1800DETAILED 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 .
Election/Restrictions
Applicant's election with traverse of claims 1-5, 10, 14-15, 19-21, 23, 25-27, 31, 33, and 35 with species election of SEQ ID NO:34 for the antisense strand in the reply filed on December 19, 2025 is acknowledged. Applicant did not provide any ground(s) for the traversal hence, applicant’s election with traverse is not found persuasive as no argument was provided.
The requirement is still deemed proper and is therefore made FINAL.
Status of Claims
Claims 1-5, 10, 14-15, 19-21, 23, 25-27, 31, 33, and 35-42 are currently pending in the instant application. Claims 36-37 and 41-42 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Accordingly, claims 1-5, 10, 14-15, 19-21, 23, 25-27, 31, 33, 35, and 38-40 are under examination on the merits in the instant application.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-5, 10, 14-15, 19-21, 23, 25-27, 31, 33, 35, and 38-40 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.
The instant claims recite “an antisense sequence listed in SEQ ID NO: 34 (DS-1016)” and “SEQ ID NO: 33 (DS-1016)” for the sense strand.
It is unclear what the parenthetical recitation of “(DS-1016)” represents as it is not an abbreviated term of SEQ ID NO:34 or SEQ ID NO:33. It is noted that the name “DS-1016” is not even disclosed in the instant specification. Hence, it is unclear what the parenthetical limitation means.
It is noted that Table 1 discloses a column “DUPLEX NO.” containing “D-1016” comprising SEQ ID NO:33 as the sense strand and SEQ ID NO:34 as the antisense strand. Now, even if “(DS-1016)” were meant to be (D-1016) disclosed in Table 1, the metes and bounds of the claimed subject matter cannot be clearly ascertained because the claims would recite the broad limitation requiring only “15 contiguous nucleotides differing by no more than 3 nucleotides from” SEQ ID NO:34 for the antisense strand and SEQ ID NO:33 for the sense strand, whereas the simultaneously recited “D-1016” is a specific duplex that must comprise the entirety of each of SEQ ID NOs:33-34, not just at least a 15-mer with a maximum number of 3 mismatches. As such, the claims simultaneously recite both the broad limitation for the antisense strand reading on many variants of SEQ ID NO:34 as well as the sense strand reading on many variants of SEQ ID NO:33 and the narrower limitation specifically requiring “D-1016” that must comprise SEQ ID NOs:33-34 within the aforementioned broad limitation, thereby rendering the metes and bounds of the claimed antisense strand and the sense strand unclear. That is, the claims are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language - “(DS-1016)” as currently recited or “(D-1016)” in accordance with Table 1 -is (a) merely exemplary of the remainder of the claims, and therefore not required, or (b) a required feature of the claims.
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).
Solely for compact prosecution purpose, “(DS-1016)” will not be taken into consideration for examination purpose.
Claims 39-40 recite “the sense strand of SEQ ID NO: 679”. For discussion purpose, SEQ ID NO:679 as listed in Table 2 is reproduced below.
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372
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As shown above, SEQ ID NO:679 contains “{sGalNAc3K2AhxC6}” at the 5’ end. Nowhere in the entire specification is the aforementioned acronym defined, nor do claims 39-40 particularly point out and distinctly claim what the aforementioned acronym in SEQ ID NO:679 should represent. As such, the metes and bounds of “the sense strand of SEQ ID NO: 679” cannot be clearly ascertained. It is noted that page 66 of the specification discloses that the “5’ end of the sense strand in each of the siRNA compounds has been linked to the GalNAc structure of Formula I below via phosphorothioate or phosphodiester linkage”, wherein the structure is reproduced below:
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Solely for compact prosecution purpose, “{sGalNAc3K2AhxC6}” at the 5’ end of SEQ ID NO:679 claimed in claims 39-40 will be interpreted as the above structure.
Claim Rejections - 35 USC § 102
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 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 1-5, 10, 14-15, 19-21, 23, 25-27, 31, 33, and 35 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Hinkle et al. (WO 2019/183164 A1, applicant’s citation).
Hinkle discloses a double-stranded RNAi composition targeting and inhibiting HSD17B, wherein the composition “AD-239380.1” comprises SEQ ID NO:3385 (5’-AAAAUGUCCUAGGAUGUUGACCU) as the antisense strand comprising, which has only one mismatch (position 22) relative to the entire 23-mer sequence of SEQ ID NO:34 claimed in the instant case, wherein “AD-239380.1” comprises SEQ ID NO:3089 (5’-GUCAACAUCCUAGGACAUUUU), which has only one mismatch (position 21) relative to the entire 21-mer sequence of SEQ ID NO:33 claimed in the instant case, wherein SEQ ID NOs:3385 and 3089 form a blunt end at the 5’ end of the antisense strand with a 2-mer overhang sequence at the 3’ end. See Table 2.
Hinkle teaches that the HSD17B-targeting double-stranded RNAi composition comprises 2’-O-methyl, 2’-F, and phosphorothioate modifications in both strands as in “AD-287411.1” comprising the chemically modified sense strand (SEQ ID NO:63) and the chemically modified antisense strand (SEQ ID NO:363), which are counterparts of the chemically unmodified SEQ ID NOs in “AD-239380.1”. See “AD-287411.1” reproduced from Table 7 as below.
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884
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Hinkle discloses that “AD-287411.1” at 10 nM inhibits HSD17B mRNA expression by about 90% in primary hepatocytes, wherein the expression levels are assessed relative to cells transfected with “a non-targeting control siRNA.” See Table 9; pages 199-200.
Hinkle teaches making a pharmaceutical composition comprising the disclosed RNAi composition formulated in a pharmaceutically acceptable buffer. See page 14.
Accordingly, claims 1-5, 10, 14-15, 19-21, 23, 25-27, 31, 33, and 35 are described by Hinkle et al.
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.
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 1-5, 10, 14-15, 19-21, 23, 25-27, 31, 33, 35, and 38-40 are rejected under 35 U.S.C. 103 as being obvious over Hinkle et al. (WO 2019/183164 A1, applicant’s citation) in view of Murray et al. (WO 2020/123410 A1).
The applied WO 2020/123410 A1 reference has a common inventor with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2).
This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
Hinkle discloses a double-stranded RNAi composition targeting and inhibiting HSD17B, wherein the composition “AD-239380.1” comprises SEQ ID NO:3385 (5’-AAAAUGUCCUAGGAUGUUGACCU) as the antisense strand comprising, which has only one mismatch (position 22) relative to the entire 23-mer sequence of SEQ ID NO:34 claimed in the instant case, wherein “AD-239380.1” comprises SEQ ID NO:3089 (5’-GUCAACAUCCUAGGACAUUUU), which has only one mismatch (position 21) relative to the entire 21-mer sequence of SEQ ID NO:33 claimed in the instant case, wherein SEQ ID NOs:3385 and 3089 form a blunt end at the 5’ end of the antisense strand with a 2-mer overhang sequence at the 3’ end. See Table 2.
Hinkle discloses a chemically modified RNAi composition “AD-287411.1” comprising chemically modified sequences of SEQ ID NO:3385 and SEQ ID NO:3089 inhibits HSD17B mRNA expression by about 90% in primary hepatocytes at 10 nM, wherein the expression levels are assessed relative to cells transfected with “a non-targeting control siRNA.” See Table 9; pages 199-200.
Hinkle teaches making a pharmaceutical composition comprising the disclosed RNAi composition formulated in a pharmaceutically acceptable buffer. See page 14.
Hinkle does not teach that position 22 of SEQ ID NO:3385 is a “U” base and position 21 of SEQ ID NO:21 is inverted abasic. Hinkle also does not teach the chemical modification pattern in each of the sense strand and antisense strand as in SEQ ID NOs:679-680 claimed in the instant case.
Murray teaches making an RNAi composition comprising the sense strand and the antisense strand having the instantly claimed modification pattern. See Pattern Designation Number “P9” in FIG. 1 as reproduced below
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332
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598
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Murray exemplifies Duplex No. 7318 in Table 1 shown below, wherein the duplexes have “P9” modification pattern.
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Murray teaches that the 5’ end of the sense strand has a conjugate “FORMULA VII”, which is reproduced below, “wherein X = O or S and wherein the ligand is attached to the 5’ end of the sense strand”. See paragraph 0150.
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Murray teaches that the 2-nt 3’-overhang of the antisense strand can be 5’-UU that need not be complementary to a target sequence (see paragraph 0036) and is evidenced by the 3’-overhang 5’-UU at positions 22-23 of the antisense strand sequence of Duplex No. 7318 and Duplex No. 7062 shown above that are modified with phosphorothioate (“s”) linkages, thereby forming “susu” as shown above.
Murray demonstrates that Duplex No. 7318 having “P9” modification pattern provides the highest level of target inhibition compared to other modification patterns. See FIG. 5.
Murray discloses that “RNAi constructs having the P9 modification pattern are more potent and produce a longer duration of gene knockdown than previously tested patterns.” (emphasis added). See paragraph 0231.
Murray discloses that the “RNAi construct having the P9 modification pattern with the inverted abasic at the 3’ end of the sense strand (duplex no. 7318) produced the greatest reduction in liver PNPL3A expression among all constructs tested” in mice in vivo (emphasis added). See paragraph 0232.
It would have been obvious to one of ordinary skill in the art before the effective filing date to modify Hinkle’s HSD17B13-targeting siRNA “AD-239380.1” composition by incorporating Murray’s “P9” modification pattern. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success in order to enhance the HSD17B13 silencing activity/potency of the prior art’s composition because a chemically modified composition comprising the nucleotide sequences contained in Hinkle’s “AD-239380.1” was already demonstrated to be effective in providing RNAi-mediated inhibition of the intended target, HSD17B13, in hepatocytes thus the nucleotide sequences of the 21-mer sense strand (SEQ ID NO:3089) and the 23-mer antisense strand (SEQ ID NO:3385) were taught to be useful for making a chemically modified HSD17B13-targeting siRNA composition as evidenced by the teachings of Hinkle, and because an siRNA composition comprising a 21-mer sense strand and a 23-mer antisense strand comprising Murray’s “P9” modification pattern was known to confer benefits/advantages as evidenced by Murray’s teachings that RNAi constructs comprising “P9” modification, which is found to be the same modification in SEQ ID NOs:679-680 claimed in the instant case, are “more potent” and provide “the greatest reduction” with “a longer duration of gene knockdown” in the intended target expression compared to other modification patterns. Since Murray’s 23-mer antisense strand in exemplified RNAi constructs has the 5’-sUsU dinucleotide 3’ overhang, wherein the 5’-UU dinucleotide 3’ overhang in the antisense strand that need not be complementary to the target sequence was also expressly taught by Murray (see paragraph 0036), it would have been obvious to replace the “C” base at position 22 of Hinkle’s SEQ ID NO:3385 with a “U” base, thereby rendering the HSD17B13-targeting RNAi composition to form the art-recognized 3’ overhang sequence of 5’-sUsU dinucleotide that is included in the desired “P9” modification pattern. Hence, one of ordinary skill in the art would have had a reasonable expectation of success in not only arriving at the exact nucleotide sequences of SEQ ID NOs:33-34 of the instant application but also incorporating exactly the same chemical modification pattern (e.g. Murray’s “FORMULA VII” at the 5’ end of the sense strand; an inverted abasic moiety at position 21 of the sense strand; 2’-F at positions 2, 7, 12, and 14 of the antisense strand) of “P9” into the 21-mer sense strand sequence and the 23-mer antisense strand sequence.
Accordingly, claims 1-5, 10, 14-15, 19-21, 23, 25-27, 31, 33, 35, and 38-40 taken as a whole would have been prima facie obvious before the effective filing date.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DANA H SHIN whose telephone number is (571)272-8008. The examiner can normally be reached Monday-Thursday: 8am - 6:30pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, RAM SHUKLA can be reached at 571-272-0735. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/DANA H SHIN/Primary Examiner, Art Unit 1635