DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on July 9, 2025 has been entered.
Applicants' arguments, filed July 9, 2025, have been fully considered but they are not deemed to be fully persuasive. The following rejections and/or objections constitute the complete set presently being applied to the instant application.
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 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.
Claim(s) 1 and 10 – 12 were rejected under 35 U.S.C. 103 as being unpatentable over Kapadia et al. (BioDrugs, 2018; available online June 29, 2018) in view of Lai et al. (Expert Opin Drug Deliv, 2013). This rejection is MAINTAINED for the reasons of record set forth herein.
Kapadia et al. discloses that challenges associated with delivery of nucleic acid therapies have led to unsatisfactory translation and clinical success of such therapies (p 297, col 2, ¶ 1). Spherical nucleic acids, SNAs, are a recently developed nanoparticle-based nucleic acid platform which have emerged as promising tool for such delivery and consist of densely packed “shells” of radially oriented nucleic acids firmly attached to a nanoparticle core (p 297, col 2, ¶ 3). The first SNAs used 13 nm diameter gold spheres, which reads on a diameter of about 15 nm, coated with single-stranded DNA molecules attached via thiolated linkers (p 298, col 1, ¶ 2), which reads on the nucleic acid being chemically conjugated to the gold nanoparticle core. SNAs can utilize single or double stranded oligonucleotides including antisense DNA, siRNA and miRNA for the outer layer (p 298, col 1, ¶ 2). SNAs have higher affinity constants for complementary nucleic acids due to a higher local concentration around the nanoparticle core compared to linear SNA and can be taken up by almost any cell type without the need for auxiliary transfection agents, are nontoxic to cells, illicit a minimal innate immune response compared to lipoplexes containing the same DNA and have no effect on blood chemistry (p 298, col 2, ¶ 2). Future work should seek to control the biodistribution of systemically delivered SNA; improve intracellular trafficking of SNAs to minimize cytosolic or nuclear delivery as desired and prevent premature oligonucleotide degradation during delivery (p 306, col 1, ¶ 2). SNAs incubated in human serum develop a corona containing proteins involved in blood coagulation, lipid transport, molecular transport and immune response (p 306, col 1, ¶ 3). Opportunities to control the protein corona to regulate the in vivo fate of SNAs should be considered (p 306, col 1, ¶ 3). siRNA and miRNA were delivered to glioblastoma tumors in mice using a gold core SNA (section 3.1.1). siRNA and miRNA binds to the RNA-induced silencing complex (RISC) when delivered into cells (p 299, col 1, ¶ 2) and thus such oligonucleotide read on the oligonucleotide miRNA inhibitors of the instant claims.
Encapsulation of such SNAs inside a peptide-conjugated liposome is not disclosed.
Lai et al. discloses that materials including small-interfering RNA (siRNA) and gene therapeutics with a well-established activity to central nervous system (CNS) receptors do not readily permeate into the brain parenchyma due to the presence of the blood brain barrier (BBB; p 1004, col 1, ¶ 2). Nanocarriers such as liposomes that are able to deliver drugs to the brain have been developed with liposomes studied largely as a potential “magic bullet” capable of circumventing the BBB (p 1004, col 1, ¶ 4). Liposomes have been adopted as the vehicle of choice for drug delivery and targeting due to their unique and attractive biological properties including biocompatibility, ability to entrap and protect water-soluble or water-insoluble molecules and the ability to deliver pharmaceuticals into cells or individual cellular compartments (p 1004, col 1, ¶ 5). Liposomes represent the most promising strategy for brain tumor therapy (p 1011, col 2, ¶ 4). For brain delivery of liposomes, liposomes are modified by decreasing particle size (< 100 nm) to produce long circulating vesicles or by linking polyethylene glycol (PEG) chains to the surface and to release the encapsulated drug in [a] target site (p 1004, col 2, ¶ 2). Later coupling of PEG-liposomes to various ligands targets allows the PEG-liposomes to be actively taken up by target cells in an approach in which liposomes are loaded with a drug such as a gene, specific ligands capable of targeting the receptors at the BBB are conjugated to the liposome surface, with transcytosis of the liposomes through the BBB leading to accumulation in the brain parenchyma with properly designed liposomes that can cross neuronal and nuclear neuronal membranes leading to accumulation of the liposome of their content in the neuronal cytoplasm or nucleus (p 1011, col 1, ¶ 2). Low-density lipoprotein receptor (LDLR) and lipoprotein receptor-related protein (LRP1 and LRP2), multi-ligand scavenger and signaling receptors, are expressed on the BBB and interact with apolipoprotein E (ApoE; p 1012, col 2, ¶ 3). ApoE and ApoE peptide fragment have been covalently linked to liposomes to achieve uptake into the CNS and PEG-liposomes modified with a highly cationic tandem dimer of ApoE residues were taken up by rat brain capillary endothelial cells in vitro (p 1012, col 2, ¶ 3). As discussed in section 5.2, various liposomes can be used to alter gene expression by the transfer of genetic material into patient cells including brain tissue such as using immunoliposomes (p 1016, col 1, ¶ 3).
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to place the SNAs of Kapadia et al. inside a liposome ApoE or fragment thereof conjugated to the liposome as a targeting peptide to increase delivery across the BBB. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because Kapadia et al. discloses that SNAs offer many benefits for the delivery of nucleic acids but could be further improved by controlling the biodistribution, intracellular trafficking and control of the protein corona of SNAs. Nucleic acids can be encapsulated inside liposomes as taught by Lai et al. Those liposomes can be coated with PEG to increase circulating times and proteins/peptides such as ApoE or a fragment thereof covalently attached to enhance crossing of the BBB and targeting to particular cells or individual cellular compartments. One of ordinary skill in the art would also reasonably expect that encapsulation of the SNAs in a liposome structure would provide additional protection against oligonucleotide degradation in addition to other benefits that would address at least some of the issues with SNAs disclosed by Kapadia et al. including controlling the biodistribution. Given the size of the gold core and the size of the attached nucleic acid cargo, the liposome surrounding such a structure must be appropriately sized to contain this cargo while also providing a liposome that is sized for sufficient time in systemic circulation to then cross the BBB as taught by Lai et al. There is no evidence of record as to the criticality of liposome size.
The number of moles of nucleic acid that could theoretically be attached (the loading capacity) and the encapsulation efficiency are not explicitly described by the applied prior art. However, SNAs by definition contain a dense coating of nucleic acids and particularly when the materials are not inexpensive and/or readily obtained in large quantities, one of ordinary skill in the art would optimize the conditions used to coat the AuNP core to not only prepare the characteristic dense coating but also minimize how many nucleic acids are not attached and thus “wasted”. There is no evidence as to the criticality of the claimed parameters.
Applicants provide additional experimental details in the Remarks filed July 9, 2025 about the preparation of the SNA using a modification of the method of Li et al. The remarks indicate that the ratio of OMI [oligonucleotide miRNA inhibitors] to gold nanoparticles (AuNPs) was a 1:50 molar ratio that were then encapsulated inside a liposome with ApoE conjugated to the liposome. The remarks discuss the conclusion from the specification as filed that the size of the claimed liposomal formulation is unexpectedly small and delivery vehicle size is strongly related to the ability of the drug delivery vehicles to cross the blood-brain barrier (BBB). The quoted section of the specification as filed suggests that intermolecular forces between the AuNPs and liposomal contents may contribute to the observed size reduction. Table 2 from the specification as filed in reproduced in the remarks as showing the size of various constructs. Additional data from the specification showing that liposomes with SNA encapsulation are smaller than liposomes without SNA encapsulation was also included in the remarks. Data showing a close to zero zeta potential and a PD (polydispersity) value showing that the compositions are similar in size. None of the technical advantages demonstrated are taught ot suggested by Kapadia or Lai and the pending claims are patentable over these references.
These arguments are unpersuasive. The data present in the specification has been discussed previously and the remarks filed do not reference new data from the specification as filed. The Examiner was unable to locate a citation in the remarks, in the specification as filed or in the cited prior art of record to the Li et al. referenced in the Remarks. Except for the information that was in the specification as filed, Arguments without factual support are mere allegations and are not found persuasive. No additional explanation as to what the change in size of liposomes based on different loading was given and while differences were observed, no explanation as to what the expected results would be. There is also the issue of any evidence of unexpected results being reasonably commensurate in scope with the claims as while size is recited, particulars of the liposomes such as lipids present and overall charge are not claimed. As the additional information was not provided in declaration form, the material of record does not establish a clear link to Li et al. and the complete document could not be reviewed, these arguments are unpersuasive and even if the discussion was provided in evidentiary form, would not be reasonably commensurate in scope with the claims. Therefore the rejection is maintained.
Conclusion
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/Nissa M Westerberg/Primary Examiner, Art Unit 1618