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 .
Claim Status
Claims 15, and 21-29 are rejected.
No claims are allowable.
New 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.
1. Claims 15, 22-26 and 28-29 are rejected under 35 U.S.C. 103 as being unpatentable over Kabanov et al., (WO 2000/047186 A1, Aug 17, 2000) (hereinafter Kabanov) in view of Alavi et al., (Hyperbranched–dendrimer architectural copolymer gene delivery using hyperbranched PEI conjugated to poly(propyleneimine) dendrimers: synthesis, characterization, and evaluation of transfection efficiency, Feb. 04, 2017) (hereinafter Alavi).
Kabanov teaches a composition, useful for gene therapy purposes, comprising a polynucleotide or derivative thereof and at least one block copolymer, and further comprising a polycation (page 5, lines 9-16). The polycation is a polyamine polymer (claim 3). Polyamines include polyethyleneimine (PEI) (i.e., tertiary amine), polypropyleneimine (PPI) (i.e., secondary amine), and copolymers of tertiary amines and secondary amines (page 18, lines 21-24). The degree of polymerization of the polycationic polymer can preferably be between about 10 and about 10,000. More preferably, the degree of polymerization shall be between about 10 and about 1,000, still more preferably, between about 10 and about 100 (page 14, line 23 – page 15, line 3). Example 24 teaches the synthesis of linear polyimine polycations (i.e., linear PPI and PEI), which are suitable for use in the composition (page 70, lines 15-20). Suitable nucleic acids include antisense nucleic acid molecules, such as, RNA and DNA (page 41, lines 14-19). The composition may include targeting molecules (page 42, lines 3-4) and targeting molecules comprise a lipid group (page 42, lines 11-12). Kabanov teaches methods of treatment comprising administering these compositions to humans and animals (page 8, lines 18-19). The compositions can be used in gene therapy treatments including gene excision therapy (i.e., gene editing) (page 43, lines 19-21). The polynucleotides can be complexed with the polycation and stabilized in the complex demonstrating increased permeability across cell membranes and are well suited for use as vehicles for delivering nucleic acid into cells (page 9, lines 8-10).
Kabanov differs from the instant claims insofar as not disclosing wherein the ratio of PEI/PPI is about 1:2 to 1:500.
However, Alavi discloses that generation 3 poly(propyleneimine) (G3-PPI) dendrimers with 1, 4-diaminobutane as a core initiator were synthesized, wherein, 10% of primary amines of G3-PPI dendrimers were replaced with bromoalkylcarboxylates with different chain lengths (6-bromohexanoic and 10-bromodecanoic). Then, to retain the overall buffering capacity and enhance transfection, the alkylcarboxylate–PPIs were conjugated to 10 kDa branched polyethylenimine (PEI) (Abstract). Alavi teaches that PPI dendrimers can be functionalized with different molecules for targeting purposes or hydrophobic molecules to enhance the transfection efficiency. PPI dendrimers compromise primary amines on the surface, which allows for electrostatical attachment to negatively charged molecules as well as the cell membrane but may destabilize it and induce cytotoxicity. Different modifications have been performed on PPI to improve transfection efficacy and reduce cytotoxicity. PEIs are effective non-viral vectors since they are able to greatly condense nucleic acids and protect them from environment. They have a high buffering capacity, but the cytotoxicity of PEIs challenges their applications in many mammalian cell lines (Discussion, page 8). However, the advantages of PEIs have been utilized to improve transfection efficacy. Hyperbranched (PEI)–dendrimer (PPI) architectural copolymers were synthesized using PEI, resulting in efficient and low cytotoxic gene delivery carriers based on cationic PPI dendrimer (left column, page 9). Excellent non-viral carriers require high gene transfection efficacy with minimum cytotoxicity and 10% substitution of primary amines of PPI dendrimers with PEI was sufficient to utilize the advantages of PEI and avoid the accumulation of amines and induction of cytotoxicity (page 10, left column).
Kabanov discloses a gene therapy composition comprising a polynucleotide and copolymers of polyethyleneimine (PEI) andpolypropyleneimine (PPI). Alavi teaches that excellent non-viral carriers require high gene transfection efficacy with minimum cytotoxicity and 10% substitution of primary amines of PPI dendrimers with PEI was sufficient to utilize the advantages of PEI and avoid the accumulation of amines and induction of cytotoxicity. Accordingly, it would have taken no more than the relative skills of one of ordinary skill in the art to have arrived at the claimed ratio of PEI/PPI through routine experimentation motivated by the desire to achieve high gene transfection efficacy with minimum cytotoxicity as taught by Alavi. Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. See MPEP 2144.05(II)(A).
2. Claim 21 is rejected under 35 U.S.C. 103 as being unpatentable over Kabanov et al., (WO 2000/047186 A1, Aug 17, 2000) (hereinafter Kabanov) in view of Alavi et al., (Hyperbranched–dendrimer architectural copolymer gene delivery using hyperbranched PEI conjugated to poly(propyleneimine) dendrimers: synthesis, characterization, and evaluation of transfection efficiency, Feb. 04, 2017) (hereinafter Alavi), and further in view of Saltzman et al. (US 2019/0133962 A1, May 09, 2019) (hereinafter Saltzman).
As discussed above, Kabanov and Alavi makes obvious the limitations of claim 15 but do not teach wherein the co-polymer is a random co-polymer.
However, Saltzman discloses compositions for efficient delivery of therapeutic agents in vivo, formed of polymeric particles from one or more therapeutic agent complexed with a polycationic polymer (abstract). Suitable polycationic polymers include polyethylene imine (PEI) ([0072]) and poly(propylenimine) ([0073]). Copolymers of two or more polymers described above, including block and/or random copolymers, may also be employed to make the polymeric particles ([0074]). Particles are used to deliver a therapeutic agent ([0080]). Examples of suitable therapeutic agents include DNA and RNA nucleic acid sequences having therapeutic, prophylactic or diagnostic activities ([0083]).
Generally, it is prima facie obvious to select a known material for incorporation into a composition, based on its recognized suitability for its intended use. See MPEP 2144.07. Kabanov discloses wherein the composition comprises a PPI/PEI copolymer for nucleic acid delivery. Accordingly, it would have been obvious to one of ordinary skill in the art to have incorporated a random co-polymer into the composition of Kabanov since it is a known and effective PPI/PEI copolymer for nucleic acid delivery as taught by Saltzman.
3. Claim 27 is rejected under 35 U.S.C. 103 as being unpatentable over Kabanov et al., (WO 2000/047186 A1, Aug 17, 2000) (hereinafter Kabanov) in view of Alavi et al., (Hyperbranched–dendrimer architectural copolymer gene delivery using hyperbranched PEI conjugated to poly(propyleneimine) dendrimers: synthesis, characterization, and evaluation of transfection efficiency, Feb. 04, 2017) (hereinafter Alavi), and further in view of Slobodkin et al., (US 2006/0093674 A1, May 04, 2011) (hereinafter Slobodkin).
As discussed above, Kabanov and Alavi makes obvious the limitations of claim 15 but do not teach wherein a molar ratio of nitrogen atoms to phosphorous atoms is less than 40.
However, Slobodkin discloses a transfecting composition comprising a nucleic acid and a biodegradable cross-linked cationic multi-block copolymer of linear poly(alkylenimine) (LPAI) and a hydrophilic linker, wherein said LPAI blocks are crossed linked together by said hydrophilic linker with a biodegradable linkage (Claim 13). The linear poly(alkylenimine) (LPAI) can be polyethyleneimine (LPEI) or polypropyleneimine (LPPI) ([0006]). The particle size and zeta potential of the cationic polymer/DNA complexes is influenced by the nitrogen to phosphate (N/P) ratio between the polymer and the DNA molecules in the polymer/DNA complexes ([0051]). Optimal condensation is achieved at N/P ratios between 5/1 to 10/1 ([0052]). The biodegradable cross-linked cationic multi-block copolymers (with a lipid moiety) are able to transfect tumor tissue, thus demonstrating therapeutic potential of these polymers for gene therapy of human diseases ([0055]).
Kabanov teaches compositions useful for gene therapy purposes, comprising DNA and PPI. Accordingly, it would have been prima facie obvious to one of ordinary skill in the art have formulated the composition of Kabanov to have a molar ratio of nitrogen atoms to phosphorous atoms between 5/1 to 10/1 because particle size and zeta potential of cationic polymer/DNA complexes is influenced by the nitrogen and phosphate ratio and optimal condensation is achieved at N/P ratios between 5/1 to 10/1 as taught by Slobodkin.
Response to Applicant’s Arguments
Applicant’s arguments have been fully considered but are moot because new rejections
have been made.
Regarding Applicant’s argument of unexpected results, Applicant argues that the L-PPI/L-PEI copolymer having a PPI/PEI ratio of 1.5:1 (e.g., a PEI/PPI ratio of 1:1.5) has a similar, low transfection efficiency compared to the L-PEI homopolymer, and a much lower transfection efficiency compared to the L-PPI- homopolymer. The L-PPI/L-PEI copolymer having a PPI/PEI ratio of 4:1 (e.g., a PEI/PPI ratio of 1:4) unexpectedly demonstrated a might higher transfection efficiency compared to the L- PEI homopolymer, an improved transfection efficiency compared to the L-PPI homopolymer, and a much higher transfection efficiency compared to the L-PPI/L-PEI copolymer having a PPI/PEI ratio of 1.5:1 (e.g., a PEI/PPI ratio of 1:1.5, lower than the claimed range). Thus, the data demonstrates a synergistic effect is obtained by a copolymer having both PPI and PEI repeating units in the polyalkyleneimine, together with the claimed excess of PPI vs. PEI repeating units.
Applicant’s arguments have been fully considered but are not found to be persuasive. Alavi teaches that different modifications have been performed on PPI to improve transfection
Efficacy (Discussion, page 8). Thus, PPI affects transfection efficiency. Alavi also teaches that low molecular weight PEIs have shown low cell toxicity but also low transfection ability (page 9, first paragraph). Thus, PEI affects transfection efficiency. Accordingly, since PPI and PEI are both known to affect transfection efficiency, one would expect a better transfection efficiency when using a combination of both compared to using any one of them alone. Further, Ariaee et al., (Alkyl cross-linked low molecular weight polypropyleneimine dendrimers as efficient gene delivery vectors, Oct. 19, 2016) (hereinafter Ariaee) teaches that there is a correlation between molecular weight of polymers and their transfection efficiency, being that polymers with higher molecular weight (HMW) are highly effective in gene transfection (Introduction, page 1096). As evidenced by Pharmacompass (1,2-Propyleneimine, accessed December 16, 2025) the molecular weight of the monomeric unit of PPI is 57.09 g/mol (page 1, Molecular Weight). As evidenced by MilliporeSigma (Polyethylenimine, branched, accessed December 16, 2025) the monomeric unit of the PEI has a formula weight of 43.07 (Questions, page 11). Thus, because a higher molecular weight (HMW) of a polymer is associated with a higher gene transfection efficacy, and PPI has a higher molecular weight than PEI, one would expect that an increase in PPI in the ratio of PPI/PEI in the copolymer would increase transfection efficiency. Therefore, the Applicant’s unexpected results of a higher transfection efficiency with the claimed ratio of polymers, having higher amount of PPI compared to PEI, does not appear to be unexpected.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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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/S.J.K./ Examiner, Art Unit 1614
/TRACY LIU/ Primary Examiner, Art Unit 1614
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