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 .
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-17, drawn to a method for loading a vesicle with a cargo molecule comprising CD24, in the reply filed on 22 September 2025 is acknowledged.
Claims 18-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 22 September 2025.
Claims 1-17 are under consideration in the instant application.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 07 June 2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
1. Specific deficiencies and the required response to this Office Action are as follows:
1a. Specific deficiency - This application contains sequence disclosures in accordance with the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.821(a)(1) and (a)(2). However, this application fails to comply with the requirements of 37 CFR 1.821 - 1.825. Specifically, amino acid sequences are present in the specification that are not in the CRF or sequence listing.
The sequence disclosures are located at:
- page 8, line 18
- page 18, line 12
- page 21, lines 12-13, 22, 24, 27
- page 22, lines 2-4
- page 23, line 10
- page 24, lines 1-7
- page 38, lines 23-24
- page 39, lines 2, 6, 12
- page 45, lines 15-16
- pages 47-49, Table 2
- pages 49-52
- page 64, lines 17-19, 22
- page 77, lines 15-17
- page 88, line 13 (the “R9” sequence disclosed as “SEQ ID NO: 1” does not match the CRF SEQ ID NO: 1)
Required response – Applicant must provide:
A "Sequence Listing" part of the disclosure, as described above in item 1); as well as
An amendment specifically directing entry of the "Sequence Listing" part of the disclosure into the application in accordance with 1.825(b)(2);
A statement that the "Sequence Listing" includes no new matter in accordance with 1.825(b)(5); and
A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.825(b)(4).
If the "Sequence Listing" part of the disclosure is submitted according to item 1) a) or b) above, Applicant must also provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter;
If the "Sequence Listing" part of the disclosure is submitted according to item 1) b), c), or d) above, Applicant must also provide:
A replacement CRF in accordance with 1.825(b)(6); and
Statement according to item 2) a) or b) above.
1b. Specific deficiency – Nucleotide and/or amino acid sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Please see the five different sequences in Figure 13. Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings.
Required response – Applicant must provide:
Replacement and annotated drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers into the Brief Description of the Drawings, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
1c. Specific deficiency - The Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is missing or incomplete. See item 1) a) or 1) b) above.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Claim Objections
2. Claims 2, 10, and 16 are objected to because of the following informalities:
2a. In claim 2, line 1, the word “surrounding” should recite “surrounded”.
2b. In claim 10, line 2, the word “where” should recite “wherein”.
2c. In claim 16, line 2, the word “type” after “cell” is extraneous and should be deleted.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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.
3. Claims 8, 10, and 15 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
3a. Claim 8 is indefinite because it recites “Table 2” in line 1. The claim is reading limitations from the specification into the claims. 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)." Please note that this issue could be overcome by amending the claim to refer to the specific sequences/SEQ ID NOs presented in Table 2.
3b. Regarding claim 10, a broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 10 recites the broad recitation “a peptide having from4 to 40 amino acids”, and the claim also recites “the peptide includes from 4 to 40 arginine residues” which is the narrower statement of the range/limitation. The claim is considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claim.
3c. Regarding claim 15, 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).
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.
4. Claims 1-17 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.
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, the method comprising contacting the vesicle with a binding complex, wherein the binding complex comprises the cargo molecule with a cell penetrating peptide (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.
The specification of the instant application teaches that one aspect of the invention is a method for loading a vesicle, such as an extracellular vesicle (EV) or lipid vesicle (LV), with a cargo molecule comprising CD24, or a biologically active fragment or variant of CD24 (page 3, lines 14-20). The specification continues to disclose that the CD24 can be a polypeptide that is synthesized or is recombinantly produced from a host cell and wherein the CD24 polypeptide may be human CD24 or a non-human animal CD24, or a biologically active fragment or variant of any of the foregoing (page 11, lines 17-20). The specification teaches that the first 26 amino acids of CD24 constitute the signal peptide while the last 23 amino acids serve as a signal for cleavage to allow for the attachment of a GPI tail (page 21, lines 1-3). The specification indicates that the mature CD24 protein is only 31 amino acids long and that the CD24 loaded on the vesicle may include such sequence or a biologically active fragment or variant thereof (page 21, lines 5-9, 21-30 through page 22, lines 1-12). The specification discloses that despite sequence variations in the amino acid sequence of the mature CD24 proteins from mouse and human, they are functionally equivalents in interaction with DAMP (page 22, lines 13-16).
Therefore, the “biologically active fragment of variant of CD24” limitation recited in the instant claims is broadly interpreted by the Examiner as reading upon any CD24 protein (from any species, with any amino acid sequence (including, insertions, deletions, or substitutions)) that is biologically active. However, the specification does not teach any CD24 protein fragments or variants other than full-length and mature human and mouse CD24 (see pages 21-22).
The first paragraph of 35 U.S.C. § 112 "requires a 'written description of the invention' which is separate and distinct from the enablement requirement." Vas-Cath Inc. v. Mahurkar, 935 F.2d 1555, 1563 (Fed. Cir. 1991). An adequate written description of a chemical invention "requires a precise definition, such as by structure, formula, chemical name, or physical properties." University of Rochester v. G.D. Searle & Co., Inc., 358 F.3d 916, 927 (Fed. Cir. 2004); Regents of the Univ. of Cal. v. Eli Lilly & Co., Inc., 119 F.3d 1559, 1566 (Fed. Cir. 1997); Fiers v. Revel, 984 F.2d 1164, 1171 (Fed. Cir. 1993). "A description of what a material does, rather than of what it is, usually does not suffice." Rochester, 358 F.3d at 923; Eli Lilly, 119 F.3d at 1568. Instead, the "disclosure must allow one skilled in the art to visualize or recognize the identity of the subject matter purportedly described." Id. In addition, possession of a genus "may be achieved by means of a recitation of a representative number of [compounds]... falling within the scope of the genus." Eli Lilly, 119 F.3d at 1569. Possession may not be shown by merely describing how to obtain possession of members of the claimed genus. See Rochester, 358 F.3d at 927.
Thus, case law dictates that to provide evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include actual reduction to practice, disclosure of drawings or structure chemical formulas, sufficient relevant identifying characteristics (such as, complete or partial structure, physical and/or chemical properties, and functional characteristics when coupled with a known or disclosed structure/function correlation), methods of making the claimed product, level of skill and knowledge in the art, predictability in the art, or any combination thereof. In the instant case, the only factors present in the claims are a structural characteristic of a CD24 fragment or a variant and a functional characteristic of being biologically active. 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. Thus, the claims are drawn to methods of loading a vesicle with a cargo molecule comprising a genus of CD24 fragments and variants.
The instant specification fails to disclose and there is no art-recognized correlation between the structure of CD24 fragments and variants and the function of being biologically active. In other words, the specification does not teach the structure which results in a CD24 fragment or variant with the required characteristics. The description of the human and mouse full-length and mature CD24 amino acid sequences are not adequate written description of an entire genus of fragments and variants of CD24 that are biologically active. For example, the art recognizes that protein function cannot be predicted from structure alone (Bork, 2000, Genome Research 10:398-400; Skolnick et al., 2000, Trends in Biotech. 18(1):34-39, especially p. 36 at Box 2; Doerks et al., 1998, Trends in Genetics 14:248-250; Smith et al., 1997, Nature Biotechnology 15:1222-1223; Brenner, 1999, Trends in Genetics 15:132-133; Bork et al., 1996, Trends in Genetics 12:425-427). See also Tokuriki et al. (Current Opinion in Structural Biology 19: 596-604, 2009), who teach that mutations are generally destabilizing. For instance, Tokuriki et al. teach at page 596, right column, last paragraph, that “as mutations accumulate, protein fitness declines exponentially...or even more than exponentially...So by the time an average protein accumulates, on average, five mutations, its fitness will decline to <20%.” Further, at page 598, left column, last paragraph, Tokuriki et al. note that 50% of mutations are destabilizing, and >15% of mutations are highly destabilizing, and of the about 5% of mutations that are stabilizing values...many of these mutations result in inactive protein. Indeed, Tokuriki et al. conclude that “a more comprehensive understanding of how mutations affect protein fitness within living cells is needed, including their combined effects on function, thermodynamic and kinetic stability, and clearance through aggregation and degradation” (see page 602, left column, 2nd paragraph). Fenton et al. (Medicinal Chemistry Research 29:1133-1146, 2020) also state that while it is well known that most substitutions at conserved amino acid positions (which they call “toggle” switches) abolish function, it is also true that substitutions at nonconserved positions (which they call “rheostat” positions) are equally capable of affecting protein function. They conclude that substitutions at rheostat positions have highly unpredictable outcomes on the activities and specificities of protein-based drugs. Bhattacharya et al. (PLoS ONE 12(3): e0171355, 2017) state that the range of possible effects of even single nucleotide variations at the protein level are significantly greater than currently assumed by existing software prediction methods, and that correct prediction of consequences remains a significant challenge (p. 18). Furthermore, when multiple mutations are introduced, there is even less predictability. For evidence thereof, see Guo et al. (PNAS USA 101(25):9205-10, 2004), who state that the effects of mutations on protein function are largely additive (page 9207, left column, full paragraph 2). Fenton et al. supra, also acknowledge this (see abstract).
Regarding CD24, Liu et al. (Trends Immunol 28(7): 315-320, 2007) teach that while the basic feature of a mucin-type structure is conserved between human and mouse mature CD24 (while the amino acid sequences are not conserved), this structural conservation suggests that it is perhaps the glycosylation pattern that is crucial for the basic function of the CD24 molecule (page 316, middle of column 2). Tan et al. (Clin Rev Allerg Immunol 50: 70-83, 2016) also disclose that several studies have confirmed that differences in glycosylation and specific carbohydrate structures of CD24 are markers for diagnostic and prognostic evaluation in different cancers and autoimmune diseases, including lupus (page 72, column 1, 2nd full paragraph; Table 2). However, there is little guidance in the specification indicating which amino acids or glycosylation patterns are considered essential for the required CD24 biological activity of the instant claims.
Applicant is reminded that generally, in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus (Enzo Biochem, Inc. v. Gen-Probe Inc., 323 F.3d 956 (Fed. Cir. 2002); Noelle v. Lederman, 355 F.3d 1343 (Fed. Cir. 2004); Regents of the University of California v. Eli Lilly Co., 119 F.3d 1559 (Fed. Cir. 1997)). A patentee must disclose “a representative number of species within the scope of the genus of structural features common to the members of the genus so that one of skill in the art can visualize or recognize the member of the genus” (see Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017) at page 1358). An adequate written description must contain enough information about the actual makeup of the claimed products – “a precise definition, such as structure, formula, chemic name, physical properties of other properties, of species falling with the genus sufficient to distinguish the gene from other materials”, which may be present in “functional terminology when the art has established a correlation between structure and function” (Amgen page 1361).
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed” (See page 1117). See also, Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017), relying upon Ariad Pharms., Inc. v. Eli Lily & Co., 94 USPQ2d 1161 (Fed Cir. 2010). The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed” (See Vas-Cath at page 1116). 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). In the instant application, the skilled artisan cannot envision the detailed chemical structure of the CD24 fragments and variants that are biologically active 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 specific protein or variant thereof is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483. In Fiddes, claims directed to mammalian FGF’s were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence.
Therefore, the full breadth of the claims does not meet the written description provision of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115). See also Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1355 (Fed. Cir. 2010).
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.
5. Claims 1-6 and 8-17 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), and Arber et al. (US 2021/0322483; priority to 16 April 2020). 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 or the pharmacological agent and CPP may form a complex as a result of non-covalent interactions, meeting the limitations of instant claims 1 and 5 (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, meeting the limitations of instant claims 6 and 7 (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 claim 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]).
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]).
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 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)). Therefore, the claimed invention as a whole was clearly prima facie obvious over the prior art.
6. Claim 7 is 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), and Arber et al. (US 2021/0322483; priority to 16 April 2020) as applied to claims 1-6 and 8-17 above, and further in view of Narasimhaswamy et al. (US 2010/0233084; cited on the IDS of 07 June 2023).
Wiklander et al., Emmanuel et al., and Arber et al. do not teach that the CPP is covalently coupled to the pharmacological agent cargo (i.e., CD24) by a cleavable linker.
Narasimhaswamy et al. teach the delivery of agents to target cells and tissues, such as across the blood brain barrier (abstract; page 1, [0003]). Narasimhaswamy et al. teach that for agents that are inactive when conjugated with a peptide carrier particle, a linker that is cleavable and can be cleaved by a suitable mechanism in a target cell can be included to promote release of the agent from the peptide carrier particle in the target cell (page 11, [0119]).
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 cleavable linker as taught by Narasimhaswamy et al. 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 a tissue, organ, cell type of interest and with the desired proper pharmacological activity. The person of ordinary skill in the art reasonably would have expected success because 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.
7. Claims 1-17 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 and 21-27 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).
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, the method comprising contacting the vesicle with a binding complex, wherein the binding complex comprises the cargo molecule with a cell penetrating peptide (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.
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 or non-covalently coupled to the cargo molecule, and wherein the binding complex becomes internalized by, or associated with, the EV.
Claim 6 of the instant application and claim 2 of the ‘988 application recite that the CPP is covalently coupled to the cargo molecule via different bonds.
Claim 7 of the instant application and claim 3 of the ‘988 application recites that the CPP is covalently coupled to the cargo molecule by a cleavable linker.
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.
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]).
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.
8. Claims 1-17 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).
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, the method comprising contacting the vesicle with a binding complex, wherein the binding complex comprises the cargo molecule with a cell penetrating peptide (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.
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.
Claim 6 of the instant application and claim 3 of the ‘154 application recite that the CPP is covalently coupled to the cargo molecule via different bonds.
Claim 7 of the instant application and claim 4 of the ‘154 application recites that the CPP is covalently coupled to the cargo molecule by a cleavable linker.
Claims 8-13 of the instant application and claims 12-13 of the ‘154 application recite the same CPPs.
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.
Conclusion
No claims are allowable.
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BEB
Art Unit 1647
17 October 2025
/BRIDGET E BUNNER/Primary Examiner, Art Unit 1647