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 .
Status of Application/Amendment/Claims
This Office action is in response to the communications filed on April 16, 2026.
Currently, claims 1-3, 14-15, 19-21, 23, 25-27, 31, 33, and 35-42 are pending in the instant application. Claims 36-37 and 41-42 are withdrawn from further consideration as being drawn to a nonelected invention. Accordingly, claims 1-3, 14-15, 19-21, 23, 25-27, 31, 33, 35, and 38-40 under examination on the merits in the instant application.
The following rejections are either newly applied or are reiterated and are the only rejections and/or objections presently applied to the instant application.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on June 18, 2026 has been considered by the examiner, except the foreign document citation number 1, which is in non-English language.
Response to Arguments and Amendments
Withdrawn Rejections
Any rejections/objections not repeated in this Office action are hereby withdrawn.
Maintained Rejections
Claim Rejections - 35 USC § 112
Claims 1-3, 14-15, 19-21, 23, 25-27, 31, 33, 35, and 38-40 remain rejected under 35 U.S.C. 112(b) as being indefinite for the reasons as set forth in the Office action mailed on January 22, 2026 and for the reasons stated below.
Applicant's arguments filed on April 16, 2026 have been fully considered but they are not persuasive. Applicant argues that the claims as amended are sufficient to overcome the rejection. Contrary to applicant’s argument, the recitation of “SEQ ID NO: 34 (D-1016)” and “SEQ ID NO: 33 (D-1016)” is not sufficient because as already noted in the last Office action, “D-1016” is the name assigned to a duplex (see “DUPLEX NO”) in Table 1, not each strand. As such, it is unclear why “(D-1016)” is written to describe/define each of SEQ ID NOs:33-34. If applicant wishes to insist on retaining the name “(D-1016)” in any of the pending claims in this application, applicant is advised to recite such name following the “RNAi construct”. Note that if such amendment should be made, applicant is further advised to limit the structural limitations of the “RNAi construct” to “D-1016”.
New Objections/Rejections Necessitated by Amendment
Claim Objections
Claims 39-40 are objected to for containing sequence rule non-compliant subject matter. Note that the nucleotide sequences recited in the claims must be accompanied by an appropriate sequence identifier (SEQ ID NO). Appropriate correction is required.
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.
Claim 40 is 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 40 depends from claim 39 and recites that the antisense strand consists of the sequence “asAfsaaugUfccuaGfgAfuguuga”. This sequence is shorter than the antisense strand sequence recited in claim 39, which requires that the antisense strand sequence must comprise the longer sequence recited in claim 39. As such, claim 40 fails to include all of the sequence limitation for the antisense strand.
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
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1-3, 14-15, 19-21, 23, 25-27, 31, 33, 35, and 38 are rejected under 35 U.S.C. 103 as being unpatentable over Hinkle et al. (WO 2019/183164 A1, of record) in view of Li et al. (US 2018/0195069 A1).
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; see underlined) relative to the entire 23-mer sequence of SEQ ID NO:34 claimed in the instant case, wherein “AD-239380.1” comprises the sense strand sequence of SEQ ID NO:3089 (5’-GUCAACAUCCUAGGACAUUUU), which has only one mismatch (position 21; see underlined) 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.
See page 202 disclosing the chemical modifications incorporated into “AD-287411.1” as reproduced below.
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Hinkle teaches making a pharmaceutical composition comprising the disclosed RNAi composition formulated in a pharmaceutically acceptable buffer. See page 14.
Hinkle teaches that “the sense strand has a total of 21 nucleotides and the antisense strand has a total of 23 nucleotides” and the 2-nt 3’ overhang nucleotides “are non complementary to the target mRNA” or “can form a mismatch with the target mRNA”. See pages 9 and 43,
Hinkle teaches that the RNAi can be optimized by incorporating “changes in overhang”. See page 35.
Hinkle does not teach that position 21 of the sense strand comprises an inverted abasic nucleotide and the antisense strand has a 2-nt 3’ overhang of “UU” instead of the “CU”.
Li teaches that the antisense strand of an siRNA duplex can be designed to have a “UU” 3’ overhang sequence and that the sense strand can be designed to have an inverted abasic nucleotide “invAb” at the 3’ end. See Tables 4-5.
Li teaches that “the inclusion of one or more inverted abasic residues or abasic sites at or near the terminal end or terminal ends of the sense strand of an RNAi agent allows for enhanced activity or other desired properties of an RNAi agent.” See paragraph 0153.
It would have been obvious to replace the 3’ end 2-nt overhang sequence of “CU” in Hinkle’s antisense strand with the “UU” sequence and also to replace the last position, position 21, at the 3’ end of the sense strand in Hinkle’s sense strand with “invAb”. One of ordinary skill in the art would have been motivated to modify the “CU” 3’-overhang sequence with the “UU” sequence in the antisense strand with a reasonable expectation of success because an siRNA having a “UU” 3’ overhang sequence in the antisense strand was an art-recognized siRNA design option as evidenced by Li, and because optimizing siRNA molecules by incorporating “changes in overhang” such as using a 2-nt 3’-overhang sequence that is “non complementary to the target mRNA” or “can form a mismatch with the target mRNA” was expressly suggested by Hinkle. One of ordinary skill in the art would have been further motivated to incorporate “invAb” at the last position at the 3’ end of the sense strand in order to enhance properties of the HSD17B-targeting siRNA molecule because including an “invAb” at the 3’ end of the sense strand of an siRNA molecule was taught to provide “enhanced activity or other desired properties of an RNAi agent” as evidenced by Li so much so that an siRNA molecule whose sense strand comprises “invAb” at the 3’ end was synthesized and used by Li. Accordingly, the instant claims are nothing but a mere obvious modification of an art-recognized HSD17B-targeting siRNA molecule.
In view of the foregoing, claims 1-3, 14-15, 19-21, 23, 25-27, 31, 33, 35, and 38 taken as a whole would have been prima facie obvious before the effective filing date.
Claims 1-3, 14-15, 19-21, 23, 25-27, 31, 33, 35, and 38-40 are rejected under 35 U.S.C. 103 as being unpatentable over Hinkle et al. (WO 2019/183164 A1, of record) in view of Rulifson et al. (WO 2019/118638 A2).
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; see underlined) relative to the entire 23-mer sequence of SEQ ID NO:34 claimed in the instant case, wherein “AD-239380.1” comprises the sense strand sequence of SEQ ID NO:3089 (5’-GUCAACAUCCUAGGACAUUUU), which has only one mismatch (position 21; see underlined) 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 that the HSD17B inhibitory RNAi composition is useful as a pharmaceutical composition for treating a subject suffering from HSD17B-associated disease such as a chronic fibro-inflammatory liver disease including NASH and NAFLD. See pages 2 and 14.
Hinkle teaches that “the sense strand has a total of 21 nucleotides and the antisense strand has a total of 23 nucleotides” and the 2-nt 3’ overhang nucleotides “are non complementary to the target mRNA” or “can form a mismatch with the target mRNA”. See pages 9 and 43,
Hinkle teaches that the “mismatch may occur in the overhang region”, wherein “G:U is preferred over G:C”. See page 49.
Hinkle teaches that the RNAi can be optimized by incorporating “changes in overhang”. See page 35.
Hinkle does not teach that the antisense strand has a 2-nt 3’ overhang of “UU”, nor does Hinkle teach that chemical modification pattern and the conjugate structure.
Rulifson teaches that the 5’ end of the sense strand of an siRNA molecule is attached to the GalNAc ligand (“GalNAc3K2AhxC6”), wherein the sense strand has a 2’-F modification at positions 9, 11, 12, 13, and 14 with remaining positions have a 2’-O-methyl modification, wherein the 3’ end has an inverted abasic moiety, wherein the antisense strand has a 2’-F modification at positions 2, 7, 12, and 14 and 2’-O-methyl modification at the remaining positions. See for instance compound “D-2402” disclosed in Table 2 at page 98 as reproduced below. Note that the antisense strand has a 3’-UU overhang sequence at positions 22-23.
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See also the following structure of “GalNAc3K2AhxC6” at page 86 as reproduced below.
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It is noted that “D-2402” provided a significant target knockdown in the liver in vivo at 83.75% with the highest level of target inhibition among 5 duplexes when measured on day 42 after administration. See Table 12.
It would have been obvious to one of ordinary skill in the art before the effective filing date to modify Hinkle’s “AD-239380.1” composition by incorporating the modification pattern of Rulifson’s siRNA molecule as shown in D-2402 including the 3’-susu overhang in the antisense strand and the inverted abasic moiety at the 3’ end of the sense strand having a “GalNAc3K2AhxC6” conjugate at the 5’ end. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success in order to make a pharmaceutically useful siRNA composition that provides the intended target inhibition in the liver in vivo in a subject because one of ordinary skill in the art would have reasonably deemed Rulifson’s modification pattern as being suitable to be incorporated into Hinkle’s composition that is taught to be useful as a pharmaceutical composition for treating a liver disease in view of the teachings of Rulifson, especially in light of the long-term in vivo effects in the liver provided by Rulifson’s D-2402 as summarized in Table 12. That is, the modification pattern that is rendered obvious to be applied to Hinkle’s composition was not only one of a finite number of in vivo, long-term tested siRNA modification patterns suitable for liver delivery and activity but the specific modification pattern was demonstrated to provide the highest level of target inhibition in the liver, which would have thus reasonably motivated one of ordinary skill in the art to readily pursue and modify Hinkle’s “AD-239380.1” in the manner shown in Rulifson’s D-2402, thereby obtaining the instantly claimed subject matter with a reasonable expectation of success.
Accordingly, claims 1-3, 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.
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.
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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/DANA H SHIN/Primary Examiner, Art Unit 1635
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