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 .
Application Status and Election
Claims 1 and 3-28 are pending.
Applicant’s election without traverse of group 1 (claims 1-18) in the oral election on May 20 2024 with attorney David Staple (Reg# 65903) remains acknowledged. Applicant elected the species of nucleic acid cargo molecule and the species of unmodified crosslinked low molecular weight PEI of 800KDa. Claims 8, 9, 11, 12, 14, 18-26 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention or species, there being no allowable generic or linking claim.
Claims 1 and 3-7, 9-11, 13, 15, 17, and 27-28 have been amended.
Examination on the merits commences on claims 1, 3-7, 10, 13, 15-17, and 27-28.
Applicants are informed that the rejections and/or objections of the previous Office action not stated below have been withdrawn from consideration in view of the Applicant' s arguments and/or amendments. Applicant’s amendments and arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow.
Claim Rejections - 35 USC § 112(a) – Written Description – MODIFIED
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim(s) 1, 3-7, 16, and 27-28 is/are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
MPEP 2163.II.A3.(a).(i) states, “whether the specification shows that applicant was in possession of the claimed invention is not a single, simple determination, but rather is a factual determination reached by considering a number of factors. Factors to be considered in determining whether there is sufficient evidence of possession include the level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.”
For claims drawn to a genus, MPEP 2163.II.A3.(a).(ii) states, “written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species” where “representative number of species’ means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.”
The claims are drawn to a nanoparticle delivery vehicle consisting of one or more cationic polymers. The specification has not adequately described the entire genus of cationic polymers for the following reasons.
Size and Breadth of Genus
Independent claim 1 is understood as representative of the pending claims scope and recites, “A composition consisting essentially of: (a) a nanoparticle of a poly(Lactic Acid-co-Glycolic Acid) (PLGA)-b- polyethylene glycol (PEG)(PLGA-PEG) copolymer, wherein the nanoparticle is coated with a cationic polymer, and(b) one or more nucleic acid cargo molecules associated with the nanoparticle; wherein the composition does not contain a targeting moiety.”
MPEP § 2163 states that a “representative number of species” means that the species which are adequately described are representative of the entire genus (see, e.g., MPEP § 2163(II)(3)(a), MPEP §2163.03(V)). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
In this case, the claims encompass the genus of all cationic polymers, where there is substantial variation within the genus. As such, the genus of “cationic polymers” is extensive and diverse and includes various structural forms of PEI (linear and branched), PAMAM dendrimers, poly-L-lysine (PLL), chitosan, and poly(-amino esters) (PBAEs)
Species disclosed in the Specification
The Specification is lacking as to a description of cationic polymers other than PEI and there are no working examples that include cationic polymers other than PEI in Examples 1-5. Figures 1-9 and pages 4-6 of the Specification teaches variations of the PEI cationic polymer such as branched and unbranched at various molecular weights. However, although the specification discloses potential PEI embodiments of cationic polymers, the specification fails to sufficiently describe representative species, i.e. PEI (linear and branched), PAMAM dendrimers, poly-L-lysine (PLL), chitosan, and poly(-amino esters) (PBAEs), sufficient for the skilled artisan to predict what other coatings for example can function as cationic polymers.
Species Disclosed in the Art
The genus of “cationic polymers” is large and diverse in the art and includes various structural forms of PEI (linear and branched), PAMAM dendrimers, poly-L-lysine (PLL), chitosan, and poly(-amino esters) (PBAEs)(pages 2-7 and abstract; Cai X, Dou R, Guo C, Tang J, Li X, Chen J, Zhang J. Cationic Polymers as Transfection Reagents for Nucleic Acid Delivery. Pharmaceutics. 2023 May 15;15(5):1502. doi: 10.3390/pharmaceutics15051502. PMID: 37242744; PMCID: PMC10223806.) Such materials effectively condense negatively charged DNA/RNA through electrostatic interactions and can facilitate nucleic acid payload delivery. Cai further teaches polymers with lower molecular weights have a reduced ability to condense nucleic acids and be uptaken by cells, but are better in terms of cytotoxicity and nucleic acid release, therefore, the molecular weight of the cationic polymer should be carefully considered during transfection (pg 2 para 1). Cai teaches some chemical modifications, such as PEGylation and cholesterol modification, significantly improve the properties of polymers (pg 2 para 1).
Therefore, there is substantial variation within the genus of “cationic polymers”. Applicant fails to adequately describe a sufficient variety of species to reflect the variation within the genus. Furthermore, the description of a representative number of species from the specification is not representative of the entire genus.
Given the lack of guidance in the art and specification regarding common structural characteristics shared by members of the genus and lack of predictability of undefined structure and function relationship sufficient to act as cationic polymers within the claimed composition, the specification disclosure is not sufficient to show that the Applicant was in possession of all cationic polymers at the time the invention was filed. Examiner suggests incorporating the elected species of PEI back into claim 1 as disclosed in the dependent claims.
In conclusion, for the reasons discussed above, the skilled artisan would not reasonably conclude that the inventor(s), at the time the application was filed, had possession of the full scope of the claimed invention of all “cationic polymers” within a nanoparticle nucleic acid delivery vehicle.
Dependent claims
Other than claims 10, 13, 15, and 17 which recite specific PEI cationic polymers, the dependent claims of claim 1 do not further limit the genus of cationic polymers so as to resolve the issues above, and therefore lack adequate written description for the reason outlined for claim 1.
Claim Rejections - 35 USC § 102 – MODIFIED MAINTAINED
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 3, 7, 13, 15-17, 27, and 28 are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by Lutz of record (Lutz Gordon, J., WO 2007133812 A2), claims 27 and 28 as evidenced by kDaCalculator (kDaCalculator, https://www.glpbio.com/molarity-calculator/, retrieved 12/27/2024, printed as pg 1/1-1/5).
Regarding claim 1, Lutz teaches PEGylated copolymers with PEI adapted to function as an effective carrier for cellular delivery of small oligonucleotides [0009]. Lutz teaches the invention encompasses the preparation and use of adaptable and versatile compounds that combine small nucleic acid agents with functionalized carriers such as nanopolymers and nanovesicles for improved delivery to tissues and cells [0061]. The carrier-NAA (NAA: nucleic acid agent polyplex NAA complexed with PEG-PEI copolymer) compounds are engineered with improved functionality including: improved transfection capacity, enhanced stability, cell/tissue specific targeting, and controlled release properties [0061]. Lutz teaches such synthetic polymers which may be used for the construction of nanovesicles are poly(ester)s [00151] where the poly(ester)s is a member selected from the group consisting of poly(lactic acid) (PLA), poly(glycolic acid) (PGA), and poly(lactide-co-glycolide) (PLGA) and block copolymers (e.g., diblock, triblock, multiblock, and star-shaped block) comprising the biodegradable poly(esters) and poly(ethylene glycol) (PEG) [00152-00153] and with a cationic polymer of poly(ethyleneimine) (PEI) [00154], i.e. polyester PLGA block copolymers which includes (PLGA-PEG)(PEG). Lutz also teaches the invention provides for functionalized nanovesicles and microbubbles, preferably of PLGA, used as carriers for delivery of carrier-NAA compounds [0018]. Lutz also teaches the PLGA nanovesicles further coated with PEG [00134]. Lutz further teaches polyethylenimine (PEI) is a well-known cationic polymer as an efficient nucleic acid carrier due to formation of PEI-nucleotide complexes that show high transfection capacity and flexibility for addition of moieties that target specific entities on cell membranes and intracellular structures [0007]. Regarding the PEI cationic polymer as a coating polymer, Lutz further teaches PEI as a coating for the PLGA copolymers. As in Example 7, Lutz teaches surface coating of PLGA nanovesicles with PEI2K(PEG5K) copolymers and TAT-functionalized PEI2K(PEG5K)io copolymers [00207] PLGA nanospheres (10 mg) with encapsulated PEI25K(PEG5 K)I0-NAA polyplex [00206].
Lutz further teaches PLGA nanovesicles will be used to deliver carrier-NAA compounds, and preferably PEG-PEI-NAA polyplexes [00129]. Lutz teaches PLGA nanovesicles will also be used to deliver NAA alone and carrier functionalized oligonucleotides cargo (CFOs), i.e. cargo molecules [00129] and [00159]. Lutz teaches PLGA-encapsulation allows the polyplexes to circulate longer in the bloodstream by masking the polyplex surface charge, and by protecting the oligonucleotide from degradation [00129]. Lutz teaches PEI25K(PEG5K)-NAA polyplexes will be encapsulated in functionalized PLGA nanovesicles and PLGA microbubbles that shield the high surface charge and provide favorable biodistribution and controlled delivery of NAA to target tissues [0087]. Lutz teaches the invention copolymers such as PEG-PEI-Nucleic Acid Agent (NAA) polyplex comprising a PEG-PEI copolymer optionally comprise one or more functionalization moieties used for targeting [0034], i.e. the invention copolymers may contain or not contain a targeting moiety. Lutz teaches the functionality of PEI as a nucleotide carrier is significantly improved by incorporating the nonionic linear polymer polyethylene glycol (PEG) into the invention’s PEG-PEI copolymers [0008]. Therefore, the PEI-PEG invention copolymers are efficient nucleic acid carriers with high transfection capacity without the addition of the optional target specific moiety.
Regarding claims 3 and 7, Lutz teaches siRNA cargo molecules to be used in the nanoparticle composition (claim 23).
Regarding claim(s) 13, 15, 16, and 17, Lutz teaches PEI derivatives with diacrylate cross-linked 800 Da PEI in the invention [00155].
Regarding claims 27 and 28, Lutz teaches the PEG has a molecular weight of 5 kDA [0019]. Lutz teaches MW PLGA ranging from about 8 to 100 kDa. [00145]. kDaCalculator teaches conversion of g/mol to kDa where 1 kDa is equal to 1000 g/mol. Therefore, 55000 g/mol is equivalent to 55,000 / 1000 = 55 kDa and 5,000 g/mol = 5 kDa. Therefore, Lutz’s 5 kDa PEG and 55 kDa PLGA is equivalent to 5,000 g/mol and 55,000 g/mol respectively.
Claim Rejections - 35 USC § 103 – Modified Maintained
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.
Claim(s) 1, 4, and 6 is/are rejected under 35 U.S.C. 103 as being unpatentable over Lutz of record (Lutz Gordon, J., WO 2007133812 A2) as applied for claim 1, in view of Bhatia of record (Bhatia, S., WO2015089465A1).
The teachings of Lutz as applied above for claim 1 are incorporated here.
Regarding claims 4 and 6, Lutz does not teach wherein the cargo molecule within the nanoparticle composition contains plasmid DNA which express CRISPR/Cas9 components.
Bhatia teaches nanoparticle technology methods to deliver a broad range of therapeutics, including nucleic acids (plasmid, siRNA, miRNA) [0316]. Bhatia teaches self-assembling nanoparticles with nucleic acid cargo molecules may be constructed with polyethyleneimine (PEI) that is PEGylated attached at the distal end of a polyethylene glycol (PEG) and with CRISPR Cas within the compositions of self-assembling nanoparticles [0297]. Bhatia teaches plasmid vectors within the nanoparticle composition that code for CRISPR-Cas system elements [0027].
It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to use Lutz’s PLGA-PEG-nucleic acid cargo nanoparticle composition to deliver Bhatia’s plasmid DNA cargo coding for CRISPR-Cas system elements. It would have merely amounted to a simple combination of prior art elements according to known methods to yield predictable results. The skilled artisan would have had a reasonable expectation that Lutz’s nanoparticle PLGA-PEG co-polymer could package and deliver plasmid cargo DNA which codes for CRISPR-Cas nucleic acid elements because Lutz teaches the nanoparticle copolymer composition formulated with PEI can package and deliver nucleic acid cargo molecules and that PEG-PEI copolymers have already been primarily used for plasmid delivery in the field. The skilled artisan would be motivated to combine Lutz’s PEI composition with Bhatia’s regulatory nucleic cargo acid elements for targeted delivery of gene modulating nucleic acid therapeutics to a subject.
Claim(s) 1 and 5 is/are rejected under 35 U.S.C. 103 as being unpatentable over Lutz of record (Lutz Gordon, J., WO 2007133812 A2) as applied for claim 1, in view of Hudecek of record (Hudecek, M., WO2017050884A1).
The teachings of Lutz as applied above for claims 1 are incorporated here.
Regarding claim 5, Lutz does not teach wherein the cargo molecule within the nanoparticle composition contains minicircle DNA.
Hudecek teaches a method of delivering minicircle DNA within nanoparticles for targeted delivery [0093].
It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to use Lutz’s PLGA-PEG-nucleic acid cargo nanoparticle composition to deliver Hudecek’s minicircle DNA cargo. It would have merely amounted to a simple substitution of prior art elements according to known methods to yield predictable results. The skilled artisan would have had a reasonable expectation that Lutz’s nanoparticle PLGA-PEG-PEI polymer could package and deliver minicircle DNA because Lutz teaches the nanoparticle copolymer composition formulated with PEI can package and deliver a variety of nucleic acid cargo molecules. The skilled artisan would be motivated to use Lutz’s PEI composition with Hudecek’s minicircle DNA for targeted gene therapy delivery to a subject.
Claim(s) 1 and 10 is/are rejected under 35 U.S.C. 103 as being unpatentable over Lutz of record (Lutz Gordon, J., WO 2007133812 A2) as applied for claim 1, in view of Cho of record (Cho, Kyung Chul, Seung Ho Choi, and Tae Gwan Park. Macromolecular Research 14 (2006): 348-353).
The teachings of Lutz as applied above for claim 1 are incorporated here.
Regarding claim 10, Lutz does not teach within the PLGA-PEG-PEI-nucleic acid cargo nanoparticle molecule a ratio of copolymers to DNA cargo as about DNA 1 ug: PLGA-PEG 0.01-5 ug: PEI 0.1-100 ug.
Cho teaches the use of pluronic polyplex nanoparticle molecules copolymerized with unmodified PEI which allows successful gene transfection with enhanced cell survival (Fig 6, pg 352 col 2, para 1). Cho teaches polyethylenimine (PEI) has been widely used to form polyplexes with plasmid DNA (pg 348 col 1 para 1). Cho teaches the polyelectrolyte complex DNA/PEI nanoparticles exhibit superior gene transfection efficiency to various cells due to stable complex structure appropriate for uptake by cells and the following “proton sponge” effect from PEI that facilitates escape of the complex from an endosomal compartment (pg 348 col 1 para 1). Cho teaches the unmodified low molecular weight PEI is less toxic compared to high molecular weight PEI which has an increased nitrogen/phosphate ratio between the PEI and DNA cargo which decreases cell viability (Fig 6 and pg 348 col 1 para 1). Cho teaches cell transfection experiments using 1ml of 40 ug/ml PEI and 40 ug/ml DNA and with varying amounts of the Pluronic-127 copolymer (pg 350 col 1 para 1) which includes a three-fold molar excess of PEI compared to the pluronic F127 PEI conjugate with 173.92 mg of the PEI compared to 5g Pluronic F127 (pg 349 col 2 para 2), i.e. within the composition ratio of cargo molecule to copolymers where DNA 1 ug: PEG-copolymer 0.01-5 ug: PEI 0.1-100 ug.
It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have used Lutz’s PLGA-PEG-nucleic acid cargo nanoparticle composition with Cho’s unmodified PEI ratios of copolymers to DNA cargo. It would have merely amounted to a simple combination of prior art elements according to known methods to yield predictable results. The skilled artisan would have had a reasonable expectation that PEI copolymerized with Lutz’s PLGA-PEG could facilitate effective cargo molecule delivery because Choi teaches unmodified low molecular weight PEI ratio to copolymer to DNA as an effective nanoparticle composition for cargo delivery. The skilled artisan would be motivated to employ unmodified low molecular weight PEI within Lutz’s nanoparticle composition delivery system because Choi teaches low molecular weight PEI copolymers allow enhanced cell viability for regulatable delivery.
Response to Arguments
Regarding the Remarks filed 12/24/25, Applicants amendments overcome the §112a Written Description rejection of record, however, amendments to claim 1 necessitate a modified §112a Written Description rejection.
Regarding the §102 rejection of record, Applicants argue (Remarks page 5) that the Lutz reference fails to teach each and every limitation. Applicant’s argument has been thoroughly reviewed and found unpersuasive for the following reasons. After a thorough review of Lutz of record, Examiner has confirmed that Lutz does teach the claimed elements as amended. Specifically, Applicants argue (Remarks page 5) that Lutz does not teach a nanoparticle comprising a poly(Lactic Acid-co-Glycolic Acid) (PLGA)-b-polyethylene glycol, i.e., a (PEG)(PLGA-PEG) copolymer and that Lutz instead teaches the use of PLGA alone and not as a block copolymer comprising both PLGA and PEG. Applicants also argue that in the Lutz reference that PEG is associated with PEI in a copolymer rather than PLGA. Applicants further argue that Lutz fails to teach a nanoparticle where a cationic polymer encapsulates PLGA- PEG. Instead, Lutz teaches that PLGA encapsulates the PEG-PEI-NAA polyplex. In other words, Applicants argue that the PEI is inside the PLGA nanoparticle rather than coating the nanoparticle comprising PLGA- PEG copolymer. However, in the modified §102 rejection above, further expounded teachings of Lutz more clearly establish (PEG)(PLGA-PEG) as the nanoparticle copolymer in the invention with a cationic polymer (PEI) surface coating. Briefly, Lutz teaches the invention encompasses the preparation and use of adaptable and versatile compounds that combine small nucleic acid agents with functionalized carriers such as nanopolymers and nanovesicles for improved delivery to tissues and cells [0061], which include multiple polyesters in multi-blocks with PLGA, PEG, and PEI [00154]. Lutz also clearly teaches the PLGA nanovesicles of the invention are further coated with PEI and not only as PEI inside the PLGA nanoparticle [00134].
Applicants further argue (Remarks page 6-7) regarding the §103 rejection of record fails because the secondary references do not cure the deficiencies of Lutz. Applicant’s arguments have been thoroughly reviewed and found unpersuasive, given Examiner’s statement regarding the Lutz reference of record teachings described above.
Conclusion
No claims are allowable.
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 extension fee 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 date of this final action.
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/JOHN CHARLES MCKILLOP/Examiner, Art Unit 1637
/EKATERINA POLIAKOVA-GEORGANTAS/Primary Examiner, Art Unit 1637
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