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 .
Applicant’s response of 07/09/2026 has been received and entered into the application file.
Claims 1, 8, 18, 90, and 99 were amended in the claim set filed 07/09/2026.
Claims 1, 8, 18, 21, 30, 36, 52, 85, 88, 90, 98-99, 126, 129, 135, 137, 141, and 146 are pending, of which claims 137, 141, and 146 were previously withdrawn.
Accordingly, claims 1, 8, 18, 21, 30, 36, 52, 85, 88, 90, 98-99, 126, 129, and 135 are pending and under consideration.
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the restriction requirements within the product groups (Groups I-V) and method groups (Groups VI-VIII) were previously withdrawn.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) are pending and under consideration.
Claims 137, 141 and 146 stand withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim, as set forth in the non-final rejection dated 04/14/2026. Election was made without traverse in the reply filed on 05/19/2025.
Status of Prior Objections/Rejections
RE: Claim Objections
►Claim 90 was previously objected to for minor informalities.
The amendments to instant claim 90 have obviated the basis of the objection of record. The objection of record is hereby withdrawn.
RE: Claim Rejections - 35 USC § 102
►Claim 99 was previously 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).
Applicant has traversed the rejection of record, asserting that amended instant claim 99 specifically recites that the antisense oligonucleotide claimed therein must comprise the nucleotide sequence selected from any one of SEQ ID NOs: 20, 28, 35, 36, 44, 45, 51, 59, 60, 71, 82, and 83. Applicant asserts that Shihama does not disclose each and every limitation of amended instant claim 99 and thus claim 99 is not anticipated by Shihama and is therefore novel over the reference.
In response, this is found persuasive. The rejection of record is hereby withdrawn. However, new grounds of rejection necessitated by amendment are set forth below.
RE: Claim Rejections - 35 USC § 103
►Claims 1, 8, 18, 21, 30, 36, 52, 85, 88, 90, 98, 129, and 135 were previously 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).
Applicant has traversed the rejection of record, asserting that amended independent instant claims 1 and 8 have been amended to require the nucleotide sequence selected from any one of SEQ ID NOs: 20, 28, 35, 36, 44, 45, 51, 59, 60, 71, 82, and 83. Applicant further asserts that the antisense oligonucleotides claimed therein are more efficient in knocking down the expression of G12D KRAS mRNA than the WT KRAS mRNA, with almost 100% inhibition being observed in some cases. Applicant points to these results to assert that the antisense oligonucleotides claimed therein are capable of specifically targeting a KRAS mRNA comprising the G12D mutation.
In response, it is found persuasive that Shihama does not disclose the nucleotide sequence selected from any one of SEQ ID NOs: 20, 28, 35, 36, 44, 45, 51, 59, 60, 71, 82, and 83. The rejection of record is hereby withdrawn. However, new grounds of rejection necessitated by amendment are set forth below.
Regarding Applicant’s arguments that the antisense oligonucleotides claimed therein are novel in that they specifically and efficiently target G12D KRAS mRNA for knockdown, this argument is not found persuasive. As previously set forth, Shihama discloses therapeutically relevant gapmer antisense oligonucleotides that specifically target mutant KRAS G12D transcripts (page 3, paragraph 5; Figures 3 and 4). Therefore, the specific targeting of mutant KRAS (i.e. G12D KRAS) for knockdown with antisense oligonucleotides cannot be considered novel over the prior art, as Shihama teaches such practice. However, the Examiner acknowledges that Shihama does not teach the entire sequence of any one of SEQ ID NOs: 20, 28, 35, 36, 44, 45, 51, 59, 60, 71, 82, and 83. New grounds of rejection necessitated by amendment are set forth below.
►Claim 126 was previously 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).
Applicant has traversed the rejection of record, asserting that claim 126 depends directly from claim 99 and therefore includes each and every element of claim 99. As set forth above, Applicant argues that Shihama does not disclose each and every limitation of amended instant claim 99 and therefore claim 126 cannot be rendered obvious over Shihama.
In response, as set forth above, it is found persuasive that Shihama does not disclose each and every limitation of amended instant claim 99, from which instant claim 126 directly depends. The rejection of record is hereby withdrawn. However, new grounds of rejection necessitated by amendment are set forth below.
New/Maintained Grounds of Objection/Rejection
Claim Interpretation
As previously set forth, 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 and 85 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 and 85, as the other recited moieties are not required by the instant claim language.
Claim Objections
Applicant is advised that should claim 1 be found allowable, claim 8 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
In the instant case, both instant claims 1 and 8 are drawn to extracellular vesicles comprising an antisense oligonucleotide comprising the nucleotide sequence selected from SEQ ID NOs: 20, 28, 35, 36, 44, 45, 51, 59, 60, 71, 820, and 83. Therefore, despite slight differences in wording, they are considered to be substantial duplicates of each other. Should claim 1 be found allowable, claim 8 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof.
Claim Rejections - 35 USC § 112(b)
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 1, 8, 18, 21, 30, 36, 52, 85, 88, 90, 98, 99, 126, 129, and 135 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.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claims 1 (from which claims 18, 21, 30, 36, 52, 85, 88, 90, 98, 129, and 135 all directly or indirectly depend), 8, and 99 (from which claim 126 depends) recite the broad recitation “an antisense oligonucleotide (ASO) which comprises a contiguous nucleotide sequence of 10 to 30 nucleotides in length), and the claims also recite “the ASO comprises the nucleotide sequence selected from any one of SEQ ID NOs: 20, 28, 35, 36, 44, 45, 51, 59, 60, 71, 82, and 83” which is the narrower statement of the range/limitation, as all of these sequences are 15-20 nucleotides in length. Therefore, it is unclear what it means to refer to an ASO that has a length of 10 to 30 nucleotides if none of the recited SEQ ID NOs have a length of less than 15 nucleotides. Put another way, the recitation of “10 to 30 nucleotides in length” necessarily encompasses ASOs including regions of complementarity of 10, 11, 12, 13, and 14 nucleotides, yet the shortest sequence of the recited sequence identifiers is 15 nucleotides. It is unclear if less than the entire sequence is required or whether the complementarity must be at least 15 nucleotides, which is the length of the shortest ASO recited in the instant claim set.
The claims are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
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.
Claims 99 and 126 are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by US 2010/0286241 A1 (hereinafter Xie).
With regard to amended 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, wherein the ASO comprises the nucleotide sequence selected from any one of SEQ ID NOs: 20, 28, 35, 36, 44, 45, 51, 59, 60, 71, 82, and 83,” Xie discloses siRNAs that target mutated hK-ras K12/Asp (i.e. G12D) at Table 3. While the disclosure of Xie is drawn to siRNAs, the Examiner sets forth that the definition of an antisense oligonucleotide set forth in the instant application reads on an siRNA under broadest reasonable interpretation. The instant specification sets forth that the term “antisense oligonucleotide” (ASO) refers to an oligomer or polymer of nucleosides, such as naturally-occurring nucleosides or modified forms thereof, that are covalently linked to each other through internucleotide linkages at paragraph [0095]. Furthermore, at paragraph [0166], it is set forth that “in some aspects, the ASO is not a siRNA,” meaning in some aspects, it can be an siRNA. Furthermore, even if one does not accept that the instant claim language also embraces siRNA species, Xie explicitly discloses that in certain embodiments, the RNA molecules taught therein are single stranded (paragraphs [0020], [0027], and [0034]) and comprise at least one nucleotide sequence selected from the group consisting of SEQ ID NOs: 1-474 and 479-488 (paragraph [0019]). SEQ ID NO: 70 of Xie (listed at Table 3) is an antisense sequence that falls within this range and comprises 100% identity to instant SEQ ID NO: 20, as shown in the alignment below.
PNG
media_image1.png
156
623
media_image1.png
Greyscale
Furthermore, as shown in the alignment below, SEQ ID NO: 70 of Xie is complementary to a nucleic acid sequence within nucleotides 5,568 to 5,606 of a KRAS G12D transcript as set forth in SEQ ID NO: 1. The Examiner notes that the alignment below was generated by aligning specifically sequences 5,568 to 5,606 of SEQ ID NO: 1 to SEQ ID NO: 70 of Xie. Therefore, the numbering in the alignment corresponds to this subset of SEQ ID NO: 1 rather than SEQ ID NO: 1 in its entirety.
PNG
media_image2.png
153
634
media_image2.png
Greyscale
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,” Xie further discloses that the nucleic acid molecules of the instant invention (such as those set above) may be conjugated to PEG or to phospholipids (paragraphs [0109] and [0110]).
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, 36, 52, 85, 88, 90, 98, 129, and 135under 35 U.S.C. 103 as being unpatentable over US 2010/0286241 A1 (hereinafter Xie) in view of WO 2018/102397 A1 (hereinafter Bolen; as cited in the IDS filed 12/07/2022; of record).
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 the nucleotide sequence selected from any one of SEQ ID NOs: 20, 28, 35, 36, 44, 45, 51, 59, 60, 71, 82, and 83,” as set forth above, Xie discloses siRNAs that target mutated hK-ras K12/Asp (i.e. G12D) at Table 3. While the disclosure of Xie is drawn to siRNAs, the Examiner sets forth that the definition of an antisense oligonucleotide set forth in the instant application reads on an siRNA under broadest reasonable interpretation. The instant specification sets forth that the term “antisense oligonucleotide” (ASO) refers to an oligomer or polymer of nucleosides, such as naturally-occurring nucleosides or modified forms thereof, that are covalently linked to each other through internucleotide linkages at paragraph [0095]. Furthermore, at paragraph [0166], it is set forth that “in some aspects, the ASO is not a siRNA,” meaning in some aspects, it can be an siRNA. Furthermore, even if one does not accept that the instant claim language also embraces siRNA species, Xie explicitly discloses that in certain embodiments, the RNA molecules taught therein are single stranded (paragraphs [0020], [0027], and [0034]) and comprise at least one nucleotide sequence selected from the group consisting of SEQ ID NOs: 1-474 and 479-488 (paragraph [0019]). SEQ ID NO: 70 of Xie (listed at Table 3) is an antisense sequence that falls within this range and comprises 100% identity to instant SEQ ID NO: 20, as shown in the alignment below.
PNG
media_image1.png
156
623
media_image1.png
Greyscale
Furthermore, as shown in the alignment below, SEQ ID NO: 70 of Xie is complementary to a nucleic acid sequence within nucleotides 5,568 to 5,606 of a KRAS G12D transcript as set forth in SEQ ID NO: 1. The Examiner notes that the alignment below was generated by aligning specifically sequences 5,568 to 5,606 of SEQ ID NO: 1 to SEQ ID NO: 70 of Xie. Therefore, the numbering in the alignment corresponds to this subset of SEQ ID NO: 1 rather than SEQ ID NO: 1 in its entirety.
PNG
media_image2.png
153
634
media_image2.png
Greyscale
Thus, Xie discloses each and every limitation of instant claim 1 with the exception of packaging the antisense oligonucleotide taught therein into an extracellular vesicle. This deficiency is cured by Bolen. 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 Xie and Bolen collectively disclose and/or motivate each and every limitation of amended instant claim 1.
With regard to amended claim 8, which recites “an extracellular vesicle comprising an antisense oligonucleotide (ASO) 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, wherein the ASO comprises the nucleotide sequence selected from any one of SEQ ID NOs: 20, 28, 35, 36, 44, 45, 51, 59, 60, 71, 82, and 83,” as set forth above, Xie discloses siRNAs that specifically target mutated hK-ras K12/Asp (i.e. G12D, as instantly claimed) at Table 3. While the disclosure of Xie is drawn to siRNAs, the Examiner sets forth that the definition of an antisense oligonucleotide set forth in the instant application reads on an siRNA under broadest reasonable interpretation. The instant specification sets forth that the term “antisense oligonucleotide” (ASO) refers to an oligomer or polymer of nucleosides, such as naturally-occurring nucleosides or modified forms thereof, that are covalently linked to each other through internucleotide linkages at paragraph [0095]. Furthermore, at paragraph [0166], it is set forth that “in some aspects, the ASO is not a siRNA,” meaning in some aspects, it can be an siRNA. Furthermore, even if one does not accept that the instant claim language also embraces siRNA species, Xie explicitly discloses that in certain embodiments, the RNA molecules taught therein are single stranded (paragraphs [0020], [0027], and [0034]) and comprise at least one nucleotide sequence selected from the group consisting of SEQ ID NOs: 1-474 and 479-488 (paragraph [0019]). SEQ ID NO: 70 of Xie (listed at Table 3) is an antisense sequence that falls within this range and comprises 100% identity to instant SEQ ID NO: 20, as shown in the alignment below.
PNG
media_image1.png
156
623
media_image1.png
Greyscale
Thus, Xie discloses each and every limitation of instant claim 8 with the exception of packaging the antisense oligonucleotide taught therein into an extracellular vesicle. This deficiency is cured by Bolen. 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 Xie and Bolen collectively disclose and/or motivate each and every limitation of amended instant claim 8.
With regard to amended claim 18, which recites “the extracellular vesicle of claim 1, wherein:…the ASO comprises one or more nucleoside analogs…”, Xie further discloses that the siRNA polynucleotides taught therein comprise at least one synthetic nucleotide analogue of a naturally occurring nucleotide (paragraphs [0019] and [0084]).
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, Xie discloses that the siRNA polynucleotides taught therein comprise at least one synthetic nucleotide analogue of a naturally occurring nucleotide (paragraphs [0019] and [0084]). Per the definition of paragraph [0084] of Xie, modifications at the sugar moiety of a nucleotide are referred to as nucleotide analogs, meaning Xie discloses that the siRNA polynucleotides taught therein comprise at least one nucleotide with a modified sugar moiety (paragraphs [0019] and [0084]), which reads on the instant claim limitations.
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. Furthermore, per the instant specification, exemplary anchoring moieties include cholesterol (paragraph [0043]). Bolen also discloses that the therapeutic agents taught therein may comprise a hydrophobic group such as cholesterol (paragraphs [00105] and [00106]). Bolen further discloses that said hydrophobic moiety may be conjugated directly to the therapeutic nucleic acid molecules disclosed therein or may be connected to the same via a linker (paragraph [00111]).
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, Xie and Bolem 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 and/or motivated by Xie 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, Xie and Bolen 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 and/or motivated by Xie 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 discloses that the therapeutic agents taught therein may be connected to a hydrophobic group such as cholesterol (which reads on the instantly claimed anchoring moiety per paragraph [0043] of the instant specification) via a linker (paragraphs [00105], [00106], and [00111]).
With regard to claim 90, which recites “the linker [of the extracellular vesicle of claim 88]…is a polypeptide…”, Bolen further discloses that linkers suitable for use as set forth above include polypeptide linkers (paragraph [00216]).
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]).
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 Xie discloses siRNAs specific to KRAS G12D at Table 3 that read on the instantly claimed “antisense oligonucleotide,” while Bolen discloses that 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]).
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 Xie 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 Xie nor Bolen explicitly disclose a kit comprising the claimed extracellular vesicle, Xie and Bolen do collectively disclose the claimed extracellular vesicle. Thus, Xie and Bolen collectively anticipate each and every limitation of instant claim 135.
Given that Xie discloses siRNAs targeting KRAS G12D specifically that read on an “antisense oligonucleotide” and comprise one or more sugar-modified nucleoside analogs, and that Bolen discloses that therapeutic nucleic acids such as antisense oligonucleotides may be packaged into exosomes for delivery thereof and further that said therapeutic nucleic acids may be linked to an anchoring moiety such as cholesterol via a polypeptide linker, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to modify the siRNAs disclosed in Xie such that they comprise an anchoring moiety such as cholesterol linked via a polypeptide linker and are packaged into an exosome (as per Bolen) to predictably generate an effective system for the delivery of said therapeutic nucleic acids that specifically target KRAS G12D. One would have been motivated to make such a modification in order to receive the expected benefit of generating an effective system for the delivery of said therapeutic nucleic acids that specifically target KRAS G12D.
Claim 30 is rejected under 35 U.S.C. 103 as being unpatentable over US 2010/0286241 A1 (hereinafter Xie) in view of WO 2018/102397 A1 (hereinafter Bolen; as cited in the IDS filed 12/07/2022; of record) as applied to claim 1 above, and further in view of Shihama et al., 2018 (hereinafter Shihama; English translation appended to the end; of record).
The combined disclosures of Xie and Bolen are described above and applied as before. However, these disclosures do not teach the ASO design of instant claim 30.
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, Xie discloses siRNAs that targeting KRAS G12D that read on the instantly claimed antisense oligonucleotide (see Table 3), while Bolen discloses packaging of therapeutic nucleic acids into extracellular vesicles for delivery thereof (abstract). However, Xie and Bolen are silent as to the instantly claimed ASO design. This deficiency is cured by Shihama. 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.
Given that Xie and Bolen collectively disclose the extracellular vesicle of instant claim 1, and that Shihama discloses antisense oligonucleotides specifically targeting KRAS G12D, wherein said antisense oligonucleotides comprise the structure of LLLLLDnLLLLL, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to modify the structure of the antisense oligonucleotide sequence disclosed in Xie as per the disclosure of Shihama to predictably generate a therapeutically effective antisense oligonucleotide specifically targeting KRAS G12D. One would have been motivated to make such a modification in order to receive the expected benefit of generating a therapeutically effective antisense oligonucleotide specifically targeting KRAS G12D.
Conclusion
No claims are allowed.
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-F 8-5.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
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.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/SARAH E ALLEN/ Examiner, Art Unit 1637
/Jennifer Dunston/ Supervisory Patent Examiner, Art Unit 1637
Prosecution Insights