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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 January 26, 2026 has been entered.
Summary
Claims 1-9 and 11-34 are pending in this office action. Claims 31-34 are new. Claim 10 is cancelled. All pending claims are under examination in this application.
Priority
The current application filed on April 3, 2023 claims domestic priority to a provisional patent application 63/326,541 filed on April 1, 2022.
Claim Objections
Claim 28 is objected to because of the following informality: The structure appears prior to the text “formula: ;”. Appropriate correction is required.
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 non-obviousness.
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 1-9 and 11-34 are rejected under 35 U.S.C. 103 as being unpatentable over Khan et al. (US2017/0079916A1) in view of Shalek et al. (WO2019/018441A1), Wu et al. (Chemical Communications, 2005), Mehta et al. (Molecular Pharmaceutics, 2018), Lallana et al. (Pharmaceutical Research, 2012), Nigavekar et al. (Pharmaceutical Research, 2004), Peng et al. (Macromolecules, 2009), Niu et al. (Chinese Chemical Letters, 2014), Carlmark et al. (Chemical Society Reviews, 2013), Gillies et al. (JACS, 2002), and Pittelkow et al. (Synthesis, 2002).
[The Examiner is going to introduce each reference and then combine them in the rejection of the instant claims.]
1. Khan et al.
Khan et al. is considered to be the closest prior art to the present invention and teaches compositions and methods for modified dendrimer nanoparticle delivery (see title). In addition, Khan et al. disclose compositions and methods for modified dendrimer nanoparticle (“MDNP”) delivery of therapeutic, prophylactic and/or diagnostic agent such as large repRNA molecules to the cells of a subject have been developed. MDNPs efficiently drive proliferation of antigen-specific T cells against intracellular antigen, and potentiate antigen-specific antibody responses. MDNPs can be multiplexed to deliver two or more different repRNAs to modify expression kinetics of encoded antigens and to simultaneous deliver repRNAs and mRNAs including the same UTR elements that promote expression of encoded antigens (see abstract).
2. Shalek et al.
Shalek et al. teach the cell atlas of healthy and diseased barrier tissues (see title). Furthermore, Shalek et al. disclose a cell atlas of barrier tissues from healthy and diseased subject. The atlas was obtained by single cell sequencing of approximately 18,036 cells in a surgical data set and 18,704 cells from scrapings. The present invention discloses novel markers for cell types. Moreover, genes associated with disease, including type 2 inflammation are identified. The invention provides for diagnostic assays based on gene markers and cell composition, as well as therapeutic targets for controlling differentiation, proliferation, maintenance and/or function of the cell types disclosed herein. In addition, novel cell types and methods of quantitating, detecting and isolating the cell types are disclosed (see abstract).
3. Wu et al.
Wu et al. teach multivalent, bifunctional dendrimers prepared by click chemistry (see title). Furthermore, Wu et al. disclose unsymmetrical dendrimers, containing both mannose binding units and coumarin fluorescent units, have been prepared using click chemistry and shown to be highly efficient, dual-purpose recognition/detection agents for the inhibition of hemagglutination (see abstract).
4. Mehta et al.
Mehta et al. teach reducing dendrimer generation and PEG chain length increases drug release and promotes anticancer activity of PEGylated polylysine dendrimers conjugated with doxorubicin via a cathepsin-cleavable peptide linker (see title). Additionally, Mehta et al. disclose PEGylation typically improves the systemic exposure and tumor biodistribution of polymeric drug delivery systems but may also restrict enzyme access to peptide-based drug linkers. The impact of dendrimer generation (G4 vs G5) and PEG length (570 vs 1100 Da) on the pharmacokinetics, tumor biodistribution, drug release kinetics, and anticancer activity of a series of PEGylated polylysine dendrimers conjugated with doxorubicin via a cathepsin-B cleavable valine-citrulline linker was therefore investigated in rodents. Although the smallest G4 PEG570 dendrimer showed the most efficient cathepsin-mediated doxorubicin release, systemic exposure and tumor uptake were limited. The largest G5 PEG1100 dendrimer showed good tumor uptake and retention but restricted drug liberation and therefore limited anticancer activity. Superior anticancer activity was achieved using an intermediate sized dendrimer that showed better drug release kinetics, systemic exposure, tumor uptake, and retention. The data suggest that balancing PEG molecular weight and dendrimer size is critical when designing chemotherapeutic dendrimers (see abstract).
5. Lallana et al.
Lallana et al. teach click chemistry with polymers, dendrimers, and hydrogels
for drug delivery (see title). Furthermore, Lallana et al. disclose that during the last decades, great efforts have been devoted to design polymers for reducing the toxicity, increasing the absorption, and improving the release profile of drugs. Advantage has been also taken from the inherent multivalency of polymers and dendrimers for the incorporation of diverse functional molecules of interest in targeting and diagnosis. In
addition, polymeric hydrogels with the ability to encapsulate drugs and cells have been developed for drug delivery and tissue engineering applications. In the long road to this successful story, pharmaceutical sciences have been accompanied by parallel
advances in synthetic methodologies allowing the preparation of precise polymeric materials with enhanced properties. In this context, the introduction of the click concept by Sharpless and coworkers in 2001 focusing the attention on modularity and
orthogonality has greatly benefited polymer synthesis, an area where reaction efficiency and product purity are significantly challenged. The purpose of this Expert Review is to discuss the impact of click chemistry in the preparation and functionalization of polymers, dendrimers, and hydrogels of interest in drug delivery (see abstract).
6. Nigavekar et al.
Nigavekar et al. teach 3H dendrimer nanoparticle organ/tumor distribution (see title). In addition, Nigavekar et al. disclose the following abstract:
Purpose. To determine the in vivo biodistribution for differently charged poly(amidoamine) (PAMAM) dendrimers in B16 melanoma and DU145 human prostate cancer mouse tumor model systems.
Methods. Neutral (NSD) and positive surface charged (PSD) generation
5 (d _5 nm) PAMAM dendrimers were synthesized by using 3H-labeled acetic anhydride and tested in vivo. Dendrimer derivatives were injected intravenously, and their biodistribution was determined via liquid scintillation counting of tritium in tissue and excretory samples. Mice were also monitored for acute toxicity.
Results. Both PSD and NSD localized to major organs and tumor. Dendrimers cleared rapidly from blood, with deposition peaking at 1 h for most organs and stabilizing from 24 h to 7 days post injection. Maximal excretion occurred via urine within 24 h post injection. Neither dendrimer showed acute toxicity.
Conclusions. Changes in the net surface charge of polycationic PAMAMs modify their biodistribution. PSD deposition into tissues is higher than NSD, although the biodistribution trend is similar. Highest levels were found in lungs, liver, and kidney, followed by those in tumor, heart, pancreas, and spleen, while lowest levels were found in brain. These nanoparticles could have future utility as systemic biomedical delivery devices (see abstract).
7. Peng et al.
Peng et al. teach dendron-like polypeptide/linear poly(ethylene oxide) biohybrids with both asymmetrical and symmetrical topologies synthesized via the combination of click chemistry and ring-opening polymerization (see title). Furthermore, Peng et al. disclose that dendron-like poly(γ-benzyl-L-glutamate)/linear poly(ethylene oxide) block copolymers with both asymmetrical and symmetrical topologies (i.e., ABn type Dm-PBLG-b-PEO and BnABn type Dm-PBLG-b-PEOb-Dm-PBLG; n ) 2m, m ) 0, 1, 2, and 3; Dm are the propargyl focal point poly(amido amine) type dendrons having 2m terminal primary amine groups) were synthesized via the combination of ring-opening polymerization (ROP) of γ-benzyl-L-glutamate N-carboxyanhydride (BLG-NCA) and click chemistry according to the “arm-first” and “core-first” strategies. In the arm-first method, the propargyl focal point dendrons Dm having 2m terminal primary amine groups were first used for initiating the ROP of BLG-NCA, generating “clickable” dendron-like Dm-PBLG homopolymers having 2m branches, which were then click conjugated with azide-terminated PEO (PEO-N3) to produce asymmetrical Dm-PBLG-b-PEO. In the core-first strategy, the propargyl focal point Dm was first click conjugated with PEO-N3 to generate primary amine-terminated PEO dendrons, which were further
used as the macroinitiators for the ROP of BLG-NCA to produce the targeted copolymers with both asymmetrical and symmetrical topologies. Their molecular structures and physical properties were characterized in detail by FT-IR, NMR, gel permeation chromatography, differential scanning calorimetry, and wide-angle X-ray diffraction. Both spherical and wormlike micelles self-assembled from these Dm-PBLG-b-PEO copolymers in aqueous solution, and mainly the PBLG composition controlled the morphology of nanostructures (see abstract).
8. Niu et al.
Niu et al. teach synthesis of ester-capped carbosilane dendrimers via a hybrid divergent–convergent method (see title). In addition, Niu et al. disclose that a series of novel ester-capped carbosilane dendrimers (G0-COOCH3–G2-COOCH3) were designed and successfully synthesized via a hybrid divergent–convergent method through a facile hydrosilylation reaction. The structures of these dendrimers were confirmed by FTIR, 1H NMR, and HRMS analyses (see abstract).
9. Carlmark et al.
Carlmark et al. teach dendritic architectures based on bis-MPA: functional
polymeric scaffolds for application-driven research (see title). Additionally, Carlmark et al. disclose that dendritic polymers are highly branched, globular architectures with multiple representations of functional groups. These nanoscale organic frameworks continue to fascinate researchers worldwide and are today under intensive investigation in application-driven research. A large number of potential application areas have been suggested for dendritic polymers, including theranostics, biosensors, optics, adhesives and coatings. The transition from potential to real applications is strongly dictated by their commercial accessibility, scaffolding ability as well as biocompatibility. A dendritic family that fulfills these requirements is based on the 2,2-bismethylolpropionic acid (bis-MPA) monomer. This critical review is the first of its kind to cover most of the research activities generated on aliphatic polyester dendritic architectures based on bis-MPA. It is apparent that these scaffolds will continue to be in the forefront of cutting-edge research as their structural variations are endless including dendrons, dendrimers, hyperbranched polymers, dendritic linear hybrids and their hybridization with inorganic surfaces (see abstract).
10. Gillies et al.
Gillies et al. teach designing macromolecules for therapeutic applications:
polyester dendrimers-poly(ethylene oxide) “bow-tie” hybrids with tunable molecular weight and architecture (see title). Also, Gillies et al. disclose that the design and preparation of new polyester dendrimer, poly(ethylene oxide) hybrid systems
for drug delivery and related therapeutic applications, are described. These systems consist of two covalently attached polyester dendrons, where one dendron provides multiple functional handles for the attachment of therapeutically active moieties, while the other is used for attachment of solubilizing poly(ethylene oxide) chains. By varying the generation of the dendrons and the mass of the poly(ethylene oxide) chains, the molecular weight, architecture, and drug loading can be readily controlled. The “bow-tie” shaped dendritic scaffold was synthesized using both convergent and divergent methods, with orthogonal protecting groups on the periphery of the two dendrons. Poly(ethylene oxide) was then attached to the periphery of one dendron using an efficient coupling procedure. A small library of eight carriers with molecular weights ranging from about 20 kDa to 160 kDa were prepared and characterized by various techniques, confirming their well-defined structures (see abstract).
11. Pittelkow et al.
Pittelkow et al. teach selective synthesis of carbamate protected polyamines using alkyl phenyl carbonates (see title). Furthermore, Pittelkow et al. disclose utilising alkyl phenyl carbonates, an economical, practical and versatile method for selective Boc, Cbz and Alloc protection of polyamines has been developed. This method allows Boc, Cbz and Alloc protection of primary amines in the presence of secondary amines by reaction of the polyamines with the alkyl phenyl carbonates. Also, this method allows mono carbamate protection of simple symmetrical aliphatic a,w-alkanediamines in high yields with respect to the diamine. Finally, the method allows selective carbamate protection of a primary amine located on a primary carbon in the presence of a primary amine located on a secondary or a tertiary carbon in excellent yields (see abstract).
Combination of Khan et al., Shalek et al., Wu et al., Mehta et al., Lallana et al., Peng et al., Niu et al., and Carlmark et al.
Regarding instant claim 1, Khan et al., Shalek et al., Wu et al., Mehta et al., Lallana et al., Peng et al., Niu et al., and Carlmark et al. teach a nanoparticle composition for delivery of a nucleic acid agent, comprising: a nucleic acid agent and a carrier. The necessary citations within Khan et al., Shalek et al., Wu et al., Mehta et al., Lallana et al., Peng et al., Niu et al., and Carlmark et al. that correspond to instant claim 1 are compiled within Table I.
Table I
Instant Claim 1
Khan et al., Shalek et al., Wu et al., Mehta et al., Lallana et al., Peng et al., Niu et al., and Carlmark et al. Citations
A nanoparticle composition for delivery of a nucleic acid agent, comprising:
Khan et al. disclose compositions and methods for modified dendrimer nanoparticle (“MDNP”) delivery of therapeutic, prophylactic and/or diagnostic agent such as large repRNA molecules (nucleic acids) to the cells of a subject have been developed (see title, abstract, and paragraph [0017] within Khan et al.)
Shalek et al. disclose delivery is by encapsulation of the programmable nucleic acid modifying agents in a lipid particle such as a lipid nanoparticle (LNP) (see paragraph [0498] within Shalek et al.). Although Shalek et al. does not disclose MDNPs, the reference does mesh very well with the nanoparticles of Khan et al., which therefore makes it analogous art.
a nucleic acid agent and a carrier, wherein the carrier comprises: a dendritic polymer skeleton, wherein the dendritic polymer skeleton further comprises:
Khan et al. disclose the use of a nucleic acid and a carrier dendritic skeleton (see title, abstract, and Figure 2A within Khan et al.).
Wu et al. disclose the use of the starting material PE-G1-Acetylene-OH en route to the desired dendritic polymer skeleton (see scheme 1, structure 2; within Wu et al.). Wu et al. additionally disclose that the key chemical transformation which allows simple and facile preparation of these dual-purpose, multifunctional materials is the copper(I)-catalyzed azide–alkyne cycloaddition, a premier ‘‘click’’ reaction (see page 5775, left column, paragraph 1 within Wu et al.).
Click chemistry is fundamental to dendrimer formation of the present application and is discussed within Wu et al., Lallana et al., Peng et al., and Carlmark et al.
The exact molecular structure of the desired dendrimer is not disclosed in the literature. However, the functional groups and polymeric groups are known, as well as the chemical transformations to incorporate the desired substituents. [Any alkyl or amine group could be installed]. The structure would thus be obvious to a skilled artisan (POSITA; person of ordinary skill in the art) based on routine synthetic organic chemistry.
one or more amines;
Carlmark et al. disclose the use of amine functional substituents to yield a carbamate (see scheme 4 within Carlmark et al.). Furthermore, Carlmark et al. disclose …dendritic structures can be divergently grown from any type of hydroxyl or amine group (see page 5866, left column, paragraph 2 within Carlmark et al.).
Peng et al. disclose the synthesis of terminal primary amines (see abstract within Peng et al.).
Niu et al. disclose the synthesis of terminal tertiary amines (see scheme 1, within Niu et al.).
Khan et al. disclose the use of primary amine surface groups (see paragraph [0075] within Khan et al.).
A skilled artisan (POSITA) could install most amines [primary, secondary, or tertiary; one or more] under routine experimental conditions.
one or more hydrophobic units,
Wu et al., Lallana et al., Peng et al., and Carlmark et al. all disclose “click chemistry” with the functional groups, azide and acetylene.
Wu et al. uses the starting material PE-G1-Acetylene-OH which incorporates the hydrophobic branched alkyl group H2C-CH(CH3)-CH2 (see scheme 1, structure 2; within Wu et al.).
A skilled artisan (POSITA) could install most alkyl groups or hydrophobic groups under routine experimental conditions.
a first moiety covalently connected to the dendritic skeleton, wherein the first moiety is selected from a group consisting of a PEG moiety and a PEG moiety alternative, wherein the first moiety comprises a weight of 100 Daltons to 750 Daltons.
PEG groups have been used by many authors within dendrimers including Lallana et al. (see page 903, page 905-906, pages 908, 909, 911, 913-917 within Lallana et al.), Peng et al. (see page 104 within Peng et al.), and Carlmark et al. (see pages 5866, 5868-5869, 5871, 5873-5875 within Carlmark et al.).
As cited within Applicant’s Remarks many of the PEG groups have a molecular weight greater than 1000 Daltons.
However, Mehta et al. disclose the use of a PEG chain length (570 Da) for enhanced bioactivity (see title, abstract, and page 4574, right column “In summary”; all within Mehta et al.). Therefore, illustrating the importance of using PEG moieties less than 750 Daltons.
The combination of the Khan et al., Shalek et al., Wu et al., Mehta et al., Lallana et al., Peng et al., Niu et al., and Carlmark et al. references make instant claim 1 obvious to a skilled artisan (POSITA).
[The remainder of the instant claims are either directly or indirectly dependent on instant claim 1, which is taught in full by the combination of Khan et al., Shalek et al., Wu et al., Mehta et al., Lallana et al., Peng et al., Niu et al., and Carlmark et al.]
Regarding instant claims 2-3 and 25-26, Khan et al., Shalek et al., Wu et al., Mehta et al., Lallana et al., Peng et al., Niu et al., and Carlmark et al. teach wherein the nucleic acid agent is composed at least in part of at least one type of ribonucleic acid or deoxyribonucleic acid. Khan et al. disclose the nucleic acids included in the nanoparticles (miRNA, siRNA, dsRNA, and cDNA) (see paragraphs [0019], [0053], and [0127] within Khan et al.)
Regarding instant claims 4 and 5, Khan et al., Shalek et al., Wu et al., Mehta et al., Lallana et al., Peng et al., Niu et al., and Carlmark et al. teach wherein the amine comprises a secondary or tertiary amine. Please see the citations and discussion within Table I (especially regarding the amine subunit).
The chemical transformations to incorporate a secondary or tertiary amine are well-known in medicinal chemistry. Almost any commercially available or synthetically designed amine group could be installed. The overall reaction scheme would thus be obvious to a skilled artisan (POSITA). This would not require inventive skill.
Regarding instant claims 6-9, Khan et al., Shalek et al., Wu et al., Mehta et al., Lallana et al., Peng et al., Niu et al., and Carlmark et al. teach wherein the hydrophobic unit comprises an alkyl chain of 1 to 28 carbon atoms or an alkenyl chain comprising 2 to 28 carbon atoms. Please see the citations and discussion within Table I (especially regarding the hydrophobic subunit). Additionally, Niu et al. disclose the intermediates G0, G1, and G2 which all have a terminal alkene comprising three carbon atoms.
The chemical transformations to incorporate an alkyl or alkenyl chain are well-known in medicinal chemistry. Almost any commercially available or synthetically designed alkyl or alkenyl group could be installed. The overall reaction scheme would thus be obvious to a skilled artisan (POSITA). This would not require inventive skill.
Regarding instant claims 11 and 24, Khan et al., Shalek et al., Wu et al., Mehta et al., Lallana et al., Peng et al., Niu et al., and Carlmark et al. teach wherein the first moiety comprises a length of 1 monomer to 15 monomer units. Please see the citations and discussion within Table I (especially regarding the PEG subunit) for the necessary rejection citations.
Regarding instant claims 13-16, Khan et al., Shalek et al., Wu et al., Mehta et al., Lallana et al., Peng et al., Niu et al., and Carlmark et al. teach further comprising a polymer-lipid conjugate such as a PEG-lipid conjugate. Khan et al. disclose that the MDNPs include hydrophililic-hydrophobic polymers such as PEG-lipid conjugates which are biocompatible, non-immunogenic and are non-toxic (see paragraph [0096] within Khan et al.). Furthermore, Khan et al. disclose that an exemplary lipid-anchored mPEG (methoxy terminated) is a 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (see paragraph [0098] within Khan et al.). Finally, Shalek et al. disclose two examples where the PEG-lipid is 10 mol percent and 1.5 mol percent, respectively (see paragraph [0580] within Shalek et al.). These percentages supplied by Shalek et al. are standard within the art. Thus, a skilled artisan (POSITA) would integrate this limitation.
Regarding instant claims 17-20, Khan et al., Shalek et al., Wu et al., Mehta et al., Lallana et al., Peng et al., Niu et al., and Carlmark et al. teach further comprising an amphipathic lipid such as a phospholipid. Khan et al. disclose that one type of hydrophobic component which is well adapted to association within a hydrophobic or lipidic bilayer is a phospholipid such as…1,2-dioleolylglyceryl phosphatidylethanolamine (DOPE) (see paragraph [0098] within Khan et al.). Additionally, Shalek et al. disclose that phospholipids are defined as helper lipids (see paragraph [0525] within Shalek et al.) and can range from 20 to 80 mol percent (see paragraph [0527] within Shalek et al.). This percentage range supplied by Shalek et al. are standard within the art. Thus, a skilled artisan (POSITA) would integrate this limitation.
Regarding instant claims 21 and 22, Khan et al., Shalek et al., Wu et al., Mehta et al., Lallana et al., Peng et al., Niu et al., and Carlmark et al. teach , further comprising cholesterol or a derivative thereof. Khan et al. disclose that one type of hydrophobic component which is well adapted toto association within a hydrophobic or lipidic bilayer is …cholesterol (see paragraph [0098] within Khan et al.). Additionally, Shalek et al. disclose that steroids such as cholesterol are defined as helper lipids (see paragraph [0525] within Shalek et al.) and can range from 20 to 80 mol percent (see paragraph [0527] within Shalek et al.). This percentage range supplied by Shalek et al. are standard within the art. Thus, a skilled artisan (POSITA) would integrate this limitation.
Regarding instant claim 23, Khan et al., Shalek et al., Wu et al., Mehta et al., Lallana et al., Peng et al., Niu et al., and Carlmark et al. teach a method of managing disease, the method comprising: administering a therapeutically effective amount of a nanoparticle composition to a subject, wherein the nanoparticle composition comprises: a nucleic acid agent and a nucleic acid carrier, wherein the carrier comprises: a dendritic-polymer skeleton; an amine; and a hydrophobic unit, wherein: the dendritic-polymer skeleton comprises a PEG moiety; and the amine connects the hydrophobic unit to the dendritic-polymer skeleton. Please see the citations and discussion within Table I for synthesizing the MDNP composition. Khan et al. disclose the administration of their MDNPs (see paragraphs [0208-0218] within Khan et al.). Therefore, a skilled artisan (POSITA) would ascertain this instant method claim.
Regarding instant claim 27, Khan et al., Shalek et al., Wu et al., Mehta et al., Lallana et al., Peng et al., Niu et al., and Carlmark et al. teach wherein the nucleic acid agent is present in a concentration in the range of about 0.01 mg to about 10 mg of nucleic acid agent per kg body weight of the subject. Khan et al. disclose that generally dosage levels of between 0.001 and 100 mg/kg of body weight daily are administered to subjects such as mammals, most preferably, humans. Generally, for intravenous injection or infusion, dosage may be lower. Preferably, the compositions are formulated to achieve a modified prokaryotic cell serum level of between about 1 and about 1000 M (see paragraph [0307] within Khan et al.).
Combination of Khan et al., Shalek et al., Wu et al., Mehta et al., Lallana et al., Nigavekar et al., Peng et al., Niu et al., and Carlmark et al.
Regarding instant claim 12, Khan et al., Shalek et al., Wu et al., Mehta et al., Lallana et al., Nigavekar et al., Peng et al., Niu et al., and Carlmark et al. teach wherein the carrier further comprises a functional group suitable for tracking the carrier. Nigavekar et al. disclose the synthesis of tritium-labeled dendrimers using 3H labeled acetic anhydride (see page 479, left column, Results and Figure 1 within Nigavekar et al.). In addition, radioactive labeling of dendrimers by 3H-containing acetic anhydride allowed proper and accurate quantification of the modified dendrimer derivatives for the true in vivo biodistribution as a function of time (see page 479, left column, Results within Nigavekar et al.). Therefore, allowing Nigavekar et al. to successfully track the material.
Combination of Khan et al., Shalek et al., Wu et al., Mehta et al., Lallana et al., Peng et al., Niu et al., Carlmark et al., Gillies et al., and Pittelkow et al.
Regarding instant claims 28-34, Khan et al., Shalek et al., Wu et al., Mehta et al., Lallana et al., Peng et al., Niu et al., Carlmark et al., Gillies et al., and Pittelkow et al. teach the dendritic polymer skeleton:
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with the correct substituents as defined within the instant claim limitations. “Click-chemistry” involves the reaction of an azide and an acetylene (see Table I within Carlmark et al.). Both the azide and acetylene reactants would be afforded synthetically from the Gillies et al. and Pittelkow et al. disclosures. As a synthetic example, the Examiner will focus on the acetylene portion. Starting from commercially available acetylene:
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A skilled artisan (POSITA) can convert this to the 4-nitrophenyl carbamate intermediate, and then form the desired amide (see Scheme 4 within Gillies et al.). The amide in question could be any commercially available or synthetic amine (see Schemes 1-3 and Table I within Pittelkow et al.). In a similar fashion, the azide portion could be synthesized to afford the desired reactant for “click-chemistry.” None of the synthetic steps are challenging and would be routine for a skilled artisan (POSITA). The review by Carlmark et al. gives routine experimental examples of “click-chemistry” (see pages 5862-5863, II. Accelerated approaches of homofunctional dendrimers, within Carlmark et al.). The dendrimer skeleton structure within instant claim 30 would be realized through the chemistry outlined above and use of commercially available PEG-azides (see PTO-892 NPL W).
In the context of instant method claims 23-27, the desired purpose defines an effect that arises from, and is implicit in the method step(s). Thus, where the purpose is limited to stating a technical effect that inevitably occurs during the performance of the claimed method step(s), and is therefore inherent in that/those step(s), that technical effect is not limiting to the subject-matter of the claim. Thus, the present method claim, defining the application/use of the composition according to claims 1-22 and defining its purpose as "use", is anticipated by any document of the state of the art describing a method of application/use although not mentioning this specific use.
Analogous Art
The Khan et al., Shalek et al., Wu et al., Mehta et al., Lallana et al., Nigavekar et al., Peng et al., Niu et al., Carlmark et al., Gillies et al., and Pittelkow et al. references are all applicable to the endeavor of the instant application. Therefore, these teachings make the references relevant to instant claims 1-9 and 11-34.
Obviousness
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the MDNP delivery of a nucleic acid disclosed by Khan et al. using the teachings of Shalek et al., Wu et al., Mehta et al., Lallana et al., Nigavekar et al., Peng et al., Niu et al., Carlmark et al., Gillies et al., and Pittelkow et al. to incorporate the necessary claim limitations. Starting with Khan et al., the skilled person only had to try the necessary claim limitations disclosed by Shalek et al., Wu et al., Mehta et al., Lallana et al., Nigavekar et al., Peng et al., Niu et al., Carlmark et al., Gillies et al., and Pittelkow et al. The combination of Khan et al., Shalek et al., Wu et al., Mehta et al., Lallana et al., Nigavekar et al., Peng et al., Niu et al., Carlmark et al., Gillies et al., and Pittelkow et al. would allow one to arrive at the present application without employing inventive skill. This combination of the MDNP delivery of a nucleic acid taught by Khan et al. along with the use of the necessary claim limitations taught by Shalek et al., Wu et al., Mehta et al., Lallana et al., Nigavekar et al., Peng et al., Niu et al., Carlmark et al., Gillies et al., and Pittelkow et al. would allow a research and development scientist (POSITA) to develop the invention taught in the instant application. It would have only required routine experimentation to modify the MDNP delivery of a nucleic acid disclosed by Khan et al. with the use of the necessary claim limitations taught by Shalek et al., Wu et al., Mehta et al., Lallana et al., Nigavekar et al., Peng et al., Niu et al., Carlmark et al., Gillies et al., and Pittelkow et al. This combined modification would have led to an enhanced MDNP delivery of a nucleic acid that would be beneficial for patients.
Response to Arguments
Applicant's arguments filed January 26, 2026 have been fully considered but they are not persuasive.
The instant claim amendments were sufficient to address the 35 U.S.C. 112(b) rejections. Therefore, the rejections are withdrawn from the Final office action dated October 24, 2025.
The new instant claims did necessitate a new ground of rejection.
Applicant Argument: The Applicant argues that the synthetic design choice of a first moiety covalently connected to the dendritic skeleton, wherein the first moiety is selected from a group consisting of a PEG moiety and a PEG moiety alternative, wherein the first moiety comprises a weight of 100 Daltons to 750 Daltons is not taught by any of the art of record.
Examiner’s Rebuttal: The new reference, Mehta et al. addresses this instant claim limitation.
PEG groups have been used by many authors within dendrimers including Lallana et al. (see page 903, page 905-906, pages 908, 909, 911, 913-917 within Lallana et al.), Peng et al. (see page 104 within Peng et al.), and Carlmark et al. (see pages 5866, 5868-5869, 5871, 5873-5875 within Carlmark et al.). As cited within Applicant’s Remarks many of the PEG groups have a molecular weight greater than 1000 Daltons.
However, Mehta et al. disclose the use of a PEG chain length (570 Da) for enhanced bioactivity (see title, abstract, and page 4574, right column “In summary”; all within Mehta et al.). Therefore, illustrating the importance of using PEG moieties less than 750 Daltons.
Applicant Argument: The Applicant argues that a full 35 U.S.C. §103 obviousness analysis has not been disclosed citing the motivation and selection process of the art of record.
Examiner’s Rebuttal: A more detailed obvious analysis is presented below:
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the MDNP delivery of a nucleic acid disclosed by Kahn et al., using the teachings of Shalek et al., Wu et al., Mehta et al., Lallana et al., Peng et al., Niu et al., Carlmark et al., and further in light of the claim-specific features described in Nigavekar et al., Gillies et al., and Pittelkow et al., in order to arrive at the subject matter of the instant claims.
The Khan et al., Shalek et al., Wu et al., Mehta et al., Lallana et al., Nigavekar et al., Peng et al., Niu et al., Carlmark et al., Gillies et al., and Pittelkow et al. references all have considerable overlap with the development of dendrimer drug formulations. In this instance, Kahn et al. disclose MDNP delivery of a nucleic acids, while Shalek et al., Wu et al., Mehta et al., Lallana et al., Peng et al., Niu et al., and Carlmark et al. supply the synthetic methods to modify the primary reference, finally, Nigavekar et al., Gillies et al., and Pittelkow et al. disclose claim-specific synthesis of functional groups. All references are directed to the development of dendrimer drug formulations and therefore constitute analogous art under MPEP §2141.01(a). A considerable amount of synthetic organic chemistry has been carried out within this art making the present invention obvious. A POSITA would have reasonably consulted the eleven references when seeking to develop a dendrimer drug formulation.
Starting with Khan et al., the skilled person only had to try the necessary claim limitations disclosed by Shalek et al., Wu et al., Mehta et al., Lallana et al., Nigavekar et al., Peng et al., Niu et al., Carlmark et al., Gillies et al., and Pittelkow et al. The combination of Khan et al., Shalek et al., Wu et al., Mehta et al., Lallana et al., Nigavekar et al., Peng et al., Niu et al., Carlmark et al., Gillies et al., and Pittelkow et al. would allow one to arrive at the present application without employing inventive skill. This combination of the MDNP delivery of a nucleic acid taught by Khan et al. along with the use of the necessary claim limitations taught by Shalek et al., Wu et al., Mehta et al., Lallana et al., Nigavekar et al., Peng et al., Niu et al., Carlmark et al., Gillies et al., and Pittelkow et al. would allow a research and development scientist (POSITA) to develop the invention taught in the instant application. It would have only required routine experimentation to modify the MDNP delivery of a nucleic acid disclosed by Khan et al. with the use of the necessary claim limitations taught by Shalek et al., Wu et al., Mehta et al., Lallana et al., Nigavekar et al., Peng et al., Niu et al., Carlmark et al., Gillies et al., and Pittelkow et al. Incorporating the disclosure of Kahn et al. into the target specific molecules presented by Shalek et al., Wu et al., Mehta et al., Lallana et al., Peng et al., Niu et al., and Carlmark et al. followed by the additional synthetic modifications disclosed by Nigavekar et al., Gillies et al., and Pittelkow et al. represents a predictable use of prior art elements according to their established functions, consistent with MPEP §2143 and KSR.
Furthermore, the additional claim limitations taught by Shalek et al., Wu et al., Mehta et al., Lallana et al., Nigavekar et al., Peng et al., Niu et al., Carlmark et al., Gillies et al., and Pittelkow et al. would have been viewed by a POSITA as routine design optimizations or known modifications to develop a dendrimer drug formulation. Implementing these features in Kahn et al.’s MDNP delivery of a nucleic acid would not require more than ordinary skill or routine experimentation.
Accordingly, the combination of Kahn et al., supplemented by Shalek et al., Wu et al., Mehta et al., Lallana et al., Nigavekar et al., Peng et al., Niu et al., Carlmark et al., Gillies et al., and Pittelkow et al. provides all the elements of the claimed invention. The resulting MDNP delivery of a nucleic acid constitutes no more than the predictable outcome of combining familiar prior art components, and therefore the claimed subject matter would have been obvious to a POSITA prior to the effective filing date of the invention.
Applicant Argument: The Applicant argues that the Examiner fails to identify a path of for the KSR rationale, “obvious to try” (MPEP 2143 E).
Examiner’s Rebuttal: The art of record defines what is “obvious to try”. It must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
The BACKGROUND section of the specification defines the problem to be solved (see instant specification paragraph [0003]):
PEGylated carriers have been widely used in the field of drug delivery and bioconjugation due to their long circulatory half-life, biocompatibility, and low toxicity. It is increasingly reported, however, that treating patients with PEGylated drugs leads to the formation of antibodies that specifically recognize PEG (i.e., anti-PEG antibodies). Consequently, treating patients who have acquired anti-PEG antibodies with existing PEGylated drugs may result in accelerated blood clearance (ABC) with enhanced accumulation of PEG-conjugates in the liver and spleen, low drug efficacy, hypersensitivity, and potentially life-threatening side effects.
A skilled artisan (POSITA), with the above knowledge from the literature would synthetically design MDNP delivery of a nucleic acids using the Khan et al., Shalek et al., Wu et al., Mehta et al., Lallana et al., Nigavekar et al., Peng et al., Niu et al., Carlmark et al., Gillies et al., and Pittelkow et al. references.
Applicant Argument: The Applicant argues that support of the Declaration under 37 C.F.R. § 1.132 supports all arguments presented.
Examiner’s Rebuttal: The Examiner agrees with the Declaration except for point 9 which states:
A POSITA seeking to make dendrimer-based nanomaterials would have understood that the available chemical space for such modification is not finite, limited, or predictable. Click chemistry and related conjugation strategies permit an effectively unlimited number of functional-group combinations, linker chemistries, substitution patterns, and molecular-weight selections. The functional groups capable of participating in such reactions are not functional equivalents, and their selection materially affects nanoparticle structure and behavior.
The art of record supports a more finite, limited, and predictable research and development direction. In the absence of the cited references, the synthetic modifications that can be carried out does become infinite and there would be undue experimentation.
Thus, the 35 U.S.C. §103 rejection for instant claims 1-9 and 11-34 is maintained.
Conclusion
No claims are allowed.
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/JOHN W LIPPERT III/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615