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 .
Application Status
This action is written in response to applicant’s correspondence received on 02/24/2026. Claims 1-25 are currently pending. Claims 1, 3-16, 20-25 are withdrawn from prosecution as being drawn to nonelected subject matter. Accordingly, claims 2, 17-19 are examined herein. The restriction requirement mailed 11/24/2025 is still deemed proper. Applicant's elected Group I and the species of “a single or pairwise composition of siRNA sequence(s) targeting RAF1 alone” without traverse in the reply filed on 02/24/2026.
Election/Restrictions
Applicant's election without traverse of Group I in the reply filed on 02/24/2026 is acknowledged. Applicant’s election of “Species group A: Seq ID #19, targeting RAF1” (Remark, 02/24/2026, page 1, 4th¶) is interpreted as the election of the species “a single or pairwise composition of siRNA sequence(s) targeting RAF1 alone”, which is one of the specified species in the Restriction Requirement: “The applicant is required to elect a single or pairwise composition of siRNA sequence(s) targeting KRAS alone, RAF1 alone, or both” (Page 4; mailed on 11/24/2025), therefore, claims 3, 5-8 do not read on this species as improperly identified by applicant (Remark, 02/24/2026, page 1, 4th¶) as they direct to a combination of siRNA molecules targeting both KRAS and RAF1, hence claims 3, 5-8 are also withdrawn along with claims 1, 4, 9-16, 20-25. The SEQ ID NOs: 7-17 are withdrawn from consideration in claim 19 because these sequences do not blast to RAF1 based on NCBI Blast alignment results, i.e. NCBI-SEQID (NPL_NCBI_SEQ ID NO 7-31 alignment with RAF1 mRNAs NM_001354689.3.pdf listed in the PTO-892; NCBI Blast data retrieved on 04/03/2026) and as being drawn to nonelected subject matter. Only SEQ ID NOs: 18-31 are examined on the merit for claim 19. The requirement is still deemed proper and is therefore made FINAL.
Claims 1, 3-16, 20-25 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected Group II, there being no allowable generic or linking claim, or a single or pairwise composition of siRNA sequence(s) targeting KRAS alone or targeting both KRAS and RAF1.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Priority
Applicant’s claim for the benefit of the following prior-filed applications under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged: PRO 63/419,360 filed on 10/26/2022.
Drawings
The drawings are objected to because 37 CFR 1.84 (u)(1) states “Partial views intended to form one complete view, on one or several sheets, must be identified by the same number followed by a capital letter.”
In the current case, the view numbers for the partial views for FIGs 2 & 5 that appear on several sheets are followed by "a, b, c … etc." instead of a capital letter such as FIG. 1A, FIG. 1B, etc.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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 2, 17-18 are rejected under 35 U.S.C. 103 as being unpatentable over Leng’08 (Systemic delivery of HK Raf-1 siRNA polyplexes inhibits MDA-MB-435 xenografts. Cancer Gene Ther. 2008 Aug;15(8):485-95) as evidenced by NCBI-LengsiRNA (NCBI Blast Data Retrieved on 04/10/2026, see the NPL_NCBI_2026_Blast_Nucleotide Sequence_Leng2008_siRNA.pdf listed in the PTO-892 form), in view of Reynolds (Rational siRNA design for RNA interference. Nat Biotechnol. 2004 Mar;22(3):326-30) as evidenced by NCBI-RefSeq (NPL_NCBI RefSeq_2019_Homo sapiens RAF1 mRNA _NM_001354689.3.pdf listed in the PTO-892 form) confirming the target is a single-stranded (ss) RNA molecule, further in view of Kim (Synthetic dsRNA Dicer substrates enhance RNAi potency and efficacy. Nat Biotechnol. 2005 Feb;23(2):222-6) regarding the selection of 19-27mer siRNA designs, as evidenced by NCBI-SEQID (NCBI Blast Data Retrieved on 04/03/2026; NPL_NCBI_SEQ ID NO 7-31 alignment with RAF1 mRNAs NM_001354689.3.pdf listed in the PTO-892 form) regarding the fact that the molecule of SEQ ID NO: 19 is part of the RAF1 mRNA sequence, and as further evidenced by Leng’24 (A Facile and Promising Delivery Platform for siRNA to Solid Tumors. Molecules. 2024 Nov 23;29(23):5541) regarding the packaging of siRNAs in nanoparticles;
Regarding claim 2, Leng’08 (2008) teaches a doublestranded siRNA molecule targeting a complementary nucleotide sequence in a single stranded (ss) mRNA molecule by reciting the following siRNA duplex: “sense, 50-UGU CCA CAU GGU CAG CAC C-dTdT-3’; antisense, 5’-GGU GCU GAC CAU GUG GAC AdTdT-3’” (Page 487, right column, lines 1-4), wherein said ss target RNA molecule encodes a RAF1 or a mutant RAF1 peptide or protein, as evidenced by NCBI-LengsiRNA (NCBI Blast Data Retrieved on 04/10/2026) blast results showing that RAF1 mRNAs, such as NM_001354689.3, have perfect match.
However, Leng’08 does not teach a siRNA molecule comprising the molecule of SEQ ID NO:19.
Reynolds (2004) teaches a rational systematic siRNA design strategy by targeting every other position along the target mRNA sequence (Page 326, Abstract, lines 11-12; First ¶, lines 2-3). Applying such a systematic approach requires no specialized knowledge about how to design siRNA duplexes, aside from knowing the target mRNA sequence. For a mRNA target sequence encoding RAF1, e.g. NM_001354689.3, this design approach would have yielded 1626 siRNA duplex design by targeting every other nucleotide position, or 3251 siRNA duplex designs by targeting every nucleotide position along the 3251nt RAF1 mRNA to ensure complete coverage, as evidenced by NCBI-RefSeq (2019).
However, Reynolds (2004) only teaches siRNA duplexes with 21-mers with 19bp duplexed region (Page 329, right column, Methods, last ¶, last 2 lines), and does not teach additional design length range for all effective siRNA duplex designs.
Kim (2005) teaches that double-stranded siRNA designs with 25bp and 27bp in length can be up to 100-fold more potent than corresponding conventional 19- or 21-mer siRNAs (Page 222, Abstract, lines 5-7; right column, lines 1-4), without inducing immune responses (Page 222, Abstract, lines 9-11).
It would have been obvious to persons with ordinary skill in the art (PHOSITAs) before the effective filing date of the claimed invention to have followed the teachings, strategies, and motivations of Leng’08, Reynolds, and Kim, as evidenced by NCBI-Leng’08 and NCBI-RefSeq, and would have modified the Raf-1 siRNA designs taught by Leng’08 (2008) by using the siRNA tiling strategies taught by Reynolds (2004) based on the knowledge of the target RAF1 mRNA sequence, as evidenced by NCBI-RefSeq (2019), further in view of Kim (2005), to have designed 19bp, 21bp, 25bp, 27bp long siRNA duplexes according to Kim’s examples targeting every nucleotide with 4 x 3251 = 13,004 total siRNA duplex designs targeting a RAF1 mRNA, i.e. providing finite options, and would have resulted in 4 siRNA duplex designs (1x 25bp and 3x 27bp) comprising the molecule of SEQ ID NO: 19 (25nt), since SEQ ID NO: 19 is blasted to RAF1 mRNAs, e.g. NM_001354689.3, as evidenced by NCBI-SEQID (NCBI Blast Data Retrieved on 04/03/2026). PHOSITAs would have arrived at the claimed invention. There would have been 4 siRNA duplex designs each for SEQ ID NO: 18 and 20 (1x 25bp and 3x 27bp) and 20 siRNA duplex designs each for SEQ ID NOs 21-31 (1x 19bp, 3x 21bp, 7x25bp, 9x27bp) comprising the molecule of respective SEQ ID NO. Hence, there is a finite number of known siRNA designs targeting a known mRNA, i.e. identified, predictable solutions, with reasonable expectation for success, thus forming an “obvious to try” rationale.
Regarding claim 17, Leng’08 further teaches a pharmaceutical composition comprising an siRNA molecule according to claim 2 and a co-polymer carrier by reciting “…polymers [H3K8b, H3K(+H)4b and H3K(+G)4b] were used as siRNA carriers …” (Page 486, right column, 3rd ¶, lines 4-5) for the purpose of “… systemic delivery of Raf-1 siRNA to inhibit the growth of tumors in vivo” (Page 486, left column, last ¶, lines 2-3), wherein the siRNA molecule and carrier are packaged as polyplexes, which are a type of nanoparticles as evidenced by Leng’24 (published in 2024; Page 2, 3rd ¶, lines 9-10).
Regarding claim 18, Leng’08 further teaches “…histidine-lysine-rich (HK) polymers with specific sequences and branching…HK polymers in complex with Raf-1 siRNA…” (Page 485, Abstract, lines 2-3), and “…polymers [H3K8b, H3K(+H)4b and H3K(+G)4b] were used as siRNA carriers …” (Page 486, right column, 3rd ¶, lines 4-5), and “H3K4b, …” (Page 486, last ¶, first line).
Claim 19 is rejected under 35 U.S.C. 103 as being unpatentable over Leng’08, in view of Reynolds, and Kim as evidenced by NCBI-LengsiRNA, NCBI-RefSeq, NCBI-SEQID, and Leng’24, and further in view of Ji (Enhanced gene silencing by the application of multiple specific small interfering RNAs. FEBS Lett. 2003 Sep 25;552(2-3):247-52).
The teachings of Leng’08, Reynolds, and Kim, as evidenced by NCBI-LengsiRNA, NBCI-RefSeq, NCBI-SEQID, and Leng’24 have been discussed above. However, none of them teaches “further comprising an siRNA molecule selected from the group consisting of SEQ ID Nos. 7-18 and 20-31”.
SEQ ID NOs. 7-17 are withdrawn from consideration because they are drawn to non-elected species. Hence, only SEQ ID NOs 18-31 are examined on the merit herein. Since claim 19 recites “selected from the group consisting of…”, SEQ ID NOs 18, 20-31 are members of a closed Markush group patently indistinct from each other and are presumed to be equivalent alternatives that share a substantial structural feature and common use. The 19bp siRNA molecules (SEQ ID NOs 21-31) and 25bp siRNA molecules (SEQ ID NOs 18, 19, 20) would all have been members of the systematic siRNA designs based on the teachings, strategies, and motivations from Reynolds and Kim as evidenced by NBCI-RefSeq, NCBI-SEQID and Leng’24 with an “obvious to try” rationale as discussed above. However, none of Leng’08, Reynolds, or Kim teaches combining two siRNA duplexes targeting RAF1 mRNA.
Ji (2003) teaches that “co-transfection of cells with two or more siRNA duplexes targeting different sites on the same mRNA resulted in an enhanced gene silencing compared with each single siRNA” (Page247, Abstract, lines 5-8).
It would have been obvious for a PHOSITA to follow the teachings, strategies, and combine motivations from Leng’08, Reynolds, Kim, and Ji, as evidenced by NCBI-LengsiRNA, NBCI-RefSeq, NCBI-SEQID, and Leng’24, to prepare a pharmaceutical composition of 2 different siRNAs targeting RAF1 to boost RNAi potency and would have arrived at the claimed inventions.
Conclusion
No claims are allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Delphinus D. Yu whose telephone number (571) 272-1576. The examiner can normally be reached Mon-Thr 7:30am to 4:30pm Fri 10am to 2pm ET.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Neil P Hammell can be reached on (571) 270-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/DELPHINUS DOU YI YU/Examiner, Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636
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