CTNF 17/646,988 CTNF 101343 DETAILED ACTION Notice of Pre-AIA or AIA Status 07-03-aia AIA 15-10-aia 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 08-25-01 AIA Applicant’s election without traverse of Group I in the reply filed on December 23, 2024 is acknowledged. Drawings 06-22 AIA The drawings are objected to because at least one drawing submitted in file is in color without granted petition to accept color drawings . Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance. Appropriate correction is required. 06-24-01 AIA Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification: The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee. Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2). Specification 07-29 AIA The disclosure is objected to because of the following informalities: The use of the term CytoSelect™, , Image-iT™, and Amicon® which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term. Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks . Appropriate correction is required. Claim Rejections - 35 USC § 112 Indefiniteness 07-30-02 AIA 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. 07-34-01 Claims 6 is 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. 07-34-10 AIA Regarding claim 6 , the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). Clarification and/or amendment is required. 07-34-01 Claims 8 is 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. Regarding claim 8, the claim recites “Table 2 or Table 11”. MPEP § 2173.05(s) states that “[w]here possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table ‘is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claims. Incorporation by reference is a necessity doctrine, not for applicant's convenience.’ Ex parte Fressola , 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993)." The instant claim is not in exceptional circumstances because the material can be practically defined using the SEQ ID NOs present in the tables. Therefore, this issue could be overcome by amending the claim to refer to the specific SEQ ID NOs presented in Table 2 or Table 11. Clarification and/or amendment is required. Claim Rejections - 35 USC § 102 07-07-aia AIA 07-07 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 – 07-08-aia AIA (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. 07-15-aia AIA Claim(s) 1, 2-5, 7-9, 21, and 23 is/are rejected under 35 U.S.C. 102 (a)(1) as being anticipated by Wiklander et al. (US 2019 0388347 A1; cited on IDS filed Jun 7, 2023) . Regarding claim 1, Wiklander discloses a method for loading an extracellular vesicle (EV) with a pharmacological agent (reads on cargo molecule) comprising contacting an EV to a pharmacological agent (reads on cargo molecule) and a cell-penetrating peptide (CPP) (¶ 5; ¶ 6; claim 1). Wiklander discloses that the pharmacological agent (reads on cargo molecule) and the CPP may be covalently conjugated into a single conjugate (reads on binding complex) (¶ 6; claim 2). Regarding claims 2 and 21, Wiklander discloses that the CPP can be covalently coupled to the cargo molecule by an amide bond (¶ 31; claim 3). Regarding claims 3 and 4, Wiklander discloses the CPP can be covalently coupled to the cargo molecule by an amide or disulfide bond. A disulfide bond is a type of cleavable linker, which becomes cleaved upon exposure of the binding complex to the appropriate cleaving agent such as a chemical agent (e.g. dithiothreitol for reducing a disulfide bond linkage) (page 12, lines 1-4 of the specification of instant application as filed). The CPP coupled to the cargo molecule by disulfide bond can be easily cleaved inside cells because intracellular environment is generally reducing, maintained by agents like glutathione and thioredoxin during in vivo evaluation like Examples 2-4 of Wiklander. Regarding claims 5 and 23, Wiklander discloses that the cargo molecule can be an anti-HGF (Hepatocyte Growth Factor) antibody (¶ 34). The anti-HGF antibody, like all other antibodies, is a glycoprotein (Patel et al. 2023; cited on PTO-892). Regarding claim 7, Wiklander discloses that the EV can comprise a targeting moiety (targeting agent) that targets the EV to a tissue, an organ, or cell type of interest (¶ 36; claim 13). Regarding claims 8 and 9, Wiklander discloses that the CPP can be VP22 (¶ 35; claim 12). VP22 is listed in Table 11 of instant application . Claim Rejections - 35 USC § 103 07-20-aia AIA 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. 07-23-aia AIA 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. 07-20-02-aia AIA 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. 07-21-aia AIA Claim (s) 1, 2-5, 7-9, and 21-26 is/are rejected under 35 U.S.C. 103 as being unpatentable over Pillay et al. (WO 2017 083423 A1; cited on PTO-892) in view of Wiklander et al. (US 2019 0388347 A1; cited on IDS filed Jun 7, 2023) . Pillay discloses a method of enhancing the permissiveness of a target cell to adeno-associated virus (AAV) infection by introducing an exosome (a type of EV) comprising a permissive-enhancing polypeptide (reads on cargo molecule) and a protein transduction domain (PTD, also known as a CPP) (page 7, lines 1-4; page 59, lines 5-8). Pillay discloses that the CPP can be covalently linked to the cargo molecule (page 59, lines 11-15), reads on instant claim 1. Pillay discloses that the CPP can be covalently coupled to the cargo molecule by a peptide bond (reads on amide bond) (page 59, lines 11-15), reads on instant claims 2 and 21, Pillay discloses the CPP can be covalently coupled to the cargo molecule by a disulfide bond. A disulfide bond is a type of cleavable linker, which becomes cleaved upon exposure of the binding complex to the appropriate cleaving agent such as a chemical agent (e.g. dithiothreitol for reducing a disulfide bond linkage) (page 12, lines 1-4 of the specification of instant application as filed), reads on instant claims 3 and 4. Pillay discloses that the cargo molecule can be a blocking agent such as an antibody (reads on glycoprotein) (page 3, lines 8-10), reads on instant claims 5 and 23. Pillay discloses that the CPP can be VP22 (page 59; lines16-21). VP22 is listed in Table 11 of instant application, reads on instant claims 8 and 9., Pillay discloses that the CPP can be YARA (SEQ ID No: 121; page 59, lines 28-30), reads on instant claim 22. Pillay discloses that the CPP (YARA) and the cargo molecule (protein) can be covalently bonded by an amide bond, reads on instant claims 24-26. Regarding claims 7, Pillay does not disclose a targeting agent. Wiklander is discussed above. It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use a targeting agent that targets the EV of Pillay to a cell type, organ, or tissue, wherein the EV is contacted with the cargo molecule coupled to the CPP. A person of ordinary skill in the art would have been motivated to make these modifications and reasonably would have expected success because Wiklander teaches the EV can comprise a targeting agent that targets the EV to a tissue, an organ, or cell type of interest . 07-21-aia AIA Claim (s) 6 is/are rejected under 35 U.S.C. 103 as being unpatentable over Pillay et al. (WO 2017 083423 A1; cited on PTO-892) in view of 김 (Kim) (KR 2019 0083503 A; cited on PTO-892; all citations from the machine translation) . Pillay is discussed above. Pillay does not disclose the cargo molecule is a detectable agent or medical imaging agent. Kim discloses a drug delivery system (DDS) comprising a cell targeting domain, a drug release domain (reads on CPP) and a target drug (reads on cargo molecule) (page 2, lines 9-12). Kim discloses that the cargo molecule can be a diagnostic or imaging agent such as a fluorescent label (page 8, lines 21-23). It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use an imaging agent as the cargo molecule of Pillay that is coupled to the CPP and contacted with the EV. A person of ordinary skill in the art would have been motivated to make these modifications and reasonably would have expected success because Kim teaches the cargo molecule of DDS can be an imaging agent for in vivo imaging . 07-21-aia AIA Claim (s) 27 is/are rejected under 35 U.S.C. 103 as being unpatentable over Pillay et al. (WO 2017 083423 A1; cited on PTO-892) in view of Strieker et al. (US 2015 0297742 A1; cited on PTO-892) . Pillay is discussed above. Pillay does not disclose two or more CPPs are covalently or non-covalently coupled to the cargo molecule. Strieker discloses a conjugate comprising a protein (cargo molecule) and one or more multivalent CPP(s) comprising at least two CPPs. (abstract; claim 1). Striker discloses that the multivalent CPPs can be covalently attached to the cargo molecule (claim 1) to improve the pharmacokinetics and/or internalization of biologically or clinically relevant and/or therapeutic proteins, in particular to improve their use for the diagnosis and treatment diseases (¶ 7). It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use at least two CPPs to covalently coupled to the cargo molecule of Pillay that is coupled to the CPP and contacted with the EV. A person of ordinary skill in the art would have been motivated to make these modifications and reasonably would have expected success because Strieker teaches at least two CPPs can be covalently attached to the cargo molecule to improve the pharmacokinetics and/or internalization of biologically or clinically relevant and/or therapeutic proteins, in particular to improve their use for the diagnosis and treatment of diseases . 07-21-aia AIA Claim (s) 1, 2-9, 21, and 23 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wiklander et al. (US 2019 0388347 A1; cited on IDS filed Jun 7, 2023) in view of 김 (Kim) (KR 2019 0083503 A; cited on PTO-892; all citations from the machine translation) . Wiklander is discussed above. Regarding claim 6, Wiklander does not disclose the cargo molecule is a detectable agent or medical imaging agent. Kim is discussed above. It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use an imaging agent as the cargo molecule of Wiklander that is coupled to CPP and contacted with the EV. A person of ordinary skill in the art would have been motivated to make these modifications and reasonably would have expected success because Kim teaches the cargo molecule of DDS can be an imaging agent for in vivo imaging . 07-21-aia AIA Claim (s) 1, 2-5, 7-9, and 21-26 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wiklander et al. (US 2019 0388347 A1; cited on IDS filed Jun 7, 2023) in view of Pillay et al. (WO 2017 083423 A1; cited on PTO-892) . Wiklander is discussed above. Regarding claims 22, and 24-26, Wiklander does not disclose the CPP is YARA. Pillay is discussed above. It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use YARA as the CPP of Wiklander that is coupled to the cargo molecule and contacted with the EV. A person of ordinary skill in the art would have been motivated to make these modifications and reasonably would have expected success because Pillay teaches YARA can be used as a CPP and Wiklander teaches the CPP can be covalently bonded to the cargo protein such as protein by an amide bond . 07-21-aia AIA Claim (s) 1, 2-5, 7-9, 21, 23, and 27 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wiklander et al. (US 2019 0388347 A1; cited on IDS filed Jun 7, 2023) in view of Strieker et al. (US 2015 0297742 A1; cited on PTO-892) . Wiklander is discussed above. Regarding claim 27, Wiklander does not disclose two or more CPPs are covalently or non-covalently coupled to the cargo molecule. Strieker is discussed above. It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use at least two CPPs to covalently coupled to the cargo molecule of Wiklander that is coupled to CPP and contacted with the EV. A person of ordinary skill in the art would have been motivated to make these modifications and reasonably would have expected success because Strieker teaches at least two CPPs can be covalently attached to the cargo molecule to improve the pharmacokinetics and/or internalization of biologically or clinically relevant and/or therapeutic proteins, in particular to improve their use for the diagnosis and treatment of diseases . Double Patenting 08-33 AIA 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 conflicting claims 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); 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 nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined 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 § 2146 et seq. 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 filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13. The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual 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 www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer. Claims 1-9 and 21-26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 6-9, and 14-17 of copending Application No. 18/047,741. Although the conflicting claims are not identical, they are not patentably distinct from each other because claims 1-9 of the instant application is/are generic to all that is recited in claims 1, 4, 6-9, and 14-17 of copending Application No. 18/047,741. That is, claims 1, 4, 6-9, and 14-17 of the ‘741 falls entirely within the scope of claims 1-9 or, in other words, claim 1-9 is anticipated by claims 1, 4, 6-9, and 14-17 of the ‘741. Regarding claim 1, claim 1 of the ‘741 recites a method for loading a vesicle with a cargo molecule comprising CD24, or a biologically active fragment or variant of CD24, the method comprising contacting the vesicle with a binding complex, wherein the binding complex comprises the cargo molecule and a cell penetrating polypeptide (CPP) covalently or non-covalently coupled to the cargo molecule, and wherein the binding complex becomes internalized by the vesicle, associated with the vesicle, or a combination thereof to produce a loaded vesicle. Claim 4 of the ‘741 recites the vesicle is an extracellular vesicle (EV) or lipid vesicle (LV). The cargo molecule comprises CD24 which is a cell surface protein (sialoglycoprotein). Regarding claim 2, claim 6 of the ‘741 recites the CPP is covalently coupled to the cargo molecule by a disulfide bond, an amide bond, a chemical bond formed between a sulfhydryl group and a maleimide group, a chemical bond formed between a primary amine group and an N-Hydroxysuccinimide (NHS) ester, a chemical bond formed via Click chemistry, or other covalent linkage. Regarding claims 3 and 4, claims 7 and 17 of the ‘741 recite the CPP is covalently coupled to the cargo molecule by a cleavable linker and after the vesicle is loaded with the binding complex, the cargo molecule is uncoupled from the binding complex. Regarding claim 5, claim 14 of the ‘741 recites the cargo molecule includes a further molecule fused directly or indirectly to the CD24 or the biologically active fragment or variant thereof, wherein the further molecule is selected from among a small molecule, a polyimide, a protein, a polypeptide, a nucleic acid, an antibody or antibody-fragment, a lipoprotein, a carbohydrate, or a glycoprotein. Regarding claim 6, claim 15 of the ‘741 recites the cargo molecule further comprises a detectable agent or medical imaging agent or is attached to a detectable or medical imaging agent, such as a fluorescent compound to serve as a marker, dye, tag, or reporter. Regarding claim 7, claim 16 of the ‘741 recites the vesicle further comprises a targeting agent that targets the vesicle to a cell type, organ, or tissue. Regarding claim 8, claim 8 of the ‘741 recites the CPP is one listed in Table 2. The Table 2 of the ‘741 is a part of Table 2 or Table 11 of instant application. Regarding claim 9, claim 9 of the ‘741 recites the CPP is selected from among the following: Tat, Antennapedia, VP22, CaP, YopM, Artificial protein B1, 30Kc19, engineered +36 GFP, and naturally supercharged human protein. Regarding claim 21, claim 6 of the ‘741 recites the CPP can be covalently coupled to the cargo molecule by amide bond. Regarding claim 22, claim 8 of the ‘741 recites the CPP can be YARA. Regarding claim 23, claim 1 recites the cargo molecule can be CD24. CD24 is a cell surface protein (sialoglycoprotein). Regarding claims 24-26, claims 1, 6, and 8 of the ‘741 recites the CPP can be YARA and the cargo molecule can be a protein, wherein the CPP is covalently bonded to the protein by an amide bond. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented. 08-37 AIA Claim s 1-9 and 21-27 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim s 1, 4, 6-9, and 14-17 of copending Application No. 18/047,741 (cited on IDS filed Jun 7, 2023) in view of Strieker et al. (US 2015 0297742 A1; cited on PTO-892) . Regarding claims 1-9 and 21-26, see the discussion above. The claims of the ‘741 are discussed above. Claims of the ‘741 do not recite two or more CPPs are covalently or non-covalently coupled to the cargo molecule. Strieker is discussed above. It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use at least two CPPs to covalently coupled to the cargo molecule of the ‘741. A person of ordinary skill in the art would have been motivated to make these modifications and reasonably would have expected success because Strieker teaches at least two CPPs can be covalently attached to the cargo molecule to improve the pharmacokinetics and/or internalization of biologically or clinically relevant and/or therapeutic proteins, in particular to improve their use for the diagnosis and treatment diseases . This is a provisional nonstatutory double patenting rejection. 08-37 AIA Claim s 1-9 and 21-27 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim s 1, 3, 4, 6, 11-13, and 21-26 of copending Application No. 17/654,154 in view of Pillay et al. (WO 2017 083423 A1; cited on PTO-892) and 김 (Kim) (KR 2019 0083503 A; cited on PTO-892; all citations from the machine translation). Regarding claim 1, claim 1 of the ‘154 recites a method for loading a pre-formed liposome with a cargo molecule, comprising contacting the pre-formed liposome with a binding complex, wherein the binding complex comprises the cargo molecule and a cell penetrating polypeptide (CPP) covalently coupled to the cargo molecule, wherein the cargo molecule comprises a protein or a polypeptide, and wherein the binding complex becomes internalized by or associated with the pre-formed liposome. Claims of the ‘154 do not disclose an EV. The ‘154 discloses the lipid vesicle (liposome) used in this invention may be an artificial EV (¶ 58). In addition to the teachings of Pillay discussed above, Pillay discloses the vesicle can be exosome or liposome (page 7, lines 2-4). It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use EV such as exosome instead of liposome of the ‘154. A person of ordinary skill in the art would have been motivated to make these modifications and reasonably would have expected success because Pillay teaches liposomes and exosomes are art recognized equivalents and it is obvious to substitute one art recognized equivalent for another absent evidence of unexpected results. Regarding claim 2, claim 3 of the ‘154 recites the CPP is covalently coupled to the cargo molecule by a disulfide bond, an amide bond, a chemical bond formed between a sulfhydryl group and a maleimide group, a chemical bond formed between a primary amine group and an N-Hydroxysuccinimide (NHS) ester, a chemical bond formed via Click chemistry, or other covalent linkage. Regarding claims 3 and 4, claim 4 of the ‘154 recites the CPP is covalently coupled to the cargo molecule by a cleavable linker. The claim 6 of the ‘154 recites further comprising uncoupling the cargo molecule and CPP of the binding complex by cleaving the cleavable linker after the binding complex becomes internalized by or associated with the pre-formed liposome. Regarding claims 5 and 23, the claim 23 of the ‘154 recites cargo molecule is a protein selected from the group consisting of an enzyme, a membrane-bound protein, a lipoprotein, and a glycoprotein. Regarding claim 6, claims of the ‘154 do not recite the cargo molecule is a detectable agent or medical imaging agent, or is attached to a detectable or medical imaging agent, such as a fluorescent compound to serve as a marker, dye, tag, or reporter. Kim is discussed above. It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use an imaging agent as the cargo molecule of the ‘154. A person of ordinary skill in the art would have been motivated to make these modifications and reasonably would have expected success because Kim teaches the cargo molecule of DDS can be an imaging agent for in vivo imaging. Regarding claim 7, claim 11 of the ‘154 recites the pre-formed liposome further comprises a targeting agent that targets the pre-formed liposome to a cell type, organ, or tissue. Regarding claim 8, claim 12 of the ‘154 recites the CPP is one listed in Table 2 or Table 11. The Table 11 is not in the ‘154 but Table 2 of the ‘154 is a part of Table 2 or Table 11 of instant application. Regarding claim 9, claim 13 of the ‘154 recites the CPP is selected from among the following: Tat, Antennapedia, VP22, CaP, YopM, Artificial protein Bl, 3OKcl9, engineered +36 GFP, naturally supercharged human protein, and gamma-AA peptide. Regarding claim 21, claim 21 of the ‘154 recites the CPP is covalently coupled to the cargo molecule by an amide bond. Regarding claim 22, claim 22 of the ‘154 recites the CPP is YARA. Regarding claim 24, claim 24 of the ‘154 recites the CPP is YARA and the cargo molecule is a protein. Regarding claims 25 and 26, claim 25 of the ‘154 recites the CPP is YARA and the cargo molecule is a protein, wherein the CPP is covalently bonded to the protein by an amide bond. Regarding claim 27, claim 26 of the ‘154 recites two or more CPPs are covalently coupled to the cargo molecule . This is a provisional nonstatutory double patenting rejection. Conclusion Any inquiry concerning this communication or earlier communications from the examiner should be directed to JONG HWAN BAEK whose telephone number is (571)272-0670. The examiner can normally be reached Mon - Thu, 9 am - 3 pm ET. Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Michael G Hartley can be reached at 571-272-0616. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /JONG HWAN BAEK/Examiner, Art Unit 1618 /Nissa M Westerberg/Primary Examiner, Art Unit 1618 Application/Control Number: 17/646,988 Page 2 Art Unit: 1618 Application/Control Number: 17/646,988 Page 3 Art Unit: 1618 Application/Control Number: 17/646,988 Page 4 Art Unit: 1618 Application/Control Number: 17/646,988 Page 5 Art Unit: 1618 Application/Control Number: 17/646,988 Page 6 Art Unit: 1618 Application/Control Number: 17/646,988 Page 7 Art Unit: 1618 Application/Control Number: 17/646,988 Page 8 Art Unit: 1618 Application/Control Number: 17/646,988 Page 9 Art Unit: 1618 Application/Control Number: 17/646,988 Page 10 Art Unit: 1618 Application/Control Number: 17/646,988 Page 11 Art Unit: 1618 Application/Control Number: 17/646,988 Page 12 Art Unit: 1618 Application/Control Number: 17/646,988 Page 13 Art Unit: 1618 Application/Control Number: 17/646,988 Page 14 Art Unit: 1618 Application/Control Number: 17/646,988 Page 15 Art Unit: 1618 Application/Control Number: 17/646,988 Page 16 Art Unit: 1618 Application/Control Number: 17/646,988 Page 17 Art Unit: 1618 Application/Control Number: 17/646,988 Page 18 Art Unit: 1618 Application/Control Number: 17/646,988 Page 19 Art Unit: 1618