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
Claims 1-2, 4-7, 9-10, 12-15, 18, and 21-26 are pending in this office action. Claims 3, 8, 11, 16-17, and 19-20 are cancelled. All pending claims are under examination in this application.
Priority
The current application was filed on July 17, 2023 is a 371 of PCT/CA2022/050051 filed January 14, 2022, which in turn claims domestic priority to provisional patent application 63/138,626 filed on January 18, 2021.
Claim Objections
Claim 18 is objected to because of the following informality:
Claim 18 has the amended text “…compound of having the…”. Please delete the “of.”. 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 1-2, 4-7, 9-10, 12-15, 18, and 21-26 are rejected under 35 U.S.C. 103 as being unpatentable over Aliabadi et al. (Acta Biomaterialia 2020, published January 15, 2020) in view of Thapa et al. (Human Gene Therapy, 2019), Bahadur et al. (Journal of Materials Chemistry B, 2015), Manuja et al. (International Journal of Pharmaceutical Sciences Review and Research, 2013), Seidel et al. (WO2019/051126A1), and Bahou et al. (WO2017/062422A1).
[The Examiner is going to introduce each new reference and then combine them where appropriate to reject the instant claims.]
1. Aliabadi et al.
Aliabadi et al. is considered the closest prior art as it teaches a systematic comparison of lipopolymers for siRNA delivery to multiple breast cancer cell lines: In vitro studies (see title). Furthermore, Aliabadi et al. disclose that small interfering RNA (siRNA) therapy is a promising approach for treatment of a wide range of cancers, including breast cancers that display variable phenotypic features. To explore the general utility of siRNA therapy to control aberrant expression of genes in breast cancer, we conducted a detailed analysis of siRNA delivery and silencing response in vitro in 6 separate breast cancer cell models (MDA-MB- 231, MDA-MB-231-KRas-CRM, MCF-7, AU565, MDA-MB-435 and MDA-MB-468 cells). Using lipopolymers for siRNA complexation and delivery, we found a large variation in siRNA delivery efficiency depending on the specific lipopolymer used for siRNA complexation and delivery. Some lipopolymers were effective in all cell types used in this study, indicating the possibility of universal carriers for siRNA therapy. The delivery efficiency for effective lipopolymers was not correlated with dextran uptake in the cells tested, which indicated a receptor-mediated internalization for siRNA complexes with lipopolymers, unlike fluid-phase transfer associated with dextran uptake. Consistent with this, specific inhibitors involved in clathrin- and caveolin-mediated endocytosis significantly ( > 50%) reduced the internalization of siRNA complexes in all cell types. Using JAK2 and STAT3 silencing in MDA-MB-231 and MDA-MB-468 cells, a general correlation between the uptake and silencing efficiency at the mRNA level was evident, but it appeared that the choice of the target rather than the cell type was more critical for consistent silencing. We conclude that siRNA therapy with lipopolymers can be undertaken in multiple breast cancer cell phenotypes with similar efficiency, indicating the general applicability of non-viral RNAi in clinical management of molecularly heterogeneous breast cancers (see abstract).
2. Thapa et al.
Thapa et al. teach breathing new life into TRAIL for breast cancer therapy:
co-delivery of pTRAIL and complementary siRNAs using lipopolymers (see title). In addition, Thapa et al. disclose that preclinical studies showed that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) therapy is safe and effective to combat cancers, but clinical outcomes have been less than optimal due to short half-life of
TRAIL protein, insufficient induction of apoptosis, and TRAIL resistance displayed in many tumors. In this study, we explored co-delivery of a TRAIL expressing plasmid (pTRAIL) and complementary small interfering RNAs (siRNAs) (silencing Bcl2-like 12 [BCL2L12] and superoxide dismutase 1 [SOD1]) to improve the response of breast cancer cells against TRAIL therapy. It is desirable to co-deliver the pDNA along with siRNA using a single delivery agent, but this is challenging given different structures of long/flexible pDNA and short/rigid siRNA. Toward this goal, we identified an aliphatic lipid-grafted low–molecular weight polyethylenimine (PEI) that accommodated both pDNA and siRNA in a single complex. The co-delivery of pTRAIL with BCL2L12- or
SOD1-specific siRNAs resulted more significant cell death in different breast cancer cells compared with separate delivery without affecting nonmalignant cells viability. Ternary complexes of lipopolymer with pTRAIL and BCL2L12 siRNA significantly retarded the growth of breast cancer xenografts in mice. The enhanced anticancer activity was attributed to increased in situ secretion of TRAIL and sensitization of breast
cancer cells against TRAIL by the co-delivered siRNAs. The lipid-grafted PEIs capable of co-delivering multiple types of nucleic acids can serve as powerful carriers for more effective complementary therapeutics (see abstract).
3. Bahadur et al.
Bahadur et al. teach additive nanocomplexes of cationic lipopolymers for improved non-viral gene delivery to mesenchymal stem cells (see title). In addition, Bahadur et al. disclose that it has been challenging to modify primary cells with non-viral gene delivery. Herein, we developed a ternary nano-formulation for gene delivery to umbilical cord blood and bone marrow derived mesenchymal stem cells (MSC) by using lipid-modified small (1.2 kDa) molecular weight polyethylenimine (PEI1.2). Linoleic acid (LA) was end-capped with carboxyl functionality by coupling with mercaptopropionic acid through thio-ester linkage, and then grafted onto PEI1.2 via N-acylation. The thio-ester LA grafted PEI1.2 (PEI-tLA) displayed a significantly lower (up to 6-fold) DNA binding capability and a higher propensity to dissociate upon polyanionic challenge. The dissociation ability of the complexes was further enhanced by incorporating hyaluronic acid (HA) into plasmid DNA (pDNA) complexes of PEI-tLA. The HA incorporation influenced the surface charge of complexes more so than the hydrodynamic size, but it clearly increased the propensity for dissociation upon a polyanionic challenge. The PEI-tLAs were less toxic on MSC and displayed significantly higher transgene expression in MSC than conventional PEI-LA. Ternary complexes of with HA (pDNA/HA = 2, w/w) further enhanced the efficiency of PEI-tLAs of low (B2 lipid/PEI) lipid substitution, which was comparable to or higher than commercial transfection reagents. We conclude that PEI-tLA of low lipid substitution can be employed as a gene carrier to design supersensitive nano-formulations (see abstract).
4. Manuja et al.
Manuja et al. teach a comprehensive review on biological activities of p-hydroxy benzoic acid and its derivatives (see title). In addition, Manuja et al. disclose that p-hydroxy benzoic acid (PHBA) is an organic chemical which can be obtained naturally as well as synthetically. The literature survey reveals its various biological properties viz. antimicrobial, antialgal, antimutagenic, antiestrogenic, hypoglycemic, anti-inflammatory, anti-platelet aggregating, nematicidal, antiviral, antioxidant etc. It is also reported to be used as preservative in many drugs, cosmetic products, pharmaceuticals, food and beverages. Some derivatives of 4-hydroxybenzoicacid are found to possess direct action on Hbs molecules, inhibit acetic acid induced oedema and used in management of sickle cell disease. The present study will give comprehensive information of the biological activities of this p-hydroxy benzoic acid and its derivatives (see abstract).
5. Seidel et al.
Seidel et al. teach antigen-presenting polypeptides with chemical conjugation sites and methods of use thereof (see title). In addition, Seidel et al. disclose that the present disclosure provides antigen-presenting polypeptides, including single-chain antigen-presenting polypeptides and multimeric antigen-presenting polypeptides comprising one or more chemical conjugation sites for incorporation of, for example, epitope containing polypeptides. The present disclosure provides nucleic acids comprising nucleotide sequences encoding antigen-presenting polypeptides comprising one or more chemical conjugation sites, as well as cells genetically modified with the nucleic acids. The single-chain and multimeric antigen-presenting polypeptides and their epitope conjugates are useful for modulating the activity of a T-cell, and accordingly, the present disclosure provides methods of modulating activity of a T-cell in vitro and in vivo as a method of treatment (see abstract).
6. Bahou et al.
Bahou et al. teach methods for increasing platelet count by inhibiting biliverdin IXb reductase (see title). In addition, Bahou et al. disclose that the present disclosure provides methods of treating a human having a disease or disorder that would benefit from increasing platelet counts. The method involves inhibiting the enzyme activity of biliverdin IXβ reductase (BLVRB) activity or inhibiting the expression of BLVRB gene (see abstract).
Combination of Alaibadi et al. and Thapa et al.
Regarding instant claim 1, Aliabadi et al. and Thapa et al. teach a compound comprising a polymer having a molecular weight ranging from about 0.5 kDa to about 5 kDa and an aliphatic lipid-di-functional thioester group. The necessary citations of Aliabadi et al. and Thapa et al. that pertain to instant claim 1 are presented in Table I.
Table I
Instant Claim 1
Aliabadi et al. and Thapa et al. Citations
A compound comprising a polymer having a molecular weight ranging from about 0.5 kDa to about 5 kDa and an aliphatic lipid-di-functional thioester group,
Aliabadi et al. disclose 0.6-2 kDa polyethylenimine (PEI) (see Fig. 1 Table B within Aliabadi et al.) which includes an aliphatic lipid-thioester group (see page 353, left column, 2.3 Polymer synthesis and characterization within Aliabadi et al.).
Thapa et al. disclose 0.6-1.8 kDa PEI which includes an aliphatic lipid-thioester group similar to the synthetic chemistry of Aliabadi et al. (see Figure I within Thapa et al.).
The synthetic scheme presented by Aliabadi et al. and Thapa et al. is not of a di-functional thioester group. However, instant claim 1 is obvious in light of a skilled artisan (POSITA; person of ordinary skill in the art) synthetically using the diacid chloride rather than monoacid chloride, as illustrated within Figure I.
Figure I
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The mono-functional thioester (t) is then reacted with a commercially available PEI. This is shown within Figure II.
Figure II
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In a similar fashion, the di-functional thioester (tt) is reacted with a commercially available PEI. This is shown within Figure III.
Figure III
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This chemistry is not difficult and employs a carboxylic acid amine coupling. A skilled artisan (POSITA) could under routine experimental conditions synthesize PEI-tt (1B). The teachings of both Alaibadi et al. and Thapa et al. would lay the synthetic foundation focusing on the mono-functional thioester (t). Since all of the PEI analogues are commercially available, the variables x-z would be within the instant claim limitation range.
wherein the polymer is selected from polyethylenimine in a branched, linear, or dendritic form, polyalkylimine, a poly(amino acid), a poly(beta-amino acid), a poly(beta-amino ester), a cationic amino acid containing a peptide or a polymer, an aminated polymer derived from water- soluble, uncharged polymers modified with amine compounds, polyethylenimine derivatized with silica, polyethylenglycol, polypropyleneglycol, or an amino acid, or dopamine, or poly(2-dimethylaminoethyl methacrylate) or a derivative thereof in combination with a polymer to create amphiphilic polymers; a polyamidoamine derivative; and poly(N-(2- hydroxypropyl)methacrylamide) or a derivative thereof, and
Aliabadi et al. disclose the use of a branched PEI (see Fig. 1 and Table B within Aliabadi et al.) for the mono-functional thioester shown in Figure IV:
Figure IV
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As disclosed above, Aliabadi et al. utilize the mono-functional ester. This synthetic chemistry could under routine experimental conditions be applied to the di-functional thioester by a skilled artisan (POSITA).
wherein the aliphatic lipid comprises a saturated or unsaturated aliphatic lipid selected from propanoyl (C3), propanedioyl (C3), pentanedioyl or glutaryl chloride (C5), hexanoic acid or hexanoyl (C6), heptanedioyl or pimeloyl chloride (C7), capryloyl (C8), lipoic acid or lipoyl (C8), nonanedioyl or azelaoyl chloride (C9), lauric acid or lauroyl (C12), dodecanedioyl (C12), palmitic acid or palmitoyl (C16), stearoyl (C18), linoleoyl (C18), oleoyl (C18), eicosanoyl (C20), eicosapentaenoyl (C20), arachidonoyl (C20), linolarachidonoyl (C20), docosanoyl (22), docosahexaenoyl (22), myristoleic acid (C14:1, cis-9), palmitoleic acid (C16:1, cis-9), stearic acid (C 18) and derivatives thereof, oleic acid (C 18:1, cis-9), elaidic acid (C 18:1, trans-9), linoleic acid (C18:2, cis-9,12), or linolenic acid (C18:3, cis-9,12,15).
Aliabadi et al. disclose the use and incorporation of several lipids which have overlap with the instant claim limitation (see Fig. 1 and Table B within Aliabadi et al.). These lipids are illustrated within Figure V:
Figure V
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As disclosed above, Aliabadi et al. utilize the mono-functional ester. This synthetic chemistry could under routine experimental conditions be applied to the di-functional thioester by a skilled artisan (POSITA).
Therefore, a skilled artisan (POSITA) would consult the disclosures of Aliabadi et al. and Thapa et al. to teach all the elements of instant claim 1.
The remainder of the instant claims which are directly dependent on claim 1 are taught in full by the combination of Aliabadi et al. and Thapa et al.
Regarding instant claim 2, Aliabadi et al. teach wherein the polymer comprises polyethylenimine, and the aliphatic lipid-thioester group has the formula IIIA or IIIB:
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wherein is the carbon chain length ranging from C3 to C22. Aliabadi et al. disclose the mono-functional thioester (t) having a carbon chain of 3<x<22 based on the lipid of choice (see Table I, Figures I-V). This synthetic chemistry could under routine experimental conditions be applied to the di-functional thioester by a skilled artisan (POSITA).
Regarding instant claim 4, Alaibadi et al. and Thapa et al. teach the compound of claim 2, having the formula IB:
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wherein the aliphatic lipid-di-functional thioester group has the formula IIIB, and a linker comprises a spacer having 3<n<22 atoms; x = 5<n<30; y = 5<n<30; and z = 1<n<5. This synthetic chemistry could under routine experimental conditions be applied to the di-functional thioester by a skilled artisan (POSITA) (see instant claim 1 and 2).
Regarding instant claim 5, Aliabadi et al. and Thapa et al. teach a compound comprising a polymer having a molecular weight ranging from about 0.5 kDa to about 5 kDa and an aliphatic lipid-thioester group. Please see the citations and discussion within instant claim 1 for the relevant rejection text.
Regarding instant claim 9, Aliabadi et al. and Thapa et al. teach wherein the nucleic acid is selected from an RNA-based nucleic acid comprising siRNA, sgRNA, microRNA, mRNA, shRNA, or combinations thereof; a DNA-based nucleic acid comprising a DNA-based oligonucleotide or antisense oligonucleotide, plasmid DNA for encoding an RNA product comprising shRNA, mRNA, sgRNA, or combinations thereof; a peptide-nucleic acid; a DNA-RNA chimera; or a nucleic acid in combination with a protein. Aliabadi et al. disclose the complexation and drug delivery of siRNA (see title and abstract within Aliabadi et al.; also see instant claim 1).
Regarding instant claim 12, Alaibadi et al. and Thapa et al. teach a method of treating or ameliorating a disease in a subject, comprising administering to the subject an effective amount of a nanoparticle comprising a compound having the formula IA:
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wherein the aliphatic lipid-thioester group has the formula IIIA, and a hydrophobic group comprises 3<n<22 atoms; x = 5<n<30; y = 5<n<30; and z = 1<n<5, complexed to mRNA; or a composition or pharmaceutical composition comprising the compound, or the nanoparticle, and a pharmaceutically acceptable carrier. Aliabadi et al. disclose the in vitro delivery against 6 separate breast cancer cell line models using the lipopolymers for siRNA complexation and delivery. Thapa et al. disclose a similar lipopolymer using plasmid DNA (pDNA) and siRNA (see abstract and Figure 1; both within Thapa et al.). Furthermore, Aliabadi et al. disclose the complexation and drug delivery of siRNA (see title and abstract within Aliabadi et al.; also see instant claim 1). A skilled artisan (POSITA) could expand the array of nucleic acids to include mRNA under routine experimental conditions. Since RNA is a negatively charged species and a complex is formed with cationic lipopolymers (see page 1542, right column, 1st paragraph within Thapa et al), a skilled artisan (POSITA) would substitute mRNA for the siRNA disclosed by Aliabadi et al. and/or Thapa et al. under routine conditions. Additionally, Thapa et al. disclose both in vitro and in vivo delivery models of this complex for breast cancer therapy (see page 1541, right column and see page 1535, right column, Animal studies; also see abstract; all within Thapa et al.). Therefore, a skilled artisan (POSITA) would use the teachings of both Alaibadi et al. and Thapa et al. to administer this lipopolymer complex to a subject.
Regarding instant claim 13, Alaibadi et al. and Thapa et al. teach wherein the disease comprises chronic and acute myeloid leukemia, chronic and acute lymphocytic leukemia, hairy cell leukemia, meningeal leukemia, myeloma, multiple myeloma, lymphoma, brain cancer, bladder cancer, breast cancer, melanoma, skin cancer, epidermal carcinoma, colon and rectal cancer, lung cancer, non-Hodgkin lymphoma, Hodgkin lymphoma, Sezary Syndrome, endometrial cancer, pancreatic cancer, kidney cancer, prostate cancer, leukemia thyroid cancer, head and neck cancer, ovarian cancer, hepatocellular cancer, cervical cancer, sarcoma, gastric cancer, gastrointestinal cancer, and uterine cancer. Alaibadi et al. disclose the use of the lipopolymer siRNA complex for breast cancer (see abstract within Alaibadi et al.). Thapa et al. also disclose the use of their lipopolymer pDNA and siRNA complex in breast cancer models (see page 1532, right column, paragraph 2 within Thapa et al.). Therefore, a skilled artisan (POSITA) would use the teachings of both Alaibadi et al. and Thapa et al. to expand and administer this lipopolymer complex to additional cancers for a greater opportunity of commercial success.
Regarding instant claim 18, Aliabadi et al. and Thapa et al. teach a method of delivering mRNA or ribonucleotide protein complexes using a compound having the formula IA:
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wherein the aliphatic lipid-thioester group has the formula IIIA, and a hydrophobic group comprises 3<n<22 atoms; x = 5<n<30; y = 5<n<30; and z = 1<n<5. Please see the discussion and citations within instant claims 12 regarding the RNA derivatives used by both Aliabadi et al. and Thapa et al. Also, please see the discussion and citations within instant claim 1. Since RNA is a negatively charged species and a complex is formed with cationic lipopolymers (see page 1542, right column, 1st paragraph within Thapa et al), a skilled artisan (POSITA) would substitute mRNA for the siRNA disclosed by Aliabadi et al. and/or Thapa et al. under routine conditions.
Combination of Alaibadi et al., Thapa et al., and Manuja et al.
Regarding instant claim 6, Aliabadi et al., Thapa et al., and Manuja et al. teach a compound comprising a polymer having a molecular weight ranging from about 0.5 kDa to about 5 kDa and alipid-ester or lipid-thioester group, wherein the polymer comprises polyethylenimine, and the lipid-ester or lipid-thioester group has the formula selected from formula IVA, IVB, IVC, or IVD:
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Please see the discussion and citations pertaining to instant claim 1. A skilled artisan (POSITA) would know that synthetically the hydroxyl group is functional group which reacts with acid chlorides to afford the desired ester. The benzoic acid derivative, gallic acid (GA), would be an excellent choice due to their biodegradable nature and the availability of the compound both synthetically and naturally (see title; abstract; Figure 8; and supporting text; all within Manuja et al.). Manuja et al. disclose within their review the use of GA (see title; abstract; sFigure 8; and supporting text; all within Manuja et al.). The desired lipid-ester or lipid-thioester could be synthetically derived following the protocol discussed within instant claim 1. This protocol would be a routine synthetic exercise for a skilled artisan (POSITA).
Regarding instant claim 7, Aliabadi et al., Thapa et al., and Manuja et al. teach the compound of instant claim 6, having the formula IIA, IIB, IIC, or IID:
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where the compound comprises a carbon chain length of 3<n<22 atoms; x = 5<n<30; y = 5<n<30; and z = 1<n<5. Maintaining the same reasoning discussed within instant claim 6, a skilled artisan (POSITA) could under routine experimental conditions obtain these PEI derivatives following the protocol outlined within instant claim 1.
Combination of Alaibadi et al., Thapa et al., and Bahadur et al.
Regarding instant claim 10, Aliabadi et al., Thapa et al., and Bahadur et al. teach the nanoparticle of instant claim 9, further comprising an additive selected from p polyacrylic acid, polymethacrylic acid, polyaspartic acid, polyglutamic acid, gelatin, hyaluronic acid, cellulose, or derivatives thereof. Thapa et al. disclose that hyaluronic acid (HA) enhanced the release of payload in complexes and resulted in higher transfection (see page 1544, left column, paragraph 1 within Thapa et al.). Bahadur et al. disclose the use of their lipopolymer and pDNA complex (see Figure 1 within Bahadur et al.). Furthermore, Bahadur et al. disclose that due to reduced binding and increased dissociation propensity, these polymers were intended to serve as candidates in designing supersensitive nano-formulations using … ‘‘HA’’ (hyaluronic acid) as an additive to the conventional binary complexes (i.e., polymer + pDNA) (see page 3980, left column, conclusions, within Bahadur et al.). Therefore, a skilled artisan (POSITA) would use the teachings of both Thapa et al. and Bahadur et al. to use the polyanion additives such as HA with the lipopolymer / nucleic acid complex (nanoparticle; see the discussion and citations within instant claim 8).
Combination of Alaibadi et al., Thapa et al., and Bahou et al.
Regarding instant claim 14, Aliabadi et al., Thapa et al., and Bahou et al. teach wherein the disease is treated or ameliorated in the subject through genetically modified hematopoietic host cells. Bahou et al. disclose a bar graph showing colony forming unit-megakaryocyte (CFU-MK) determinations (N = 9 wells/3 experiments) of genetically-modified hematopoietic-derived stem cells (CD34+HSCs) that… (see paragraph [0042]; Fig. 4d; both within Bahou et al.). Moreover, Bahou et al. disclose that their broad phenotypic heterogeneity suggested that rare allelic variants (genomic modifier loci) affecting blood cell counts could be phenotypically unmasked in clonally-expanded hematopoietic disorders (see paragraph [0060] within Bahou et al.).
Therefore, a skilled artisan could use the teachings of Bahou et al. under routine experimental conditions to employ host cells that are genetically-modified hematopoietic-derived stem cells in combination with the lipopolymer-nucleic acid complex taught by Aliabadi et al. and Thapa et al.
Combination of Alaibadi et al., Thapa et al., and Seidel et al.
Regarding instant claim 15, Aliabadi et al., Thapa et al., and Seidel et al. teach wherein the host cells are selected from T-cells including helper T-cells, or Natural Killer cells. Seidel et al. disclose that by providing a chemical conjugation site for the incorporation of an epitope in TMAPPs, such TMAPPs that are unconjugated to an epitope may be used as a T-cell receptor ("TCR") presentation platform into which various epitopes (e. g., peptide anitgens) may be covalently bound, and the resulting epitope conjugate used for modulating the activity of a T-cell bearing a TCR specific to the epitope. The effect of TMAPP-epitope conjugates on T-cells with TCRs specific to the epitope conjugate depends on which, if any, MODs are present in the TMAPP. In the absence of any stimulatory MOD in the TMAPP-epitope conjugate, prolonged exposure to the TMAPP-epitope conjugate may result in T-cell anergy or suppression of T-cell stimulation. The action of TMAPP epitope conjugates having MODs (e. g., IL-2, CD80, 4-IBBL…polypeptides) depends on the stimulatory or inhibitory effect of the MODs. MOD-containing TMAPP-epitope conjugates function as a means of selectively delivering the MODs to T-cells specific for the conjugated (covalently bound) epitope, resulting in MOD-driven T-cell responses (e. g., proliferation of epitope specific T-cells). The combination of the reduced affinity of the MOD(s) for their Co-MOD(s), and the affinity of the epitope for a TCR, provides for enhanced selectivity of a TMAPP-epitope conjugate while retaining the activity of the MODs. Accordingly, the present disclosure provides methods of modulating the activity of T-cells in vitro and in vivo, and the use of TMAPPs as therapeutics in methods of treatment (see paragraph [0007] within Seidel et al.). Moreover, Seidel et al. disclose that "T cell" includes all types of immune cells expressing CD3, including T-helper cells (CD4+cells), cytotoxic [killer] T-cells (CDS+ cells), T-regulatory cells (Treg), and NK-T cells (see paragraph [0057] within Seidel et al.).
Therefore, a skilled artisan could use the teachings of Seidel et al. under routine experimental conditions to employ host cells that are T-cells including helper T-cells and killer T-cells in combination with the lipopolymer-nucleic acid complex taught by Aliabadi et al. and Thapa et al.
Combination of Alaibadi et al., Thapa et al., Manuja et al., and Bahadur et al.
Regarding instant claims 21 and 22, Aliabadi et al., Thapa et al., Manuja et al., and Bahadur et al. teach a nanoparticle comprising the compound of instant claims 4 or 7 complexed to a nucleic acid, or a composition comprising the nanoparticle or the compound, and a pharmaceutically acceptable carrier. Aliabadi et al. disclose that the lipopolymer complexes are ~200 nm (nanoparticle; see page 364, left column, 1st paragraph within Aliabadi et al.). In addition, Aliabadi et al. disclose that the nucleic acid, siRNA, is complexed and delivered using the lipopolymer (see instant claim 1) (see title and abstract within Aliabadi et al.). Moreover, Aliabadi et al. disclose that all the PEI derivatives used in this study were soluble in pure water (see page 353, right column, 1st paragraph within Aliabadi et al.), and that all lipopolymers used in this study were water-soluble (see page 355, right column, 3.1 Lipopolymers and siRNA binding within Aliabadi et al.). Thus, ensuring water can be used as a solvent for administration. Water is a pharmaceutically acceptable carrier for drug delivery. Please see the citations and discussion within instant claim 4 for the necessary rejection text.
Regarding instant claims 23 and 24, Aliabadi et al., Thapa et al., Manuja et al., and Bahadur et al. teach a method of treating, preventing, or ameliorating a disease in a subject, comprising administering to the subject an effective amount of a nanoparticle comprising the compound of instant claims 4 or 7 complexed to a nucleic acid; or a composition comprising the compound or the nanoparticle, and a pharmaceutically acceptable carrier. Please see the citations and discussion within instant claims 4, 12, and 21-22 for the necessary rejection text.
Regarding instant claims 25 and 26, Aliabadi et al., Thapa et al., Manuja et al., and Bahadur et al. teach a method of delivering mRNA or RNP complexes using the compound of instant claims 4 or 7. Please see the citations and discussion within instant claims 4, 7, 18, and 21-22 for the necessary rejection text.
Analogous Art
The Aliabadi et al., Thapa et al., Bahadur et al., Manuja et al., Seidel et al., and Bahou et al. references are directed to the same field of endeavor as the instant claims, that is, a compound comprising a polymer having a molecular weight ranging from about 0.5 kDa to about 5 kDa and an aliphatic lipid-thioester group.
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 nucleic acid lipopolymer composition disclosed by Aliabadi et al., using the teachings of Thapa et al., Bahadur et al., Manuja et al., Seidel et al., and Bahou et al. to incorporate the necessary claim limitations. Motivation to combine the Aliabadi et al., Thapa et al., and Bahadur et al. references would rely on the common topic of the lipopolymer-nucleic acid complexation and administration. Furthermore, the Manuja et al. reference illustrates the common usage of phenol-based benzoic acid derivatives including PHBA and GA and gives a skilled artisan (POSITA) a synthetic handle to synthesize the derivatives of instant claims 6 and 7. Finally, both the Seidel et al. and Bahou et al. references allow a skilled artisan (POSITA) to incorporate the correct host cells in the successful treatment of a variety of diseases.
Starting with Aliabadi et al., the skilled person only had to try the necessary claim limitations disclosed by Thapa et al., Bahadur et al., Manuja et al., Seidel et al., and Bahou et al. The combination of Aliabadi et al., Thapa et al., Bahadur et al., Manuja et al., Seidel et al., and Bahou et al. would allow one to arrive at the present application without employing inventive skill. This combination of the nucleic acid lipopolymer composition taught by Aliabadi et al. along with the use of the necessary claim limitations taught by Thapa et al., Bahadur et al., Manuja et al., Seidel et al., and Bahou et al. would allow a research and development scientist (POSITA) to develop the invention taught in the instant application. promote plant growth of cultivated plants present in a target area.
It would have only required routine experimentation to modify the nucleic acid lipopolymer composition disclosed by Aliabadi et al. with the use of the necessary claim limitations taught by Thapa et al., Bahadur et al., Manuja et al., Seidel et al., and Bahou et al. This combined modification would have led to an enhanced the nucleic acid lipopolymer composition that would be beneficial for patients.
In the context of instant method claims 12-16, 18, and 23-26 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 the prior art, 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.
Response to Arguments
Applicant's arguments filed January 15, 2026 have been fully considered but they are not persuasive.
The instant claim amendments were sufficient to address the 35 U.S.C. 112(a) rejections, the 35 U.S.C. §102 rejection, and the claim objections. Therefore, they are all withdrawn from the Non-Final office action dated October 17, 2025.
The amendments did not necessitate a new ground of rejection.
Applicant Argument: The Applicant argues that the prior art of record when combined does not teach or suggest all the claim limitations.
Examiner’s Rebuttal: The Examiner respectfully disagrees. A skilled artisan (POSITA) could make the inventive “jump” (small hurdle) to use the di-acid chloride (see Figure I) instead of the mono-acid chloride as illustrated by the Aliabadi et al. and Thapa et al. references (see instant claim 1). In a similar fashion, the synthetic chemistry to cross-link PEI versus yielding a cleavable hydrophobic derivative of PEI would be straightforward to a skilled artisan (POSITA) (through amide coupling).
Applicant Argument: The Applicant argues that mRNA delivery has not been used with the thioesters of the present invention.
Examiner’s Rebuttal: A skilled artisan (POSITA) could expand the array of nucleic acids to include mRNA (since siRNA and pDNA are cited) under routine experimental conditions. Since RNA is a negatively charged species and a complex is formed with cationic lipopolymers (see page 1542, right column, 1st paragraph within Thapa et al), a skilled artisan (POSITA) would substitute mRNA for the siRNA disclosed by Aliabadi et al. and/or Thapa et al. under routine conditions.
Applicant Argument: The Applicant argues that the benefits of using the di-functional thioester group enhances drug delivery and was not recognized by either Aliabadi et al. and/or Thapa et al. (unexpected results).
Examiner’s Rebuttal: The Examiner respectfully disagrees. Evidence of unexpected results must be weighed against evidence supporting prima facie obviousness in making a final determination of the obviousness of the claimed invention. In re May, 574 F.2d 1082, 197 USPQ 601 (CCPA 1978) (Claims directed to a method of effecting analgesia without producing physical dependence by administering the levo isomer of a compound having a certain chemical structure were rejected as obvious over the prior art. Evidence that the compound was unexpectedly nonaddictive was sufficient to overcome the obviousness rejection. Although the compound also had the expected result of potent analgesia, there was evidence of record showing that the goal of research in this area was to produce an analgesic compound which was nonaddictive, enhancing the evidentiary value of the showing of nonaddictiveness as an indicium of nonobviousness.). [see M.P.E.P. 716.02(c)]. In this instance, the prior art of record is stronger than the unexpected results. The prima facie case for obviousness presented within the 35 U.S.C. §103 section of this office action affords a “direct pathway” of research for a skilled artisan (POSITA) to develop and obtain similar results as observed by the inventors.
Applicant Argument: The Applicant argues that the Examiner incorrectly cites p-hydroxy benzoic acid.
Examiner’s Rebuttal: The p-hydroxy benzoic acid has been withdrawn from the citation leaving gallic acid (GA) as cited by the Examiner. GA meets the claim limitation used for structure IVA.
Applicant Argument: The Applicant argues that there is no guidance for the use of GA and its potential use as a linker for lipid-conjugated cationic polymers useful for nucleic acid delivery.
Examiner’s Rebuttal: A skilled artisan (POSITA) would know that synthetically the hydroxyl group is functional group which reacts with acid chlorides to afford the desired ester. The benzoic acid derivative, gallic acid (GA), would be an excellent choice due to their biodegradable nature and the availability of the compound both synthetically and naturally (see title; abstract; Figure 8; and supporting text; all within Manuja et al.). Manuja et al. disclose within their review the use of GA (see title; abstract; Figure 8; and supporting text; all within Manuja et al.). The desired lipid-ester or lipid-thioester could be synthetically derived following the protocol discussed within instant claim 1. This protocol would be a routine synthetic exercise for a skilled artisan (POSITA).
Applicant Argument: The Applicant argues that the deletion of polyanion additives from instant claim 10 makes it allowable over the prior art of record.
Examiner’s Rebuttal: Instant claim 10 has one of the group members that meets the instant claim limitation as hyaluronic acid. Hyaluronic acid is cited within both Thapa et al. and Bahadur et al., and therefore meets the claim limitation.
Thus, the 35 U.S.C. §103 rejection for instant claims 1-2, 4-7, 9-10, 12-15, 18, and 21-26 is maintained.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/JOHN W LIPPERT III/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615
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