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 .
Status of Application, Amendments and/or Claims
The amendment of 21 April 2026 has been entered in full. Claims 1, 2, 8, 10, 15, and 16 are amended. Claims 5-7 and 18-20 are cancelled. Claims 21-24 are added.
Claims 1-4, 8-17, and 21-24 are under consideration in the instant application.
Withdrawn Objections and/or Rejections
1. The Sequence Listing Requirement deficiencies set forth at pages 2-7 of the previous Office Action of 22 October 2025 are withdrawn in view of Applicant’s amendments to the instant specification and submission of a new sequence listing (21 April 2026).
2. The objections to claims 2, 10, and 16 as set forth at page 7 of the previous Office Action of 22 October 2025 are withdrawn in view of the amended claims (21 April 2026).
3. The rejections of claims 8, 10, and 15 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph as set forth at pages 7-8 of the previous Office Action of 22 October 2025 are withdrawn in view of the amended claims (21 April 2026).
4. The rejection of claims 1-6 and 8-17 under 35 U.S.C. 103 as being unpatentable over Wiklander et al. (US 2019/0388347 or WO 2018/011153), Emmanuel et al. (US 2022/0333132; priority to 03 September 2019), and Arber et al. (US 2021/0322483; priority to 16 April 2020) as set forth at pages 16-19 of the previous Office Action of 22 October 2025 is withdrawn in view of the amended and cancelled claims (21 April 2026). Specifically, Wiklander et al., Emmanuel et al., and Arber et al. do not teach a cleavable linker or exposing the pharmacological agent/CPP complex to radiation for cleavage.
5. The rejection of claim 7 under 35 U.S.C. 103 as being unpatentable over Wiklander et al. (US 2019/0388347 or WO 2018/011153), Emmanuel et al. (US 2022/0333132; priority to 03 September 2019), Arber et al. (US 2021/0322483; priority to 16 April 2020), and Narasimhaswamy et al. (US 2010/0233084) as set forth at pages 19-20 of the previous Office Action of 22 October 2025 is withdrawn in view of the amended and cancelled claims (21 April 2026). Narasimhaswamy et al. do not teach exposing a pharmacological agent/CPP complex to radiation for cleavage.
New Claim Objections
6. Claims 1, 23, and 24 are objected to because of the following informalities:
6a. In claim 1, subparts (1)-(2) should be renumbered utilizing “(i)-(ii)” or “(a)-(b)” so as to prevent confusion with claim numbering.
6b. In claim 23, line 1 recites two articles before “biologically active fragment” (wherein the a biologically active”). Please note that this issue could be overcome, for example, by removing the word “a”.
6c. In claims 23 and 24, the CD24 sequences are amino acid sequences, not sequence identifiers (SEQ ID NO:). Thus, for clarity, the claims should be amended to recite, for example, "the biologically active fragment or variant of CD24 comprises [or, consists of, etc.] the amino acid sequence of SEQ ID NO: 36 or 38-41” (claim 23); and “the biologically active fragment or variant of CD24 comprises [or, consists of, etc.] the amino acid sequence of SEQ ID NO: 36 or an amino acid sequence at least 60% identical to SEQ ID NO: 36”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
7. Claim 17 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 17 recites the method of claim 1, wherein after the vesicle is loaded with the binding complex, the cargo molecule is uncoupled from the binding complex.
However, claim 1 recites a method for loading a vesicle with a cargo molecule comprising CD24, or a biologically active fragment or variant of CD24 comprising at least 60% sequence identity to the amino acid sequence of human mature CD24 polypeptide, the method comprising contacting the vesicle with a binding complex, wherein the binding complex comprises the cargo molecule and a cell penetrating peptide (CPP) covalently coupled to the cargo molecule by a cleavable linker, the method comprising (1) contacting the vesicle with the binding complex, wherein the binding complex becomes internalized by the vesicle, associated with the vesicle, or a combination thereof, and (2) exposing the binding complex to radiation to cleave the cargo molecule from the CPP to produce a loaded vesicle.
Amended claim 1, step 2, now recites that the binding complex (comprising the cargo molecule and CPP) is exposed to radiation to cleave the cargo molecule from the CPP. Therefore, the cargo molecule is uncoupled from the binding complex in the last step of claim 1. In turn, claim 17 (which recites the same step) fails to further limit the subject matter of the claim upon which it depends.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Maintained Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
8. Claims 1-4, 8-17, and 21-24 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. The basis for this rejection is set forth in detail for claims 1-17 at pages 9-15 of the previous Office Action of 22 October 2025.
Amended claim 1 is directed to a method for loading a vesicle with a cargo molecule comprising CD24, or a biologically active fragment or variant of CD24 comprising at least 60% sequence identity to the amino acid sequence of human mature CD24 polypeptide, the method comprising contacting the vesicle with a binding complex, wherein the binding complex comprises the cargo molecule and a cell penetrating peptide (CPP) covalently coupled to the cargo molecule by a cleavable linker, the method comprising (1) contacting the vesicle with the binding complex, wherein the binding complex becomes internalized by the vesicle, associated with the vesicle, or a combination thereof, and (2) exposing the binding complex to radiation to cleave the cargo molecule from the CPP to produce a loaded vesicle.
New claims 24 recites that the biologically active fragment or variant of CD24 is SEQ ID NO. 36 or at least 60% sequence identity of SEQ ID NO. 36.
(i) At page of the Response of 21 April 2026, Applicant argues that claim 1 has been amended to recite “a biologically active fragment or variant of CD24 comprising at least 60% sequence identity to the amino acid sequence of human mature CD24 polypeptide”. Applicant indicates that at page 21, lines 7-14, the full-length 80-amino acid sequence of human CD24 is the following: MGRAMVARLGLGLLLLALLLPTQIYSSETTTGTSSNSSQSTSNSGLAPNPTNATTKAAGGALQSTASLFVVSLSLLHLYS (SEQ ID NO: 35) (wherein the underlined amino acids 1-26 are the N-terminal signal peptide; the bolded amino acids 27-59 are the mature peptide; and the remaining 60-80 are the pro-peptide (cleaved). Applicant submits that in view of the teachings of the specification and the amendment to claim 1, the skilled artisan would appreciate the scope of the biologically active fragment or variant of CD24. Applicant contends that the skilled artisan would start with human CD24, particularly the mature peptide section, and make modifications to produce different fragments or variants.
Applicant’s arguments and claim amendments have been fully considered but are not found to be persuasive. The broad brush discussion of a skilled artisan identifying and generating CD24 fragments or variants having at least 60% sequence identity to the human mature CD24 amino acid sequence (SEQ ID NO: 36) does not constitute a disclosure of a representative number of members. The specification and prior art do not provide adequate written description and evidence that the inventors had possession of the claimed genus of CD24 fragments or variants that have at least 60% sequence identity to the human mature CD24 amino acid sequence (SEQ ID NO: 36) and the function of being biologically active at the time the application was filed. There is no identification of any particular sequence or structure of the CD24 protein that must be conserved in order to provide the required function of being biologically active. MPEP §2163(I)(A) states that “[a]n invention described solely in terms of a method of making and/or its function may lack written descriptive support where there is no described or art-recognized correlation between the disclosed function and the structure(s) responsible for the function.” Furthermore, the numerous references cited by the Examiner at pages 12-13 of the previous Office Action of 22 October 2025 (Bork, Skolnick et al., Doerks et al., Smith et al., Brenner, Bork et al., Tokuriki et al., Fenton et al., Bhattacharya et al., Guo et al., Liu et al., and Tan et al.) in the written description rejection provide evidence that the prior art recognizes that protein function cannot be predicted from structure alone.
Applicant is reminded that an adequate written description of a chemical invention also requires a precise definition, such as by structure, formula, chemical name, or physical properties, and not merely a wish or plan for obtaining the chemical invention claimed. See, e.g., Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 927, 69 USPQ2d 1886, 1894-95 (Fed. Cir. 2004) (The patent at issue claimed a method of selectively inhibiting PGHS-2 activity by administering a non-steroidal compound that selectively inhibits activity of the PGHS-2 gene product, however the patent did not disclose any compounds that can be used in the claimed methods. While there was a description of assays for screening compounds to identify those that inhibit the expression or activity of the PGHS-2 gene product, there was no disclosure of which peptides, polynucleotides, and small organic molecules selectively inhibit PGHS-2. The court held that "[w]ithout such disclosure, the claimed methods cannot be said to have been described."). See also MPEP 2163(II)(A)(3)(a), Centocor Orth Biotech, Inc. v. Abbott Labs, 636 F.3d 1341 (Fed. Cir. 2011), and Regents of the Univ. of Cal. v. Eli Lilly & Co., Inc., 119 F.3d 1559, 1566 (Fed. Cir. 1997).
In the instant application, the skilled artisan cannot envision the detailed chemical structure of the genus of fragments and variants of human mature CD24 comprising at least 60% sequence similarity to a human mature CD24 polypeptide of the encompassed claims, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The fragment or variant sequence that is biologically active is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. A “mere wish or plan” to obtain the claimed invention is not sufficient (Centocor Orth Biotech, Inc. v. Abbott Labs, 636 F.3d 1341 (Fed. Cir. 2011); Regents of the Univ. of California, 119 F.3d at 1566).
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.
9. Claims 1-4, 8-17, and 21-24 are rejected under 35 U.S.C. 103 as being unpatentable over Wiklander et al. (US 2019/0388347 (cited on the IDS of 07 June 2023) or WO 2018/011153), Emmanuel et al. (US 2022/0333132; priority to 03 September 2019), Arber et al. (US 2021/0322483; priority to 16 April 2020), and Baccile et al. (Tetrahedron Lett 53(15): 1933-1935, 2012). It is noted that US 2019/0388347 and WO/2018011153 (of Wiklander et al.) have the same disclosure. Thus, for brevity, relevant portions of US 2019/0388347 will be cited below.
Wiklander et al. teach a method for extracellular vesicle (EV) loading comprising the step of exposing a population of EVs to at least one pharmacological agent cargo and at least one cell penetrating polypeptide (CPP), meeting the limitations of instant claims 1 and 4 (page 1, [0006]; page 4, [0029]). Wiklander et al. state that the terms “extracellular vesicle”, “EV”, and “exosome” are interchangeable and may relate to any type of lipid-based structure (with vesicular morphology or with any other type of suitable morphology) that can act as a delivery or transport vehicle for pharmacological agents of interest, meeting the limitations of instant claim 2 (page 3, [0024]). Wiklander et al. disclose that the pharmacological agent and the CPP may be covalently conjugated into a single conjugate, meeting the limitations of instant claim 1 (page 1, [0006]). Wiklander et al. teach that the CPP and the pharmacological agent may be covalently conjugated by a variety of different bonds or linkers (page 5, [0031]). Wiklander et al. teach that the CPP may selected from a large variety of CPPs, including Tat, VP22, B1, and “Arg9” (which consists of nine arginine residues), meeting the limitations of instant claims 8-12 (pages 3-4, [0026]; page 6, column 1, [0035]). Wiklander et al. disclose that the EV may comprise at least one targeting moiety displayed on the surface of the EV to further enhance its therapeutic potential by targeting a tissue, an organ, or cell type of interest, meeting the limitations of instant claim 16 (page 7, [0036]).Wiklander et al. indicate that the pharmacological agent may be released from the CPP, meeting the limitations of instant claims 1 and 17 (page 1, [0009], page 5, [0033]). Lastly, Wiklander et al. indicate that the pharmacological agent cargo encompasses a wide variety of different types of molecules, including peptides (page 1, [0006]).
(I) First, Wiklander et al. do not teach that the pharmacological agent cargo comprises CD24. Wiklander et al. also do not teach that the pharmacological agent cargo includes a further molecule fused directly or indirectly to the CD24.
Emmanuel et al. teach non-cell particles comprising CD24 on an exposed surface of the particle (wherein the particles comprise a lumen comprising a cytosol, wherein the lumen is surrounded by a lipid bilayer), meeting the limitations of instant claims 1 and 2 (page 1, [0006]; page 2, [0018-0020]; page 8, [0083]; page 17, [0183]; page 29, [0326-00335]). Emmanuel et al. disclose that the CD24 is recombinant and may comprise transmembrane amino acids, meeting the limitations of instant claims 3, 13, and 14 (page 1, [0008, 0010]; page 6, [0068]; page 10, [0114-0115]); page 14, [0146]). Emmanuel et al. teach that CD24 may be modified to contain a functional group at its distal end, such as a histidine tag or biotin, meeting the limitations of instant claims 14 and 15 (page 17, [0177-0178]). It is noted that Emmanuel et al. teach that CD24 may comprise the amino acid sequence of SEQ ID NO: 1, 2, or 3 (page 1, [0007, 0009]; page 6, [0068]; page 11, [0122]; bottom of page 75). The amino acid sequence of SEQ ID NO: 1 of Emmanuel et al. is the full human CD24 sequence (bottom of page 75). It is noted that the amino acid sequence of SEQ ID NO: 3 of Emmanuel et al. comprises a sequence that is 100% identical to the amino acid sequence of SEQ ID NO: 36 of the instant application, meeting the limitations of instant claims 1, 23, and 24 (see sequence alignment, below).
Qy= instant SEQ ID NO: 36
Db= SEQ ID NO: 3 of Emmanuel et al.
Title: US-18-047-741A-36
Perfect score: 163
Sequence: 1 SETTTGTSSNSSQSTSNSGLAPNPTNATTKAAG 33
Scoring table: BLOSUM62
Gapop 10.0 , Gapext 0.5
Searched: 1 seqs, 54 residues
Total number of hits satisfying chosen parameters: 1
Minimum DB seq length: 0
Maximum DB seq length: inf
Post-processing: Minimum Match 0%
Maximum Match 100%
Listing first 50 summaries
Database : US-17-639-843-3.fasta:*
RESULT 1
US-17-639-843-3
Query Match 100.0%; Score 163; DB 1; Length 54;
Best Local Similarity 100.0%;
Matches 33; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 SETTTGTSSNSSQSTSNSGLAPNPTNATTKAAG 33
|||||||||||||||||||||||||||||||||
Db 1 SETTTGTSSNSSQSTSNSGLAPNPTNATTKAAG 33
Similarly, Arber et al. also teach a composition comprising cell-derived particles (such as extracellular vesicles) presenting heterologous CD24 (abstract; page 1, [0003]; page 6, [0130, 0133]; SEQ ID NO: 9, page 2, [0028]). Arber et al. disclose a method of producing cell-derived particles comprising modifying cells to present CD24 and isolating the cell-derived particles from a biological sample (page 2, [0020]).
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to modify the method for extracellular vesicle (EV) loading comprising the step of exposing a population of EVs to a complex comprising at least one pharmacological agent cargo and at least one cell penetrating polypeptide (CPP) as taught by Wiklander et al. by utilizing CD24 as the pharmacological agent cargo in the complex with CPP as taught by Emmanuel et al. and Arber et al. The person of ordinary skill in the art would have been motivated to make that modification because (i) CD24 interacts with Siglec 10 on macrophages to inhibit phagocytosis (Emmanuel et al., page 6, [0068-0069]); (ii) CD24 suppresses hyperactivity of the immune system and prevents cytokine storm (Arber et al., page 1, [0003, 0009-0010]; page 5, [0112]); and (iii) the methods of Wiklander et al. (using CPP for vesicle loading) overcome common problems associated with loading pharmacological agents into EVs for therapeutic applications (page 1, [0003-0005]). One skilled in art also would have been motivated to complex CD24 with a CPP for vesicle loading because Emmanuel et al. teach that any variety of methods may be used to expose CD24 on the surface of a non-cell particle such as to display, present, express or link (directly or indirectly) CD24 to the surface, so long as CD24 retains the ability to bind Siglec-10 and/or has the biological activity of evading phagocytosis (page 8, [0086]). The person of ordinary skill in the art reasonably would have expected success because Wiklander et al. successfully load EVs by exposing a population of EVs to a complex comprising at least one pharmacological agent cargo and at least one cell penetrating polypeptide (CPP) (see Examples 1-7 of Wiklander et al.) at the time the invention was made. Additionally, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense (KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007)).
(II) Second, Wiklander et al. do not teach (i) that the linker covalently linking the CPP and the pharmacological agent is a photo-cleavable linker or (ii) a step of exposing the pharmacological agent/CPP complex to radiation to cleave the pharmacological agent.
Baccile et al. teach the utilization of photocleavable linkers to transiently conjugate CPP to bioactive peptides (page 1933, column 1, 3rd paragraph). Baccile et al. indicate that photocleavable linkers can be cleaved with spatial and temporal control (page 1933, column 1, 2nd paragraph). Baccile et al. disclose that CPPs, such as TAT and MyrK4, can be linked to peptide substrates for Abl kinase and CaM kinase II (cargo molecules) via a photocleavable linker comprising an amide bond (page 1934, scheme 3, Table 1). Baccile et al. teach that the CPP transports the cargo molecule into cells and the cargo molecule is released by exposing the binding complex to UV light (page 1934, column 2, 2nd paragraph; page 1933, Figure 1; page 1935, column 1, 1st paragraph).
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to modify the method for extracellular vesicle (EV) loading comprising the step of exposing a population of EVs to a complex comprising at least one pharmacological agent cargo (i.e., CD24) and at least one cell penetrating polypeptide (CPP) as taught by Wiklander et al. and Emmanuel et al. by covalently coupling the CPP to CD24 by a photo-cleavable linker as taught by Baccile et al. and exposing the pharmacological agent/CPP complex to radiation (such as UV light) to cleave the pharmacological agent. The person of ordinary skill in the art would have been motivated to make that modification in order to provide a method to release the pharmacological agent cargo (i.e., CD24) from the CPP at the site of the targeted tissue, organ, cell type of interest and with the desired proper pharmacological activity (see Baccile et al., page 1933, column 1, 2nd paragraph). The person of ordinary skill in the art reasonably would have expected success because photo-cleavable linkers were already being successfully utilized in linked constructs at the time the invention was made. Additionally, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense (KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007)).
Therefore, the claimed invention as a whole was clearly prima facie obvious over the prior art.
Double Patenting
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.
10. Claims 1-4, 8-17, and 21-24 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5-9, and 21-29 of copending Application No. 17/646,988 in view of Emmanuel et al. (US 2022/0333132; priority to 03 September 2019) and Arber et al. (US 2021/0322483; priority to 16 April 2020). The basis for this rejection is set forth for claims 1-17 at pages 21-24 of the previous Office Action of 22 October 2025.
Claim 1 of the instant application recites a method for loading a vesicle with a cargo molecule comprising CD24, or a biologically active fragment or variant of CD24 comprising at least 60% sequence identity to the amino acid sequence of human mature CD24 polypeptide, the method comprising contacting the vesicle with a binding complex, wherein the binding complex comprises the cargo molecule and a cell penetrating peptide (CPP) covalently coupled to the cargo molecule by a cleavable linker, the method comprising (1) contacting the vesicle with the binding complex, wherein the binding complex becomes internalized by the vesicle, associated with the vesicle, or a combination thereof, and (2) exposing the binding complex to radiation to cleave the cargo molecule from the CPP to produce a loaded vesicle.
Meanwhile, claim 1 of the ‘988 application recites a method for loading an extracellular vesicle (EV) with a cargo molecule, comprising contacting the EV with a binding complex, wherein the binding complex comprises the cargo molecule and a cell penetrating polypeptide (CPP) covalently coupled to the cargo molecule by a cleavable linker, the method comprising (1) contacting the extracellular vesicles with the binding complex, wherein the binding complex becomes internalized by, or associated with, the extracellular vesicles, and (2) exposing the binding complex to radiation to cleave the cargo molecule from the CPP.
Claims 8-13 of the instant application and claims 8-9 of the ‘988 application recite the same CPPs.
Claim 16 of the instant application and claim 7 of the ‘988 application recite that the vesicle further comprises a targeting agent.
Instant claim 21 and claim 28 of the ‘988 application recite that the binding complex is exposed to light to cleave the cargo molecule from the CPP.
Claim 22 of the instant application and claim 29 of the ‘988 application recite that the cleavable linker is a photo-cleavable linker.
The claims of the ‘988 application do not recite that the cargo molecule is CD24.
Emmanuel et al. teach non-cell particles comprising CD24 on an exposed surface of the particle (wherein the particles comprise a lumen comprising a cytosol, wherein the lumen is surrounded by a lipid bilayer) (page 1, [0006]; page 2, [0018-0020]; page 8, [0083]; page 17, [0183]; page 29, [0326-00335]). Emmanuel et al. disclose that the CD24 is recombinant and may comprise transmembrane amino acids (page 1, [0008, 0010]; page 6, [0068]; page 10, [0114-0115]); page 14, [0146]). Emmanuel et al. teach that CD24 may be modified to contain a functional group at its distal end, such as a histidine tag or biotin (page 17, [0177-0178]). It is noted that Emmanuel et al. teach that CD24 may comprise the amino acid sequence of SEQ ID NO: 1, 2, or 3 (page 1, [0007, 0009]; page 6, [0068]; page 11, [0122]; bottom of page 75). The amino acid sequence of SEQ ID NO: 1 of Emmanuel et al. is the full human CD24 sequence (bottom of page 75). It is noted that the amino acid sequence of SEQ ID NO: 3 of Emmanuel et al. comprises a sequence that is 100% identical to the amino acid sequence of SEQ ID NO: 36 of the instant application.
Similarly, Arber et al. also teach a composition comprising cell-derived particles (such as extracellular vesicles) presenting heterologous CD24 (abstract; page 1, [0003]; page 6, [0130, 0133]). Arber et al. disclose a method of producing cell-derived particles comprising modifying cells to present CD24 and isolating the cell-derived particles from a biological sample (page 2, [0020]).
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to modify a method for loading an extracellular vesicle (EV) with a cargo molecule, comprising contacting the EV with a binding complex, wherein the binding complex comprises the cargo molecule and a cell penetrating polypeptide (CPP) as recited by the claims of the ‘988 application by utilizing CD24 as the cargo molecule in the complex with CPP as taught by Emmanuel et al. and Arber et al. The person of ordinary skill in the art would have been motivated to make that modification and would have expected success because (i) CD24 interacts with Siglec 10 on macrophages to inhibit phagocytosis (Emmanuel et al., page 6, [0068-0069]); and (ii) CD24 suppresses hyperactivity of the immune system and prevents cytokine storm (Arber et al., page 1, [0003, 0009-0010]; page 5, [0112]). One skilled in art also would have been motivated to complex CD24 with a CPP for extracellular vesicle loading because Emmanuel et al. teach that any variety of methods may be used to expose CD24 on the surface of a non-cell particle such as to display, present, express or link (directly or indirectly) CD24 to the surface, so long as CD24 retains the ability to bind Siglec-10 and/or has the biological activity of evading phagocytosis (page 8, [0086]). Additionally, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense (KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007)).
This is a provisional nonstatutory double patenting rejection.
11. Claims 1-4, 8-17, and 21-24 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-6, 11-13, and 21-26 of copending Application No. 17/654,154 in view of Emmanuel et al. (US 2022/0333132; priority to 03 September 2019) and Arber et al. (US 2021/0322483; priority to 16 April 2020). The basis for this rejection is set forth for claims 1-17 at pages 24-26 of the previous Office Action of 22 October 2025.
Claim 1 of the instant application recites a method for loading a vesicle with a cargo molecule comprising CD24, or a biologically active fragment or variant of CD24 comprising at least 60% sequence identity to the amino acid sequence of human mature CD24 polypeptide, the method comprising contacting the vesicle with a binding complex, wherein the binding complex comprises the cargo molecule and a cell penetrating peptide (CPP) covalently coupled to the cargo molecule by a cleavable linker, the method comprising (1) contacting the vesicle with the binding complex, wherein the binding complex becomes internalized by the vesicle, associated with the vesicle, or a combination thereof, and (2) exposing the binding complex to radiation to cleave the cargo molecule from the CPP to produce a loaded vesicle.
Meanwhile, claim 1 of the ‘154 application 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 8-13 of the instant application and claims 12-13 of the ‘154 application recite the same CPPs.
Claim 22 of the instant application and claim 29 of the ‘988 application recite that the cleavable linker is a photo-cleavable linker.
The claims of the ‘154 application do not recite that the cargo molecule is CD24.
Emmanuel et al. teach non-cell particles comprising CD24 on an exposed surface of the particle (wherein the particles comprise a lumen comprising a cytosol, wherein the lumen is surrounded by a lipid bilayer) (page 1, [0006]; page 2, [0018-0020]; page 8, [0083]; page 17, [0183]; page 29, [0326-00335]). Emmanuel et al. disclose that the CD24 is recombinant and may comprise transmembrane amino acids (page 1, [0008, 0010]; page 6, [0068]; page 10, [0114-0115]); page 14, [0146]). Emmanuel et al. teach that CD24 may be modified to contain a functional group at its distal end, such as a histidine tag or biotin (page 17, [0177-0178]).
Similarly, Arber et al. also teach a composition comprising cell-derived particles (such as extracellular vesicles) presenting heterologous CD24 (abstract; page 1, [0003]; page 6, [0130, 0133]). Arber et al. disclose a method of producing cell-derived particles comprising modifying cells to present CD24 and isolating the cell-derived particles from a biological sample (page 2, [0020]).
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to modify 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 CPP as recited by the claims of the ‘154 application by utilizing CD24 as the cargo molecule in the complex with CPP as taught by Emmanuel et al. The person of ordinary skill in the art would have been motivated to make that modification and would have expected success because (i) CD24 interacts with Siglec 10 on macrophages to inhibit phagocytosis (Emmanuel et al., page 6, [0068-0069]); and (ii) CD24 suppresses hyperactivity of the immune system and prevents cytokine storm (Arber et al., page 1, [0003, 0009-0010]; page 5, [0112]). One skilled in art also would have been motivated to complex CD24 with a CPP for extracellular vesicle loading because Emmanuel et al. teach that any variety of methods may be used to expose CD24 on the surface of a non-cell particle such as to display, present, express or link (directly or indirectly) CD24 to the surface, so long as CD24 retains the ability to bind Siglec-10 and/or has the biological activity of evading phagocytosis (page 8, [0086]). Additionally, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense (KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007)).
This is a provisional nonstatutory double patenting rejection.
(i) At the bottom of page 8 of the Response of 21 April 2026, Applicant states that once all the rejections addressed above have been withdrawn, Applicant will address the double patenting rejections.
Applicant’s arguments have been fully considered but are not found to be persuasive. The provisional rejections of the instant claims on the grounds of provisional nonstatutory double patenting as being unpatentable over claims in copending Applications 17/646,988 and 17/654,154 as set forth in detail above and in the previous Office Action of 22 October 2025 are maintained. Applicant seems to traverse the rejections, but does not present any arguments pointing out the specific distinctions that render the instant claims patentable over the ‘988 and ‘154 application claims. Applicant is reminded that only objections or requirements as to form not necessary to further consideration of the claims may be held in abeyance until allowable subject matter is indicated (see 37 CFR 1.11(b)). Applicant is encouraged to submit terminal disclaimers at Applicant’s earliest convenience.
Conclusion
No claims are allowable.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
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BEB
Art Unit 1647
17 June 2026
/BRIDGET E BUNNER/Primary Examiner, Art Unit 1647
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