) corresponding to the limitations of a ligand for a blood brain barrier receptor 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, especially neuropeptides, and the nanoparticles may be especially helpful for the treatment of the disseminated and very aggressive brain tumors (Abstract and page 65, ¶ Intro). While Kreuter does not enumerate all neurodegenerative disorders, it reasonably implies that nanoparticles are used to deliver drugs (therapeutic agents) against CNS-related indications, especially brain tumors and other CNS-active drugs (therapeutic agents) that otherwise could not cross the BBB. Thus Kreuter’s nanoparticulate systems for brain delivery of therapeutic agents is a recognized challenge in treating CNS pathology and the NPs have previously been applied to it. Moreover, the recitation of wherein in the neurodegenerative or retinal disorder comprises Alzheimer’s disease…dementia represent intended uses of the claimed delivery method and do not further limit the steps of the method.
Regarding claim 6, Kreuter teaches BBB, endothelial cells of the cerebral capillaries and essentially comprises the major interface between the blood and the brain (page 65-65). Therefore, the recitation of “wherein the glial cell is a microglia, an astrocyte, an ependymal cell, a Schwann cell, a satellite cell, an oligodendrocyte lineage cell, or a combination thereof”, are representative of specific glial cell types that are known in CNS cell populations and upon following BBB crossing, it would have been highly reasonable that exposure to such cells would be encountered, and thus there are no distinctive targeting requirement.
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).
Regarding claims 1 and 4, Ishihara teaches 2-methacryloyloxyethyl phosphorylcholine (MPC) copolymers, polymerization schemes and reaction products forming phosphorylcholine containing polymers (page 324-328, ¶ Materials and ¶ Discussion). Claim 4 recites a phosphorylcholine group having a specified structure, and Ishihara expressly teaches phosphorylcholine monomers and reaction products incorporated into polymer backbones for biomedical applications (page 324-325, and Figure 1)
Regarding claim 5, as noted above, Ishihara teaches phosphorylcholine containing polymers and copolymers and it would have been highly reasonable that once a nanogel crosses the BBB, and in contact with CNS tissue, BBB receptor expression on endothelial cells and exposure to glial 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 do not add additional method steps or structural limitations. Thus, Examiner interprets this as a biological effect of antibody activity without additional delivery step and provides no structural limitation.
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 phosphorylcholine groups into the polymeric nanogel system as taught by Ishihara to improve circulation stability and biocompatibility of the delivery vehicle. The claimed features therefore represent the combination of known elements performing their expected functions to achieve a predictable result. The additional limitations recited in dependent claims 2-8 relate to selection of known antibodies, intended disease indications, reasonable exposure to CNS cell types, or functional therapeutic outcomes, and do not add patentable distinction to the claimed method and thus are obvious over the applied combination of references. A PHOSITA would have been motivated to combine the teachings of Nukolova, Kreuter and Ishihara for at least the following reasons: 1) There is a recognized problem in the art, in that the blood-brain barrier was a well known impediment to the delivery of therapeutic agents, including antibodies, to the central nervous system. Kreuter explicitly identify BBB penetration as a major challenge and teach ligand-mediated nanoparticle strategies to overcome this barrier. 2) Modifying a know nanogel delivery system of Nukolova with known BBB-targeting ligands as taught by Kreuter would have predictably resulted in enhanced brain delivery of the therapeutic agent via receptor-mediated transcytosis, thus the combination renders no change in principle of operation.
One of ordinary skill in the art would have been motivated to incorporate of phosphorylcholine groups into polymeric materials improves biocompatibility and in vivo performance as taught by Ishihara. Incorporating such groups into the nanogel system represents routine optimization of a known delivery vehicle using known polymer chemistry.
From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention.
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