Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant's election with traverse of Group I, claims 1-5, 7, 8, 10-12 and 17, and the species:
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in the reply filed on 6/4/26 is acknowledged. The traversal is on the ground(s) that the claims require that the polymeric component in the hybrid nanoparticles constitute at least 80% by weight of the total material constituting the nanoparticles and Keller is completely silent with regard to this feature. This is not found persuasive because Keller does not place a limit on how much polymeric material can be present, teaches that the ratio of components can be “adapted” to obtain differential surface potential, which means that the ratio can be optimized, and the mass ratio of 5:25:50 polymer:siRNA:cationic amphiphile is a preferred embodiment (Page 9, 1st paragraph); not a limiting embodiment. Applicant also asserts that Keller teaches particles of 1000-2000 nm and that this range is outside the usual submicron range of nanoparticulate drug-delivery systems. This argument is not found persuasive because the independent claim 1 does not recite any particular nanoparticle size and Keller expressly teaches that microparticles prepared by the methods of the present invention may range in size up to 500 nanometers (Page 8, last paragraph).
The requirement is still deemed proper and is therefore made FINAL.
Claims 13-16 and 17 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected groups and species (PLGA is not a modified natural polymer of claim 17), there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 6/4/26.
Claim Status
Claims 6 and 9 are cancelled.
Claims 1-5, 7, 8 and 10-17 are pending.
Claims 13-17 are withdrawn.
Claims 1-5, 7, 8 and 10-12 are presented for examination on the merits as they read on the elected subject matter.
Priority
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The foreign priority document is not in English. Should applicant desire to obtain the benefit of foreign priority under 35 U.S.C. 119(a)-(d) prior to declaration of an interference, a certified English translation of the foreign application must be submitted in reply to this action. 37 CFR 41.154(b) and 41.202(e).
Failure to provide a certified translation may result in no benefit being accorded for the non-English application. Accordingly, the effective filing date for application of prior art is the international filing date of: 12/22/2022.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 6/19/24 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. See Page 2, lines 1 and 24. and Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Claim Rejections - 35 USC § 103
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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
Claims 1-5, 7, 8, 11 and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Xu et al. (US20210330597; of record) in view of Nascimento et al. (International Journal of Pharmaceutics 514 (2016) 103–111) and Hattori et al. (Journal of Drug Delivery Science and Technology 2019;52:1042-1050) and Cheng et al. (Advanced Drug Delivery Reviews 99 (2016) 129–137) and Spanjaard US20100104622).
This application currently names joint inventors. In considering patentability of the claims under 35 U.S.C. 103, the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of 35 U.S.C. 103(c) and potential 35 U.S.C. 102(e), (f) or (g) prior art under 35 U.S.C. 103.
Applicant claims hybrid nanoparticles comprising a polymeric component encapsulating a lipid core comprising cationic liposomes or lipoplexes comprising a cationic lipid and a helper lipid.
Examiner comment: in claim 1, the limitation of: “said hybrid nanoparticles being obtainable by nano-precipitation of a solution of the polymeric component in a dispersion of the cationic liposomes or lipoplexes” is a product-by-process limitation and has been considered but is not given patentable weight in the examination of a composition of matter claim. See MPEP 2113 Product-by-Process Claims [R-08.2017]
I. PRODUCT-BY-PROCESS CLAIMS ARE NOT LIMITED TO THE MANIPULATIONS OF THE RECITED STEPS, ONLY THE STRUCTURE IMPLIED BY THE STEPS
Level of Ordinary Skill in the Art
(MPEP 2141.03)
MPEP 2141.03 (I) states: “The “hypothetical ‘person having ordinary skill in the art’ to which the claimed subject matter pertains would, of necessity have the capability of understanding the scientific and engineering principles applicable to the pertinent art.” Ex parte Hiyamizu, 10 USPQ2d 1393, 1394 (Bd. Pat. App. & Inter. 1988). The level of skill is that of a lipid-based nanocarrier for RNA delivery research scientist, as is the case here, then one can assume comfortably that such an educated artisan will draw conventional ideas lipid based RNA nanocarriers such as liposomes, lipid nanoparticles and nanoemulsions with common strategies to improve the performance of lipid nanocarriers, including hybrid nanocarriers1, and targeting moieties2— without being told to do so.
In addition, the prior art itself reflects an appropriate level (MPEP 2141.03(II)).
Determination of the scope and content of the prior art
(MPEP 2141.01)
Regarding claim 1, Xu et al. is directed to a nanoparticle delivery system comprises a plurality of nanoparticle depots, each of which has a particle-in-particle
structure, and is composed of a polymeric nanoparticle, which encapsulates cationic molecule/nucleic acid complexes, facilitating enhanced retention and prolonged release
of the gene payload (Abstract), which is a hybrid nanoparticle system. Xu et al. claim:
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The cationic molecule can be a cationic lipid molecule (Abstract; [0008, 0121, 0176, 0204] and the polymer shell is made of PGLA (Claims 9-10). Xu et al. teach that the cationic molecule is used in an amount in a range of from 20% to 55% by weight of a total of the cationic polymer and the poly (D,L-lactic-co-glycolic acid) (PLGA)-polyethylene glycol (PEG) block co-polymer [0259], which means in the embodiment of 20% cationic molecule there is 80% PLGA-PEG block copolymer. Xu et al. also teach: “To optimize pGFP encapsulation efficiency and transfection efficacy, the present inventors have prepared a series of PLGA-PEG/PBAE/pGFP (PNP/pGFP) nanoparticle formulations by fixing the amount of PLGA-PEG (8 mg) and pGFP (30 μg) and varying only the amounts of PBAE from 0 mg, 2 mg, 4 mg, to 6 mg.” [0123]. The Examiner notes that the embodiment with 8 mg PLGA-PEG and 2 mg PBAE is 80% PLGA-PEG and 20% PBAE with regard to the carrier. To obtain the nanoparticles, Xu et al. teach precipitation [0076].
Regarding claims 2-4, Xu et at. teach the polymeric nanoparticle comprises a biodegradable amphiphilic material comprising a poly(lactic acid) (PLA),
a poly(glycolic acid) (PGA), a poly(D,L-lactic-co-glycolic acid) (PLGA) (elected species), or combinations thereof (Claim 9), which includes a single polymer or mixtures of polymers.
Regarding claim 8, Xu et al. teach delivery of an siRNA, a microRNA, an mRNA, a plasmid, or their antisense, single stranded, double-stranded, or circular varieties (Claim 7).
Regarding claim 11, Xu et al. teach that the PLGA-PEG component allows for further modifications such as targeting ligands [0150].
Regarding claim 1, Nascimento et al. is directed to lipoplexes for targeted delivery of siRNA (Title; Abstract) utilizing the cationic lipid [2-(2-3 didodecyloxypropyl)hydroxyethyl] ammonium bromide (DE) because it has “demonstrated promising transfection efficiency in different cell lines” (Page 104, left column; 1st paragraph).
Regarding claims 1 and 7, Hattori et al. teach optimized combination of cationic lipids and neutral helper lipids such as dioleoylphosphatidylethanolamine DOPE and cholesterol (Title; Abstract) and teach a 1:1 molar ratio (Page 1043, left column 2.3.; page 1044, Table 1).
Regarding claims 1 and 7, Cheng et al. teach the role of helper lipids in lipid nanoparticles designed for therapeutic oligonucleotides such as siRNA including cholesteroal, phosphatidylcholine and dioleoylphosphatidylethanolamine to improve intracellular delivery as well as lipid nanoparticle stability (Abstract; Sections 2.1-2.6; Figure 3). Cheng et al. teach: “LNPs for ON delivery typically contain a cationic lipid and other components that are commonly called “helper lipids”.” (Page 130, right column 1.3.) Cheng et al. teach: “Helper lipids are typically included as LNP components to provide particle stability, blood compatibility, and to enhance ON delivery efficiency.” (Page 131, right column 2.) Cheng et al. teach: “LNP composition should be customized to the specific application and route of administration and optimized and validated based on empirical experimentation. However, there seem to be some general rules that can be used as guidelines for LNP design. For in vitro delivery, when LNPs have direct access to the cells, high zeta potential and fusogenic helper lipids without PEGylation is likely to the best result… Therefore, LNPs for in vivo delivery generally need to have low zeta potential and have stabilizing helper lipids such as PC, CHOL, and a PEGylating lipid.” (Page 134, 3.1. Optimal LNP composition).
Regarding claims 11 and 12, Spanjaard teaches that carrier systems for the delivery of therapeutic RNA comprise targeting ligands (Title; Abstract; claims 1 and 21). Spanjaard teaches: “A carrier molecule with a targeting moiety attached will allow the complex to be directed to a target cell with a target corresponding to the targeting moiety.” [0054] Spanjaard teaches: “Because the ligand has a specific affinity for the receptor, the ligand binds to the receptor selectively over other molecules. This selective binding allows for the selective delivery of the polyanionic therapeutic to the target cell.” [0050] Spanjaard teaches that the targeting ligand is selected from the group consisting of an antigen, a hapten, a vitamin, a protein, a polypeptide, biotin, nucleic acids, DNA, RNA, aptamers, polynucleic acids, a polysaccharide, a carbohydrate, a lectin, a lipid and combination thereof (Claim 14; [0050]) and antibody or Fab or fragment thereof (Claim 14; see also [0032, 0050]). A vitamin would read on a small molecule.
Ascertainment of the difference between the prior art and the claims
(MPEP 2141.02) and Finding of prima facie obviousness
Rational and Motivation (MPEP 2142-2143)
The difference between the instant application and Xu et al. is that Xu et al. do not expressly teach hybrid nanoparticles wherein the polymeric component constitutes at least 80% by weight of the total material and wherein the cationic lipid is selected from [2-(2,3-didodecyloxypropyl)-hydroxyethyl] ammonium bromide that comprises a hydrophilic head with a permanent positive charge having ammonium groups. This deficiency in Xu et al. is cured by the teachings of Nascimento et al.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the hybrid nanoparticles of Xu et al., wherein the polymeric component constitutes at least 80% by weight of the total material and wherein the cationic lipid is selected from [2-(2,3-didodecyloxypropyl)-hydroxyethyl] ammonium bromide that comprises a hydrophilic head with a permanent positive charge having ammonium groups as suggested by Nascimento et al., and produce the instant invention. One of ordinary skill in the art would have been motivated to do this because Xu et al. teach optimization and an embodiment with 80% polymeric component and it would be just optimization to have at least 80% by weight of the polymeric component with respect to the total material with a reasonable expectation of success. Xu et al. is open to the inclusion of other cationic molecules known to the ordinary artisan and Nascimento et al. guides the artisan to [2-(2,3-didodecyloxypropyl)-hydroxyethyl] ammonium bromide because it has “demonstrated promising transfection efficiency in different cell lines” and is for delivering siRNA. Accordingly, it is a functionally equivalent cationic molecule for use in the nanoparticle delivery system of Xu et al. The ordinary artisan would employ [2-(2,3-didodecyloxypropyl)-hydroxyethyl] ammonium bromide in the nanoparticle delivery system of Xu et al. with a reasonable expectation of success. "The combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results." KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 417 (2007). Moreover, “Where two known alternatives are interchangeable for a desired function, an express suggestion to substitute one for the other is not needed to render a substitution obvious." In re Fout 675 F.2d 297, 301 (CCPA 1982).
The difference between the instant application and Xu et al. is that Xu et al. do not expressly teach the weight ratio between the cationic lipid and the helper lipid is 50:50 weight ratio and wherein the helper lipid is selected from phosphatidylethanolamine, phosphatidylcholine, cholesterol, or mixtures thereof. This deficiency in Xu et al. is cured by the teachings of Hattori et al. and Cheng et al.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the hybrid nanoparticles of Xu et al. with the weight ratio between the cationic lipid and the helper lipid is weight ratio 50:50 and wherein the helper lipid is selected from phosphatidylethanolamine, phosphatidylcholine, cholesterol, or mixtures thereof, as suggested by Hattori et al. and Cheng et al., and produce the instant invention. One of ordinary skill in the art would have been motivated to do this because Xu et al. is open to the inclusion of other components and is for in vivo administration [0113, 0122, 0147] and Hattori et al. and Cheng et al. render obvious adding conventional helper lipids such as phosphatidylethanolamine, phosphatidylcholine, cholesterol, or mixtures thereof because they provide particle stability, blood compatibility, and to enhance ON delivery efficiency as taught by Cheng et al. A weight ratio of 50:50 cationic lipid to helper lipid is obvious to the ordinary artisan through the teachings of Hattori et al. and optimized as suggested by Cheng et al. Consequently, the ordinary artisan would have had a reasonable expectation of success in adding the claimed helper lipids to the nanoparticle delivery system of Xu et al. in a weight ratio of 50:50 cationic lipid to helper lipid.
The difference between the instant application and Xu et al. is that Xu et al. do not expressly teach wherein the ligand is an antibody, antigen-binding antibody fragment (Fab), aptamer, peptide, carbohydrate, small molecules, or a combination of the foregoing. This deficiency in Xu et al. is cured by the teachings of Spanjaard.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the hybrid nanoparticles of Xu et al. wherein the ligand is an antibody, antigen-binding antibody fragment (Fab), aptamer, peptide, carbohydrate, small molecules, or a combination of the foregoing, as suggested by Spanjaard, and produce the instant invention. One of ordinary skill in the art would have been motivated to do this because Xu et al. teach modifying with a targeting ligand and Spanjaard teaches conventional targeting ligands known to the ordinary artisan. Consequently, the ordinary artisan would have a reasonable expectation of success in employing any of the claimed targeting ligands, alone or in combination, with the nanoparticle delivery system of Xu et al.
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Xu et al. (US20210330597; of record) in view of Nascimento et al. (International Journal of Pharmaceutics 514 (2016) 103–111) and Hattori et al. (Journal of Drug Delivery Science and Technology 2019;52:1042-1050) and Cheng et al. (Advanced Drug Delivery Reviews 99 (2016) 129–137) and Spanjaard US20100104622), as applied to claims 1-5, 7, 8, 11 and 12 above, in further view of Mandel et al. (Nanomedicine: Nanotechnology, Biology, and Medicine 9 (2013) and Sivadasan et al. (Pharmaceutics 2021, 13, 1291; 27 pages).
Applicant claims:
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Determination of the scope and content of the prior art
(MPEP 2141.01)
The references of Xu et al., Nascimento et al., Hattori et al., Cheng et al. and Spanjaard are discussed in detail above and that discussion is incorporated by reference.
Regarding claim 10, Mandel et al. teach core–shell-type lipid–polymer hybrid nanoparticles (CSLPHNs) that can entrap multiple therapeutic agents (Abstract; Table 1) where an advantage of CSLPHNs is to entrap and deliver multiple hydrophilic and hydrophobic therapeutic agents simultaneously (Page 476, left column, Advantages of CSLPHNs).
Regarding claim 10, Sivadasan et al. teach that hydrophobic drugs can be encapsulated within hydrophobic polymer nucleus and: “Polymeric lipid hybrid nanoparticles (PLNs) are a reliable drug delivery vehicle for hydrophobic drugs with relatively high concentrations and sustained release levels.” (Page 15, 4. Drug Delivery Mechanisms of PLNs; Page 17, Table 4; Figure 4 D).
Ascertainment of the difference between the prior art and the claims
(MPEP 2141.02) and Finding of prima facie obviousness
Rational and Motivation (MPEP 2142-2143)
The difference between the instant application and Xu et al. as modified by Nascimento et al., Hattori et al., Cheng et al. and Spanjaard is that Xu et al. as modified by Nascimento et al., Hattori et al., Cheng et al. and Spanjaard do not expressly teach adding a hydrophobic drug. This deficiency in Xu et al. as modified by Nascimento et al., Hattori et al., Cheng et al. and Spanjaard is cured by the teachings of Mandel et al. and Sivadasan et al. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the hybrid nanoparticles of Xu et al. as modified by Nascimento et al., Hattori et al., Cheng et al. and Spanjaard, with a hydrophobic drug, as suggested by Mandel et al. and Sivadasan et al., and produce the instant invention. One of ordinary skill in the art would have been motivated to do this because Xu et al. is open to the inclusion of other therapeutic agents, Sivadasan et al. teach that not only can the particles contain hydrophobic drugs but also the core contain drug molecules and the polymeric coating can contain drug molecules (Figure 4, D) as shown below:
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.
The art of Mandel et al. teaches simultaneous delivery of multiple hydrophilic and hydrophobic therapeutic agents from core–shell-type lipid–polymer hybrid nanoparticles. It is then obvious to add a hydrophobic drug to the core-shell lipid-polymer nanoparticle delivery system of Xu et al. as modified by Nascimento et al., Hattori et al., Cheng et al. and Spanjaard, for at least an additive effect in of the combined therapeutic agents. The ordinary artisan would take advantage of this desirable feature, as taught by Mandel et al. and Sivadasan et al., and do so with a reasonable expectation of success. The artisan would expect a hydrophobic drug to find itself in the hydrophobic PGLA region.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103.
From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the combined references, especially in the absence of evidence to the contrary.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERNST V ARNOLD whose telephone number is (571)272-8509. The examiner can normally be reached M-F 7-3:30.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Brian Y Kwon can be reached at 571-272-0581. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ERNST V ARNOLD/Primary Examiner, Art Unit 1613
1 See for example Table 3 and related text in: Xue et al. (Current Pharmaceutical Design. 2015;21:3140-3147).
2 Table 4, Id.
Prosecution Insights