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 .
Priority
Applicant’s claim to priority from PCT/US2020/015259 filed 01/27/2020 is hereby acknowledged.
Application Status
This Application is a National Stage entry under U.S.C. § 371 of PCT/US2020/015259 filed 01/27/2020.
Amendments of claims filed 09/19/2025 are hereby acknowledged. Claims 1-41 are cancelled. Claim 56 is currently amended. Claims 42-50 and 56-60 are pending and under examination in this office action.
Any objection or rejection not reiterated herein has been overcome by Applicant’s amendments and/or arguments, and is therefore withdrawn.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 09.19/2025 is hereby acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Drawings
Amendments to Drawings filed 09/19/2025 are hereby acknowledged. The replacement sheets for Drawings are acceptable.
Specification
Amendments to Specification filed 09/19/2025 are hereby acknowledged. The clean copy for replacement is acceptable.
Claim Rejections - 35 USC § 102
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.
(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.
Claims 42-50 and 56-60 are rejected under 35 U.S.C. §102(a)(1) as being anticipated by Bolen (Bolen, J. et al. US 2018/0193270 A1, published July 12, 2018).
Regarding claims 42-43 and 56-57, In view of instant Specification in which it is stated: “As used herein, the term “embedded” or grammatical variations thereof, when referring to biological materials, means to set or attach the biological material firmly into the receiving material or substrate while leaving some portion of the biological material exposed to the environment” and “As used therein, the term “encapsulated” or grammatical variations thereof, when referring to biological materials, means to set or attach the biological material firmly into the receiving material or substrate such that the receiving material completely surround the biological material preventing exposure to the environment” (see § [0062]), Examiner interprets “comprising an exosome-polycation matrix embedded with a nucleic acid” as a nucleic acid tethered to a polycationic ligand in complex with/encapsulated within a micro-vesicle that is an exosome, since the claim also recites “ wherein the exosome-polycation matrix comprises an isolated exosome complexed with a polycation”.
Indeed, Bolen teaches that “In some embodiments, the present invention provides a therapeutic agent-loaded exosome (“therapeutic-loaded exosome”). As used herein, the term “loaded” in the reference to a “therapeutic-loaded exosome” refers to an exosome having one or more therapeutic agents that are encapsulated inside the exosome; associated with or partially embedded within the lipid membrane of the exosome (i.e. partly protruding inside the interior of the exosomes); associated with or bound to the outer portion of the lipid membrane and associated components (i.e., partly protruding or fully outside the exosome); or entirely disposed within the lipid membrane of the exosome (i.e. entirely contained within the lipid membrane)” (see § [0047] of Bolen). Therefore, it is interpreted that Bolen teaches exosomes with different types of structures and relationships with the therapeutic agent.
Bolen teaches an oligonucleotide tethered to a ligand that is polycationic (see ¶ [0444]-[0445]), with different formulations for conjugation (¶ [0367], A,B,C) complexed into a microvesicle that is an exosome (page 151, claims 12 and 22).
Bolen teaches a composition that is a delivery system, that can be used as a transfection reagent, according to ¶ [0360]: “to target a gene in a cell line or in cells which are outside an organism”. Therefore, even though Bolen teaches a structure that can be used in patients as a primary inventive concept, as stated in MPEP § 2111.02 “Effect of preamble”, Section II “ Preamble statements reciting purpose or intended use”, “If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, then the preamble is not considered a limitation and is of no significance to claim construction”. Therefore Bolen teaches the structure of the product claimed in claim 42.
Regarding claim 43, Bolen teaches that therapeutic oligonucleotides can be delivered using microvesicles, exosomes isolated from milk, or colostrum (see ¶ [0043]-[0046]; [0054]-[0055]; page 151, claims 23 and 38).
Regarding claim 56 and 57, MPEP § 2113, Section I states : “ Product-by-process claims are not limited to the manipulations of the recited steps, only the structure implied by the steps”. Therefore, Bolen anticipates the claims, even though Bolen teaches a method to isolate and purify the exosomes and the complexation with oligonucleotides (see section 4, ¶ [0924]-[0932]; see claims 40-45).
Regarding claims 44-47 and 58-59, Bolen teaches an oligonucleotide tethered to a ligand that is polycationic (see ¶ [0445]), including polyethylenimine (line 16) and polylysine (¶ [0212], [0226], [0445]). Bolen teaches polyplexes synthesized with block copolymers (¶ [0224]), including PEI with different molecular weights from 2KDa to 28KDa, combinations of PEI with PEG ( ¶ [0226]).
Regarding claims 48, 56 and 60, Bolen teaches that the therapeutic cargo can be an siRNA (¶ [0167]-[0170], [0211], [0214]-[0215], [0220]). Bolen also teaches that the siRNA can be an siRNA targeting VEGF (siVEGF) (¶ [0363]).
Regarding claim 49, Bolen teaches the conjugation of siRNA with a fluorescent dye, DY677 (¶ [1288]-[1290]).
Regarding claim 50, Bolen teaches a composition that further comprises a pharmaceutically acceptable vehicle, or carrier (¶ [0066]; page 151, claims 24 and 36).
Response to Arguments
Applicant's arguments filed 09/19/2025 have been fully considered but they are not persuasive.
Applicant argues on page 7 of 12 of “Remarks” that “Applicant respectfully disagrees that Bolen teaches or suggests a composition for a transfection reagent comprising an exosome-polycation matrix embedded with a nucleic acid. Applicant also respectfully disagrees with Examiner's interpretation of "comprising an exosome-polycation matrix embedded with a nucleic acid" which Examiner has interpreted as "a nucleic acid tethered to a polycationic ligand in complex with / encapsulated within a micro-vesicle that is an exosome."
In response, in absence of a specific definition in the disclosure addressing the terms “exosome-polycation matrix”, in view of Applicant’s definition of “embedded” in § [0062] and comparing the definitions provided by Bolen in Bolen’s disclosure ( § [0047]), and in further view of the lack of further limitations in the claims on the structure of the composition, Examiner applied a broad and reasonable interpretation (BRI) to the terms. MPEP § 2111 states “ Claims must be given their broadest reasonable interpretation in light of the specification”.
In § [0047], Bolen clearly claims embodiments that encompass the instant composition: “In some embodiments, the present invention provides a therapeutic agent-loaded exosome (“therapeutic-loaded exosome”). As used herein, the term “loaded” in the reference to a “therapeutic-loaded exosome” refers to an exosome having one or more therapeutic agents that are encapsulated inside the exosome; associated with or partially embedded within the lipid membrane of the exosome (i.e. partly protruding inside the interior of the exosomes); associated with or bound to the outer portion of the lipid membrane and associated components (i.e., partly protruding or fully outside the exosome); or entirely disposed within the lipid membrane of the exosome (i.e. entirely contained within the lipid membrane)” (see § [0047] of Bolen).
Regarding Applicant’s argument, on page 8 of 12, stating : “Further, modification of the nucleic acid - by the addition of the cationic ligand or cationically- charged segment - can affect the functionality of the nucleic acid at the target delivery site. A modification in functionality can affect the ability of the nucleic acid to knockdown target gene expression, to introduce gene expression, to enhance gene expression, or to increase immune recognition of disease cells. However, modifying the surface of the exosome, as in the claims at issue, eliminates the need for modification of the nucleic acid thereby minimizing the risk of affecting the therapeutic functionality of the nucleic acids being delivered to the target sites”, Examiner would like to remind that the structure claimed is not specific enough given the BRI of the claims. The claims are drawn to a composition. The function of the composition is not the object of the claim, nor the end-result of the use of the composition. In response to applicant's argument, a recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim.
The process by which the composition is obtained, is also not relevant to the patentability of the claimed product ; MPEP § 2113, Section I states : “ Product-by-process claims are not limited to the manipulations of the recited steps, only the structure implied by the steps”.
Regarding Applicant’s argument, on same page, stating “The source of the exosomes (claims 43 and 57), the particular polycation selected (claims 44 - 47 and 58 - 59), the particular nucleic acid selected (claims 48 and 60), the inclusion of a fluorescent dye (claim 49), and the inclusion of a pharmaceutically-acceptable vehicle, carrier, or excipient (claim 50), do not change the that Bolen teaches a composition that modifies the nucleic acid before encapsulation in the exosome whereas the present invention mitigates the negative surface charge of the exosome before embedding the nucleic acid” , In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., mitigation of negative surface charge before embedding the nucleic acid) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). However, as claimed, the composition is not distinguishable from Species claimed in Bolen’s embodiments and as discussed above, the method of making the product does not carry additional patentability weight in a claim drawn to a product.
Double Patenting
The non-statutory 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 non-statutory 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 non-statutory 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 non-statutory 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 42-60 are rejected on the ground of non-statutory double patenting as being unpatentable over claims 1, 11, 13, 15, 17-19 of U.S. Patent No. 10,420,723 B2 (published September 24, 2019) in view of Bolen (Bolen, J. et al. US 2018/0193270 A1, published July 12, 2018).
Regarding claims 42-43, 51-52, and 56-57, claims 1 and 11, 13, 15, 17-19 of Patent ‘723 are drawn to a composition encapsulate by a milk-derived micro vesicle, comprising one or more siRNA molecules. Patent’723 also teaches micro vesicles isolated from raw milk, or colostrum.
Regarding claims 50 and 55, claim 13 of Patent ‘723 teaches a composition further comprising a pharmaceutically acceptable vehicle, carrier, or excipient.
Regarding claims 44-49, 53-54 and 58-60, Patent’723 does not teach the polycation and specifics about the polycation, i.e. PEIs or PEI conjugates, or dyes in the composition. Patent’723 does not teach the use as a transfection reagent.
However, Bolen teaches an oligonucleotide tethered to a ligand that is polycationic (see ¶ [0444]-[0445]), with different formulations for conjugation (¶ [0367], A,B,C) complexed into a microvesicle that is an exosome (page 151, claims 12 and 22).
Bolen teaches a composition that is a delivery system, that can be used as a transfection reagent, according to ¶ [0360]: “to target a gene in a cell line or in cells which are outside an organism”. Therefore Bolen teaches the structure of the product claimed in claims 42 and 51.
Bolen also teaches that therapeutic oligonucleotides can be delivered using micro vesicles, exosomes isolated from milk, or colostrum (see ¶ [0043]-[0046]; [0054]-[0055]; page 151, claims 23 and 38).
Regarding claims 44-47 and 58-59, Bolen teaches an oligonucleotide tethered to a ligand that is polycationic (see ¶ [0445]), including polyethylenimine (line 16) and polylysine (¶ [0212], [0226], [0445]). Bolen teaches polyplexes synthesized with block copolymers (¶ [0224]), including PEI with different molecular weights from 2KDa to 28KDa, combinations of PEI with PEG ( ¶ [0226]).
Regarding claims 48, 53, 56 and 60, Bolen teaches that the therapeutic cargo can be an siRNA (¶ [0167]-[0170], [0211], [0214]-[0215], [0220]). Bolen also teaches that the siRNA can be an siRNA targeting VEGF (siVEGF) (¶ [0363]).
Regarding claims 49 and 54, Bolen teaches the conjugation of siRNA with a fluorescent dye, DY677 (¶ [1288]-[1290]).
Regarding claims 50 and 55, Bolen also teaches a composition that further comprises a pharmaceutically acceptable vehicle, or carrier (¶ [0066]; page 151, claims 24 and 36).
It would have been obvious to one with ordinary skills in the art, before the effective filing date, to have modified the composition taught by Patent ‘723 and add the polycations using PEI or PEI conjugates complexing as polymers with the siRNA as taught by Bolen. One with ordinary skills in the art, motivated in increasing the stability and life of the oligonucleotides would have performed this modification with a reasonable expectation of success, since oligonucleotides’ modifications have become routine in the art, and arrived at the claimed invention.
Claims 42-43, 50-52, and 55 are rejected on the ground of non-statutory double patenting as being unpatentable over claims 1-2, 4-6, 8-10 of U.S. Patent No. 9,943,482 B2 (published April 17, 2018) in view of Bolen (Bolen, J. et al. US 2018/0193270 A1, published July 12, 2018).
Regarding claims 42-43, and 51-52, claims 1-2, 4-5 and 8 of Patent ‘482 are drawn to a composition comprising milk-derived micro vesicle, comprising one or more miRNA molecules. Claims 9-10 of Patent’482 also teach micro vesicles isolated from raw milk, or colostrum.
Regarding claims 50 and 55, claim 6 of Patent ‘482 teaches a composition further comprising a pharmaceutically acceptable vehicle, carrier, or excipient.
Patent’482 does not teach the polycation and specifics about the polycation, i.e. PEIs or PEI conjugates, or dyes in the composition. Patent’482 does not teach the use as a transfection reagent.
However, Bolen teaches an oligonucleotide tethered to a ligand that is polycationic (see ¶ [0444]-[0445]), with different formulations for conjugation (¶ [0367], A,B,C) complexed into a microvesicle that is an exosome (page 151, claims 12 and 22).
Bolen teaches a composition that is a delivery system, that can be used as a transfection reagent, according to ¶ [0360]: “to target a gene in a cell line or in cells which are outside an organism”. Therefore Bolen teaches the structure of the product claimed in claims 42 and 51.
Bolen also teaches that therapeutic oligonucleotides can be delivered using micro vesicles, exosomes isolated from milk, or colostrum (see ¶ [0043]-[0046]; [0054]-[0055]; page 151, claims 23 and 38).
It would have been obvious to one with ordinary skills in the art before the effective filing date, to have modified the composition taught by Patent ‘482 and add the polycations using PEI or PEI conjugates complexing as polymers with the siRNA as taught by Bolen. One with ordinary skills in the art, motivated in increasing the stability and life of the oligonucleotides would have performed this modification with a reasonable expectation of success, since oligonucleotides’ modifications have become routine in the art, and arrived at the claimed invention.
Response to Arguments
Applicant's arguments filed 09/19/2025 have been fully considered but they are not persuasive.
Regarding Applicant’s arguments on page 11 of 12, stating “Examiner has issued a nonstatutory double patenting rejection for claims 42 - 60 as being unpatentable over US 10,420,723 and US 9,943,482 in view of Bolen. Applicant respectfully traverses Examiner's double patenting rejection. Neither US 10,420,723 nor US 9,943,482 teach or suggest an EPM, rather both patents claim compositions comprising isolated exosomes. Adding the limitations taught by Bolen does not change the isolated exosome into the EPM of the present application. Thus, Applicant believes that the claims of the present application are patentably distinct from US 10,420,723 and US 9,943,482”, Examiner would like to remind that there is no specific definition provided in the Specification for the terms “EPM”, therefore the BRI was applied. See above in response to arguments about 35 U.S.C. §102 rejections.
AFFIDAVIT / DECLARATION
The declaration under 37 CFR 1.132 filed 09/19/2025 is sufficient to overcome the rejection of claims 42-50 and 56-60 under 35 U.S.C. § 103 based upon Fu ( Fu et al. ExRNA, Vol. 1 (2019), p:24(1-14)).
However, The Declaration under 37 CFR 1.132 filed 09/19/2025 is insufficient to overcome the rejection of claims 42-50 and 56-60 under 35 U.S.C. § 102 (a)(1) based upon Bolen (Bolen, J. et al. US 2018/0193270 A1) as set forth in the last Office action because:
The Declaration is specifically addressing Fu. The rejections of claims 42-60 under 35 U.S.C. §103 have been withdrawn in view of Applicant’s arguments.
As described above, the independent claims 42 and 56 are anticipated by Bolen in view of lack of precise definition for the terms “exosome-polycation matrix” (EPM).
Dr. Gupta argues that the “EPM” is a chemical species that is separate and distinct. However, as claimed, the composition does not present any limitation that distinguishes the “EPM” from species claimed in Bolen’s embodiments. There is no specific chemical structure claimed with a specific arrangement in the Specification, that one with ordinary skills in the art could reproduce. Dr Gupta also refers to charges on the surface of the “EPM”, but there is no language in the claim to address this specific limitation. Dr. Gupta also refers to measured zeta potentials, but there are no limitation in the claim drawn to specific zeta potential of the claimed structure either. In conclusion, the characteristics that could distinguish the exosome from the instant invention from the prior art are not claimed.
Conclusion
No claim is allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/A.D./Examiner, Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636