DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 02/27/2026 pursuant to the amended claim set filed 01/28/2026 has been entered.
Claims 1 and 137 were amended in the claim set filed 01/28/2026.
Election/Restrictions
Applicant previously elected without traverse Group I (claims 1, 18, 21, 27, 29, 30, 36, 52, 85, 88, 90, and 98) in the reply filed on 05/19/2025. While this requirement was upheld in the previous actions, upon further consideration, the restriction requirements within the product groups (Groups I-V) and method groups (Groups VI-VIII) are hereby withdrawn. For purposes of examination, previous Groups I-V directed to products are now Group I, and previous Groups VI-VIII directed to methods are now Group II.
Accordingly claims 1, 8, 18, 21, 30, 36, 52, 85, 88, 90, 98, 99, 126, 129, and 135 (Group I) is pending and under consideration.
Claims 137, 141 and 146 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 05/19/2025.
Furthermore, because a claimed invention previously withdrawn from consideration under 37 CFR 1.142 has been rejoined, the restriction requirement between Groups I-V and Groups VI-VIII as set forth in the Office action mailed on 03/19/2025 is hereby withdrawn. In view of the withdrawal of the restriction requirement as to the rejoined inventions, applicant(s) are advised that if any claim presented in a divisional application is anticipated by, or includes all the limitations of, a claim that is allowable in the present application, such claim may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application.
Once the restriction requirement is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable. See In re Ziegler, 443 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971). See also MPEP § 804.01.
Status of Prior Objections/Rejections
RE: Claim Rejections - 35 USC § 103
►Claims 1, 18, 21, 30, and 98 were previously rejected under 35 U.S.C. 103 as being unpatentable over US 8,889,642 B2 (hereinafter Shemi) in view of WO 2017/053722 A1 (hereinafter Revenko; as cited in the IDS filed 12/07/2022; of record) and WO 2018/102397 A1 (hereinafter Bolen; as cited in the IDS filed 12/07/2022; of record), as evidenced by Watts and Corey, 2011 and Lam et al., 2015.
Applicant has traversed the rejection of record, asserting that the mechanisms by which the antisense strands of siRNAs and antisense oligonucleotides (ASO) function are functionally distinct. Applicant further asserts that amended instant claim 1 recites that the ASO comprises a nucleotide sequence selected from any one of SEQ ID NOs: 20, 28, 35, 36, 44, 45, 51, 59, 60, 71, 82, and 83, none of which are disclosed in the cited prior art.
In response, while the Examiner appreciates that there are functional distinctions between duplex RNAi agents such as siRNAs and single-stranded ASOs, as set forth by applicant, these agents both share the features of antisense strands that bind to a target RNA through Watson-Crick base pairing (reviewed in Watts and Corey, 2011: of record). The instant claim language requires only that the claimed extracellular vesicle comprises an ASO (as disclosed in Bolen and previously set forth) comprising a contiguous nucleotide sequence of 10 to 30 nucleotides in length that is complementary to specified nucleotides within a KRAS G12D transcript, wherein the ASO comprises a nucleotide sequence selected from any one of the recited sequences set forth above. As previously set forth, the instant specification defines an ASO as “an oligomer or polymer of nucleosides…that are covalently linked to each other through internucleotide linkages…[and are] at least partially complementary to a target nucleic acid, such that the ASO hybridizes to the target nucleic acid sequence” (paragraph [0095]1). Therefore, under broadest reasonable interpretation, any oligomer or polymer of nucleosides covalently linked to each other that are at least partially complementary to a target nucleic acid (i.e. nucleotides 5,568 to 5,606 of a KRAS G12D transcript) for purposes of hybridizing to said nucleic acid and further comprising any dinucleotide or larger oligonucleotide from the claimed SEQ ID NO would read on the instantly claimed ASO. In order to claim the entirety of a recited sequence, the claim must recite “the nucleotide sequence” rather than “a nucleotide sequence.” Furthermore, any other required features must be recited in the claim language. Accordingly, while Applicant’s arguments have been fully considered, they are not found persuasive. However, the amendments to instant claim 1 have necessitated new grounds of rejection, as set forth below.
►Claims 36, 85, 88, and 90 were previously rejected under 35 U.S.C. 103 as being unpatentable over US 8,889,642 B2 (hereinafter Shemi) in view of WO 2017/053722 A1 (hereinafter Revenko; as cited in the IDS filed 12/07/2022; of record) and WO 2018/102397 A1 (hereinafter Bolen; as cited in the IDS filed 12/07/2022; of record), as evidenced by Watts and Corey, 2011 and Lam et al., 2015 as applied to claim 1, and further in view of Haraszti et al., 2018 (of record).
Applicant has traversed the rejection of record, asserting that claims 36, 85, 88, and 90 depend directly or indirectly from amended claim 1 and are therefore not obvious over the cited art for at least the same reasons as amended claim 1.
In response, this is found persuasive. The amendments to instant claim 1, from which all the previously rejected claims directly or indirectly depend have necessitated new grounds of rejection, as set forth below.
►Claim 52 was previously rejected under 35 U.S.C. 103 as being unpatentable over US 8,889,642 B2 (hereinafter Shemi) in view of WO 2017/053722 A1 (hereinafter Revenko; as cited in the IDS filed 12/07/2022; of record), WO 2018/102397 A1 (hereinafter Bolen; as cited in the IDS filed 12/07/2022; of record), and Haraszti et al., 2018 (of record), as evidenced by Watts and Corey, 2011 and Lam et al., 2015 as applied to claim 36, and further in view of US 10,195,290 B1 (hereinafter Dooley; as cited in the IDS filed 07/29/2024; of record).
Applicant has traversed the rejection of record, asserting that claim 52 depends indirectly from amended claim 1 and is therefore not obvious over the cited art for at least the same reasons as amended claim 1.
In response, this is found persuasive. The amendments to instant claim 1, from which the previously rejected claim indirectly depends have necessitated new grounds of rejection, as set forth below.
New/Maintained Grounds of Objection/Rejection
Claim Interpretation
With regard to claims 52, 85, 88, and 90, which directly or indirectly depend from instant claim 36, the Examiner notes that instant claim 36 recites “the extracellular vesicle of claim 1…further comprises:
an anchoring moiety, wherein the ASO is linked to the anchoring moiety;
a scaffolding moiety;
an exogenous targeting moiety; or
any combination of (i) to (iii)”
(bolded emphasis added), which requires only one/any one of the recited moieties to be included in the instantly claimed extracellular vesicle. Thus, the claimed extracellular vesicle requires either an anchoring moiety, a scaffolding moiety, an exogenous targeting moiety, or any combination thereof. The recitation of claims 52, 85, 88, and 90 are drawn to the scaffold moieties and anchoring moieties of instant claim 36, but these recitations do not require the inclusion of these moieties. Therefore, any extracellular vesicle comprising only one/any one of the recited moieties must also read on the extracellular vesicle of dependent claims 52, 85, 88, and 90, as the other recited moieties are not required by the instant claim language.
Claim Objections
Claim 90 is objected to because of the following informalities:
The recitation of instant claim 90 ends with improper punctuation. There are two periods punctuating the sentence of instant claim 90. In order to comport with standard grammatical and/or linguistic conventions, it would be remedial to amend instant claim 90 such that it is properly punctuated with a single period. Additionally, item (i) of instant claim 90 is not followed by a semicolon to properly separate the recitation of item (i) from subsequent items (ii)-(viii). In order to comport with standard grammatical and/or linguistic conventions, it would be remedial to amend instant claim 90 such that item (i) is properly followed by a semicolon to separate its recitation from that of subsequent items.
Appropriate correction is required.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim 99 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Shihama et al., 2018 (hereinafter Shihama; English translation appended to the end).
With regard to claim 99, which recites “an antisense oligonucleotide (ASO) comprising a contiguous nucleotide sequence of 10 to 30 nucleotides in length that is complementary to a nucleic acid sequence within nucleotides 5,568 to 5,606 of a KRAS G12D transcript which is set forth in SEQ ID NO: 1,” Shihama discloses gapmer antisense oligonucleotides specific to KRAS G12D (abstract). Shihama specifically discloses that the study described therein developed precise nucleic acid drugs that can selectively suppress the expression of mutant KRAS genes (i.e. G12D) without affecting wild-type KRAS genes (page 3, paragraph 5). The gapmer antisense nucleic acids of Shihama are disclosed at page 6, all of which are 21 nucleotides in length. Furthermore, as shown in the alignment below, PS7 of Shihama targets a portion of residues 5,568-5,606 of instant SEQ ID NO: 1, as instantly claimed. Thus, Shihama anticipates each and every limitation of instant claim 99.
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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.
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, 8, 18, 21, 30, 36, 52, 85, 88, 90, 98, 129, and 135 are rejected under 35 U.S.C. 103 as being unpatentable over Shihama et al., 2018 (hereinafter Shihama; English translation appended to the end) in view of WO 2018/102397 A1 (hereinafter Bolen; as cited in the IDS filed 12/07/2022; of record).
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With regard to amended claim 1, which recites “an extracellular vesicle (EV) comprising an antisense oligonucleotide (ASO) which comprises a contiguous nucleotide sequence of 10 to 30 nucleotides in length that is complementary to a nucleic acid sequence within nucleotides 5,568 to 5,606 of a KRAS G12D transcript, which is set forth in SEQ ID NO: 1, wherein the ASO comprises a nucleotide sequence selected from any one of SEQ ID NOs: 20, 28, 35, 36, 44, 45, 51, 59, 60, 71, 82, and 83,” Shihama discloses gapmer antisense oligonucleotides specific to KRAS G12D (abstract). Shihama specifically discloses that the study described therein developed precise nucleic acid drugs that can selectively suppress the expression of mutant KRAS genes (i.e. G12D) without affecting wild-type KRAS genes (page 3, paragraph 5). The gapmer antisense nucleic acids of Shihama are disclosed at page 6, all of which are 21 nucleotides in length. The Examiner notes that the instant phrasing “comprises a nucleotide sequence” embraces any nucleotide sequence with at least a shared dinucleotide sequence as compared to the instant sequence. As shown in the alignment below, instant SEQ ID NO: 20 and antisense gapmer compound PS11 of Shihama (page 6) share 93.3% sequence identity, satisfying the requirement of sharing at least a dinucleotide sequence.
Furthermore, given the shared sequence identity between instant SEQ ID NO: 20 and PS7 of Shihama, it is considered that these antisense oligomers must target the same region of a KRAS G12D transcript as recited at instant claim 1. This is supported by the alignment shown below, which shows that PS11 of Shihama targets a portion of residues 5,568-5,606 of instant SEQ ID NO: 1.
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Accordingly, it is considered that Shihama discloses all the limitations of amended instant claim 1, with the exception of packaging the antisense oligonucleotide into an extracellular vesicle. However, the disclosure of Bolen cures this deficiency as set forth below.
Bolen discloses that exosomes (used interchangeably with "extracellular vesicle[s]" per paragraph [0041]) are effective delivery vehicles for therapeutic agents such as antisense oligonucleotides (abstract; paragraph [0009]).
Thus, it is considered that Shihama and Bolen collectively disclose each and every limitation of amended instant claim 1.
With regard to claim 8, which recites “an extracellular vesicle comprising an antisense oligonucleotide (AS) which comprises a contiguous nucleotide sequence of 10 to 30 nucleotides in length that is complementary to a region of a nucleic acid sequence of a KRAS mutant transcript, wherein the region of the nucleic acid sequence that the ASO is complementary to comprises a mutation compared to a corresponding region of a wild-type KRAS transcript,” as set forth above, Shihama discloses gapmer antisense oligonucleotides specific to KRAS G12D (abstract). Shihama specifically discloses that the study described therein developed precise nucleic acid drugs that can selectively suppress the expression of mutant KRAS genes (i.e. G12D) without affecting wild-type KRAS genes (page 3, paragraph 5). The gapmer antisense nucleic acids of Shihama are disclosed at page 6, all of which are 21 nucleotides in length. These gapmer antisense nucleic acids are disclosed to have a sequence where the mutation site is located at the 10th position from the 5’ end to specifically target KRAS G12D (page 7, paragraph 1). Importantly, PS11, PS7, and PS5 gapmer antisense nucleic acids of Shihama all showed little effect on wild-type KRAS gene expression (Figure 3; page 10, paragraph 2). Thus, these gapmer antisense nucleic acids must target a mutant KRAS transcript rather than the wild-type KRAS transcript, as instantly claimed.
Accordingly, it is considered that Shihama discloses all the limitations of instant claim 8, with the exception of packaging the antisense oligonucleotide into an extracellular vesicle. However, the disclosure of Bolen cures this deficiency as set forth below.
Bolen discloses that exosomes (used interchangeably with "extracellular vesicle[s]" per paragraph [0041]) are effective delivery vehicles for therapeutic agents such as antisense oligonucleotides (abstract; paragraph [0009]).
Thus, it is considered that Shihama and Bolen collectively disclose each and every limitation of instant claim 8.
With regard to claim 18, which recites "(a) the ASO [of the extracellular vesicle of claim 1] is a gapmer, a mixmer, or a totalmer; (b) the ASO comprises one or more nucleoside analogs; (c) the ASO comprises one or more 5'-methyl cytosine nucleobases; (d) the ASO is from 14 to 20 nucleotides in length; or (e) any combination of (a) to (d)," as set forth above, Shihama discloses gapmer antisense oligonucleotides specific to KRAS G12D (abstract; page 6). Thus, it is considered that Shihama discloses each and every additional limitation of instant claim 18.
With regard to claim 21, which recites "one or more of the nucleoside analogs [of the extracellular vesicle of claim 18] are a sugar modified nucleoside," as set forth above, Shihama discloses gapmer antisense oligonucleotides specific to KRAS G12D (abstract; page 6). These gapmer antisense nucleic acids are further disclosed to comprise 2’-OMe residues, which is a known sugar modification as also disclosed at paragraph [0018] of the instant specification. Furthermore, the instant specification discloses that sugar modified nucleosides are considered to be nucleoside analogs at paragraph [0018]. Thus, it is considered that Shihama discloses each and every additional limitation of instant claim 21.
With regard to claim 30, which recites "the extracellular vesicle of claim 1, wherein the ASO has a design selected from LLLDnLLL, LLLLDnLLLL, LLLLLDnLLLLL, LLLMMDnMMLLL, LLLMDnMLLL, LLLLMMDnMMLLLL, LLLLMDnMLLLL, LLLLLLMMDnMMLLLLL, LLLLLLM On MLLLLL, or combinations thereof, wherein L is a nucleoside analog, D is DNA, M is 2'-MOE, and n can be any integer between 4 and 24," as set forth above, Shihama discloses gapmer antisense oligonucleotides specific to KRAS G12D such as PS11 (abstract; page 6). Per the instant specification, sugar modified nucleosides are considered to be nucleoside analogs, as instantly claimed (paragraph [0018]). Thus, PS11 of Shihama, which comprises 5 sugar-modified ribonucleic acid residues flanking a middle DNA section of 11 deoxyribonucleic acid residues, reads on the instantly claimed structure of LLLLLDnLLLLL. Thus, it is considered that Shihama discloses each and every additional limitation of instant claim 30.
With regard to claim 36, which recites "the extracellular vesicle of claim 1 ... further comprises:
an anchoring moiety, wherein the ASO is linked to the anchoring moiety;
a scaffolding moiety;
an exogenous targeting moiety; or
any combination of (i) to (iii),"
Bolen further discloses that the oligonucleotide agents disclosed therein (including antisense oligonucleotides) are particularly useful when targeted to the liver (paragraphs [0009] and [00419]). Targeting to the liver may be accomplished by incorporating an exogenous targeting moiety such as N-Acetyl-Galactosamine (paragraphs [00409], [00421], [00531], [00551], [00407]) to the therapeutic agent to facilitate its delivery to the liver. Thus, it is considered that Bolen discloses each and every additional limitation of instant claim 36.
With regard to claim 52, which recites “the scaffold moiety [of the extracellular vesicle of claim 36] comprises a Scaffold X, Scaffold Y, or both Scaffold X and Scaffold Y,” as set forth above, Bolen and Shihama collectively disclose the extracellular vesicle of instant claim 36, which comprises an ASO targeting KRAS G12D and an exogenous targeting moiety. Additionally, as set forth above (see section Claim Interpretation), claim 52 further limits the extracellular vesicle of claim 36, which does not require a scaffolding moiety. Thus, the extracellular vesicle collectively disclosed by Shihama and Bolen satisfies the requirement of an extracellular vesicle comprising an ASO targeting KRAS G12D and an exogenous targeting moiety in instant claims 1, 36, and 52. Accordingly, it is considered that Bolen discloses each and every additional limitation of instant claim 52.
With regard to claim 85, which recites “the anchoring moiety [of the extracellular vesicle of claim 36] comprises sterol, GM1, a lipid, a vitamin, a small molecule, a peptide, or a combination thereof,” as set forth above, Bolen and Shihama collectively disclose the extracellular vesicle of instant claim 36, which comprises an ASO targeting KRAS G12D and an exogenous targeting moiety. Additionally, as set forth above (see section Claim Interpretation), claim 85 further limits the extracellular vesicle of claim 36, which does not require an anchoring moiety. Thus, the extracellular vesicle collectively disclosed by Shihama and Bolen satisfies the requirement of an extracellular vesicle comprising an ASO targeting KRAS G12D and an exogenous targeting moiety in instant claims 1, 36, and 85. Accordingly, it is considered that Bolen discloses each and every additional limitation of instant claim 85.
With regard to claim 88, which recites “the ASO [of the extracellular vesicle of claim 36] is linked to the anchoring moiety by a linker,” as set forth above, Bolen and Shihama collectively disclose the extracellular vesicle of instant claim 36, which comprises an ASO targeting KRAS G12D and an exogenous targeting moiety. Additionally, as set forth above (see section Claim Interpretation), claim 88 further limits the extracellular vesicle of claim 36, which does not require an anchoring moiety. Thus, the extracellular vesicle collectively disclosed by Shihama and Bolen satisfies the requirement of an extracellular vesicle comprising an ASO targeting KRAS G12D and an exogenous targeting moiety in instant claims 1, 36, and 88. Accordingly, it is considered that Bolen discloses each and every additional limitation of instant claim 88.
With regard to claim 90, which recites “the linker [of the extracellular vesicle of claim 88]:
is a polypeptide[;]
is a non-polypeptide moiety;
comprises ethylene glycol;
comprises HEG, TEG, PEG, or any combination thereof;
comprises acrylic phosphoramidite, adenylation…or any combination thereof;
comprises a maleimide moiety;
comprises valine-alanine-p-aminobenzylcarbamate or valine-citrulline-p-aminobenzylcarbamate; or
any combination of (i) to (vii),”
as set forth above, Bolen and Shihama collectively disclose the extracellular vesicle of instant claims 36 and 88, which comprises an ASO targeting KRAS G12D and an exogenous targeting moiety. Additionally, as set forth above (see section Claim Interpretation), claim 90 further limits the extracellular vesicle of claim 88, which further limits the extracellular vesicle of claim 36, which does not require an anchoring moiety. Thus, the extracellular vesicle collectively disclosed by Shihama and Bolen satisfies the requirement of an extracellular vesicle comprising an ASO targeting KRAS G12D and an exogenous targeting moiety in instant claims 1, 36, 88, and 90. Accordingly, it is considered that Bolen discloses each and every additional limitation of instant claim 90.
With regard to claim 98, which recites "the extracellular vesicle [of claim 1] is an exosome," as set forth above, Bolen discloses that exosomes (used interchangeably with "extracellular vesicle[s]" per paragraph [0041]) are effective delivery vehicles for therapeutic agents such as antisense oligonucleotides (abstract; paragraph [0009]). Thus, it is considered that Bolen discloses each and every additional limitation of instant claim 98.
With regard to claim 129, which recites “a pharmaceutical composition comprising the extracellular vesicle of claim 1, and a pharmaceutically acceptable diluent, carrier, salt, or adjuvant,” as set forth above Shihama discloses gapmer antisense oligonucleotides specific to KRAS G12D (abstract; page 6), while Bolen discloses that such antisense oligonucleotides may be packaged into exosome (used interchangeably with "extracellular vesicle[s]" per paragraph [0041]) for delivery of therapeutic agents such as antisense oligonucleotides (abstract; paragraph [0009]). Per Bolen, such extracellular vesicles carrying therapeutic antisense oligonucleotides may be provided within a pharmaceutical composition, said pharmaceutical composition further comprising a pharmaceutically acceptable adjuvant, vehicle, or carrier (paragraph [0066]). Thus, it is considered that Bolen discloses each and every additional limitation of instant claim 129.
With regard to claim 135, which recites “a kit comprising the extracellular vesicle of claim 1, and instructions for use,” as set forth above, it is considered that Shihama and Bolen collectively disclose the extracellular vesicle of claim 1. Furthermore, the recited preamble of “a kit” does not generate or otherwise result in a structural difference of the product claimed therein, meaning the claim body recites a structurally complete invention, while the preamble only states a purpose or intended use for the invention and is thus not a claim limitation given patentable weight (see MPEP § 2111.02(II)). Furthermore, per MPEP § 2111.05(I)(B), printed instructions of a kit comprising a printed set of instructions for using the contents of the kit are not given patentable weight if it cannot be shown that the instructions are related to the particular contents of the kit (i.e. in a kit containing a set of chemicals and a printed set of instructions for using the chemicals, the instructions are not related to that particular set of chemicals. In re Ngai, 367 F.3d at 1339, 70 USPQ2d at 1864). Accordingly, while neither Shihama nor Bolen explicitly disclose a kit comprising the claimed extracellular vesicle, Shihama and Bolen do collectively disclose the claimed extracellular vesicle. Thus, Shihama and Bolen collectively anticipates each and every limitation of instant claim 135.
Given that Shihama discloses a gapmer antisense oligonucleotide specifically targeting KRAS G12D (within nucleotides 5,568-5,606 of instant SEQ ID NO: 1) and comprising 2’-OMe sugar modifications in an LLLLLDnLLLLL configuration, and that Bolen discloses that extracellular vesicles such as exosomes are effective delivery vehicles for therapeutic agents such as antisense oligonucleotides, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to subsequently package the antisense oligonucleotides of Shihama into exosomes or pharmaceutical compositions comprising the same as disclosed in Bolen to predictably deliver therapeutically effective antisense oligonucleotides to specifically inhibit KRAS G12D expression. One would have been motivated to make such a modification in order to receive the expected benefit of effectively delivering therapeutic antisense oligonucleotides to inhibit KRAS G12D expression.
Claim 126 is rejected under 35 U.S.C. 103 as being unpatentable over Shihama et al., 2018 (hereinafter Shihama; English translation appended to the end) as applied to claim 99 above (see section Claim Rejections - 35 USC § 102), and further in view of WO 2018/102397 A1 (hereinafter Bolen; as cited in the IDS filed 12/07/2022; of record).
The disclosure of Shihama is described above and applied as before. However, this disclosure does not teach the conjugate of instant claim 126.
With regard to claim 126, which recites “a conjugate comprising the ASO of claim 99, wherein the ASO is covalently attached to at least one non-nucleotide or non-polynucleotide moiety,” as set forth above, Shihama anticipates the ASO of claim 99. However, Shihama does not disclose a conjugate comprising said ASO. This deficiency is cured by Bolen. Bolen discloses that the therapeutic agents taught therein (including antisense oligonucleotides) may be conjugated to a hydrophobic group such as a sterol, steroid, or lipid to facilitate loading of the therapeutic agent into the exosome and/or delivery of the therapeutic agent to a target tissue or organ (paragraph [0009]). As is known to those of ordinary skill in the art, sterols, steroids, or lipids are not nucleotide-based molecules. Therefore, it is considered that Bolen discloses each and every additional limitation of instant claim 126.
Given that Shihama discloses therapeutically relevant gapmer ASOs specifically targeting mutant KRAS G12D transcripts, and that Bolen discloses that conjugation of antisense oligonculeotides to a hydrophobic group such as a sterol, steroid, or lipid facilitates loading of the same into the exosome and/or delivery of the same to a target tissue or organ, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to conjugate the gamper ASOs disclosed in Shihama to a hydrophobic group such as a sterol, steroid, or lipid (as disclosed in Bolen) to predictably facilitate improved loading into an exosome and/or delivery of said oligonucleotide to a target tissue or organ. One would have been motivated to make such a modification in order to receive the expected benefit of improving loading into an exosome and/or delivering said ASO to a target tissue or organ.
Conclusion
No claims are allowed.
Claim 90 is objected to.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Sarah E Allen whose telephone number is (571)272-0408. The examiner can normally be reached M-Th 8-5, F 8-12.
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/SARAH E ALLEN/ Examiner, Art Unit 1637
/J. E. ANGELL/ Primary Examiner, Art Unit 1637
1 The Examiner notes that the previous action erroneously referred to paragraph [0096] of the instant specification. This error has been corrected in the present action.
Prosecution Insights