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 .
Applicant’s election without traverse of group I, as well as the species SEQ ID NOs: 552 and 669 (duplex), 2’-O-methyl, and phosphorothioate in the reply filed on 7/18/25 is acknowledged.
Claims 74, 82, 85, 86, and 90 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 7/18/25.
Claim Objections
Claims 29 and 31 are objected to because of the following informalities: The claims depend from a subsequent claim, which is not permitted. Appropriate correction is required. Cancelling claims 29 and 31 and adding them as new claims 96 and 97 would obviate this objection.
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) 29, 31, 56, 67, 68, and 95 is/are rejected under 35 U.S.C. 103 as being unpatentable over Brown et al. (WO 2015/100436 A1) (supported by 61/937,838 2/10/14 and 61/921,181 12/27/13), in view of Allerson et al. (J. Med. Chem, 2005, 48, 901-904), Kraynack et al. (RNA, 2006, 12, 163-176), and Manoharan (Department of Drug Discovery, Alnylam Pharmaceuticals, 2011, 1).
Brown et al. teach methods and compositions for the specific inhibition of glycolate oxidase (HAO1) by double-stranded RNA (title). Brown et al. teach a siRNA wherein the antisense strand comprises instant SEQ ID NO: 669 (see SEQ ID NO: 522 of Brown et al.) and the sense strand comprises the complement thereof (see SEQ ID NO: 138 of Brown et al.).
Brown et al. teaches (page 161):
5'-GCCAGAAUGUGAAAGUCAUCGACaa-3' (SEQ ID NO: 138)
3'-CACGGUCUUACACUUUCAGUAGCUGUU-5' (SEQ ID NO: 522)
HA01-1094 Target: 5'-GTGCCAGAATGTGAAAGTCATCGACAA-3' (SEQ ID NO: 906)
The sense strand has 25 nucleotides and the antisense strand has 27 nucleotides. Therefore, Brown et al. teaches siRNAs wherein each strand has a different length. Selection of a siRNA wherein the sense strand is 21 nucleotides and the antisense strand is 23 nucleotides, as instantly claimed, is considered a matter of design choice and is within the size limitations taught by Brown et al. for siRNAs.
Brown et al. teaches that the dsNA is attached to a GalNAc moiety, a cholesterol and/or a cholesterol targeting ligand at the 5’ or 3’ end. Brown et al. teach zero to two 3’ overhang regions, each region being six or fewer nucleotides in length.
Brown et al. teaches modifications including 2'-O-methyl, 2'-methoxyethoxy, 2'-fluoro, 2'-allyl, 2'-0 [2-(methylamino)-2-oxoethyl], 4'-thio, 4'-CH2-0-2'-bridge, 4'-(CH2)2-0-2'-bridge, 2' LNA, 2'-amino or 2'-O-(N-methlycarbamate).
Brown et al. teaches that the dsNA possesses a deoxyribonucleotide, a dideoxyribonucleotide, an acyclonucleotide, a 3'-deoxyadenosine (cordycepin), a 3'-azido-3'-deoxythymidine (AZT), a 2',3'-dideoxyinosine (ddl), a 2',3' dideoxy-3'-thiacytidine (3TC), a 2',3'-didehydro-2',3'-dideoxythymidine (d4T), a monophosphate nucleotide of 3'-azido-3'-deoxythymidine (AZT), a 2',3'-dideoxy-3' thiacytidine (3TC) and a monophosphate nucleotide of 2',3'-didehydro-2',3' dideoxythymidine (d4T), a 4-thiouracil, a 5-bromouracil, a 5-iodouracil, a 5-(3-aminoallyl) uracil, a 2'-O-alkyl ribonucleotide, a 2'-O-methyl ribonucleotide, a 2'-amino ribonucleotide, a 2'-fluoro ribonucleotide, or a locked nucleic acid modified nucleotide.
Brown et al. teaches that the dsNA includes a phosphonate, a phosphorothioate or a phosphotriester phosphate backbone modification. Brown et al. teach a pharmaceutical composition that includes the dsNA of the invention and a pharmaceutically acceptable carrier and teach incorporation into a host cell (Figure 2).
Brown et al. teaches incorporation of phosphorothioates at the 5’ and 3’ terminal position (page 139).
Brown et al. teach that a dsNA of the invention has 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or more (e.g., 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 26, or more, up to the full length of the strand) ribonucleotides, optionally including modified ribonucleotides (2'-O-methyl ribonucleotides, phosphorothioate linkages, etc.).
Brown et al. teach that it is contemplated that, as for any of the duplexed oligonucleotides of the invention can possess any range of modifications disclosed herein or otherwise known in the art, including, e.g., 2'-O-methyl, 2' fluoro, inverted basic, GalNAc moieties, etc.
Therefore, Brown et al. teaches a siRNA comprising the instant sequences and teaches that the siRNA can be fully modified including 2’-O-methyl and 2’-fluoro modifications and teaches conjugation to a GalNac ligand.
Brown et al. teaches incorporation of GalNAc moieties, but does not disclose the specific structure recited. Brown et al. does not teach attachment via a bivalent or trivalent linker. Brown et al. teaches incorporation of a phosphorothioate linkage at the terminal regions, but does not teach more than one.
Brown et al. demonstrates that combinations, quantities, and placement of the known modifications is a matter of design choice and routine optimization via teaching a plethora of possible options at pages 57-139, Tables 2 and 7, and Figures 9 and 10.
It was known to fully modify the sense and antisense strand with 2’-O-methyl modifications and 2’-F modifications, as taught by Allerson et al. Allerson et al. teach reduction of endogenous PTEN mRNA in HeLa cells by fully 2’-F/2’-OMe modified 19-base-pair oligonucleotide duplexes (Figure 2). Allerson et al. is additional evidence of full modification with a combination of 2’-F and 2’-O-methyl modifications. It would have been obvious to modify the siRNAs of Brown et al. at 100% modification in view of the teachings of Brown et al. and Allerson et al. with a reasonable expectation of active siRNAs.
Brown et al. teaches incorporation of phosphorothioates at the 5’ and 3’ terminal position (page 139). Additionally, it was also known to fully modify with phosphorothioate modifications, as taught by Kraynack et al. Kraynack et al. teach that siRNA duplexes comprised of fully modified 2’-OMe sense strands can mediate target mRNA reduction, and that complete substitutions with phosphorothioates in either or both strands is tolerated. Kraynack et al. teach that as expected, duplexes containing a full 2’-OMe-modified sense strand displayed improved resistance against serum nucleases, as did PS-modified strands, when compared to unmodified duplexes (page 167). Therefore, it would have been obvious to incorporate the phosphorothioates of Kraynack et al. and one would expect these benefits to result in the same modifications in the siRNA of Brown et al.
Additionally, the instantly recited structures of GalNac were known to be incorporated into siRNAs for delivery, as taught by Manoharan (page 1). Manoharan teaches that they conjugated GalNAc residues to siRNA to deliver these therapeutic agents to liver hepatocytes to silence disease-causing genes produced in liver. Manoharan et al. teach that subcutaneous administration of these conjugates resulted in significantly enhanced liver exposure and efficacy relative to the unconjugated siRNA with ED50s in the low mg/kg range. Furthermore, tolerability assessment in rats revealed a large therapeutic index for siRNA-GalNAc conjugates (page 1). It would have been obvious to incorporate the specific GalNAc conjugates of Manoharan and one would reasonably expect that incorporation of these conjugates into the composition of Brown et al. would result in successful delivery, particularly given that Brown et al. teaches the incorporation of GalNac.
Response to Arguments
Applicant argues that Brown et al. teach dsRNAs that inhibit the expression of HAO1 and provide more than 14,000 nucleotide sequences of such agents. Brown et al. that the dsRNAs disclosed therein may include modified nucleotides which may be modified at the sugar, phosphate and/or base moiety of a nucleotide (see, e.g., page 25, last paragraph through page 27, first paragraph of Brown, et al.). Brown, et al. further teach that "modifications may exist upon these agents in patterns on one or both strands of the double stranded ribonucleic acid (dsRNA)" (see, e.g., page 27, second paragraph of Brown, et al.) and at page 57, through page 149, and in Figures 7A, 8A, 9A-9D, 10A-10K, Brown et al. provide hundreds and hundreds of possible patterns of nucleotide modifications for the sense strand, for the antisense strand, and/or for the sense strand and the antisense strand.
Applicant's arguments have been fully considered but they are not persuasive. The prior art is not limited to teaching a single species and all species taught by the prior art are considered equally obvious selections. Similarly, the instant specification discloses pages 142-153 of additional siRNA sequences. The instantly recited sequence is taught by Brown et al. and Brown et al. teaches to incorporate the instantly recited types of modifications. Brown et al. teaches a siRNA comprising the instant sequences and teaches that the siRNA can be fully modified including 2’-O-methyl and 2’-fluoro modifications and teaches conjugation to a GalNac ligand. The instant claims are not directed to any specific pattern of modification that is not obvious in view of the prior art and has demonstrated an unexpected result, but rather are directed to full modification with any combination of 2’-O-methyl and 2’-fluoro modifications.
Applicant argues that with respect to ligands, Brown et al. teach that suitable ligands may be a GalNAc moiety, a cholesterol and a cholesterol targeting ligand (see, e.g., page 8, first paragraph of Brown, et al.) but none of the dsRNAs exemplified in Brown, et al. were conjugated to a ligand for delivery and, instead, were formulated as LNPs (see, e.g., Examples 4 and 9 of Brown, et al.). Brown et al. is not required to exemplify the ligand. Brown et al. clearly teaches that the siRNA can comprise the ligand. It was known in the art that conjugation to the GalNAc derivative as claimed significantly enhances liver exposure and efficacy, as taught by Manoharan.
Applicant argues that Allerson, et al. teach 19-mer siRNAs targeting a PTEN gene. However, Allerson, et al. fail to teach or suggest even one single double stranded RNAi agent, or salt thereof, targeting HAO1 or each of the recited modifications. Allerson et al. was not relied upon for such teachings. The instant rejection is a rejection under 35 USC 103 rather than 102 and it is therefore the combination of references that render the claims obvious.
Applicant argues that Kraynack et al. teach siRNAs targeting a PTEN gene or a hAgo2 gene. However, Kraynack et al. fail to teach or suggest even one single double stranded RNAi agent, or salt thereof, targeting HAO1. Kraynack et al. was not relied upon for such teachings. The instant rejection is a rejection under 35 USC 103 rather than 102 and it is therefore the combination of references that render the claims obvious.
Applicant argues that Kraynack, et al. teach that that all of the nucleotides of a strand comprise a phosphorothioate linkage but fail to teach or suggest double stranded RNAi agents, or salts thereof targeting HAO1 which include two phosphorothioate internucleotide linkages at the 5'-terminus of the sense strand, two phosphorothioate internucleotide linkages at the 5'- terminus of the antisense strand, and two phosphorothioate internucleotide linkages at the 3'- terminus of the antisense strand. Applicant is arguing limitations that are not claimed. The instant claims utilize open language and therefore comprise the phosphorothioates at the terminal positions argued by applicant but can comprise additional phosphorothioates including full modification with phosphorothioates.
Applicant argues that Manoharan also fail to teach or suggest fails to teach or suggest even one single double stranded RNAi agent, or salt thereof, targeting HAO1, let alone double stranded RNAi agents, or each of the recited modifications. Manoharan et al. was not relied upon for such teachings. The instant rejection is a rejection under 35 USC 103 rather than 102 and it is therefore the combination of references that render the claims obvious.
Applicant argues that the art cited by the Examiner teaches thousands of nucleotide sequences targeting HA01, a large genus of possible nucleotide modifications, a large genus of possible patterns of nucleotide modifications, and a large genus of ligands. Contrary to applicant’s arguments, the instant claims are not limited to any specific pattern of modifications, but are directed to a very large genus of possible combinations at varying positions of 2’F and/or 2’-O-methyl modifications. Each of the modifications were known to be incorporated and combined at varying percentages including full modification. The benefits of each were known.
Additionally, contrary to applicants arguments regarding the AstraZeneca case, the instant genus does not encompass an infinite number of possible modified sequences. The genus is large, but has a finite number of possible combinations. There would have certainly been an expectation of success to incorporate very commonly utilized modifications, 2’-O-methyl and 2’-F, into varying combinations to formulate fully modified strands, and to incorporate a routinely utilized ligand.
Applicant argues that the non-obviousness of the claimed invention is further evidenced by the superior and unexpected results achieved when the invention is put to practice. In particular, Applicant has demonstrated the double stranded RNAi agents, or salts thereof, like those claimed, e.g., comprising a sense strand and an antisense strand forming a double stranded region, wherein the antisense strand comprises the nucleotide sequence 5'- UUGUCGAUGACUUUCACAUUCUG-3' of SEQ ID NO: 669, wherein the sense strand is 21 nucleotides in length and the antisense strand is 23 nucleotides in length, wherein all of the nucleotides of the sense strand comprise a modification selected from the group consisting of a 2'-O-methyl modification and a 2'-fluoro modification, wherein the sense strand comprises two phosphorothioate internucleotide linkages at the 5'-terminus, wherein all of the nucleotides of the antisense strand comprise a modification selected from the group consisting of a 2'-O-methyl modification and a 2'-fluoro modification, wherein the antisense strand comprises two phosphorothioate internucleotide linkages at the 5'-terminus and two phosphorothioate internucleotide linkages at the 3'-terminus, and wherein the sense strand is conjugated to a ligand comprising one or more GalNAc derivatives attached through a branched bivalent or trivalent linker at the 3'-terminus, like duplex AD-65626, potently inhibit HAO1 expression in primary cynomolgus hepatocytes and primary mouse hepatocytes (see, e.g., Tables 7 and 8). Applicant further demonstrated in the working examples that administration of single dose and multiple doses of AD-65626 potently inhibited HAO1 in vivo and has good ED50 (see, e.g., Figures 15- 17).
Contrary to applicants arguments, the specification does not demonstrate any unexpected result for the recited genus of possible modification patterns. The 2’-O-methyl and/or 2’-F modifications are not required at any specific positions and the incorporation of phosphorothioate modifications is not limited to the recited positions.
The claims are a combination of elements that were known in the art to benefit siRNA molecules.
Applicant argues that Applicant has demonstrated that administration of a single dose of AD-65626 results in dose-responsive serum glycolate increase (see, e.g., Figures 18 and 19). Applicant is arguing a single species of the instant claims, although the claims are not limited to the species.
Conclusion
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 Amy R Hudson whose telephone number is (571)272-0755. The examiner can normally be reached M-F 8:00am-6:00pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Neil Hammell can be reached at 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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/AMY ROSE HUDSON/Primary Examiner, Art Unit 1636
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