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 .
Claims 1, 3-6, 10, 11-25, 28-31, 33-35 are pending in the application. Claims 15-25, 8-31, 33 and 34 are withdrawn. Claims 1, 3-6, 10, 11-14 and 35 are currently under examination.
This office action is in response to the amendment filed on 7/9/2026.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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, 3-6, 10-14 is/are rejected under 35 U.S.C. 103 as being unpatentable over Malone (cited previously), in view of Rieder (US20180326038) and Lin et al (Biomed Microdevices, 2016, Vol.18, no. 41, pages 1-11) and Fanning (cited previously).
Malone discloses a capsid comprising recombinant engineered Arc polypeptide and endogenous Gag (endo-gag) polypeptides that can form capsids, and may be loaded with heterologous molecules for delivery to a target of interest (paragraph [0003]). Malone discloses the cargos may be a therapeutic agent (paragraph [0118], [0127]). Malone discloses Arc or endo-gag comprises a capsid assembly/forming domain (paragraph [0054]), and each of recombinant or engineered Arc or endo-gag polypeptide forms a capsid subunit (paragraph [0106], page 14, line 4-5). Malone discloses various vector and expression system for expressing Arch and endo-Gag polypeptides, including pFLAG, pTRCHis2 series, and pFLAG-Myc-CMV, which comprises epitope tags FLAG, Myc and His (paragraph [0189], [0193]). Malone gives an example of the 6xHis tagged recombinant Arc and endo-Gag (paragraph 0273, line 13-14). Malone discloses endo-gag based capsid including proteins PEG10, RTL3, RTL6, RTL8A and RTL8B (paragraph [0014], [0107], lines 10-13), all of which belong to Sushi-class protein as evidenced by Figure 2 of the present application. The endo-gag polypeptides thus meets the limitation of Gag-homology proteins because they encompasses same protein as recited in claim 1, Sushi-class proteins.
The teaching from Malone is silent on whether the epitope tag is expressed on the surface of the capsid, and wherein the epitope tag is the glycoprotein of vesicular stomatitis virus (VSVG) as a fusogenic membrane glycoprotein.
Rieder teaches a method of genetically engineer FMD viruses by insertion of protein tags into the selected regions of the capsid of the FMD, and said tagged FMD viruses are suitable to be used in various diagnostic and therapeutic applications as well as in applications wherein production of the FMD virus and/or its components are desired (paragraph [0006]). Rieder teaches the tags are strategically inserted into viral capsid proteins in targeted regions predicated to be exposed on the surface of the viral capsid (paragraph [0050]). Rieder teaches the epitope tags that may be used include 6xHis, Flag, V5, Myc, HA and NE (paragraph [0065]), and gives examples of using 6xHis to decorate FMDV capsid surface (paragraph [0096]).
Fanning et al. teach a method of isolation and functional characterization of ZO-1, using C-terminally VSVG tagged constructs (Figure 1 and legend, page 3, Material and Methods section, paragraph 1).
Lin et al. teach overexpression of the spike glycoprotein of vesicular stomatitis virus (VSVG) has been shown to induce the release of fusogenic vesicles which are capable of direct transport of cytoplasmic, nuclear and surface proteins to target cells, and proteins of interest can be encapsidated in the particle of a fusion protein Gag and efficiently delivered to recipient cells (page 1, 1st col., 2nd paragraph). Lin et al. demonstrated that fusogenic plasma membrane vesicles (fPMVs) containing bioactive macromolecules and mitochondria by a simple mechanical extrusion of VSVG expression Ad293 cells, wherein cytoplasmic proteins and mitochondria entrapped in fPMVs can efficiently be transferred to target cells (page 2, 1st col., last paragraph).
It would have been obvious to an ordinary skilled in the art that epitope tags may be strategically inserted into the endo-gag peptide to be assembled into capsid displaying on the outer surface of the capsid based on the combined teaching from Malone and Rieder. The ordinary skilled in the art would recognize that the epitope tag such as His taught in the Malone reference may be used to purify the endo-gag polypeptide or in a different position to be expressed on the outer surface of the capsid as demonstrated by Rieder. An ordinary skilled in the art reading Fanning would recognize that VSVG are routinely used as a protein tag for isolation and characterization of the protein of interest as demonstrated by Fanning et al., and Malone teaches using VSV envelope protein to target cells of interest for delivery (paragraph [0250] and [0254]). The ordinary skilled in the art would recognize VSVG tagging, would have additional advantage of fusogenic delivery of encapsulated contents as taught by Lin et al. The ordinary skilled in the art would have reasonable expectation of success to insert the epitope tag VSVG to be displayed on the capsid surface following combined teaching from Malone, Rieder, Fanning and Lin. Therefore, the claimed invention of claim 1 would have been prima facie obvious to an ordinary skilled in the art at the time the application was filed.
Regarding claim 4, Malone discloses the heterologous cargo comprises nucleic acid (paragraph [0127]).
Regarding claim 5-6, Malone disclose that endo-gag polypeptide is a human Endo-Gag polypeptide, and its RNA binding domain is modified to bind to a RNA cargo that is not native to human endo-Gag (paragraph [0042]), which meets the claim limitation of “reprogram binding specificity.”
Regarding claim 10, Malone discloses endo-gag based capsid including a protein RTL3, PEG10, RTL6, RTL8A and RTL8B (paragraph [0014], [0107], lines 10-13).
Regarding claim 11, Malone teaches making modification to Arc with its RNA binding domain to bind to a cargo that is not native to human Arc (paragraph [0041]), which meets the limitation of carrier tag as defined by the present specification.
Regarding claim 12, Malone further teaches delivery component further comprises liposome, micelle, microvesicle (paragraph [0237]).
Regarding claims 3 and 13, Malone further teaches the delivery component further comprises a viral envelope protein for specifically targeting the capsid to a target cell (paragraph [0250]), which meets the limitation of engineered capsid to provide cell specific uptake (claim 3) and a targeting molecules (claim 13).
Regarding claim 14, Malone teaches the targeting molecule is viral proteins comprises cell specific binding protein, that binds to cell surface molecule (paragraph [0250], [0255]), which meets the limitation of ligands for receptors on a surface of a target cell of interest.
Claim(s) 35 is/are rejected under 35 U.S.C. 103 as being unpatentable over Malone, Reider, Fanning and Lin, as applied to claims 1, 3-6, 10-14 above, and further in view of Barile (Pharmacology & Therapeutics 2017, Vol. 174, pages 63-78).
The teaching from Malone, Reider, Fanning and Lin has been discussed above.
However, none of the reference teaches the capsid is contained in an exosomes.
Barile teaches virtually all cells in the organism secrete extracellular vesicles, a heterogeneous population of lipid bilayer membrane-enclosed vesicles that transport and deliver payloads of protein and nucleic acids to recipient cells (abstract). Barile teaches exosomes may be loaded with therapeutic cargo molecules, including a variety of molecules, such as siRNA, miRNA mimic, synthetic drugs, proteins and viral vectors (page 70, 1st and 2nd col., under section 13). Barile teaches exosome offers appealing feature for therapeutic delivery, including biocompatibility, stability in the circulation, biological barrier permeability, low immunogenicity, and low toxicity (page 70, 1st col., 2nd paragraph).
It would have been obvious to an ordinary skilled in the art that exosomes may be used to deliver the capsid having a cargo rendered obvious by combined teaching from Malone, Reider, Fanning and Lin, based on the teaching from Malone and Barile. Malone teaches the delivery system further comprises liposome, micelle, microvesicle (paragraph [0237]), although not specifically teach exosome, an ordinary skilled in the art reading Barile would recognize that exosome may also be used in the delivery system due to their “appealing feature for therapeutic delivery, including biocompatibility, stability in the circulation, biological barrier permeability, low immunogenicity, and low toxicity (page 70, 1st col., 2nd paragraph). The ordinary skilled in the art would have reasonable expectation of success to include exosomes in the delivery system following combined teaching from Malone, Reider, Fanning, Lin and Barile. Therefore, the claimed invention of claim 35 would have been prima facie obvious to an ordinary skilled in the art at the time the application was filed.
Response to Arguments
In response to the rejection, Applicant argues that Fanning and Rieder do not teach the full length VSVG glycoprotein required by claim 1 because the “VSVG tag” in both references is an 11 amino acid immunodetection Epitope, not the 510 amino acid fusogenic transmembrane protein. Applicant argues that claim 1 requires “the glycoprotein of vesicular stomatitis virus” expressed on the outer surface of the capsid “as a fusogenic membrane glycoprotein.”
This argument is not persuasive because claim 1 recites “a capsid comprising (i) one or more human Gag-homology protein comprising an export compartment domain capable of directing self-assembly into the capsid…and an epitope tag, wherein the epitope tag is the glycoprotein of VSVG, and wherein the VSVG epitope tag is expressed on the outer surface of the capsid as a fusogenic membrane protein.” There is no limitation requiring the VSVG epitope tag is the full length 510 amino acid fusogenic transmembrane protein. The specification (paragraph [0106] and [0205]) teaches epitope tags including VSVG glycoprotein, but does not limit the VSVG epitope tag to any particular length. The specification teaches fusogenic activity of the vesicle can be modulated by forming the vesicle with a blend of non-phospholipid fusogenic composed of a highly fusogenic non-phospholipid and a non-fusogenic phospholipid (paragraph [0154]), but does not describe any size limitation of the VSVG as a fusogenic membrane protein. Since an “epitope tag” is understood in the art as a short, engineered peptide sequence fused to a protein, the 11 amino acid tag taught by Fanning and Reider meets this claim limitation. Even if the full length VSVG is required (as alleged by Applicant), the vector encoding full length VSVG (pLP-VSVG) was taught by Lin et al. (page 41, 2nd col., 2nd paragraph).
Applicant further argues that Lin does not teach VSVG as a fusogenic membrane glycoprotein on the surface of a protein capsid, but it operates in lipid bilayer plasma membrane vesicle context. Applicant argues that claim 1 requires VSVG expressed as an epitope tag on the outer surface of a non-enveloped Sushi-class capsid, where it functions as a fusogenic membrane glycoprotein. Applicant argues that VSVG expressed as an epitope tag on the outer surface of a non-enveloped capsid is structurally different from the VSVG expressed in lipid bilayer.
This argument is not persuasive because the obviousness rejection is based upon the combined teaching from Malone, in view of Rieder Lin et al (Biomed Microdevices, 2016, Vol.18, no. 41, pages 1-11) and Fanning. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In the instant case, even if the full length VSVG is required to function as fusogenic glycoprotein, the full length VSVG is taught by Lin, whereas how to express a epitope tag on the outer surface of viral capsid is taught by Rieder. As such, expressing a full length VSVG on the outer surface of a capsid as claimed would have been routine experimentation rather than a method of innovation. Moreover, the recitation “as a fusogenic membrane glycoprotein” does not provide any structural limitation as alleged by Applicant because the specification does not provide any teaching that “as a fusogenic membrane glycoprotein” requires a particular structure of the “VSVG epitope tag.”
Applicant argues that the cited combination provides no motivation to depart from Malone’s pseudotyping architecture to arrive at the configuration of claim 1. Applicant argues that claim 1 requires VSVG to function not merely as a surface tag but specifically as a “fusogenic membrane glycoprotein,” the function that enables direct cytoplasmic delivery by bypassing the endosome-to-lysosome pathway. Applicant states that paragraph [0348] describes Applicants decorating the vesicle surface with VSVG specifically “to increase the direct fusion of the extracellular vesicle and the cytoplasm”, and Figure 26 of the specification illustrates that “VSVG is able to induce direct fusion between cellular and viral membranes.” Applicant argues that the use of VSVG is distinct from the VSVG of Fanning and Rieder because paragraph [00105] establishes that the claimed system encompasses “non-enveloped capsids” as a distinct embodiments from “extracellular vesicle-enclosed capsids”, confirming the export compartment of claim 1 operates without a surrounding lipid bilayer into which VSVG would integrate as a classical transmembrane fusogen. Applicant argues the examiner has not identified any reasoning to reach at the presently claimed invention.
The above argument has been fully considered but deemed unpersuasive. As discussed above, the recitation of “as a fusogenic membrane glycoprotein” does not provide any structural limitation to VSVG according to the present specification. In response to applicant's argument that the claimed system must enables direct cytoplasmic delivery by bypassing the endosome-to-lysosome pathway, a recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. In the present instance, this function appears to result from “decorating the VSVG” as described in example 3. And Figure 26 appears to be prior art known feature of VSVG “previous reports suggested that VSVG is able to induce direct fusion between membranes (see paragraph [0424]). As such, expressing a epitope of VSVG on the outer surface of the capsid as rendered obvious by the combination of prior art would meet the claim limitation. With regard to the argument directed to [0105] establishes that the claimed system encompasses “non-enveloped capsids” as a distinct embodiments from “extracellular vesicle-enclosed capsids”, it is noted that the features upon which applicant relies is not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). In response to the argument that the delivery system operates without a surrounding lipid bilayer into which VSVG would integrate as a classical transmembrane fusogen, it is not persuasive because there is no limitation in claim 1 that excludes the surrounding of lipid bilayer. Moreover, claim 35 in fact recites “wherein the engineered delivery system further comprises an exosome, wherein the capsid is contained in the exosome.” In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, an ordinary skilled in the art reading Fanning would recognize that VSVG are routinely used as a protein tag for isolation and characterization of the protein of interest as demonstrated by Fanning et al., and Malone teaches using VSV envelope protein to target cells of interest for delivery (paragraph [0250] and [0254]). The ordinary skilled in the art would recognize VSVG tagging, would have additional advantage of fusogenic delivery of encapsulated contents as taught by Lin et al. Therefore, for reason discussed in previous office action and set forth above, this rejection is still considered protein and thus maintained.
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CELINE X QIAN whose telephone number is (571)272-0777. The examiner can normally be reached M-F (8-4:00).
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/CELINE X QIAN/ Primary Examiner, Art Unit 1637
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