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 February 26, 2026.
Currently, claims 1-4, 7-8, 15, 17, and 22-33 are pending in the instant application. Claims 24-32, which were previously withdrawn from further consideration as being drawn to a nonelected invention as a result of a restriction requirement, are hereby rejoined and fully examined for patentability. Because all claims previously withdrawn from consideration under 37 CFR 1.142 have been rejoined, the restriction requirement as set forth in the Office action mailed on June 30, 2025 is hereby withdrawn.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 Once the restriction requirement is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable.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.
Accordingly, claims 1-4, 7-8, 15, 17, and 22-33 are 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.
Response to Arguments and Amendments
Withdrawn Rejections
Any rejections/objections not repeated in this Office action are hereby withdrawn.
Maintained Rejections
Double Patenting
Claims 1-4, 7-8, 15, 17, 22-23, and 33 remain provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 4-5, 7-11, 14, 26-37, 44-46, and 49-55 of Application No. 18/262,302 for the reasons as set forth in the Office action mailed on October 29, 2025 and for the reasons stated below.
Applicant's arguments filed on February 26, 2026 have been fully considered but they are not persuasive. Applicant argues that the rejection should be withdrawn pursuant to MPEP §804. In response, it is noted that the instant provisional rejection is not the only outstanding rejection in the instant application. Hence, this rejection is maintained.
Response to Arguments
Applicant’s arguments with respect to previous grounds of rejection not maintained herein have been considered but are moot.
New Rejections
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 24-28 and 30-31 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.
Claims 24-28 recite “(b) maintaining the cell produced in step (a)”. In response, it is noted that step (a) does not pertain to producing a cell. Hence, it is unclear what is meant by “the cell produced in step (a)”.
Claim 30 recites “(e.g., nonalcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH))”. It is unclear whether the parenthetical recitation following “e.g.,” is part of the claimed invention, thereby rendering the claim indefinite. See MPEP § 2173.05(d).
Claim 31 recites “(e.g., total cholesterol levels, or LDL cholesterol levels)”. It is unclear whether the parenthetical recitation following “e.g.,” is part of the claimed invention, thereby rendering the claim indefinite. See MPEP § 2173.05(d).
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-4, 7-8, 15, 17, and 22-32 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
In the remarks filed on February 26, 2026, applicant appears to argue that the phrase “corresponds to” in line 4 of claim 2 should be interpreted as each of the recited SEQ ID NOs is complementary to the each of the recited antisense strand SEQ ID NOs in order, respectively.
The instant claims are drawn to a dsRNA agent for inhibiting human MARC1 expression comprising up to 2 mismatched bases with the recited SEQ ID NOs for each of the antisense strand and the sense strand. In fact, claims 1, 3-4, 7-8, 15, 17, and 22-32 merely recite the sequence requirement for the antisense strand only, wherein the sense strand is not required to be fully complementary to the recited antisense strand sequences.
Now, regarding the four pairs of dsRNA agents encompassed by the claims, Table 5 discloses the following results when transfected in Hep3B cells.
1. SEQ ID NOs:1637 and 1285 (AD-890425.1) – 53% human MARC1 mRNA remaining (thus 47% reduction).
2. SEQ ID NOs:1454 and 1102 (AD-890426.1) – 16.8% remaining (thus 83.2% reduction).
3. SEQ ID NOS:1413 and 1061 (AD-890427.1) – 8% remaining (thus 92% reduction).
4. SEQ ID NOs:1498 and 1146 (AD-890428.1) – 21.8% remaining (thus 78.2% reduction).
As shown above, “AD-890425.1” and “AD-890472.1” provided significantly different MARC1 mRNA expression %inhibition results that differ by about 2-fold (47% vs. 92%), when the nucleotide sequences for sense and antisense strands in the two AD agents differ only by two nucleotides. As such, the recited function of inhibiting human MARC1 expression is expressly demonstrated to significantly differ for dsRNA agents comprising nucleotide sequences having up to 2 mismatched bases in each of the sense strand and the antisense strand of the recited SEQ ID NOs. Again, claims 1, 3-4, 7-8, 15, 17, and 22-32 are not even drawn to the sequence variants of the four dsRNA agents listed above as the claims do not recite any structural limitations for the sense strand sequence. As such, the instant specification is deficient in adequately describing the requisite structure-function correlation for the entire genus of structurally different dsRNA agents in view of the significantly different MARC1 mRNA inhibition levels provided by two specific dsRNAs that differ by only two nucleotides in each strand as explained above. In addition, none of the dsRNA agent encompassed by claim 1 is adequately described to have an in vivo therapeutic effect in a subject including a “human” subject when “intravenously” injected.
In fact, the actual in vivo function of dsRNA, especially the recited therapeutic functions such as reducing total cholesterol levels that are associated with NAFLD and NASH, was expressly demonstrated to be unpredictable as evidenced by the two very divergent, opposite effects provided by two dsRNA agents, which showed similar functionalities in target mRNA inhibition levels both in vitro and in vivo. For instance, “AD-646025” provided 1.4% mouse MARC1 remaining at 10 nM (thus 98.6% reduction) and “AD-646147” provided 2.1% mouse MARC1 remaining at 10 nM (thus 97.9% reduction) in Hep3B cells in vitro. See Table 6. Further, “AD-646025” provided about 93% reduction in Marc1 mRNA expression and “AD-646147” provided about 80% reduction in mice in vivo. See Figures 4A-4B. Despite the similar target inhibition activity levels provided by the two aforementioned dsRNA agents, the two agents showed starkly different, opposite effects in cholesterol levels in high fat/high fructose-fed mice that mimic the NASH phenotype such that “AD-646147” not only failed to decrease total serum cholesterol levels in the mice but also increased the total serum cholesterol levels, whereas “AD-646025” reduced total serum cholesterol levels compared to the PBS-treated mice. See FIG. 7B reproduced below.
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As shown above, the opposite effects (increased serum cholesterol levels vs. decreased serum cholesterol levels) provided by the two dsRNA agents, which in fact showed similar activity profile in reducing target mRNA expression in vitro and in vivo clearly support that the mere in vitro human MARC1 mRNA expression reduction results in Hep3B cells cannot be extrapolated to in vivo therapeutic functions, especially for the structurally divergent dsRNA agents encompassed by the instant claims as evidenced by the 2-fold % reduction in human MARC1 mRNA expression in vitro by two dsRNA agents that differ by only two nucleotides in each strand as amply explained above.
In view of the aforementioned experimental findings disclosed in the instant application, one of ordinary skill in the relevant art would not deem that any dsRNA having up to 2 mismatched bases with the disclosed SEQ ID NOs in the four aforementioned dsRNA agents encompassed by the instant claims would be reasonably predicted to have the required function of inhibiting human MARC1 expression, let alone the required function of treating a disorder including NAFLD and NASH in a human subject.
Accordingly, it is concluded that the instant specification fails to reasonably convey that the instant co-inventors had possession of the entire genus of dsRNA agents and the claimed method as of the filing date sought in the instant application.
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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/DANA H SHIN/Primary Examiner, Art Unit 1635
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