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 .
DETAILED ACTION
Response to Amendment
Status of the Claims
Receipt of Applicant’s response, filed 19 Nov 2025 has been entered.
Claims 1-4, 7-18, 20 and 24 remain pending in the application.
Claims 1, 2, 7, 10, 13, 17, 18, and 24 are amended.
Claims 5, 6, 19, 21-23 and 25-35 are cancelled.
Claims 18, 20 and 24 are withdrawn from further consideration by the examiner, pursuant to 37 CFR 1.142(b), as being drawn to a non-elected invention / species.
Claims 1-4 and 7-17 are under consideration to the extent of the elected species, i.e., that the polymer is a polymethacrylate.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 19 Nov 2025 are in compliance with the provisions of 37 CFR 1.97, except where noted. Accordingly, the information disclosure statement is being considered by the examiner.
Objections Withdrawn
Objections to the Specification
The specification objections set forth in the Non-Final Office Action mailed 20 May 2025 are hereby withdrawn in light of applicant’s amendments of the specification.
Objections to the Claims
The claim objections set forth in the Non-Final Office Action mailed 20 May 2025 are hereby withdrawn in light of applicant’s amendments of the claims.
Rejections Withdrawn
Rejections Pursuant to 35 USC § 112
The rejections of claims 1-17 pursuant to 35 U.S.C. 112(b) set forth in the Non-Final Office Action mailed 20 May 2025 are hereby withdrawn in light of applicants amendment of the claims.
Rejections Pursuant to 35 USC § 102
The rejection of claims 1 and 5-7 pursuant to 35 U.S.C. 102(a)(1) set forth in the Non-Final Office Action mailed 20 May 2025 are hereby withdrawn in light of applicant’s amendment of the claims.
Rejections Pursuant to 35 USC § 103
The rejection of claims 1-6, 8, 9, and 12 under 35 U.S.C. 103 as being unpatentable over Guo et al. (WO 2017/176894, published 12 Oct 2017) is withdrawn in light of applicant’s amendment of the claims.
Rejections Maintained
Claim Rejections - 35 USC § 103
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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.
Claims 1-4, 7, 8 and 11-15 are rejected under 35 U.S.C. 103 as being unpatentable over Banichelli et al. (J. Phys. Chem. B 2010, 114, 7348–7358, as listed in the IDS filed 28 July 2022) in view of Guo et al. (WO 2017/176894, published 12 Oct 2017), Tan et al. (WO 2009/146147, published 03 Dec 2009).
Banichelli teaches the anchoring of cholesterol-tagged oligonucleotides to phospholipid bilayers followed by membrane-assisted hybridization of the complementary strand in solution (abstract). Banichelli teaches oligonucleotides functionalized with a single cholesteryl-tetraethyleneglycol (Chol-TEG-2’) or multiple cholesterol (page 7348 left column, page 7349 left column, Figure 1). Banichelli teaches that cholesterol-conjugated oligonucleotides can be directly incorporated into lipid bilayers through spontaneous insertion of one or more cholesteryl moieties into the bilayer and that cholesterol embeds within the hydrophobic interior of the bilayer, forming a mobile anchor, while the hydrophilic spacer-oligonucleotide part protrudes outward from the membrane extending into the aqueous phase (page 7356 middle of left column). Attaching cholesterol to the oligonucleotides renders obvious anchoring of a hydrophobically modified oligonucleotide as in claims 1 and 11. Banichelli teaches a conformation of the cholesterol-tagged oligonucleotides anchored to a bilayer in Figure 10.
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After insertion of the cholesteryl-oligonucleotide into the vesicle, Banichelli teaches hybridization of the DNA-decorated vesicles with the soluble complementary strands in solution (page 7355 left column, Figure 11). Banichelli teaches that hybridization thermodynamics of the membrane-anchored oligonucleotide with a complementary sequence is not affected by the membrane; i.e., the stability of the double-stranded DNA is the same as in solution ([age 7357 right column 3rd paragraph of conlclusions). Hybridization of complementary DNA oligonucleotides renders obvious a second oligonucleotide hybridized to the first oligonucleotide as in claim 1. Banichelli teaches that DNA decorated vesicles may be used in the biomedical field for drug delivery (page 7348 end of right column – page 7349 left column) and that the vesicles decorated with programmable DNA sequences may be driven to ordered 3D-aggregation by the programmable hybridization of oligonucleotides protruding in the surrounding solution and that the flexible construction schemes would result in the formation of metastructures with unusual electronic and optical properties (page 7357 right column – page 7358 left column).
Banichelli does not teach that the vesicle is an extracellular vesicle obtained from a living cell, tissue, organ or organism (claims 1 and 11) or attachment to the elected species of polymer, a polymethacrylate. Banichelli further does not teach linking to the biological/therapeutic/binding agents as in claims 5-7, 10 and an excipient (claims 8 and 15). These deficiencies are made up for in the teachings of Guo and Tan.
Guo teaches RNA ligand-displaying exosomes for specific delivery of therapeutics to cell by RNA nanotechnology (title). Guo teaches exosomes as naturally derived nanovesicles from the endosome membrane of cells (page 1 lines 16-17), and Guo teaches that naturally derived exosomes are biocompatible and are regularly released from many different cells and that the combination of specialized lipids and arrays of membrane proteins contributes to the efficient fusion between exosome and recipient cell and that the use of exosomes can eliminate the need for endosome-escape strategies that have plagued the therapeutic arena (page 42 lines 25-29). Guo teaches cholesterol as a membrane-anchoring moiety and that conjugation of cholesterol to oligonucleotides can facilitate uptake into cells (page 3 lines 16-18).
Regarding the linking to a binding reagent and a biologically active agent such as a therapeutic agent as in instant claims 5 and 6, Guo teaches that the RNA ligand has one or more functional moieties (page 3 lines 10-11) and that the functional moieties may be a targeting moiety, therapeutic moiety or a diagnostic moiety such as a protein binding RNA aptamer (page 3 lines 22-30). Guo teaches an embodiment where the exosome comprises at least one targeting moiety and a moiety capable of treating the disease in the subject (page 4 lines 5-12) and that the targeting ligand allows for specific cell binding (page 4 line 21). Attachment to the RNA ligand of a therapeutic moiety and a targeting ligand that allows for cell binding renders obvious a binding reagent and a biologically active agent as in claims 5, 6 and 17. Regarding claim 7, Guo teaches reprogramming naturally derived exosomes for targeted delivery of miRNA, siRNA and dsDNA cargoes to cancer cells (page 42 lines 5-7) and teaches encapsulating the cargo and that these components are therapeutic payloads (Figure 1, page 12 lines 12-14). Encapsulating the cargo in the exosome renders obvious “loaded inside the lumen of the extracellular vesicle” as in claim 7. Regarding claims 8 and 15, Guo teaches that the exosomes are delivered as a composition and that the composition may include excipients (page 37 lines 15-22).
Tan teaches target-responsive hydrogels based on crosslinking DNA aptamers (abstract). It is noted that Tan also refers to aptamers as oligonucleotides (page 4 lines 31-32, page 5 line 20). Tan teaches that hydrogels are a network of polymer chains used for drug delivery, tissue engineering and other applications (page 1 lines 10-16, page 9 lines 19-20). Tan teaches that hydrogels offer many unique properties such as being highly adaptable to modifications and incorporating a wide variety of functionalities such as biological molecules into hydrogel structures (page 1 lines 22-31). Tan teaches that the hydrogel system may have competitive binding of a target to the aptamer and cause a decrease of cross-linking density and dissolution of the hydrogel for potential drug release and other applications (page 2 lines 25-29). Tan teaches that the method can be adapted for use in the selective release of therapeutic agents in specific environments where targets are found, thus creating a highly selective controllable release system (page 3 lines 1-5). Tan teaches that suitable monomers for the hydrogels include various methacrylate polymers such as diethylaminoethyl methacrylate (page 6 lines 23- page 7 line 5) which has a saturated carbon backbone as in claims 3 and 13. It is noted that the additional limitations for the acrylic polymer in claims 4 and 14 are all optional and thus not required. Tan teaches that the hydrogel is obtained by crosslinking complementary aptamer-incorporated polymers to obtain the polymer network structure, or crosslinked by way of a crosslinker or crosslinking aptamer and that polymerization of monomers can be initiated by chemicals, irradiation or any other techniques known to those skilled in the art (page 7 line 29- page 8 line 3).
Therefore, it would have been prima facie obvious to one of ordinary skill in the
art, before the effective filing date of the claimed invention to have anchored cholesterol-tagged oligonucleotides to a natural exosome from a cell and to have hybridized a complementary oligonucleotide comprising a polymer such as diethylaminoethyl methacrylate to the oligonucleotide anchored in the exosome. Anchoring cholesterol-oligonucleotides in lipid bilayers and attaching complementary oligonucleotide strands is known from Banichelli and the structures may be used in drug delivery applications and in driven to ordered 3D aggregation. It would be obvious to one of ordinary skill in the art to use natural exosomes in place of the bilayers of Banichelli as exosomes are biocompatible and there is efficient fusion between exosomes and recipients cells such that the need for endosome-escape strategies can be avoided, as taught by Guo. One would have a reasonable expectation of success as exosomes have been shown by Guo to be suitable with similar oligonucleotide structures by anchoring cholesterol RNA in the layers and encapsulating therapeutic compounds in the exosomes. It would have been obvious to link a polymer such as diethylaminoethyl methacrylate to the oligonucleotide as part of forming a hydrogel as hydrogels are known to be used in drug delivery applications and they are adaptable to modification such as incorporating biological molecules and can be used as part of a highly selective controllable release system, as taught by Tan. One would have a reasonable expectation of success as hydrogel formation from crosslinked DNA aptamers (oligonucleotides) is known from Tan.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references.
Response to Arguments
Applicant's arguments filed 19 Nov 2025 have been fully considered but they are not persuasive. Applicant states that Banichelli ascribes no particular value to hybridization but only notes it as an interesting phenomenon and that one would not think to experiment with hybridization (page 9 of remarks). The examiner does not find this persuasive as the hybridized structures are clearly taught by Banichelli and their structures is described as not affected by the membrane (page 7357 right column). The hybridized structures are thus present in the compositions of Banichelli. Further, in view of the teachings of Tan, the hybridized structure becomes additionally obvious for their use in forming hydrogel structures with the crosslinked DNA aptamers. The applicant argues that EV’s and hydrogels are distinct systems with distinct considerations in terms of structures and function and the functionalities described in the office action may be of interest to hydrogel but are not relevant to EVs and are thus no concern to the skilled artisan (pages 9-10 of remarks). The examiner does not find this persuasive as the rejection is built on the combination Banicelli, Guo and Tan and the obviousness of forming a hydrogel structure. Thus, the functionality of the hydrogel taught by Tan would be relevant to the combination. Further, the examiner notes that the applicant referred to functionality such as “a decrease of cross-linking density and dissolution of the hydrogel” but, as noted in the rejection, Tan teaches other properties of the hydrogel such as being highly adaptable to modifications and the ability to incorporate various functionalities and its use for applications such as drug delivery. All of these features add to the obviousness of combining the teachings. There is an overlap between the structures and teachings of Banicelli and Tan that render their combination as obvious. Vesicles comprising the hybridized oligonucleotides and that may be used for drug delivery are known from Banicelli whereas using hybridized oligonucleotides in combination with polymers to form hydrogels for drug delivery is known from Tan. Thus, the structures of an oligonucleotide hydrogel and an oligonucleotide vesicle are known from the art and they are both known for similar purposes of drug delivery rendering it obvious to combine their structures for the same purpose of drug delivery. Their combination merely represents and obvious alternative means of drug delivery. Additionally, as noted in the rejection, Banicelli teaches that the vesicles decorated with programmable DNA sequences may be driven to ordered 3D-aggregation by the programmable hybridization of oligonucleotides protruding in the surrounding solution and that the flexible construction schemes would result in the formation of metastructures with unusual electronic and optical properties (page 7357 right column – page 7358 left column). This further adds to the obviousness as the vesicles of Banicelli are suggested in use as a 3D aggregation structure, providing another connection to the concept of a 3D structure that may form from use as a hydrogel.
The applicant compares the functional properties described by Tan for the hydrogels to properties of EVs in the present application and argues that some of the considerations such as local environment features taught by Tan are not relevant to the claimed EVs and that the crosslinked aptamers of Tan are structural instead of for targeted delivery (page 10 of remarks). The examiner does not find this persuasive as the reason or motivation to modify the reference may often suggest what the inventor has done, but for a different purpose or to solve a different problem. It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant. See, e.g., In re Kahn, 441 F.3d 977, 987, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006) (motivation question arises in the context of the general problem confronting the inventor rather than the specific problem solved by the invention). In KSR Int' l Co. v. Teleflex Inc., 550 U.S. 398 (2007), the Supreme Court cautioned that, "[i]n determining whether the subject matter of a patent claim is obvious, neither the particular motivation nor the avowed purpose of the patentee controls. What matters is the objective reach of the claim. If the claim extends to what is obvious, it is invalid under § 103." Id. at 419. The structure described above of the oligonucleotide vesicles with polymers as a hydrogel renders obvious the vesicles of the instant claims, even if the applicant has identified additional properties or uses. The applicant argues that the rejection by the examiner amounts to picking and choosing elements from disparate references with no purpose to the primary reference (page 10 of remarks). The examiner disagrees and again notes that the structures taught by Banicelli and Tan are similar in that they both use hybridized oligonucleotides and their use is similar, namely for drug delivery. Thus, the relevance of the teachings is considered as a whole in relation to what is obvious and the combination of the teachings of Banicelli with Guo and Tan are obvious for the reasons described above and render obvious the vesicles of the instant claims.
Claims 9, 10, 16 and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Banichelli et al. (J. Phys. Chem. B 2010, 114, 7348–7358, as listed in the IDS filed 28 July 2022) in view of Guo et al. (WO 2017/176894, published 12 Oct 2017), Tan et al. (WO 2009/146147, published 03 Dec 2009) as applied to claims 1-4, 7, 8 and 11-15 above and further in view of Jones et al. (JPP 2005, 57: 1251–1259).
The teachings of Banichelli, Guo and Tan are described supra.
Banichelli, Guo and Tan do not teach a cross-linking with a cross linker comprising poly(ethylene oxide) as in claims 9 and 16. This deficiency is made up for in the teachings of Jones.
Jones teaches the effects of crosslinker concentration and type on the physicochemical and drug release properties of a model hydrogel (page 1258 left column). Jones teaches tetraethyleneglycol diacrylate (TEGDA), diethyleneglycol dimethacrylate (DEGDMA) and polyethyleneglycol dimethacrylate (PEGDMA) as crosslinkers (abstract). These crosslinkers differ in the number of repeating ethylene oxide units (page 1256 right column). Jones teaches that the crosslinker affects the mechanical and swelling properties of the hydrogel (abstract).
Therefore, it would have been prima facie obvious to one of ordinary skill in the
art, before the effective filing date of the claimed invention to have used a crosslinker such as PEGDMA (which comprises poly(ethylene oxide)) as part of the oligonucleotide exosome hydrogel rendered obvious from Banichelli, Guo and Tan. Formation of the hydrogels with a cross linker is obvious as it is taught by Tan as a means of forming the hydrogels. Crosslinkers are able to affect eth mechanical and swelling properties of hydrogels and PEGDMA is a known crosslinker for forming hydrogels, as taught by Jones. Thus, one would have a reasonable expectation of success in using the crosslinker PEGDMA as crosslinkers are taught a suitable for the invention and PEGDMA is a known crosslinker and thus merely represents using a known prior art element for its known use, namely as a crosslinker.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references.
Response to Arguments
Applicant's arguments filed 19 Nov 2025 have been fully considered but they are not persuasive. Applicant states that Banichelli is silent as to hydrogels and that there would be no reason to substitute the poly(ethylene oxide) cross linking of Jones for the cross-linked aptamers of Tan (page 11 of remarks). The examiner does not find this persuasive as it would be obvious to include the poly(ethylene oxide) cross linkers as another means of controlling the properties of the hydrogel. As noted in the rejection, Jones teaches that the crosslinker affects the mechanical and swelling properties of the hydrogel and the polymers are known crosslinkers for hydrogels. It would have been obvious to one of ordinary skill to incorporate additional cross linking moieties for additional control over the swelling and mechanical properties of the formed hydrogel.
Conclusion
No claims are allowed.
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 extension fee 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 date of this final action.
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/E.C.M./Examiner, Art Unit 1619
/ANNA R FALKOWITZ/Primary Examiner, Art Unit 1600