RNAS FOR COMPLEMENT INHIBITION

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 . A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 9/23/26 has been entered. Applicant’s election without traverse of group I, SEQ ID NOs: 126 and 300, in the reply filed on 8/8/25 is acknowledged. Claims 18, 22-25, 32, 33, 43, 48, 52, and 56-61 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 8/8/25. Applicant previously argued that claims 56-64 should not be withdrawn because the recited sequences are modified versions of the elected sequences. However, in applicant’s response filed on 8/8/25, applicant elected the species of SEQ ID NOs: 126 and 300, not one of the other duplexes with a specific modification pattern. Upon allowability of the elected form of the sequences, the species would be rejoined. Specification The disclosure is objected to because there are structures that are not fully legible on pages 41, 60-63, 65-67, 129, 147, 149, 155, for example. Appropriate correction is required. 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. Claim(s) 2, 11-15, 19-21, 38, and 39 is/are rejected under 35 U.S.C. 103 as being unpatentable over Keating et al. (US 12,365,896 B2), in view of Khvorova et al. (US 2008/0090997 A1), Khvorova et al. (WO 2020/041769 A1), and Kim et al. (Nature Biotechnology, 23, 2, 2005, 222-226). Keating et al. teach a siRNA comprising a sense strand and an antisense strand, wherein the antisense strand is 23 nucleotides in length and the sense strand is 21 nucleotides in length, wherein the antisense strand comprises a nucleotide sequence of 19 nucleotides that is 100% identical to instant SEQ ID NO: 300 (see column 154, AD572039.1) The antisense strand of Keating et al. comprises a nucleotide sequence of 19 nucleotides that differs by 0 nucleotides (instant claims 2 and 4). It is noted that Keating et al. has support for the siRNA in 62/924,210, filed 10/22/19 (see Table 4, AD572039.1). Instant SEQ ID NO: 300 has the addition of UC at the 3’ end to the antisense sequence of Keating et al. The sequence of Keating et al. has an additional 4 nucleotides at the 5’ end (AGAA). However, Keating et al. teaches that the siRNAs are 19-25 in length (column 4). Design of the specific sequence of Keating et al. in the size range taught by Keating et al. (25-nt in length) by adding two nucleotides to the 5’ end would result in a siRNA that comprises instant SEQ ID NO: 300 and a sense sequence that comprises instant SEQ ID NO: 126. It is noted that adding two nucleotides to the 5’ end of the antisense strand of Keating et al. or to the 3’ end would have been obvious, as there are only two options of ends to arrive at the 25-nt embodiment taught by Keating et al. The same is true for adding 4 nt to either end of the sense strand of Keating et al. for the 25 nt embodiment of Keating et al. The sense strand of Keating et al. already comprises instant SEQ ID NO: 126 without modification. It would have been obvious to design the siRNA of Keating et al. within the size range taught by Keating et al. as a matter of design choice. Applicant has not demonstrated any unexpected property for the instantly recited genus of siRNAs of varying length possibilities that comprise the instant sequences (instant claim 2). The sense strand of Keating et al. comprises a nucleotide sequence of 19 nucleotides (21 nucleotides total) that is 100% identical to SEQ ID NO: 126 (see nucleotides 1-19 of SEQ ID NO: 1043, mRNA target sequence of the siRNA). SEQ ID NO: 1043 of Keating et al. comprises instant SEQ ID NO: 126 (instant claim 3). See the PE2E sequence search result (us-17-798-339-300.szlim50.rni) as follows: RESULT 4 US-17-721-530-1115 Sequence 1115, US/17721530 Patent No. 12365896 GENERAL INFORMATION APPLICANT: ALNYLAM PHARMACEUTICALS, INC. TITLE OF INVENTION: COMPLEMENT COMPONENT C3 IRNA COMPOSITIONS AND METHODS OF USE TITLE OF INVENTION: THEREOF FILE REFERENCE: 121301-10502 CURRENT APPLICATION NUMBER: US/17/721,530 CURRENT FILING DATE: 2022-04-15 PRIOR APPLICATION NUMBER: PCT/US2020/056563 PRIOR FILING DATE: 2020-10-21 PRIOR APPLICATION NUMBER: 62/924,210 PRIOR FILING DATE: 2019-10-22 NUMBER OF SEQ ID NOS: 4652 SEQ ID NO 1115 LENGTH: 23 Query Match 90.5%; Score 19; Length 23; Best Local Similarity 100.0%; Matches 19; Conservative 0; Mismatches 0; Indels 0; Gaps 0; Qy 1 UUUAUUACAGGUGAGUUGA 19 Db 5 UUUAUUACAGGUGAGUUGA 23 Keating et al. teach that at least one strand comprises a 3′ overhang of at least 1 nucleotide. In another embodiment, at least one strand comprises a 3′ overhang of at least 2 nucleotides (column 4). Keating et al. teaches that the overhang can form a mismatch with the target mRNA or it can be complementary to the gene sequences being targeted or can be another sequence (column 31). Keating et al. teaches that in one embodiment, each residue of the sense strand and antisense strand is independently modified with LNA, CRN, cET, UNA, HNA, CeNA, 2′-methoxyethyl, 2′-O-methyl, 2′-O-allyl, 2′-C-allyl, 2′-deoxy, 2′-hydroxyl, or 2′-fluoro. The strands can contain more than one modification. In one embodiment, each residue of the sense strand and antisense strand is independently modified with 2′-O-methyl or 2′-fluoro (column 35) (instant claims 11 and 12). Keating et al. teaches incorporation of phosphorothioate modifications and teaches incorporation of two phosphorothioate internucleotide linkage modifications within position 1-5 of the sense strand (counting from the 5′-end of the sense strand), and two phosphorothioate internucleotide linkage modifications at positions 1 and 2 and two phosphorothioate internucleotide linkage modifications within positions 18-23 of the antisense strand (counting from the 5′-end of the antisense strand) (columns 52-53) (instant claim 13). Keating et al. teaches that every nucleotide can comprise a phosphorothioate group (columns 3-4) which anticipates each of the quantities and positions required in instant claims 13-15. Keating et al. teaches that the dsRNA agent further comprises a ligand. In one embodiment, the ligand is conjugated to the 3′ end of the sense strand of the dsRNA agent (instant claim 19). In one embodiment, the ligand is an N-acetylgalactosamine (GalNAc) derivative. In one embodiment, the ligand is one or more GalNAc derivatives attached through a monovalent, bivalent, or trivalent branched linker (column 4). Keating et al. teaches that the sense strand is conjugated to one or more GalNAc derivatives attached through a bivalent or trivalent branched linker (column 42) (instant claim 20). Keating et al. teaches that in a particular embodiment, an RNAi agent of the present invention comprises: a sense strand having an ASGPR ligand attached to the 3′-end, wherein said ASGPR ligand comprises three GalNAc derivatives attached through a trivalent branched linker (column 61) (instant claim 21). Keating et al. teach incorporation of the siRNA into a composition comprising a pharmaceutically acceptable carrier (column 20) (instant claim 38). Keating et al. teach that in vivo delivery may be performed indirectly by administering one or more vectors that encode and direct the expression of the iRNA (column 100) (instant claim 39). Keating et al. does not teach that the antisense strand comprises instant SEQ ID NO: 300 as required by instant claim 4. However, the siRNA of Keating et al. targets the same region as instantly recited of the same target sequence and Keating et al. teach that the siRNAs are 19-25 in length (column 4). Therefore, it would have been obvious to alter the length of the siRNA of Keating et al. to be 25 nucleotides and arrive at a siRNA comprising instant SEQ ID NOs: 300 and 126. Keating explicitly teaches: The double stranded region may be 19-30 nucleotide pairs in length; 19-25 nucleotide pairs in length; 19-23 nucleotide pairs in length; 23-27 nucleotide pairs in length; or 21-23 nucleotide pairs in length (column 4); and teaching: In certain embodiments, one or both of the strands of the double stranded RNAi agents of the invention is up to 66 nucleotides in length, e.g., 36-66, 26-36, 25-36, 31-60, 22-43, 27-53 nucleotides in length (column 9); and teaching: The duplex region may be of any length that permits specific degradation of a desired target RNA through a RISC pathway, and may range from about 19 to 36 base pairs in length, e.g., 25 base pairs in length (column 14). Applicant has not demonstrated any unexpected property for the instantly recited genus of siRNAs of varying length, wherein clearly the target region was known. Additionally, Keating et al. teach that at a single 10nM dose of the siRNA, the Avg % C3 mRNA remaining was 16.6%, evidence that the siRNA targeting the same region as the instantly recited siRNA was active and inhibitory of the target (column 160). Although obvious in view of the teaching of Keating et al. alone regarding size range for siRNAs, it would have additionally been obvious to design the siRNA of Keating et al. to be 25 nt in length because Kim et al. teach: In attempts to identify RNAi triggers that effectively function at lower concentrations, we found that synthetic RNA duplexes 25–30 nucleotides in length can be up to 100-fold more potent than corresponding conventional 21-mer small interfering RNAs (siRNAs) (abstract). Kim et al. teach: The enhanced potency of the longer duplexes is attributed to the fact that they are substrates of the Dicer endonuclease, directly linking the production of siRNAs to incorporation in the RNA-induced silencing complex (abstract). Therefore, it would have been obvious to design the siRNA of Keating et al. to be 25 nt in length, within the size range taught by Keating et al. with the motivation and expectation of achieving the benefits of Kim et al. of increased potency, especially in view of the activity of taught by Keating et al. regarding the siRNA targeting the same region. Kim et al. offers motivation to employ a 25-nt Dicer-substrate duplex corresponding to the same region of a previously taught inhibitory siRNA to obtain enhanced RNAi potency associated with Dicer processing. With regards to a siRNA consisting of the instant sequences: It is noted that Khvorova et al. (US 2008/0090997 A1) teaches siRNAs targeting Complement Component 3 (C3) (title) and teaches a sense sequence that consists of instant SEQ ID NO: 126 (see column 40, page 84, SEQ ID NO: 601). The only difference in the instant siRNA is an addition of 2 nt to the antisense strand (22 nt antisense strand vs 20 nt sense strand). It would have been obvious to extend the antisense strand of Khvorova et al. (US 2008/0090997 A1) by 2 nt because Khvorova et al. (WO 2020/041769 A1) expressly discloses: [0112] In particular embodiments, an siRNA of the invention comprises an antisense strand that is about 22 nucleotides in length and a sense strand that is about 20 nucleotides in length. Khvorova et al. (WO 2020/041769 A1) discloses exemplary patterns 1E/1F as being the instant strand lengths. Therefore, it would have been obvious as a matter of design choice to design the siRNA of Khvorova et al. (US 2008/0090997 A1) with the 20 nt sense strand taught by Khvorova et al. (US 2008/0090997 A1) and with a 22 nt antisense strand, resulting in a siRNA consisting of the instantly recited siRNA. Response to Arguments It is noted that applicant’s arguments appear to be specific for a siRNA consisting of instant SEQ ID NOs:300 and 126, although the claims are directed to siRNAs of any siRNA length that comprise the recited sequences. Applicant argues that Keating does not disclose modifying the particular sequences in a way that would reach the specifically claimed siRNA sequence comprising an antisense strand that comprises SEQ ID NO: 300, and a sense strand that comprises SEQ ID NO: 126. Contrary to applicant’s arguments, Keating does in fact offer motivation to modify the length by explicitly teaching: The double stranded region may be 19-30 nucleotide pairs in length; 19-25 nucleotide pairs in length; 19-23 nucleotide pairs in length; 23-27 nucleotide pairs in length; or 21-23 nucleotide pairs in length (column 4); and teaching: In certain embodiments, one or both of the strands of the double stranded RNAi agents of the invention is up to 66 nucleotides in length, e.g., 36-66, 26-36, 25-36, 31-60, 22-43, 27-53 nucleotides in length (column 9); and teaching: The duplex region may be of any length that permits specific degradation of a desired target RNA through a RISC pathway, and may range from about 19 to 36 base pairs in length, e.g., 25 base pairs in length (column 14). Therefore, Keating et al. explicitly teaches that the siRNA can be 25 nucleotides in length. Keating is not required to exemplify every disclosed siRNA as every possible length that is disclosed. Although applicant argues that Keating does not disclose any of the following modifications to AD-572039.1 that are all required to reach the present claimed siRNA sequence: (1) removing the first 4 nucleobases (AGAA) from the 5' end of the antisense strand SEQ ID NO: 964; (2) adding 2 specific nucleobases (UC) to the 3' end of the antisense strand SEQ ID NO: 964; (3) adding 2 specific nucleobases (UC) to the 5' end of the sense strand SEQ ID NO: 865; and (4) removing 4 nucleobases (UUCU) from the 3' end of the sense strand SEQ ID NO: 865. Contrary to applicant’s argument, all that is required is for the antisense strand of Keating et al. to be extended 2 nt, which is in the size range taught by Keating et al., to result at a siRNA comprising the instant sequences. Design of both strands of Keating et al. to be 25 nt in length also results in a siRNA comprising the instant sequences. It is not required to remove any sequence of Keating et al. or to shift the sequence. Applicant’s arguments appear to be directed to arriving at a siRNA consisting of the instantly recited sequences, although the instant claims are directed to siRNAs comprising the instant sequences. Therefore, applicant is arguing limitations that are not claimed. Applicant argues that Keating et al. does not provide guidance on how to modify the disclosed siRNA sequences, it simply describes general length ranges of siRNAs. Thus, the cited disclosure (and Keating as a whole) cannot provide the particular motivation necessary to prompt a person of ordinary skill in the art to arrive at the presently claimed siRNA sequences. It was certainly routine and easily within the technical grasp of one of ordinary skill in the art to understand how to design any given siRNA to be a particular length and the options are a finite number of results. Additionally, Keating et al. teaches the activity of the siRNA, offering motivation to utilize this siRNA or siRNAs of the size range taught by Keating et al. Applicant argues that it was not until the present application was filed that the presently claimed siRNA was identified and shown to knockdown C3 gene expression (see, e.g., Example 3, Table 14). Applicant does not specify which siRNA ID of Table 14 is the one that applicant believes that they have demonstrated an unexpected property for. The siRNA of Keating et al. is active and inhibitory of the target, so it is not unexpected for a siRNA targeting the same region and extending one strand by 2 nt to be active or inhibitory of the target. It is unclear as well if the siRNA that applicant is arguing having an unexpected result has specific chemical modifications at specific positions or not. Applicant is invited to specifically point out which siRNA of the specification produces what exact unexpected result that is commensurate in scope with the instant genus. The specification does not demonstrate any unexpected property for the instant genus of siRNAs of any siRNA length comprising the instant sequences. The claims are not closed to any specific siRNA that applicant has demonstrated any unexpected result for. The claims are directed to a genus of siRNAs wherein each strand can have different lengths. Conclusion Any inquiry concerning this communication or earlier communications from the examiner should be directed to Amy R Hudson whose telephone number is (571)272-0755. The examiner can normally be reached M-F 8:00am-6:00pm. Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. 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If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /AMY ROSE HUDSON/Primary Examiner, Art Unit 1636