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 .
Priority
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been filed on 02/28/2024.
Claim Status
Claim 1-19 are currently pending and are under examination in this Office action.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 07/15/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Drawings
The drawings are objected to because of improper labelling of the figures. First, figures are labeled such as “Figure 1” etc., whereas 37 C.F.R. 1.84 Standards for Drawings requires view numbers must be preceded by the abbreviation "FIG." Second, figures comprising partial views must be identified by the same number followed by a capital letter, for example, “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 Objections
Claim 14 is objected to because of the following informalities: there is a period inserted within the middle of claim 14’s text. Appropriate correction is required.
Claim Interpretation
Claim 6 recites “…and optionally wherein the second strand consist of SEQ ID NO: 48.” The examiner is interpreting optional limitations as not required. Therefore, claim 6 is being interpreted as requiring only a first strand sequence consisting of SEQ ID No. 721 and a second strand.
Claims 10 recites “…and optionally wherein the second strand sequence comprises mAmUmCmAmAmAfGfCfUmCmUmGmUmUmUmGmU(ps)mG (ps) mU (SEQ ID No: 759), and claim 13 recites “…and optionally wherein the second strand sequence comprises [ST23(ps)]3 ST41 (ps) mA mU mC mA mA mA fG fC fU mC mU mG mU mU mU mG mU (ps) mG (ps) mU (SEQ ID No: 730).” The examiner is interpreting optional limitations as not required. Therefore, claims 10 and 13 are being interpreted as requiring only a first strand sequence comprising (vp)-mU fC mA fC mA fA mA fC mA fG mA fG mC fU mU fU mG (ps) fA (ps) mU (SEQ ID No. 740) and a second strand.
Claims 1-2, 7, 9, 12, and 14-19 recite limitations in the alternative. The examiner is interpreting such claims as only requiring only any one of the members of the respective limitations in the alternative.
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 15-17 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of treating a disease, disorder or syndrome associated with aberrant activation or over-activation of the complement pathway involving over-expression or ectopic expression or localization or accumulation of CFB, does not reasonably provide enablement for a method of treating any disease, disorder or syndrome, or a complement-mediated disease, disorder or syndrome wherein the disease, disorder, or syndrome is not associated with CFB-dependent complement dysregulation or where CFB is not over-expressed, ectopically expressed, localized, or accumulated. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
To determine whether a claim is enabled, it is evaluated using the factors set forth in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988). An analysis of the Wands factors indicated that enabling a method across the scope of claims 15-17 would require undue experimentation:
The Breath of the Claim(s): The scope of claims 15-16 is exceptionally broad, encompassing treating any disease, disorder or syndrome, while the scope of claim 17 is limited to any complement-mediated disease, disorder or syndrome.
Nature of the Invention: a liver-targeted gene-silencing therapy against CFB.
The State of the Prior Art: The prior art recognizes complement as a complex biological system involved in numerous physiological and pathological processes; however, the existence of complement involvement in a disease does not establish that inhibition of any particular complement component, including CFB, will provide a therapeutic benefit. One complement inhibitor, Eculizumab, is clinically approved in kidney disease. See Garred P, et al., (Pharmacol Rev. 2021 Apr;73(2):792-827), abstract and introduction.
The level of Ordinary Skill in the Art: A PhD trained scientist with extensive postdoctoral experience in gene silencing and therapeutic development.
The Level of Predictability in the Art: The level of predictability is low. Although complement pathway activation has been implicated in numerous diseases, the complement system is highly complex and involves multiple activation pathways and regulatory mechanisms, see Garred P, et al., whole article. Inhibition of one complement factor does necessarily confer a therapeutic benefit for every disease involving complement activation. In particular, whether inhibition of CFB provides a therapeutic effects depends on whether CFB contributes to the pathological mechanism underlying the particular disease, disorder, or syndrome. The instant specification does not demonstrate that reduction and/or activation of CFB expression provides a therapeutic benefit across the full scope of diseases encompasses by claims 15-17.
The Amount of Direction Provided by the Inventor: the specification provides direction regarding the use of CFB-targeting nucleic acids for reducing CFB expression and provided experimental data demonstrating CFB knockdown following administration of the disclosed nucleic acids. The specification further identifies certain complement-associated diseases in which CFB inhibition is proposed as a therapeutic strategy. However, the specification does not provide sufficient guidance for determining which diseases, disorders, or syndromes outside of those associated with CFB-dependent complement dysregulation would be successfully treated by CFB inhibition. The specification provided no guidance regarding the required level of CFB inhibition, patient selection criteria, disease-specific mechanisms involving CFB, or methods for determining whether a particular complement-mediated disease is responsive to CFB inhibition.
The Existence of Working Examples: The instant specification provides working examples demonstrating that the claimed nucleic acids reduce CFB expression in human, monkey, and mouse hepatocytes in vitro, and liver knockdown after subcutaneous dosing in mice and non-human primates. However, these examples demonstrate target engagement rather than therapeutic efficacy. The specification does not provide working examples demonstrating treatment of the open-ended genus of disease, disorders, or syndromes encompassed by claims 15-16, nor does it demonstrate that CFB inhibition provides a therapeutic benefit for every complement-mediated disease encompassed by claim 17.
The Quantity of Experimentation Needed to Make or Use the Invention Based on the Content of the Disclosure: an undue amount of experimentation would be required to practice the full scope of claims 15-17. A skilled artisan would need to identify which diseases, disorders, or syndromes are dependent upon CFB activity, determine whether CFB inhibition alters disease progression in each condition, establish appropriate dosing and treatment regimens, and demonstrate therapeutic efficacy for each disease indication. Such experimentation would require extensive disease-specific studies rather than routine optimization. Accordingly, the specification does not enable a skilled artisan to practice the full scope of claims 15-17 without undue open-ended experimentation.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 4, 6-7, 9, 11-12, and 14-19 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Samarsky D. (US20230135763A1, effective filing date 07/17/2021) as evidenced by Meuleman P, et al., ( Antiviral Res.;80(3):231-8, published 2008).
Regarding claims 1 and 6, Samarsky teaches “an oligomeric compound capable of inhibiting expression of complement factor B (CFB), comprising a first nucleobase sequence that is at least partially complementary to at least a portion of RNA transcribed from an CFB gene,” and “further comprising a second nucleobase sequence that is at least partially complementary to said first nucleobase sequence,” see claims 1 and 2. Samarsky further teaches that the “oligomeric compound has or comprises the nucleobase sequence of any one of the sequences selected from the group consisting of SEQ ID NOs: 501 to 750, 755 and 756,” see claim 37. Among these sequences taught by Samarsky, is SEQ ID NO: 606, which is a hairpin RNA that comprises a sequence that has 100% identity to the instant claimed sequence SEQ ID NO: 721. See sequence search results in file wrapper and reproduced below for convenience:
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The hairpin. SEQ ID NO: 606, taught by Samarsky is a structure that has a first strand and a second strand that hybridize as defined by the instant specification “the first and second strand are preferably able to hybridize to each other and therefore to form a duplex region over a region of at least 15 nucleotides, preferably 16, 17, 18 or 19 nucleotides (see instant spec. pg. 6 lines 11-13),” see [0091].
Samarsky further teaches SEQ ID NO: 185, which has 100% complementarity to instant SEQ ID NO: 57.
Samarsky further teaches SEQ ID NO: 102, which has 100% complementarity to instant SEQ ID NO: 47.
Samarsky further teaches SEQ ID NOs: 689 and 941, which have 100% complementarity to instant SEQ ID NO: 724.
Regarding claim 4, Samarsky teaches that “the oligomeric compounds described herein cause a significant reduction of gene expression of complement factor B,” and that “the oligomeric constructs as described,” such as SEQ ID NO: 606, mediate “RNAi in mammals,” see [0256][0279][0292].
Regarding claim 7, Samarsky teaches “the oligomeric compound according to claim 1, which comprises internucleoside linkages and wherein at least one internucleoside linkage is a modified internucleoside linkage,” see claim 38. Samarsky further teaches “shows 252 hairpins with full modification information (modified sugars and, where applicable, modified phosphates),” see [0286] and Table 3. SEQ ID NO: 858 taught by Samarsky comprises sequence with 100% identity to SEQ ID NO: 721 of instant claim 1 and further comprises at least one modified nucleotide.
Regarding claim 9, Samarsky teaches “modified internucleoside linkages may be placed at the termini,” and further teaches “the internucleoside linkages connecting first and second nucleoside and second and third nucleoside counting from the 5′ terminus, and/or the internucleoside linkages connecting first and second nucleoside and second and third nucleoside counting from the 3′ terminus are modified,” see [0069]. Samarsky further teaches ““phosphorus linking group” means a linking group comprising a phosphorus atom and can include naturally occurring phosphorous linking groups as present in naturally occurring RNA or DNA, such as phosphodiester linking groups, or modified phosphorous linking groups that are not generally present in naturally occurring RNA or DNA, such as phosphorothioate,” see [0076].
Regarding claim 11-12, Samarsky teaches a linkage connecting the terminal nucleoside of the 3′ terminus with a ligand, such as GalNAc,…” see [0069], and “conjugate groups comprise a cleavable moiety (e.g., a cleavable bond or cleavable nucleoside) and ligand portion that can comprise one or more ligands, such as a carbohydrate cluster portion, such as an N-Acetyl-Galactosamine, also referred to as “GalNAc”, cluster portion” see [0082].
Regarding claim 14, Samarsky teaches : “a pharmaceutical composition comprising an oligomeric compound according to claim 1, and a physiologically acceptable excipient,” see claim 80. Samarsky teaches using PBS as vehicle/solvent when delivering RNAi, see [0402].
Regarding claim 15, Samarsky teaches “ a method of treating, ameliorating and/or preventing a disease or disorder comprising administering to a subject suffering from said disorder an effective amount of a compound according to claim 1;” thus, Samarsky teaches administering compounds having 100% identity to compounds of instant claim 1. See claim 88.
Regarding claim 16-19, Samarsky teaches a method of treating a disease, disorder or syndrome comprising administration of a composition comprising a nucleic acid that has 100% identity to compounds recited in instant claim 1 in a solvent ([0413]: “On Day 0, all study animals will be dosed by subcutaneous injection according to the Study Outline below.” [0414]: “Study Outline…CFB mxRNA…#106-13(4)…” [0435]: “FIG. 5 shows an overview of the study protocol.” [0402]: “Vehicle: Phosphate Buffered Saline.” [0438]: “The data demonstrate significant knock-down at both mRNA and protein level for both compounds, where 106-13(4) outperforms 13(5).” [0408]: “Humanized liver uPA-SCID mice are reported to have up to 95% human hepatocyte engraftment; normal human liver histology and function; human-specific metabolism and excretion pathways; expression of human genes, mRNA, and proteins; human-like lipid profiles, production of human albumin and human-like biliary excretion, and a wide range of research applications. Thus, humanized liver uPA-SCID mice are an ideal test system for the evaluation of therapeutics that involve CFB targets as CFB is produced in the liver.”). As evidenced by Meuleman, uPA-SCID mice are an individual in need of treatment as they display a disease, disorder or syndromes that warrants treatment (abstract “uPA+/+-SCID mice, suffering from a transgene-induced liver disease”).
Further regarding claim 17, Samarsky teaches wherein said disease or disorder is a complement component-associated disease or disorder or a disease or disorder requiring reduction of CFB expression levels,” see claim 89.
Further regarding claim 18, Samarsky teaches wherein the disease, disorder or syndrome is associated with “complement system dysfunction including aberrant upregulation of complement components such as CFB,” see claim 90.
Further regarding claim 19, Samarsky teaches that the disease, disorder or syndrome is selected from autoimmune disease, complement system dysfunction including aberrant upregulation of complement components such as CFB, age-related macular degeneration (AMD) including dry AMD and geographic atrophy, paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), C3 glomerulopathy (C3G), Ig-mediated kidney pathologies such as IgA nephropathy and primary membranous nephropathy, asthma, rheumatic disease, rheumatoid arthritis, systemic lupus erythematosus (SLE), anti-neutrophil cytoplasmic antibody (ANCA) vasculitis, antiphospholipid antibody syndrome (APS), glomerulonephritis, psoriasis, dermatomyositis bullous pemphigoid, Shiga toxin E. coli-related hemolytic uremic syndrome, myasthenia gravis (MG), neuromyelistis optica (NMO), dense deposit disease, C3 neuropathy, cold agglutinin disease, humoral and vascular transplant rejection, graft dysfunction, myocardial infarction, sensitization towards a transplant, and sepsis,” see claim 90.
Claims 1-4, 7, and 11 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Khvorova A. et al., (US20070088154A1).
Regarding claims 1-4, Khvorova teaches “siRNA targeting complement factor B,” see title. Khvorova further teaches “an siRNA molecule consisting of: (a) a duplex region; and (b) either no overhang regions or at least one overhang region, wherein each overhang region has six or fewer nucleotides, wherein the duplex region is nineteen base pairs in length and consists of a sense region that has a sequence that is the same as SEQ ID NO: 458 and an antisense region that has a sequence that is the complement of SEQ ID NO: 458,” see claim 12. Khvorova further teaches “wherein said antisense region and said sense region are each 19 nucleotides in length,” see claim 3. SEQ ID NO: 458 (i.e., CAAGAGAAGUCGUUUCAUU) has 100% sequence identity to instant SEQ ID NO: 58, and by inherency the complement of SEQ ID NO: 458 (i.e., 5’- AAUGAAACGACUUCUCUUG) has 100 % identity to instant SEQ ID NO: 57. See alignment below for instant SEQ ID NO: 57 vs the complement of SEQ ID NO: 458,
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Regarding claim 7, Khvorova teaches “siRNAs modified with internucleotide linkages,” modified bases, and “sugar-modified ribonucleotides in which the 2′-OH is replaced by a group such as an H, OR, R, halo, SH, SR, NH2, NHR, NR2, or CN, wherein R is an alkyl moiety,” see [0067-0069], [0181], and [0184].
Regarding claim 11, Khvorova teaches “coupling of the polynucleotides to specific conjugates or ligands,” see [0197].
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 1-3, 5, 8, 10, and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Samarsky D. (US20230135763A1, effective filing date 07/17/2021) or Khvorova A. et al., (US20070088154A1) as applied to claims 1, 4, 6-7, 9, 11-12, and 14-19 above, and further in view of Dames S. et al., (US20200208158A1, published 07/02/2020).
The teachings of Samarsky and Khvorova are incorporated herein by reference to the respective preceding 102 rejections.
Regarding claims 1-2 and 5, Samarsky teaches an antisense sequence, SEQ ID NO: 102, which is 100% complementary to instantly claimed antisense strand, SEQ ID NO: 47. The complement of either Samarsky’s SEQ ID NO: 102 or instant SEQ ID NO: 47 is the instantly claimed sense strand, SEQ ID NO: 48.
Regarding claims 2-3 and 5, Samarsky teaches that duplex “means two or more complementary strand regions, or strands, of an oligonucleotide or oligonucleotides, hybridized together by way of non-covalent, sequence-specific interaction therebetween,” see [0095]. Samarsky further teaches “complementary oligomeric compounds need not have nucleobase complementarity at each nucleoside,” and that “some mismatches are tolerated,” see [0103]. While Samarsky teaches asymmetric complementarity, Samarsky also teaches “complementary oligomeric compounds or regions are 100% complementary,” or a “fully complementary oligomeric compound or region thereof comprises no mismatches or unhybridized nucleobases with respect to its target sequence or a self-complementary region of the oligomeric compound,” see [0103]-[0108].
Regarding claim 8, Samarsky teaches “vp represents vinyl phosphonate” and is a commonly used notation in the art.
Samarsky nor Khvorova teach 19-mer antisense strands having 100% identity to instant SEQ ID NO: 721.
While Samarsky teaches the antisense strand, SEQ ID NO: 102, which is the exact complement to instant sense strand SEQ ID NO: 48, and suggest that complementary strand may be “fully complementary,” Samarsky does not explicitly teach a sense strand, with a SEQ ID NO, having 100% identity to SEQ ID NO: 48.
Samarsky nor Khvorova teach the specific combination of modifications to the antisense (and optionally, emphasis added, to the sense strand) as recited in instant claims 8, 10, and 13.
Dames teaches double-stranded nucleic acid, e.g., siRNA, for inhibiting expression of TMPRSS6, see claims 1 and 17. Dames further teaches the double-stranded TMPRSS6-targeting RNA are conjugated to ligands such as GalNac, which enables efficient delivery to hepatocytes, see claims 5-7 and 18. Dames further teaches alternating 2'-OMe / 2'-F modification patterns to improve potency and stability while retaining silencing activity, see modifications section, Table 1, and claims 3 and 17. Dames further teaches modifying the siRNA strands with terminal phosphorothioate to protect against nuclease degradation and support in vivo performance, see Stability sections, examples 22-24, and claims 8-10.
Dames further teaches that “the first strand and/or said second strand may each be from 17-35 nucleotides in length and at least one duplex region may be from 10-25 nucleotides in length,” and that “the duplex may comprise two separate strands or it may comprise a single strand which comprises the first strand and the second strand,” see [0019].
Dame further teaches that “terminal modifications useful for modulating activity include modification of the 5' end with phosphate or phosphate analogs,” and that “nucleic acids of the invention, on the first or second strand, may be 5' phosphorylated or include a phosphoryl analog at the 5' prime terminus,… “5 '-phosphate modifications include those which are compatible with RISC mediated gene silencing,” such as “… 5’ – vinylphosphonate,” and that the 5 '-end nucleotide of the antisense strand carries a 5 '-(E)-vinylphosphonate (vp), see [0167][0405][0682].
Dames teaches ST23(ps)]3 ST41(ps) in claim 7 and [0495] (which is the same ligand recited in instant SEQ ID NO: 730), and that this conjugated ligand makes the siRNA more stable in serum, see FIG. 52 and [0690], structure reproduced below for convenience:
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Dame further teaches antisense strands comprising 2’-F modification at all even positions 2,4,6,8,10,12,14,16,and18, 2’OMe at all odd positions 1,3,5,7,9,11,13,15,17,and19, a 5’-vinylephosphonate, and PS linkages at the last two bases at the 3’-end, see SEQ ID NO: 293 and others throughout the entire publication. This modification combination is the same as recited in instant SEQ ID NO: 740.
Dame further teaches, sense strands comprising 2’-F modification at positions 7, 8, and 9 while all other positions are 2’-OMe and further comprises PS linkages at the last two bases at the 3’-end, as in instant SEQ ID NOs: 730 and 759, see duplex ID STS12009V27L4-SEQ ID NO: 238, [0626], Table 7.
Regarding claims 1-3 and 5, it would have been obvious to a person having of ordinary skill in the art (PHOSITA) to modify the 5’ terminal nucleotide of Samarsky’s antisense strand (SEQ ID NO: 102) to introduce a single terminal mismatch with the complementary sense strand, thereby arriving at instant SEQ ID NO: 721, because Dames expressly teaches that the 5’-most nucleotide of the antisense strand may be changed to another nucleotide, preferably A or U (which instant SEQ ID NO: 721 represents an A->U modification of Samarsky’s SEQ ID NO: 102), as a design strategy for siRNA compounds. It would have further been obvious to duplex the modified antisense stand with the complement of the unmodified antisense strand (i.e., the complement of Samarsky’s SEQ ID NO: 102, corresponding to instant SEQ ID NO: 48) to produce a 19-mer siRNA comprising 18 complementary base pairs and a single terminal mismatch, thereby promoting preferential loading of the antisense strand into the RNA-induced silencing complex (RISC) for use as the guide strand to direct cleavage of the intended target mRNA. A PHOSITA would have a reasonable expectation of success because Samarsky had already demonstrated effective targeting of the CFB transcript using the disclosed siRNA sequence, and Dames teaches that modification of the 5’ terminal nucleotide of the antisense strand is a recognized design strategy for optimizing siRNA functionality. Accordingly, the proposed modification represents nothing more than the application of a known siRNA optimization technique to a known CFB-targeting siRNA.
Regarding claims 8, 10, and 13, it would have been obvious to a person having of ordinary skill in the art (PHOSITA) to further modify the CFB-targeting siRNA of Samarsky by incorporating a 5’-(E)-vinylphosphonate at the 5’ terminus of the antisense strand and by incorporating the specific alternating 2’-O-methyl/2’-fluoro sugar modification pattern, and the terminal phosphorothioate linkages, thereby arriving at the modified antisense strand of instant SEQ ID NO: 740. It would have further been obvious to incorporate the ST23(ps)3-ST41(ps) GalNAc conjugate, the specific 2’-O-methyl/2’-fluoro sugar modification pattern (namely 2’fluoro at positions 7, 8, and 9), and the terminal phosphorothioate linkages as taught by dames into the complimentary sense strand of Samarsky’s antisense strand, thereby arriving at SEQ ID NOs: 750 and 730. A PHOSITA would have been motivated to do so because Dames expressly teaches that these modifications are compatible with RISC-mediated gene silencing and are employed to improve siRNA potency, metabolic stability, nuclease resistance, serum stability, and efficient hepatocyte delivery while retaining RNA interference activity. Because Samarsky is likewise directed to therapeutic siRNAs targeting the liver-produced CFB transcript, a PHOSITA would have recognized these modifications as directly applicable to Samarsky’s CFB-targeting siRNA to optimize its pharmacological properties without altering its known target specificity. A PHOSITA would have had a reasonable expectation of success because Samarsky had already demonstrated that the disclosed CFB-targeting sequence effectively mediated RNA interference, while Dames demonstrates that the recited chemical modification pattern(s) successfully retains RNA interference activity while improving in vivo performance. Accordingly, applying Dames’ established chemical modification strategy to the known CFB-targeting siRNA of Samarsky represents routine optimization of a known RNAi therapeutic.
Conclusion
SEQ ID NOs: 722 and 723 are free of the prior art.
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to COREY LANE BRETZ whose telephone number is (571)272-7299. The examiner can normally be reached M-F 7:30am - 6:30pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Ram Shukla can be reached at (571) 272-0735. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/COREY LANE BRETZ/Patent Examiner, 1635
/RAM R SHUKLA/Supervisory Patent Examiner, Art Unit 1635
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