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
Applicant's amendments and remarks filed on December 23, 2025 are acknowledged. Claims 2, 4, 5, 7-10, 12-22, 24-26, 28-30, 32, 34-40, 44, 47-49, 51-77, and 80-142 have been canceled. Claims 1, 23, 41, 45, 46, and 78 were amended. Claims 1, 3, 6, 11, 23, 27, 31, 33, 41, 42, 43, 45, 46, 50, 78, 79, and 143 are pending and are examined on the merits herein.
This action is NON-FINAL due to new grounds of rejection not necessitated by amendment.
Election/Restrictions
Applicant’s election without traverse of the following species in the reply filed on July 14, 2025 is acknowledged:
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Withdrawn Objections
In view of Applicant’s amendments and response, the objections to the drawings are withdrawn.
In view of Applicant’s amendments and response, the claim objections are withdrawn.
Withdrawn Rejections
In view of Applicant’s amendments and response, the 35 U.S.C 112(b) rejections are withdrawn.
Priority
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Information Disclosure Statement
The information disclosure statement (IDS) submitted on December 23, 2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Drawings
The drawings were received on December 23, 2025. These drawings are found acceptable by the examiner.
Specification
It is noted that the amendment to the specification filed on December 23, 2025 does not comply with the requirements of 37 CFR 1.121(b) because the full text of replacement paragraph [0071] is not shown with markings relative to the immediate prior version of the paragraph. Specifically, paragraph [0071] of the specification filed on February 14, 2022 reads in part “2.5 µM”; however, amended paragraph [0071] reads in part “2.5 M”. Therefore, the amendment to the specification has not been entered.
The disclosure is objected to because of the following informalities:
FIG. 14A contains the abbreviations “IT”, “TIW”, “IP”, and “DIW”; however, the figure itself and paragraph [0061] of the specification do not define the abbreviations.
FIG. 17A contains the abbreviations “IT”, “TIW”, “IP”, and “DIW”; however, the figure itself and paragraph [0065] of the specification do not define the abbreviations.
Paragraph [0066] line 2 reads in part “constructs ttthat can be expressed” and should read “constructs that can be expressed”.
Paragraph [0071] reads in part “0.624 µM” and should read “0.625 µM” (emphasis added).
Paragraph [0072] reads in part “scatter plot illustratring the duration of Stat6 protein knowck down” and should read “scatter plot illustrating the duration of Stat6 protein knock down” (emphasis added).
Paragraph [0073] indicates that it’s the brief description section for FIGs. 24A-24L; however, all of the figures in parentheses refer to FIG. 23 instead of FIG. 24. In addition, paragraph [0073] reads “iNOS (FIGs. 23G-23H)” two times and both instances should read “iNOS (FIGs. 24G-24I)” (missing FIG. “I”).
Paragraph [0075] reads in part “exo-STAT6-ASO (FIGs. FIG. 26B-26D)”. There should only be one instance of “FIG”.
FIG. 26A contains the abbreviations “IP”, “TIW”, and “DIW”; however, the figure itself and paragraph [0075] of the specification do not define the abbreviations.
Appropriate correction is required.
Response to Arguments
Applicant's arguments filed December 23, 2025 have been fully considered but they are not persuasive.
It is noted that the amendment to the specification filed on December 23, 2025 does not comply with the requirements of 37 CFR 1.121(b) because the full text of replacement paragraph [0071] is not shown with markings relative to the immediate prior version of the paragraph. Specifically, paragraph [0071] of the specification filed on February 14, 2022 reads in part “2.5 µM”; however, amended paragraph [0071] reads in part “2.5 M”. Therefore, the amendment to the specification has not been entered.
Claim Rejections - 35 USC § 112
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.
Claims 42 and 43 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.
Claim 42 is indefinite at the recitation of “Scaffold X”. Paragraph [0121] of the specification discloses that the term “Scaffold X” refers to exosome proteins that have recently been identified on the surface of exosomes. The specification further refers to U.S. Patent No. 10,195,290 as an example and thus is not limiting Scaffold X to the proteins in patent ‘290. In view of the specification, the scope of the term “Scaffold X” will change over time as to what is considered as recently identified and thus rendering the limitation in the claim indefinite.
Claim 43 is indefinite at the recitation of “Scaffold Y”. Paragraph [0122] of the specification discloses that the term “Scaffold Y” refers to exosome proteins that were newly identified within the lumen of exosomes. The specification further refers to WO 2019/099942 as an example and thus is not limiting Scaffold Y to the proteins in application ‘942. In view of the specification, the scope of the term “Scaffold Y” will change over time as to what is considered as newly identified and thus rendering the limitation in the claim indefinite.
New Matter
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.
Claims 1, 3, 6, 11, 23, 27, 31, 33, 41, 42, 43, 45, 46, 50, 78, 79, and 143 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. This is a new matter rejection.
In the reply filed on December 23, 2025, claim 1 was amended to recite “wherein the contiguous nucleotide sequence includes the contiguous nucleotides set forth in SEQ ID NO: 151 or SEQ ID NO: 151 with one or two mutations”.
Applicant’s remarks filed on December 23, 2025 asserts that support for the claim amendments is found throughout the specification and claims as originally filed, and refers to PCT claim 24 and the sequence listing. PCT/US20/46559 claim 24 (reproduced below) provides support for SEQ ID NO: 151 with one or two mismatches and the sequence listing provides support for SEQ ID NO: 151, but neither provides support for SEQ ID NO: 151 with one or two mutations.
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The instant specification discloses in paragraph [0014] that in some aspects the ASO comprises a nucleotide sequence selected from SEQ ID NOS: 91-193 with one or two mismatches. Although the term mutation includes a mismatch, a mutation is broader in scope and includes for example an insertion and a deletion. The instant specification uses the term mutation in the context of proteins (e.g., paragraphs [0125], [0126], [0467], [0468], [0469], [0471], [0473], and [0498]) but does not provide support for mutations in the claimed nucleic acid molecule.
The original specification, drawings and claims were thoroughly reviewed and no support could be found for the amendment. Accordingly, the amendment is a departure from the disclosure as originally filed, and Applicant has not pointed to a specific portion of the original disclosure that provides support.
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.
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, 6, 11, 23, 27, 31, 78, and 79 are rejected under 35 U.S.C. 103 as being unpatentable over Shanahan Jr. et al. (US 8,518,904) in view of Bleicher et al. (WO 2019/122282; reference cited by Applicant).
Regarding claims 1, 23, and 79, Shanahan Jr. et al. teaches compositions comprising oligonucleotides targeted to nucleic acid encoding STAT 6 [abstract]. Instant SEQ ID NO: 151 (designated as Qy) has a match to positions 1994 to 1978 of Shanahan Jr. et al. SEQ ID NO: 4 (designated as Db) as shown in the alignment below.
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Shanahan Jr. et al. SEQ ID NO: 4 is the human STAT6 RNA (GenBank accession number NM_003153.1). Shanahan Jr. et al. teaches SEQ ID NO: 41 (designated as Db) which has a match to instant SEQ ID NO: 151 (designated as Qy) as shown in the alignment below.
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ISIS # Region Target SID Target site Sequence % inhibition SID Ctrl SID
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The sequence of Shanahan Jr. comprises a contiguous nucleotide sequence of 14 nucleotides in length that comprises the contiguous nucleotide sequences set forth in SEQ ID NO: 151 with one or two mutations that are deletion mutations of the three terminal nucleotides (e.g., one three nucleotide deletion or two shorter deletions totalling 3 nucleotides). Shanahan Jr. et al. also teaches that preferred compounds are oligonucleotides about 15 to 30 nucleobases [column 6, lines 43-45]. Further, Shanahan Jr. et al. teaches chimeric oligonucleotides “gapmers” that are 20 nucleotides in length composed of a central “gap” region consisting of ten 2’-deoxynucleotides which is flanked on both sides by five-nucleotide “wings” [Example 15].
Regarding claim 6, Table 1 (reproduced above) shows that SEQ ID NO: 41, a chimeric phosphorothioate oligonucleotide having 2’-MOE wings and a deoxy gap, is capable of achieving 88% inhibition of human STAT6 mRNA levels [columns 35-36].
Regarding claim 11, Shanahan Jr. et al. teaches that the modified oligonucleotides may also contain one or more substituted sugar moieties [column 14, first full paragraph].
Regarding claim 27, Shanahan Jr. et al. teaches oligonucleotides containing modified backbones or non-natural internucleoside linkages [column 12, fourth full paragraph].
Regarding claims 31 and 78, Shanahan Jr. et al. teaches that chemically linking the oligonucleotide to one or more moieties or conjugates enhances the activity, cellular distribution, or cellular uptake of the oligonucleotide. Further, conjugate moieties include, but are not limited to, lipid moieties such as cholesterol [column 15, last paragraph bridging to column 16].
However, Shanahan Jr. et al. does not teach packaging of antisense oligonucleotides into extracellular vesicles. Shanahan Jr. et al. also does not teach a linker linking the antisense oligonucleotide to the extracellular vesicle (claim 79).
Bleicher et al. teaches that antisense oligonucleotides may be effectively delivered via exosomes [page 56, lines 3-32]. Bleicher et al. also teaches that the antisense oligonucleotide may be conjugated, e.g., with a lipophilic conjugate such as cholesterol, which may be covalently attached to the antisense oligonucleotide via a biocleavable linker [page 56, last paragraph].
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to package the oligonucleotide of Shanahan Jr. et al. into an exosome as disclosed in Bleicher et al. One would have been motivated to make such a modification to effectively deliver the oligonucleotide because Bleicher et al. taught that antisense oligonucleotides may be effectively delivered via exosomes.
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to further engineer the extracellular vesicle of Shanahan Jr. et al. and Bleicher et al. to comprise an exogenous peptide targeting moiety. One would have been motivated to make such a modification to improve the pharmacology of the oligonucleotide as taught by Bleicher et al.
Claims 3 and 33 are rejected under 35 U.S.C. 103 as being unpatentable over Shanahan Jr. et al. (US 8,518,904) in view of Bleicher et al. (WO 2019/122282; reference cited by Applicant) as applied to claims 1, 6, 11, 23, 27, 31, 78, and 79 above, and further in view of Gallego-Perez et al. (WO 2020/082005) and Wang et al. (Oncotarget 2015).
Regarding claims 3 and 33, the teachings of Shanahan Jr. et al. and Bleicher et al. are discussed above. Bleicher et al. also teaches that conjugation of the oligonucleotide to one or more non-nucleotide moieties may improve the pharmacology of the oligonucleotide, modify or enhance the pharmacokinetic properties of the oligonucleotide, or the conjugate may target the oligonucleotide to a specific organ, tissue or cell type [page 57, second paragraph].
However, Shanahan Jr. et al. and Bleicher et al. do not teach an extracellular vesicle capable of targeting a cell selected from the group consisting of a macrophage, a myeloid-derived suppressor cell, a monocyte, a basophil, a neutrophil, an eosinophil, and any combination thereof.
Gallego-Perez et al. teaches that extracellular vesicles (EVs) can be targeted to MDSCs by expressing on the surface of the EVs a targeting moiety which binds to a cell surface moiety expressed on the surface of the MDSCs. Examples of suitable targeting moieties are short peptides, scFv and complete proteins, so long as the targeting moiety can be expressed on the surface of the exosome [0047]. Gallego-Perez et al. also teaches that in some embodiments the cell targeting ligand is ICAM1 [0048].
Wang et al. teaches that signal transducer and activator of transcription family proteins (STATs), including Stat1, Stat3, and Stat6, are the main regulators of MDSC expansion and activation [page 43995, right column, first full paragraph]. Wang et al. also teaches that most of the factors that induce MDSC activation trigger STAT signaling pathways including STAT6 to induce cell survival, proliferation, differentiation, and expansion of MDSC [page 43998, right column, last paragraph bridging to page 43999, left column]. Wang et al. demonstrated that STAT inhibitors are useful in MM (multiple myeloma) treatment through targeting of MDSC activation [page 44000, right column, first paragraph].
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to target a myeloid derived suppressor cell using the extracellular vesicle of Shanahan Jr. et al. and Bleicher et al. with a targeting moiety such as a short peptide, scFV or complete protein on the surface of the extracellular vesicle as taught by Gallego-Perez et al. because Gallego-Perez et al. taught that extracellular vesicles can be targeted to MDSCs by expressing on the surface of the extracellular vesicle a targeting moiety which binds to a cell surface moiety expressed on the surface of the MDSCs and Wang et al. taught that most of the factors that induce MDSC activation trigger STAT signaling pathways including STAT6 to induce cell survival, proliferation, differentiation, and expansion of MDSC. One would have been motivated to target MDSC cells in order to provide the extracellular vesicle for the purpose of treating multiple myeloma because Bleicher et al. taught that antisense oligonucleotides may be effectively delivered via exosomes and Wang et al. demonstrated that STAT inhibitors are capable of treating multiple myeloma through targeting of MDSC activation.
Claims 3, 33, 41, 42, 43, 45, 46, 50, and 143 are rejected under 35 U.S.C. 103 as being unpatentable over Shanahan Jr. et al. (US 8,518,904) in view of Bleicher et al. (WO 2019/122282; reference cited by Applicant) as applied to claims 1, 6, 11, 23, 27, 31, 78, and 79 above, and further in view of McConnell et al. (WO 2019/099942; reference cited by Applicant).
Regarding claims 3, 33, 41, 42, 43, 45, 46, 50, and 143, the teachings of Shanahan Jr. et al. and Bleicher et al. are discussed above.
However, Shanahan Jr. et al. and Bleicher et al. do not teach an extracellular vesicle capable of targeting a cell selected from the group consisting of a macrophage, a myeloid-derived suppressor cell, a monocyte, a basophil, a neutrophil, an eosinophil, and any combination thereof. Shanahan Jr. et al. and Bleicher et al. do not teach an exogenous targeting moiety or a scaffold moiety. Shanahan Jr. et al. and Bleicher et al. also do not teach Scaffold X or the PTGFRN protein. Shanahan Jr. et al. and Bleicher et al. also do not teach Scaffold Y or the BASP1 protein. Shanahan Jr. et al. and Bleicher et al. also do not teach that the ASO, the exogenous targeting moiety, or both, is linked to the EV by the scaffold moiety.
McConnell et al. teaches that the lumen-engineered exosomes produced by using the newly-identified exosome proteins contain modified proteins more highly enriched in their lumen than exosomes in the prior art. Further, the lumen-engineered exosomes have greater, more specific, or more controlled biological activity. In addition, a lumen-engineered exosome comprising a therapeutic or biologically relevant exogenous sequence fused to an exosome protein or a fragment thereof (e.g., BASP1 or a fragment thereof) can have more of the desired engineered characteristics than fusion to scaffolds known in the art [0115]. McConnell et al. also teaches combinatorial engineering of exosomes using fusions to BASP1 and PTGFRN [0175]. McConnell et al. teaches fusion proteins having a targeting moiety wherein the targeting moiety is used for targeting the exosome to a specific organ, tissue, or cell capable of treatment using the exosome and wherein the targeting moiety is an antibody or an antigen-binding fragment thereof [0107].
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to further engineer the extracellular vesicle to comprise a scaffold moiety such as BASP1 and PTGFRN, as disclosed in McConnell et al., linking the exogenous targeting moiety to the extracellular vesicle to predictably produce a surface engineered exosome that effectively and robustly presents a targeting moiety or a therapeutically relevant protein on the surface of said exosome. One would have been motivated to make such a modification in order to receive the expected benefit of producing surface engineered exosomes for presentation of a targeting moiety or a therapeutically relevant protein on the surface of said exosome.
Response to Arguments
Applicant's arguments filed December 23, 2025 have been fully considered but they are not persuasive.
Applicant asserts that Shanahan Jr. et al. and Bleicher et al. do not render obvious the limitations of amended claim 1. Specifically, Applicant asserts that Shanahan Jr. et al. and Bleicher et al. are completely silent on an ASO comprising 10 to 30 contiguous nucleotides including the contiguous nucleotides set forth in SEQ ID NO: 151 or SEQ ID NO: 151 with one or two mutations.
Contrary to Applicant’s assertions, positions 1994 to 1978 of Shanahan Jr. et al. SEQ ID NO: 4, human STAT6 RNA, has a match to instant SEQ ID NO: 151. Shanahan Jr. et al. SEQ ID NO: 41 is an antisense oligonucleotide that targets SEQ ID NO: 4 at the target site of 1972. Therefore, SEQ ID NO: 41 (designated as Db) has a match to instant SEQ ID NO: 151 (designated as Qy) as shown in the alignment below.
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Applicant asserts that the siRNA in Rossomando et al. comprises RNA units while the ASOs of the claimed invention do not comprise RNA and comprise one or more DNA units. Applicant also asserted the following:
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The Rossomando et al. reference was used in combination with Shanahan Jr. et al. and Bleicher et al. to render obvious the limitations of previously presented claim 25. Applicant has canceled claim 25 thus rendering the rejection moot. However, to address Applicant’s arguments, it is noted that an opinion has been made; however, no evidentiary support has been provided for the opinion. The arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997) ("An assertion of what seems to follow from common experience is just attorney argument and not the kind of factual evidence that is required to rebut a prima facie case of obviousness."). Nonetheless, Applicant’s arguments that the siRNA in Rossomando et al. comprises RNA units while the ASOs of the claimed invention do not comprise RNA is found persuasive. Therefore, a new grounds of rejection has been made and presented in this Office action.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHRISTINA TRAN whose telephone number is (571)270-0550. The examiner can normally be reached M-F 7:30 - 5:00pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jennifer Dunston can be reached at (571) 272-2916. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/C.T./
Examiner, Art Unit 1637
/Jennifer Dunston/Supervisory Patent Examiner, Art Unit 1637