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 .
DETAILED ACTION
Acknowledgement is hereby made of receipt and entry of the communication filed on Jun. 9, 2026. Claims 2-11, 13-18, 20, 22, 26-28 and 59-63 are pending and currently examined.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
(New Rejection) Claims 2-11, 13-18, 20, 22, 26-28 and 59-63 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The base claim 1 is directed to a method of treating a subject with a tumor resistant to an immune checkpoint inhibitor (ICI), comprising administering to the subject (i) a composition comprising a nanoparticle comprising lipid bilayers and nucleic acid layers, and (ii) the ICI.
It is not clear how to interpret the limitation of “a subject with a tumor resistant to an immune checkpoint inhibitor (ICI)”. First, the word “resistant” is a relative term. It is not clear to what degree or under what condition the subject with a tumor is “resistant” to an ICI for the subject and the ICI to be encompassed by the claimed invention. Additionally, since the claim requires treating the subject with the ICI, one of skill in the art would assume that the treatment would be effective. Therefore, it is not clear why a tumor is “resistant” to an ICI when it can be treated by the ICI.
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 of this title, 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.
(Previous Rejection – Withdrawn) Claims 2-11, 13-18, 20, 22, 26-28 and 59-61 were rejected under 35 U.S.C. 103 as being unpatentable over Koide et al. (Journal of Controlled Release 228 (2016) 1-8), Es et al. (Colloids and Surfaces A 555 (2018) 280-289), and Sayour et al. (Int. J. Mol. Sci. 2018, 19, 2890), in view of Colombo et al. (Journal of Controlled Release, 2015, 201: 22–31), and further in view of Rao et al. (Ann Transl Med 2017;5(23):468).
This rejection is withdrawn in view of the amendment filed on Jun. 9, 2026 and in favor of the new rejections below. Applicant’s arguments regarding withdrawn rejections are moot.
(New Rejection) Claims 2-11, 13-18, 20, 22, 26-27 and 59-61 are rejected under 35 U.S.C. 103 as being unpatentable over Koide et al. (Journal of Controlled Release 228 (2016) 1-8), Es et al. (Colloids and Surfaces A 555 (2018) 280-289), and Sayour et al. (Int. J. Mol. Sci. 2018, 19, 2890), in view of Colombo et al. (Journal of Controlled Release, 2015, 201: 22–31), and further in view of Rao et al. (Ann Transl Med 2017;5(23):468) and Park et al. (Experimental & Molecular Medicine (2018) 50:109).
Base claim 2, as amended, is directed to a method of treating a subject with a tumor resistant to an immune checkpoint inhibitor (ICI), comprising systemically administering to the subject (i) a composition comprising a nanoparticle comprising a positively-charged surface and an interior comprising (a) a core and (b) at least two nucleic acid layers, wherein each nucleic acid layer is positioned between cationic lipid bilayers, wherein the nanoparticle comprises a zeta potential of +40 mV to +60 mV, comprises a diameter of about 250 nm to about 500 nm, and does not comprise a neutral lipid, and the core of the nanoparticle comprises a cationic lipid bilayer or is empty, and (ii) the ICI.
Koide teaches that the authors report a simple, only one step, and efficient method for siRNA encapsulation into a lipidic nanocarrier by freeze-thawing: siRNA was entrapped between the lipid layers of multi-layer liposomes by freeze-thawing of lipoplexes composed of polycation liposomes (PCLs) and siRNA. They found that the lipoplex formed a “packed multi-layer” structure after the freeze-thawing of “single-layer” PCL and siRNA complex, suggesting that siRNA exists between the lipid layers working as a binder. PEGylated freeze-thawed lipoplexes delivered a higher amount of siRNA to a tumor in vivo compared with the PEGylated conventional ones. These results provide an attractive strategy for “one-step” encapsulation of siRNA into liposomes by freeze-thawing. See Abstract.
Fig. 2(i)-(l) of Koide shows a schematic presentation of PLC or lipoplex structures, see below:
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Fig.2(l) shows lipoplexes comprising a multilayered structure that is indistinguishable from that of the multi-lamellar RNA-NPs shown in Figure 1A of the instant invention.
Koide teaches that Dioleoylphosphatidylethanolamine (DOPE), cholesterol, and dicetylphosphate-diethylenetriamine (DCP-DETA; 1:1:1 as a molar ratio) were dissolved in t-butyl alcohol and freeze-dried. PCLs were produced by hydration of the lipid mixture with DEPC-treated RNase-free water. Liposomes were sized by extrusion 10 times through a polycarbonate membrane filter having 100-nm pores (Nucleopore, Maidstone, UK). Liposomes and siRNA were mixed and incubated for 20 min at room temperature to form liposome/siRNA complexes. To prepare freeze-thawed lipoplex, the complexwas frozen in liquid nitrogen and thawed in a water bath at 43 °C with vortexing. The particle size and ζ-potential of the complexes diluted with 0.5 mM PBS (pH = 7.4) were measured by using a Zetasizer Nano ZS (Malvern, Worcs, UK). For the in vivo study, lipoplexes were decorated with polyethylene glycol (PEG) by incubating them with DSPE-PEG6000 (10 mol% to total lipids) at 40 °C for 10 min. Dipalmitoylphosphatidylcholine (DPPC), 1,2-dioleoyl-3-trimethylammonium - propane (DOTAP) and dicetyl phosphatetetraethylenepentamine (DCP-TEPA) liposomes (DOPE:cholesterol: DPPC, DOTAP or DCP-TEPA = 1:1:1) were also prepared by same procedure. See page 2, right column, para 2. Koide teaches that the increase of siRNA-encapsulating capacity was also observed in DOTAP- or DCP-TEPA-containing liposomes (Supplementary Fig. 2a,b), but not in DPPC-containing liposomes with neutral surface charge (Supplementary Fig. 2c). Therefore, it is suggested that, in general, cationic liposomes can increase siRNA-encapsulating capacity by the freeze-thawing. See page 4, right column, para 2. These teachings indicate that multilayered lipoplexes with lipid bilayers and RNA molecule layers in between are made, using various cationic lipids.
Koide teaches that to determine the biodistribution of siRNA in tumor-implanted mice, colon26 NL-17 carcinoma cells were subcutaneously implanted into the mice. Twenty days after tumor implantation, PEGylated conventional or freeze-thawed lipoplexes, as well as naked siRNA, were intravenously injected into the mice. Ex vivo imaging showed that siRNA delivered with PEGylated freeze-thawed lipoplexes had not only accumulated in the liver, spleen, and kidneys but also in the tumor at 48 h after the intravenous injection. These results demonstrate that the conventional lipoplex induced efficient knockdown in vitro; however, the most of siRNA were detached from the PCL after the PEGylation. On the other hand, siRNA formulated in freeze-thawed lipoplex showed the characteristic of long-term circulation, except that bound to the outer surface of the lipoplex, and accumulated in the tumor, suggesting that encapsulated siRNA by the freeze-thawing of lipoplex stably holds siRNA during circulation and may induces efficient knockdown in vivo after systemic administration. See page 7, left column, para 4. These teachings indicate that the multilayered RNA-containing lipoplexes made by freeze-thawing are administered to animals in a tumor model.
Es teaches a study on evaluation of siRNA and cationic liposomes complexes as a model for in vitro siRNA delivery to cancer cells. It teaches that controlled release of genetic material such as small interfering RNA (siRNA) using lipid-based non-viral vectors has gained substantial importance in gene therapy applications. Therefore, the interaction between siRNA and these vectors must be well understood. This study aims to investigate the effect of different molar charge ratios (R+/-) between positive charges from microfluidics-produced cationic liposomes (CL) and negative charges from siRNA and on physico-chemical and morphological properties of the lipoplexes (CL/siRNA) as well as their in vitro luciferase silencing effect in HeLa cells. According to Cryo-TEM analysis, the lipoplexes had multi-lamellarity. In vitro transfection efficiency of lipoplexes in HeLa cells was tested at three different siRNA concentrations (10, 25, and 35 nM). Significant knockdown of luciferase by siRNA lipoplexes was observed based on reduced luciferase activity of transfected HeLa cells. See Abstract.
Fig. 3 of Es presents Cryo-TEM images of lipoplexes at molar charge ratios of 2.33, 3.27, and 4.21, showing that multi-lamellar liposome nanoparticles are formed at different R+/- conditions. The scale bars represent 200 nm. Arrows indicate the multilamellar lipoplexes.
Sayour teaches that cancer vaccines may be harnessed to incite immunity against poorly immunogenic tumors. However, poor antigenicity coupled with systemic and intratumoral immune suppression have been significant drawbacks. RNA encoding for tumor associated or specific epitopes can serve as a more immunogenic and expeditious trigger of anti-tumor immunity. RNA stimulates innate immunity through toll like receptor stimulation producing type I interferon, and it mediates potent adaptive responses. Since RNA is inherently unstable, delivery systems have been developed to protect and deliver it to intended targets in vivo. In this review, the authors discuss liposomes as RNA delivery vehicles and their role as cancer vaccines. See Abstract.
Sayour teaches that cancer immunotherapy is a burgeoning field with evidence for anti-tumor activity in several randomized phase III trials. Much of the excitement surrounding this technology is centered on the concept of immune checkpoint blockade where T cell co-inhibitory signals are antagonized with monoclonal antibodies (mAbs). However, immune checkpoint inhibition appears to work predominantly in cancers with high mutational burdens. Evidence suggests that a preexisting T cell response is required for a response to immune checkpoint blockade, which could be enriched in mutation rich tumors. If this is true, the utility of checkpoint inhibitors could be tempered for many cancers with low mutational burdens or immunologically poor tumor microenvironments. To broaden the response to immunotherapy, cancer vaccines may be harnessed to incite response against poorly immunogenic tumors. See page 1, para 1. These teachings suggest that immune check point blockade and cancer vaccines are two treatments that can be used in treating cancers with different advantages.
Sayour teaches that the type of immune response that is elicited by liposomes is often affected by the lipid material’s surface properties. Liposomes may be polar or non-polar. Polar lipids are effective agents for mRNA transfection and are typically composed of hydrophilic head groups that are attached to linker bonds connected with non-polar tails. The non-polar tails from separate molecules join one another so that the positively charged hydrophilic heads (repelled by one another) face along opposite sides. As more liposomes join together, these NPs form micelle-like structures that are composed of a positively charged outer surface, a positively charged inner core, and a lipid layer in between. Positively charged liposomes can simply be mixed with negatively charged nucleic acids (i.e., RNA) for the formation of RNA-liposomes. A proposed schema for RNA-liposome complexation is shown in Figure 1. Briefly after the addition of positively charged liposomes to negatively charged RNA, electrostatic interactions dominate. Negatively charged RNA adheres to the surface of the particle creating a net negative charge that may be enveloped by another positively charged particle. This effectively traps the nucleic acid RNAs between the lipid envelopes, protecting them from degradation. This process can be repeated so that multiple layers of mRNA coat successive outer layers before being enveloped by new liposomes, forming multi-lamellar vesicles. These multi-lamellar vesicles can maintain their small sizes due to the internal electrostatic interactions that keep the particle tightly packaged. See page 3, para 3. Figure 1 of Sayour shows a schematic presentation of multi-lamellar RNA-containing liposomes that can be used as RNA carrier (shown below).
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Sayour teaches that while still in the early stages, RNA-liposomes have been tested in human clinical studies. A dose-escalation study explored the safety and activity of tetravalent RNA-lipoplex vaccines (targeting four tumor-associated antigens) in patients with advanced melanomas (clinicaltrials.gov: NCT02410733). Aside from transitory flu-like illnesses, the vaccines have been safe and well tolerated with activity based on the induction of IP-10 and type I interferon. More personalized RNA-liposomal cancer vaccines are currently being investigated in multi-institutional human clinical trials. Phase 1a/1b studies are underway, investigating personalized RNA-loaded liposomes in combination with immune checkpoint inhibitors, atezolizumab (mAbs targeting PD-L1), for patients with refractory solid tumors (clinicaltrials.gov: NCT03289962). See page 8, para 2.
Accordingly, Koide and Es teach construction of multilayered/multi-lamellar cationic liposome nanoparticles loaded with RNA molecules, produced by different methods, and their potential application in cancer therapies; Sayour teaches the concept and practice of delivering RNA molecules by cationic liposome nanoparticles as cancer vaccines as well as immune checkpoint inhibitors as combination therapies for cancers; Sayour further teaches the construction of multilayered RNA-loaded liposome nanoparticles and their pros and cons. Koide further teaches that the lipoplex nanoparticles are administered to subject animals (mice bearing tumor implant) via a tail vein (see page 4, left column, para 2), indicating that the administration is performed systemically.
Regarding the limitation of nanoparticle size of about 250-500 nm, Koide teaches nanoparticles with various sizes, including sizes in the claimed range. See Table 1. Regarding the limitation that the core of the nanoparticle comprises a cationic lipid bilayer or is empty, Koide and Sayour teach lipid bilayer nanoparticles with a cationic lipid bilayer core or empty. See Figure 2 of Koide and Figure 1 of Sayour.
However, Koide, Es and Sayour do not teach a multilamellar nanoparticle that comprises a zeta potential of +40 mV to +60 mV and does not comprise a neutral lipid (both Koide and Es teach that the siRNA-containing multilamellar lipid nanoparticles used in the studies contain neutral lipids, e.g., DOPE and/or DPPC, and Sayour is silent on the components of the disclosed multilamellar lipid nanoparticles).
Colombo teaches that understanding the delivery dynamics of nucleic acid nanocarriers is fundamental to improve their design for therapeutic applications. The authors investigated the carrier structure–function relationship of lipid–polymer hybrid nanoparticles (LPNs) consisting of poly(DL-lactic-co-glycolic acid) (PLGA) nanocarriers modified with the cationic lipid dioleoyltrimethyl-ammoniumpropane (DOTAP). A library of siRNA-loaded LPNs was prepared by systematically varying the nitrogen-to-phosphate (N/P) ratio. Atomic force microscopy (AFM) and cryo-transmission electron microscopy (cryo-TEM) combined with small angle X-ray scattering (SAXS) and confocal laser scanning microscopy (CLSM) studies suggested that the siRNA-loaded LPNs are characterized by a core–shell structure consisting of a PLGA matrix core coated with lamellar DOTAP structures with siRNA localized both in the core and in the shell. Release studies in buffer and serum-containing medium combined with in vitro gene silencing and quantification of intracellular siRNA suggested that this self-assembling core–shell structure influences the siRNA release kinetics and the delivery dynamics. A main delivery mechanism appears to be mediated via the release of transfection-competent siRNA–DOTAP lipoplexes from the LPNs. Based on these results, they suggest a model for the nanostructural characteristics of the LPNs, in which the siRNA is organized in lamellar superficial assemblies and/or as complexes entrapped in the polymeric matrix. See Abstract.
Colombo teaches that the siRNA-loaded LPNs were prepared with the DESE method by emulsifying siRNA solution with DOTAP and PLGA binary mixture. See page 23, left column, para 2. Colombo teaches that different nanoparticle formulations (2a–2e) were prepared with systematically varying the N/P ratio from1–62 by varying the siRNA loading at a constant DOTAP:PLGA weight ratio (15:85, Table 1), that the zeta-potential was significantly affected by the N/P ratio, and an N/P ratio dependent increase in the zeta-potential was observed ranging from−27.0±7.9mV for 2a to+42.6±2.5mV for 2e (p< 0.001). See page 24, right column, para 2. Fig. 8 of Colombo shows the model for the structural characteristics of siRNA-loaded LPNs, indicating that the LPNs comprise multiple layers of lipid bilayers with siRNAs in between. See Fig. 8A.
Accordingly, Colombo teaches the production and application of multilamellar LPNs for the delivery of therapeutic nucleic acid molecules. Its teachings indicate that siRNA-loaded LPNs comprise cationic lipid, DOTAP, and do not comprise a neutral lipid, and that the LPNs can be made to have a zeta potential of +42.6±2.5mV, which is within the range as currently claimed.
However, Koide, Es, Sayour and Colombo are silent on treating a subject with a tumor resistant to an immune checkpoint inhibitor (ICI) with the ICI.
Rao reviews about predictors of response and resistance to checkpoint inhibitors in solid tumors. Rao teaches that checkpoint inhibitors (blocking antibodies to PD-1, PD-L1, CTLA-4) have proven effective against several tumor types. Unfortunately, only a minority of tumors within each subtype responds, and checkpoint inhibitors can cause significant toxicity. There is a flurry of activity around determining patient and tumor factors of response and resistance to this class of medication. Rao teaches that Roh et al. examined clinical and correlative characteristics of advanced melanoma patients as their melanoma progressed through treatments with CTLA-4 inhibitors and PD-1 inhibitors. Of an initial cohort of 56 patients, 54 were treated with CTLA-4 inhibitor, and 7 of them responded (1). The non-responders were then treated with the PD-1 inhibitor, and 14 (28%) responded (1). Using serial biopsies, the authors identified several tumor factors that favor response and resistance (1). Of note, their definition of response is either radiographic partial or complete remission or stable disease lasting at least 6 months (1). See page1, left column, para 1 and 2.
Park reviews the prospects of immune checkpoint blockade in cancer – from response prediction to overcoming resistance. Park teaches that the remarkable successes of immune checkpoint-blocking antibodies in clinical settings have encouraged researchers to focus on developing various immunologic strategies to combat cancer. However, such immunotherapies still face difficulties in controlling malignancy in many patients due to the heterogeneity of both tumors and individual patients. The authors discuss how tumor-intrinsic cues, tumor environmental metabolites, and host-derived immune cells might impact the efficacy and resistance often seen during immune checkpoint blockade treatment. Furthermore, they introduce biomarkers identified from human and mouse models that predict clinical benefits for immune checkpoint blockers in cancer. See Abstract.
Park teaches that the first clinical development of a CTLA-4-blocking antibody, ipilimumab, proved that immune checkpoints would be attractive targets for cancer therapy, and that once the CTLA-4 signal was shown to restrict the activity of T cells, agents that shut down this signaling molecule became candidates for combination treatment with existing cancer therapeutics. See page 2, right column. Park teaches that to improve therapeutic efficacy, a number of preclinical and clinical studies have been conducted to examine if combination treatment of immune checkpoint blockers with conventional treatments, such as chemotherapies, targeted therapies, radiation therapies, and other immunotherapeutic agents, could improve outcomes. See page 3, right column, para 4, and Table 2.
Accordingly, teachings of Rao and Park indicate that most tumor types are in certain degree resistant to certain immune checkpoint inhibition/blockade treatments, and that an ICI may be tested and found active to a tumor. Teachings of Park further indicate that it is contemplated and practiced at the time of invention to combine the immune checkpoint inhibition/blockage treatments with other cancer therapies.
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the current invention to combine the teachings of Koide, Es, Sayour, Colombo, Rao and Park to arrive at the invention as claimed. One would have been motivated to do so to substitute the neutral lipid-containing lipid nanoparticles disclosed in Koide and Es with the LPNs disclosed in Colombo, which do not comprise neutral lipids, to evaluate the effect of the LPNs of Colomba in the delivery of therapeutic nucleic acid molecules, such as in studies disclosed in Koide, Es, and/or Sayour. Additionally, such a combination, or a substitution of one element for another known in the field to have the same function, is evidence that the claimed invention may be found obvious. See e.g., KSR International v. Teleflex Inc., 82 U.S.P.Q.2d 1385, at 1395. Therefore, the instant 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 references, especially in the absence of evidence to the contrary.
As to the requirement of administration of an immune checkpoint inhibitor to a subject with an ICI-resistant tumor, one would have been motivated to do so to evaluate the effect of combining the multilayered/multilamellar RNA-liposomal nanoparticles with an immune checkpoint inhibitor to find out if a combination therapy would improve the treatment effect produced by each individual treatment, based on the teachings of Rao and Park. Such a combination, or a substitution of one element for another known in the field to have the same function, is evidence that the claimed invention may be found obvious. See e.g., KSR International v. Teleflex Inc., 82 U.S.P.Q.2d 1385, at 1395.
Regarding claims 5-11and 27, which specify structural and component features of the multilayer nanoparticles, Koide, Es, Sayour and Colombo each teaches processes for production of various multilamellar lipid nanoparticles containing nucleic acid molecules, with different components and structural features, including ones as claimed. See e.g. Fig. 2 of Koide and Fig. 8 of Colombo.
Regarding claims 17-18, 20, 22 and 60, Sayour teaches liposomes (composed of DOTMA with DOPE) encapsulating mRNA encoding for tumor associated antigens or neo-epitopes (see page 6, para 2), and that RNA-liposomes can be embedded with multiple mRNAs encoding for immunomodulatory cytokines and offer a promising, simpler alternative to cell therapy vaccines (i.e., dendritic cell vaccines) (see page 3, para 2).
Further regrading claim 22, Sayour teaches that mRNA encoding for model antigens (i.e., OVAlbumin) and physiologically relevant antigens (i.e., E7 from human papilloma virus, tyrosinase related protein 2) encapsulated in lipofectamine RNAiMAX (at composite anionic zeta potentials) could be systemically administered for transfection of APCs in the spleen and liver, and initiation of an immunologic response. See page 3, para 2. Here, the OVAlbumin is a protein not expressed by a tumor or by a human.
Regarding claims 26 and 59, Sayour teaches that by extracting total RNA (tRNA) from as little as 500 biopsied cells, these personalized RNA-liposomes can be generated against malignancies (i.e., brain tumors) that are difficult to access surgically. While tRNA contains ribosomal and transfer RNA, we can generate a cDNA library through RT-PCR on mRNA present from the initial tRNA extraction. This cDNA may then be in vitro transcribed and amplified for copious generation of mRNA, representing a tumor-specific charged RNA, NPs become complexed with mRNA for loading of dendritic cells or APCs with tumor antigens (Figure 2). See para spanning pages 6-7.
(New Rejection) Claims 28 and 62-63 are rejected under 35 U.S.C. 103 as being unpatentable over Koide et al. (Journal of Controlled Release 228 (2016) 1-8), Es et al. (Colloids and Surfaces A 555 (2018) 280-289), and Sayour et al. (Int. J. Mol. Sci. 2018, 19, 2890), in view of Colombo et al. (Journal of Controlled Release, 2015, 201: 22–31), Rao et al. (Ann Transl Med 2017;5(23):468) and Park et al. (Experimental & Molecular Medicine (2018) 50:109), as applied above, and further in view of Pardi et al. (Nature reviews Drug discovery 17.4 (2018): 261-279).
These claims further specify that the composition is systemically administered via intramuscular administration.
Relevance of Koide, Es, Sayour, Colombo, Rao and Park is set forth above. However, they are silent on intramuscular administration of the related compositions.
Pardi reviews about mRNA vaccines. It teaches that systemically delivered mRNA–LNP complexes mainly target the liver owing to binding of apolipoprotein E and subsequent receptor-mediated uptake by hepatocytes8, and intradermal, intramuscular and subcutaneous administration have been shown to produce prolonged protein expression at the site of the injection. See page 266, right column, para 2. Pardi teaches that the magnitude and duration of in vivo protein production from mRNA–LNP vaccines can be controlled in part by varying the route of administration - intramuscular and intradermal delivery of mRNA–LNPs has been shown to result in more persistent protein expression than systemic delivery routes. See page 266, right column, para 3.
Accordingly, teachings of Pardi indicate that administration of mRNA-LNPs (lipid nanoparticles) via the intramuscular route is known and commonly practiced in the art at the time of invention with the advantage of more persistent protein expression than systemic delivery routes.
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the current invention to combine the teachings of Koide, Es, Sayour, Colombo, Rao, Park and Pardi to arrive at the invention as claimed. One would have been motivated to do so, e.g., to evaluate the intramuscular administration route in the delivery of the claimed LNP-nucleic acid compositions, based on the teachings of Pardi.
As to the limitation of claims 62-63 that the method further comprises administering a second composition comprising a nanoparticle comprising a positively-charged surface and an interior comprising (a) a core and (b) at least two nucleic acid layers, wherein each nucleic acid layer is positioned between cationic lipid bilayers and comprises mRNA encoding a tumor antigen, Sayour teaches that various nucleic acid molecules may be administered to host subjects by the lipid nanoparticles, including mRNAs encoding tumor antigens as well as immune modulators. See discussions above. One of skill in the art would have found it obvious to administer compositions comprising mRNAs encoding different proteins of interest based on study needs.
Double Patenting Rejection
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the claims at issue are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); and In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on a nonstatutory double patenting ground provided the reference application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP §§ 706.02(l)(1) - 706.02(l)(3) for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/forms/. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to http://www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
(Previous Rejection – Withdrawn) Claims 2-11, 13-18, 20, 22, 26-28 and 59-61 were rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-13 of US Patent 12,514,930 in view of the prior art references cited in the 103 rejection above.
This rejection is withdrawn in view of the amendment filed on Jun. 9, 2026 and in favor of the new rejections below. Applicant’s arguments regarding withdrawn rejections are moot.
(New Rejection) Claims 2-11, 13-18, 20, 22, 26-28 and 59-63 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-13 of US Patent 12,514,930 in view of the prior art references cited in the 103 rejections above.
Although the conflicting claims are not identical, they are not patentably distinct from each other. Both sets of claims encompass a method for treating a subject with tumor comprising administering to the subject a composition comprising a liposome comprising a cationic lipid and nucleic acid molecules complexed with the cationic lipid and an immune checkpoint inhibitor. The differences between the two sets of claims include: 1) the reference claims are silent on the multilamellar feature of the nucleic acid-liposomes which is required by the instant claims, 2) the reference claims specify mRNA while the instant claims specify generic nucleic acids, and 3) the instant claims specify that the liposomes do not comprise neutral lipid and have diameter of about 250-500 nm and a zeta potential in the range of +40 to +60 mV which are not required by the reference claims.
As indicated in the art rejection above, it is known in the art to produce therapeutic RNA-loaded multilamellar LPNs that do not comprise a neutral lipid; it is known and studied in the art of cancer therapies to combine the therapeutically effective RNA-loaded cationic liposomes with ICIs in cancer treatment; and it is also known and studied in the art to produce multilayered/multilamellar liposomes loaded with therapeutic RNA molecules for the potential cancer therapeutic effects.
It would have been prima facie obvious for one of ordinary skill in the art to arrive from the reference claims to the instant claims, based on the teachings of the prior art references cited in the art rejection above.
Accordingly, claims 2-11, 13-18, 20, 22, 26-28 and 59-63 are unpatentable over claims 1-13 of US Patent 12,514,930.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NIANXIANG (NICK) ZOU whose telephone number is (571)272-2850. The examiner can normally be reached on Monday - Friday, 8:30 am - 5:00 pm, EST. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, MICHAEL ALLEN, on (571) 270-3497, can be reached. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/NIANXIANG ZOU/
Primary Examiner, Art Unit 1671
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