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 June 3, 2026 are acknowledged. Claims 2, 4, 5, 7-10, 12-22, 24-26, 28-30, 32, 34-40, 43-45, 47-77, and 80-142 have been canceled. Claims 1, 42, and 46 were amended. Claims 1, 3, 6, 11, 23, 27, 31, 33, 41, 42, 46, 78, 79, and 143 are pending and are examined on the merits herein.
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Withdrawn Objections
In view of Applicant’s amendments and response, the objections to the specification are withdrawn.
Withdrawn Rejections
In view of Applicant’s amendments and response, the 35 U.S.C. 112(b) and 35 U.S.C. 112(a) new matter rejections are withdrawn.
Priority
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New Grounds of Rejections Necessitated by Amendment
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 11 and 27 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 11 recites “The extracellular vesicle of claim 1, wherein the ASO comprises one or more nucleoside analogs.” Claim 11 depends on claim 1 and claim 1 recites in part wherein the ASO comprises the following chemical structure
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LNA is a nucleoside analog; therefore, claim 11 does not further limit the claim which it depends on.
Claim 27 recites “The extracellular vesicle of claim 1, wherein the contiguous nucleotide sequence comprises one or more modified internucleoside linkages.” Claim 27 depends on claim 1 and claim 1 recites in part wherein the ASO comprises the following chemical structure
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Phosphorothioate is a modified internucleoside linkage; therefore, claim 27 does not further limit the claim which it depends on.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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; reference previously cited by the Examiner) in view of Bleicher et al. (WO 2019/122282; reference cited by Applicant) and Bermingham et al. (WO 2020/117703).
The following is a new rejection, necessitated by the amendment to the claims in
the reply filed June 3, 2026.
Regarding claims 1, 6, 11, 23, 27, 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 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]. Shanahan Jr. et al. also teaches that the modified oligonucleotides may also contain one or more substituted sugar moieties [column 14, first full paragraph]. A further preferred modification of the sugar includes Locked Nucleic Acids (LNAs) [column 14, lines 57-58]. Further, Shanahan Jr. et al. teaches oligonucleotides containing modified backbones or non-natural internucleoside linkages [column 12, fourth full paragraph]. Preferred modified oligonucleotide backbones containing a phosphorus atom therein include phosphorothioates [column 12, last paragraph]. Shanahan Jr. et al. teaches that antisense oligonucleotides may contain nucleobase modifications or substitutions (e.g., 5-methylcytosine) [column 14, last paragraph bridging to column 15]. Further, Shanahan Jr. et al. teaches that 5-methylcytosine substitutions have been shown to increase nucleic acid duplex stability and are presently preferred base substitutions [column 15, lines 44-46]. Table 1 (reproduced below) 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].
ISIS # Region Target SID Target site Sequence % inhibition SID Ctrl SID
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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. does not teach an antisense oligonucleotide or the antisense oligonucleotide design as recited in claim 1 wherein the ASO reduces STAT6 expression by at least 50% at 2 nM. Shanahan Jr. et al. does not explicitly teach that an ASO comprising LNA wings and a deoxy gap is capable of reducing STAT6 mRNA or protein expression in a human cell (claim 6). 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]. Bleicher et al. teaches gapmer antisense oligonucleotides comprising three distinct structural regions from 5’ to 3’: F-G-F’ wherein F and F’ comprise one or more sugar modified nucleosides such as LNA and “G” refers to the gap region comprising a stretch of contiguous DNA nucleotides [page 44, first full paragraph]. Further, the overall length of the gapmer design may be 12 to 32 nucleosides [page 44, last paragraph], the gap region may consist of 11 contiguous DNA nucleosides, and methylation of cytosine DNA in the gap region is advantageous to reduce potential toxicity [page 45, lines 17-18 and 20-21].
Bermingham et al. teaches compositions to treat trinucleotide repeat expansion disorders [abstract]. Bermingham et al. also teaches that in some aspects, the oligonucleotide exhibits at least 50% mRNA inhibition at a 2 nM oligonucleotide concentration when determined using a cell assay when compared with a control cell [page 5, last paragraph bridging to page 6].
Although Shanahan Jr. et al. does not teach an antisense oligonucleotide, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to design an antisense oligonucleotide according to claim 1 wherein the ASO reduces STAT6 expression by at least 50% at 2 nM and is capable of reducing STAT6 mRNA or protein expression in a human cell using the design principles taught by Shanahan Jr. et al. and Bleicher et al. because it would have amounted to applying known design principles to a known STAT6 RNA sequence to yield predictable results. One of ordinary skill in the art would have been motivated to do so because Shanahan Jr. et al. taught that there are no known therapeutic agents that effectively inhibit the synthesis of STAT 6 and thus there remains a long felt need for additional agents capable of effectively inhibiting STAT 6 function [column 2, last full paragraph]. Shanahan Jr. et al. also taught the human STAT6 RNA sequence and taught the design of gapmers, Bleicher et al. taught that antisense gapmers are used to inhibit a target nucleic acid via RNase H mediated degradation [page 44, first full paragraph] and taught the design of gapmers, and Bermingham et al. taught that 50% inhibition can be achieved at a concentration of 2 nM.
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., Bleicher et al., and Bermingham et al. into an extracellular vesicle and link the antisense oligonucleotide to the extracellular vesicle by a linker because Shanahan Jr. et al., Bleicher et al., and Bermingham et al. taught an antisense oligonucleotide according to claim 1 wherein the ASO reduces STAT6 expression by at least 50% at 2 nM and Bleicher et al. taught that antisense oligonucleotides may be effectively delivered via exosomes and also taught that antisense oligonucleotides may be conjugated with a lipophilic conjugate which may be covalently attached to the antisense oligonucleotide via a biocleavable linker. One of ordinary skill in the art would have made such a modification because it would have amounted to combining known prior art elements to yield predictable results.
Claims 3 and 33 are rejected under 35 U.S.C. 103 as being unpatentable over Shanahan Jr. et al. (US 8,518,904; reference previously cited by the Examiner) in view of Bleicher et al. (WO 2019/122282; reference cited by Applicant) and Bermingham et al. (WO 2020/117703) 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; reference previously cited by the Examiner) and Wang et al. (Oncotarget 2015; reference previously cited by the Examiner).
Regarding claims 3 and 33, the teachings of Shanahan Jr. et al., Bleicher et al., and Bermingham 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., Bleicher et al., and Bermingham 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 (claim 3). Shanahan Jr. et al., Bleicher et al., and Bermingham et al. also do not teach an exogenous targeting moiety (claim 33).
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., Bleicher et al., and Bermingham 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, 46, and 143 are rejected under 35 U.S.C. 103 as being unpatentable over Shanahan Jr. et al. (US 8,518,904; reference previously cited by the Examiner) in view of Bleicher et al. (WO 2019/122282; reference cited by Applicant) and Bermingham et al. (WO 2020/117703) 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, 46, and 143, the teachings of Shanahan Jr. et al., Bleicher et al., and Bermingham et al. are discussed above.
However, Shanahan Jr. et al., Bleicher et al., and Bermingham 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 (claim 3). Shanahan Jr. et al., Bleicher et al., and Bermingham et al. do not teach an exogenous targeting moiety (claim 33) or a scaffold moiety (claim 41). Shanahan Jr. et al., Bleicher et al., and Bermingham et al. also do not teach wherein the scaffold moiety is PTGFRN protein (claims 42 and 46). Shanahan Jr. et al., Bleicher et al. and Bermingham et al. also do not teach that the ASO, the exogenous targeting moiety, or both, is linked to the EV by the scaffold moiety (claim 143).
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 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 June 3, 2026 have been fully considered but they are not persuasive.
Applicant asserts the following:
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These arguments are not found persuasive. Shanahan Jr. et al. teaches compounds and compositions capable of modulating STAT6 expression wherein the compositions comprise oligonucleotides targeted to nucleic acid encoding STAT6 [abstract]. Shanahan Jr. et al. also teaches that a series of antisense compounds were designed to target different regions of the human STAT 6 RNA using published sequences (GenBank accession number NM_003153.1, SEQ ID NO: 4) [column 34, last paragraph]. Further, Shanahan Jr. et al. teaches that preferred target segments are locations on the target nucleic acid to which the preferred antisense compounds hybridize [column 9, first full paragraph]. While the specific sequences of certain preferred target segments are set forth, additional preferred target segments may be identified by one having ordinary skill [column 9, second full paragraph]. Finally, once one or more target regions, segments or sites have been identified, antisense compounds are chosen which are sufficiently complementary to the target to give the desired effect [column 9, fifth full paragraph]. 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”. The wings are composed of 2’-methoxyethyl (2’-MOE) nucleotides. The internucleoside linkages are phosphorothioate throughout the oligonucleotide and all cytidine residues are 5-methylcytidines [column 34, Example 15]. Shanahan Jr. et al. also teaches that preferred compounds are oligonucleotides about 15 to 30 nucleobases [column 6, lines 43-45] and that antisense oligonucleotides may contain modified backbones (e.g., phosphorothioates), one or more substituted sugar moieties (e.g., 2’-MOE, LNA), and nucleobase modifications or substitutions (e.g., 5-methylcytosine) [Section F, columns 12-15] (emphasis added).
Shanahan Jr. et al. does not teach that the ASO reduces STAT6 expression by at least 50% at 2 nM; however, Bermingham et al. does teach that an oligonucleotide exhibits at least 50% mRNA inhibition at a 2 nM oligonucleotide concentration. Therefore, based on the teachings of Bermingham et al., one of ordinary skill in the art before the effective filing date of the claimed invention would design an antisense oligonucleotide according to claim 1 wherein the ASO reduces STAT6 expression by at least 50% at 2 nM using the design principles taught by Shanahan Jr. et al. and Bleicher et al. because it would have amounted to applying known design principles to a known STAT6 RNA sequence to yield predictable results.
With respect to Applicant’s arguments regarding the Bleicher et al. reference, Bleicher et al. was previously used in combination with Shanahan Jr. et al. to render obvious the limitations of the claims because Shanahan Jr. et al. did not teach packaging of antisense oligonucleotides into extracellular vesicles and Shanahan Jr. et al. did not teach a linker linking the antisense oligonucleotide to the extracellular vesicle.
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.
Claims 1, 3, 6, 11, 23, 27, 31, 33, 41, 42, 46, 78, 79, and 143 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 91, and 116 of copending Application No. 17/763,996 in view of Shanahan Jr. et al. (US 8,518,904; reference previously cited by the Examiner), Bleicher et al. (WO 2019/122282; reference cited by Applicant), Bermingham et al. (WO 2020/117703), Gallego-Perez et al. (WO 2020/082005; reference previously cited by the Examiner), Wang et al. (Oncotarget 2015; reference previously cited by the Examiner), and McConnell et al. (WO 2019/099942; reference cited by Applicant).
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Instant SEQ ID NO: 151 (designated as Qy) has a 100% match to ‘996 SEQ ID NO: 185 (designated as Db) as shown in the alignment below.
Query Match 100.0%; Score 17; DB 1; Length 20;
Best Local Similarity 100.0%;
Matches 17; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 GCAAGATCCCGGATTCG 17
|||||||||||||||||
Db 1 GCAAGATCCCGGATTCG 17
However, ‘996 does not teach the antisense oligonucleotide design as recited in the instant claims wherein the ASO reduces STAT6 expression by at least 50% at 2 nM and is capable of reducing STAT6 mRNA or protein expression in a human cell. ‘996 does not teach that the extracellular vesicle is 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. ‘996 also does not teach wherein the extracellular vesicle further comprises an anchoring moiety, an exogenous targeting moiety, or a scaffold moiety (e.g., PTGFRN protein), wherein the ASO is linked to the anchoring moiety by a linker, or wherein the ASO, the exogenous targeting moiety, or both, is linked to the EV by the scaffold moiety.
Shanahan Jr. et al. 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]. Shanahan Jr. et al. also teaches that the modified oligonucleotides may also contain one or more substituted sugar moieties [column 14, first full paragraph]. A further preferred modification of the sugar includes Locked Nucleic Acids (LNAs) [column 14, lines 57-58]. Further, Shanahan Jr. et al. teaches oligonucleotides containing modified backbones or non-natural internucleoside linkages [column 12, fourth full paragraph]. Preferred modified oligonucleotide backbones containing a phosphorus atom therein include phosphorothioates [column 12, last paragraph]. Shanahan Jr. et al. teaches that antisense oligonucleotides may contain nucleobase modifications or substitutions (e.g., 5-methylcytosine) [column 14, last paragraph bridging to column 15]. Further, Shanahan Jr. et al. teaches that 5-methylcytosine substitutions have been shown to increase nucleic acid duplex stability and are presently preferred base substitutions [column 15, lines 44-46]. Table 1 (reproduced below) 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].
ISIS # Region Target SID Target site Sequence % inhibition SID Ctrl SID
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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].
Bleicher et al. teaches that antisense oligonucleotides may be effectively delivered via exosomes [page 56, lines 3-32]. 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]. 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]. Bleicher et al. teaches gapmer antisense oligonucleotides comprising three distinct structural regions from 5’ to 3’: F-G-F’ wherein F and F’ comprise one or more sugar modified nucleosides such as LNA and “G” refers to the gap region comprising a stretch of contiguous DNA nucleotides [page 44, first full paragraph]. Further, the overall length of the gapmer design may be 12 to 32 nucleosides [page 44, last paragraph], the gap region may consist of 11 contiguous DNA nucleosides, and methylation of cytosine DNA in the gap region is advantageous to reduce potential toxicity [page 45, lines 17-18 and 20-21].
Bermingham et al. teaches compositions to treat trinucleotide repeat expansion disorders [abstract]. Bermingham et al. also teaches that in some aspects, the oligonucleotide exhibits at least 50% mRNA inhibition at a 2 nM oligonucleotide concentration when determined using a cell assay when compared with a control cell [page 5, last paragraph bridging to page 6].
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].
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 modify the antisense oligonucleotide of ‘996 and arrive at the instantly claimed antisense oligonucleotide wherein the ASO reduces STAT6 expression by at least 50% at 2 nM and is capable of reducing STAT6 mRNA or protein expression in a human cell using the design principles taught by Shanahan Jr. et al. and Bleicher et al. because it would have amounted to applying known design principles to yield predictable results. One of ordinary skill in the art would have been motivated to do so because Shanahan Jr. et al. taught that there are no known therapeutic agents that effectively inhibit the synthesis of STAT 6 and thus there remains a long felt need for additional agents capable of effectively inhibiting STAT 6 function [column 2, last full paragraph]. Shanahan Jr. et al. and Bleicher et al. taught the design of gapmers, Bleicher et al. also taught that antisense gapmers are used to inhibit a target nucleic acid via RNase H mediated degradation [page 44, first full paragraph], and Bermingham et al. taught that 50% inhibition can be achieved at a concentration of 2 nM.
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 '996 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.
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 '996 to comprise a scaffold moiety such as 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.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 3, 6, 11, 23, 27, 31, 33, 41, 42, 46, 78, 79, and 143 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 45, 48, 53, 57, 59, and 64 of copending Application No. 18/552,778 in view of Shanahan Jr. et al. (US 8,518,904; reference previously cited by the Examiner), Bleicher et al. (WO 2019/122282; reference cited by Applicant), Bermingham et al. (WO 2020/117703), Gallego-Perez et al. (WO 2020/082005; reference previously cited by the Examiner), Wang et al. (Oncotarget 2015; reference previously cited by the Examiner), and McConnell et al. (WO 2019/099942; reference cited by Applicant).
Instant SEQ ID NO: 151 (designated as Qy) has a match to ‘778 SEQ ID NO: 185 (designated as Db) as shown in the alignment below.
Query Match 100.0%; Score 17; DB 1; Length 20;
Best Local Similarity 100.0%;
Matches 17; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 GCAAGATCCCGGATTCG 17
|||||||||||||||||
Db 1 GCAAGATCCCGGATTCG 17
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However, ‘778 does not teach the antisense oligonucleotide design as recited in the instant claims wherein the ASO reduces STAT6 expression by at least 50% at 2 nM and is capable of reducing STAT6 mRNA or protein expression in a human cell. ‘778 does not teach that the extracellular vesicle is 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. ‘778 does not teach that the extracellular vesicle further comprises an anchoring moiety wherein the ASO is linked to the anchoring moiety by a linker; an exogenous targeting moiety; wherein the ASO is linked to the EV by a linker; or wherein the ASO, the exogenous targeting moiety, or both is linked to the EV by the scaffold moiety.
Shanahan Jr. et al. 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]. Shanahan Jr. et al. also teaches that the modified oligonucleotides may also contain one or more substituted sugar moieties [column 14, first full paragraph]. A further preferred modification of the sugar includes Locked Nucleic Acids (LNAs) [column 14, lines 57-58]. Further, Shanahan Jr. et al. teaches oligonucleotides containing modified backbones or non-natural internucleoside linkages [column 12, fourth full paragraph]. Preferred modified oligonucleotide backbones containing a phosphorus atom therein include phosphorothioates [column 12, last paragraph]. Shanahan Jr. et al. teaches that antisense oligonucleotides may contain nucleobase modifications or substitutions (e.g., 5-methylcytosine) [column 14, last paragraph bridging to column 15]. Further, Shanahan Jr. et al. teaches that 5-methylcytosine substitutions have been shown to increase nucleic acid duplex stability and are presently preferred base substitutions [column 15, lines 44-46]. Table 1 (reproduced below) 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].
ISIS # Region Target SID Target site Sequence % inhibition SID Ctrl SID
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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].
Bleicher et al. teaches that antisense oligonucleotides may be effectively delivered via exosomes [page 56, lines 3-32]. 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]. 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]. Bleicher et al. teaches gapmer antisense oligonucleotides comprising three distinct structural regions from 5’ to 3’: F-G-F’ wherein F and F’ comprise one or more sugar modified nucleosides such as LNA and “G” refers to the gap region comprising a stretch of contiguous DNA nucleotides [page 44, first full paragraph]. Further, the overall length of the gapmer design may be 12 to 32 nucleosides [page 44, last paragraph], the gap region may consist of 11 contiguous DNA nucleosides, and methylation of cytosine DNA in the gap region is advantageous to reduce potential toxicity [page 45, lines 17-18 and 20-21].
Bermingham et al. teaches compositions to treat trinucleotide repeat expansion disorders [abstract]. Bermingham et al. also teaches that in some aspects, the oligonucleotide exhibits at least 50% mRNA inhibition at a 2 nM oligonucleotide concentration when determined using a cell assay when compared with a control cell [page 5, last paragraph bridging to page 6].
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].
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 modify the antisense oligonucleotide of ‘778 and arrive at the instantly claimed antisense oligonucleotide wherein the ASO reduces STAT6 expression by at least 50% at 2 nM and is capable of reducing STAT6 mRNA or protein expression in a human cell using the design principles taught by Shanahan Jr. et al. and Bleicher et al. because it would have amounted to applying known design principles to yield predictable results. One of ordinary skill in the art would have been motivated to do so because Shanahan Jr. et al. taught that there are no known therapeutic agents that effectively inhibit the synthesis of STAT 6 and thus there remains a long felt need for additional agents capable of effectively inhibiting STAT 6 function [column 2, last full paragraph]. Shanahan Jr. et al. and Bleicher et al. taught the design of gapmers, Bleicher et al. also taught that antisense gapmers are used to inhibit a target nucleic acid via RNase H mediated degradation [page 44, first full paragraph], and Bermingham et al. taught that 50% inhibition can be achieved at a concentration of 2 nM.
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 ‘778 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.
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the composition of '778 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.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 3, 6, 11, 23, 27, 31, 33, 41, 42, 46, 78, 79, and 143 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 4, 6, 12, 13, 22, 26, 32, 36, 45, 53, 56 of copending Application No. 18/248,036 in view of Bermingham et al. (WO 2020/117703) and McConnell et al. (WO 2019/099942; reference cited by Applicant).
‘036 SEQ ID NO: 151 from FIG. 1 (reproduced below) is the same sequence and design as instant SEQ ID NO: 151 recited in instant claim 1.
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However, ‘036 does not teach wherein the ASO reduces STAT6 expression by at least 50% at 2 nM and is capable of reducing STAT6 mRNA or protein expression in a human cell. ‘036 also does not teach that the scaffold moiety is PTGFRN.
Bermingham et al. teaches compositions to treat trinucleotide repeat expansion disorders [abstract]. Bermingham et al. also teaches that in some aspects, the oligonucleotide exhibits at least 50% mRNA inhibition at a 2 nM oligonucleotide concentration when determined using a cell assay when compared with a control cell [page 5, last paragraph bridging to page 6].
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 modify the antisense oligonucleotide of ‘036 wherein the ASO reduces STAT6 expression by at least 50% at 2 nM and is capable of reducing STAT6 mRNA or protein expression in a human cell because ‘036 taught an antisense oligonucleotide and Bermingham et al. taught that 50% inhibition can be achieved at a concentration of 2 nM. One of ordinary skill in the art would have made such a modification because it would have amounted to combining known prior art elements to yield predictable results.
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 ‘036 to comprise a scaffold moiety such as 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.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/C.T./
Examiner, Art Unit 1637
/Jennifer Dunston/Supervisory Patent Examiner, Art Unit 1637
Prosecution Insights