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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 4/30/26 has been entered.
Applicant’s election without traverse of group I, and the species SEQ ID NOs: 310, 338, 339, 620, and 631, B is a heterocyclic nucleobase, L1 and L2 are, independently, internucleoside linking groups linking the compound of formula (I) to a polynucleotide; Y is NR1, R1 a group -[C(=O)]m-R2-(O-CH2-CH2)p-R3, wherein m is 0, p is 0, R2 is a C5 alkylene group, and R3 is a C5 heterocycle; X1 and X2 are each, independently, a hydrogen atom; and o each of Ra, Rb, Rc and Rd is, independently, H (at least claim 1 is generic), B is a pyrimidine; A1, A2 and A3 are each OH, and A4 is NHC(=O)-R5, wherein R5 is a C1 alkyl group (at least claims 1 and 11 are generic); lgT3 from Table A , and C027.003 in the reply filed on 5/27/25 is acknowledged.
Claims 12, 28, 29, and 35-39 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 5/27/25.
Improper Markush Rejection
Claims 11 and 13-20 are rejected on the judicially-created basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). The improper Markush grouping includes species of the claimed invention that do not share both a substantial structural feature and a common use that flows from the substantial structural feature. The members of the improper Markush grouping do not share a substantial feature and/or a common use that flows from the substantial structural feature for the following reasons: The claims are directed to a multitude of structures that have different structural requirements and function differently in the cell. One cannot be substituted for another with expectation of identical activity. A search for one would not necessarily return art for another with a different structure. Each requires a separate and distinct search and corresponding examination.
In response to this rejection, Applicant should either amend the claim(s) to recite only individual species or grouping of species that share a substantial structural feature as well as a common use that flows from the substantial structural feature, or present a sufficient showing that the species recited in the alternative of the claims(s) in fact share a substantial structural feature as well as a common use that flows from the substantial structural feature. This is a rejection on the merits and may be appealed to the Board of Patent Appeals and Interferences in accordance with 35 U.S.C. 134 and 37 CFR 41.31(a)(1).
When the Markush grouping is for alternatives of chemical compounds, they shall be regarded as being of a similar nature where the following criteria are fulfilled:
(A) All alternatives have a common property or activity; and
(B) (1) A common structure is present, i.e., a significant structural element is shared by all of the alternatives; or
(B) (2) In cases where the common structure cannot be the unifying criteria, all alternatives belong to a recognized class of chemical compounds in the art to which the invention pertains.
In paragraph (B)(1), above, the words “significant structural element is shared by all of the alternatives” refer to cases where the compounds share a common chemical structure which occupies a large portion of their structures, or in case the compounds have in common only a small portion of their structures, the commonly shared structure constitutes a structurally distinctive portion in view of existing prior art, and the common structure is essential to the common property or activity. The structural element may be a single component or a combination of individual components linked together.
In paragraph (B)(2), above, the words “recognized class of chemical compounds” mean that there is an expectation from the knowledge in the art that members of the class will behave in the same way in the context of the claimed invention. In other words, each member could be substituted one for the other, with the expectation that the same intended result would be achieved.
In order for the members of the Markush group to belong to “recognized class of chemical compounds” there must be an expectation that the members of the class will behave in the same way in the context of the claimed invention. In other words, each member of the class could be substituted one for the other with the expectation that the same intended result would be achieved. In the instant case, activity of any specific structure as claimed is dependent upon the specific structural requirements of each. There is no expectation that any one of the structures as claimed can be substituted for any of the other with different structural requirements with the expectation of the same activity.
As set forth in MPEP2117, “Note that where a Markush group includes only materials from a recognized scientific class of equivalent materials or from an art-recognized class, "the mere existence of such a group in an application tend[s] to prove the equivalence of its members and when one of them [is] anticipated the group [is] therefore rendered unpatentable, in the absence of some convincing evidence of some degree of non-equivalency of one or more of the remaining members." In re Ruff, 256 F.2d 590, 598-99, 118 USPQ 340, 348 (CCPA 1958)("[A]ctual equivalence is not enough to justify refusal of a patent on one member of a group when another member is in the prior art. The equivalence must be disclosed in the prior art or be obvious within the terms of Section 103." Id. at 599, 118 USPQ at 348).”
In the instant case, art against any one structure would not be evidence against any of the remaining members that have completely different structures and do not have identical activity.
Response to Arguments
Applicant argues that each of the structures have the common core structure of claim 11. However, each have additional structural requirements and art against the structure of claim 11 would not anticipate each of the different recited structures, each requiring a different search and examination specific for each of the recited structural requirements for each structure.
However, as instantly drafted, claim 1 link(s) the inventions of claims 11 and 13-20. The restriction requirement among the linked inventions is subject to the nonallowance of the linking claim(s), claim 1. Upon the allowance of the linking claim(s), the restriction requirement as to the linked inventions shall be withdrawn and any claim(s) depending from or otherwise including all the limitations of the allowable linking claim(s) will be entitled to examination in the instant application. Applicant(s) are advised that if any such claim(s) depending from or including all the limitations of the allowable linking claim(s) is/are presented in a continuation or divisional application, the claims of the continuation or divisional application may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application. Where a restriction requirement is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable. In re Ziegler, 44 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971). See also MPEP § 804.01.
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.
Claim 12 is 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.
Claim 12 has an embodiment wherein the antisense strand or both of the strands further comprise a 3’ overhang. Since the recited antisense sequences already have tt 3’ overhangs, the metes and bounds of claim 12 are not definite.
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)(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.
Claim(s) 1, 6, 7, 9, 10, 21, 25-27, and 30-34 is/are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Dudek et al. (WO 2019/204021 A1).
Dudek et al. teach a siRNA that comprises instant SEQ ID NO:310 and the complement thereof (see nucleotides 3-21 of SEQ ID NO: 429 of Dudek et al on page 65 and the complement, SEQ ID NO: 882). The complement comprises each of instant SEQ ID NOs: 323, 329, 331, 339, 341, 343, and 345 without the tt overhang (instant claims 1 and 30). Dudek et al. teaches incorporation of 3’ tt overhangs and therefore anticipates a dsRNA comprising instant SEQ ID NO: 310 and 339 as explained below.
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See result #34 of the PE2E search file titled “us-17-638-339-310.szlim100.rng” as follows:
ID BGW62355 standard; mRNA; 25 BP.
DT 12-DEC-2019 (first entry)
DE Human PCSK9 gene targeted RNAi oligonucleotide sense strand, SEQ 429.
KW antiarteriosclerotic; antilipemic; atherosclerosis; cardiant;
KW cerebroprotective; coronary artery disease; drug delivery;
KW end stage renal disease; gene silencing; hypercholesterolemia;
KW hypercholesterolemia autosomal dominant 3; kexin-9; metabolic-gen.;
KW nephrotropic; neural apoptosis regulated convertase 1;
KW peripheral vascular disease; proprotein convertase subtilisin;
KW renal disease; ss; stroke; therapeutic; vasotropic.
OS Homo sapiens.
CC PN WO2019204021-A1.
CC PD 24-OCT-2019.
CC PF 01-APR-2019; 2019WO-US025253.
PR 18-APR-2018; 2018US-0659693P.
PR 19-MAR-2019; 2019US-0820558P.
CC PA (DICE-) DICERNA PHARM INC.
CC PI Dudek HT, Park J;
DR WPI; 2019-88273N/86.
CC PT New oligonucleotide useful in composition for decreasing symptoms of
CC PT hypercholesterolemia, atherosclerosis, and/or symptoms or complications in mammal, preferably human.
CC PS Claim 49; SEQ ID NO 429; 107pp; English.
CC The present invention relates to a novel oligonucleotide, useful in
CC preparing a composition for reducing the expression of proprotein
CC convertase subtilisin/kexin-9 (PCSK9, NARC-1, neural apoptosis regulated
CC convertase 1, HCHOLA3, hypercholesterolemia autosomal dominant 3) gene.
CC The oligonucleotide comprises an antisense strand comprises a sequence of
CC SEQ ID NOs: 1193-1232, 1257-1265 and 1269-1271 (see BGW63119-BGW63158,
CC BGW63183-BGW63191 and BGW63195-BGW63197). The invention also provides: an
CC oligonucleotide comprising antisense strand of SEQ ID NOs: 1233-1244 (see
CC BGW63159-BGW63170); a composition comprising the oligonucleotide and an
CC excipient; a method for delivering the oligonucleotide to a subject by
CC administering the composition to the subject; and a method for decreasing
CC one or more symptoms of hypercholesterolemia, atherosclerosis and/or one
CC or more symptoms or complications thereof in a subject. The
CC oligonucleotide is also useful in treating hypercholesterolemia,
CC atherosclerosis, and/or one or more symptoms or complications in a
CC subject, wherein the complications are chosen from coronary artery
CC disease, stroke, peripheral artery disease, and kidney problems (such as
CC chronic kidney disease).
SQ Sequence 25 BP; 7 A; 1 C; 3 G; 0 T; 14 U; 0 Other;
Query Match 100.0%; Score 19; Length 25;
Best Local Similarity 100.0%;
Matches 19; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 UUAUUAAUAUGGUGACUUU 19
Db 3 UUAUUAAUAUGGUGACUUU 21
Dudek et al. teach: [0009] In some embodiments, an oligonucleotide comprises a 3 '-overhang sequence of one or more nucleotides in length, in which the 3 '-overhang sequence is present on the antisense strand, the sense strand, or the antisense strand and sense strand (instant claims 10 and 33).
Dudek et al. teach: [00042] In some embodiments, an overhang comprises one or more unpaired nucleotides extending from a duplex region at the 5' terminus or 3' terminus of a double- stranded oligonucleotide. In certain embodiments, the overhang is a 3' or 5' overhang on the antisense strand or sense strand of a double-stranded oligonucleotide. The overhang is 1-5 nucleotides [00064] (instant claims 10 and 33).
Dudek et al. teach: [00067] In some embodiments, oligonucleotides may be in the range of 21 to 23 nucleotides in length. In some embodiments, oligonucleotides may have an overhang ( e.g. ., of 1, 2, or 3 nucleotides in length) in the 3’ end of the sense and/or antisense strands. In some embodiments, oligonucleotides (e.g., siRNAs) may comprise a 21 nucleotide guide strand that is antisense to a target RNA and a complementary passenger strand, in which both strands anneal to form a l9-bp duplex and 2 nucleotide overhangs at either or both 3’ ends. See, for example, US9012138, US9012621, and US9193753, the contents of each of which are incorporated herein for their relevant disclosures. US 9012138 discloses 2 nt tt 3’ overhangs (column 28).
Dudek et al. teach: [00011] In some embodiments, an oligonucleotide comprises at least one modified nucleotide. In some embodiments, the modified nucleotide comprises a 2'-modification. In some embodiments, the 2'-modification is a modification selected from: 2'-aminoethyl, 2'-fluoro, 2'-0-methyl, 2'-0-methoxyethyl, and 2'-deoxy-2'-fluoro-P-d-arabinonucleic acid. In some embodiments, all of the nucleotides of an oligonucleotide are modified (instant claims 6 and 31).
Dudek et al. teach: [00092] A modified internucleotide linkage may be a phosphorodithioate linkage, a phosphorothioate linkage, a phosphotriester linkage, a thionoalkylphosphonate linkage, a thionoalkylphosphotriester linkage, a phosphoramidite linkage, a phosphonate linkage or a boranophosphate linkage. In some embodiments, at least one modified internucleotide linkage of any one of the oligonucleotides as disclosed herein is a phosphorothioate linkage (instant claims 7 and 21).
Dudek et al. teach: [000104] GalNAc is a high affinity ligand for asialoglycoprotein receptor (ASGPR), which is primarily expressed on the sinusoidal surface of hepatocyte cells and has a major role in binding, internalization, and subsequent clearance of circulating glycoproteins that contain terminal galactose or N-acetylgalactosamine residues (asialoglycoproteins). Conjugation (either indirect or direct) of GalNAc moieties to oligonucleotides of the instant disclosure may be used to target these oligonucleotides to the ASGPR expressed on these hepatocyte cells (instant claims 9 and 32).
Dudek et al. teach: [000105] In some embodiments, an oligonucleotide of the instant disclosure is conjugated directly or indirectly to a monovalent GalNAc. In some embodiments, the oligonucleotide is conjugated directly or indirectly to more than one monovalent GalNAc ( i.e. ., is conjugated to 2, 3, or 4 monovalent GalNAc moieties, and is typically conjugated to 3 or 4 monovalent GalNAc moieties). In some embodiments, an oligonucleotide of the instant disclosure is conjugated to one or more bivalent GalNAc, trivalent GalNAc, or tetravalent GalNAc moieties (instant claims 9 and 32).
Dudek et al. teach: [000107] Appropriate methods or chemistry ( e.g. ., click chemistry) can be used to link a targeting ligand to a nucleotide. In some embodiments, a targeting ligand is conjugated to a nucleotide using a click linker. In some embodiments, an acetal-based linker is used to conjugate a targeting ligand to a nucleotide of any one of the oligonucleotides described herein.
Dudek et al. teach: [000110] Accordingly, in some embodiments, a formulation comprises a lipid nanoparticle. In some embodiments, an excipient comprises a liposome, a lipid, a lipid complex, a microsphere, a microparticle, a nanosphere, or a nanoparticle, or may be otherwise formulated for administration to the cells, tissues, organs, or body of a subject in need thereof (instant claim 34).
Dudek et al. teach: [000123] In certain aspects, the disclosure provides a method for preventing in a subject, a disease, disorder, symptom, or condition as described herein by administering to the subject a therapeutic agent (e.g., an oligonucleotide or vector or transgene encoding same). In some embodiments, the subject to be treated is a subject who will benefit therapeutically from a reduction in the amount of PCSK9 protein, e.g., in the liver (instant claim 25).
Dudek et al. teach cells comprising the dsRNA (instant claim 26).
Dudek et al. teach: [000112] In some embodiments, a pharmaceutical composition is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), transmucosal, and rectal administration. Typically, the route of administration is intravenous or subcutaneous.
Dudek et al. teach: [000113] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. For intravenous or subcutaneous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL.TM. (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, and sodium chloride in the composition. Sterile injectable solutions can be prepared by incorporating the oligonucleotides in a required amount in a selected solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization (instant claim 27).
Therefore, the claims are anticipated by Dudek et al.
Response to Arguments
Applicant argues that the nucleotide sequences of SEQ ID NOs: 323, 329, 331, 339, 341, 343, or 345 each comprises a 3' overhang, which comprises two consecutive dTs, as shown, for example, in Table 3 at page 52 of the specification as filed. In contrast, SEQ ID NO: 882 of Dudek, which is the complement of SEQ ID NO: 429, as cited by the Office, does not have a 3' dTdT overhang.
However, Dudek et al. teaches incorporation of 2 nt tt 3’ overhangs, as set forth above and therefore anticipate the dsRNA comprising instant SEQ ID NOs: 310 and 339.
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) 1, 2, 5-7, 9-11, 13-15, 17-21, 23-27, and 30-34 is/are rejected under 35 U.S.C. 103 as being unpatentable over Dudek et al. (WO 2019/204021 A1) as applied to claims 1, 6, 7, 9, 10, 21, 25-27, and 30-34, above, and further in view of McSwiggen et al. (WO 2008/011431 A2).
Dudek et al. teach a siRNA that comprises instant SEQ ID NO:310 and the complement thereof (see nucleotides 3-21 of SEQ ID NO: 429 of Dudek et al on page 65 and the complement, SEQ ID NO: 882). The complement comprises each of instant SEQ ID NOs: 323, 329, 331, 339, 341, 343, and 345 without the tt overhang (instant claims 1 and 30). Dudek et al. teaches incorporation of 3’ tt overhangs and therefore anticipates a dsRNA comprising instant SEQ ID NO: 310 and 339 as explained below.
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32
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See result #34 of the PE2E search file titled “us-17-638-339-310.szlim100.rng” as follows:
ID BGW62355 standard; mRNA; 25 BP.
DT 12-DEC-2019 (first entry)
DE Human PCSK9 gene targeted RNAi oligonucleotide sense strand, SEQ 429.
KW antiarteriosclerotic; antilipemic; atherosclerosis; cardiant;
KW cerebroprotective; coronary artery disease; drug delivery;
KW end stage renal disease; gene silencing; hypercholesterolemia;
KW hypercholesterolemia autosomal dominant 3; kexin-9; metabolic-gen.;
KW nephrotropic; neural apoptosis regulated convertase 1;
KW peripheral vascular disease; proprotein convertase subtilisin;
KW renal disease; ss; stroke; therapeutic; vasotropic.
OS Homo sapiens.
CC PN WO2019204021-A1.
CC PD 24-OCT-2019.
CC PF 01-APR-2019; 2019WO-US025253.
PR 18-APR-2018; 2018US-0659693P.
PR 19-MAR-2019; 2019US-0820558P.
CC PA (DICE-) DICERNA PHARM INC.
CC PI Dudek HT, Park J;
DR WPI; 2019-88273N/86.
CC PT New oligonucleotide useful in composition for decreasing symptoms of
CC PT hypercholesterolemia, atherosclerosis, and/or symptoms or complications in mammal, preferably human.
CC PS Claim 49; SEQ ID NO 429; 107pp; English.
CC The present invention relates to a novel oligonucleotide, useful in
CC preparing a composition for reducing the expression of proprotein
CC convertase subtilisin/kexin-9 (PCSK9, NARC-1, neural apoptosis regulated
CC convertase 1, HCHOLA3, hypercholesterolemia autosomal dominant 3) gene.
CC The oligonucleotide comprises an antisense strand comprises a sequence of
CC SEQ ID NOs: 1193-1232, 1257-1265 and 1269-1271 (see BGW63119-BGW63158,
CC BGW63183-BGW63191 and BGW63195-BGW63197). The invention also provides: an
CC oligonucleotide comprising antisense strand of SEQ ID NOs: 1233-1244 (see
CC BGW63159-BGW63170); a composition comprising the oligonucleotide and an
CC excipient; a method for delivering the oligonucleotide to a subject by
CC administering the composition to the subject; and a method for decreasing
CC one or more symptoms of hypercholesterolemia, atherosclerosis and/or one
CC or more symptoms or complications thereof in a subject. The
CC oligonucleotide is also useful in treating hypercholesterolemia,
CC atherosclerosis, and/or one or more symptoms or complications in a
CC subject, wherein the complications are chosen from coronary artery
CC disease, stroke, peripheral artery disease, and kidney problems (such as
CC chronic kidney disease).
SQ Sequence 25 BP; 7 A; 1 C; 3 G; 0 T; 14 U; 0 Other;
Query Match 100.0%; Score 19; Length 25;
Best Local Similarity 100.0%;
Matches 19; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 UUAUUAAUAUGGUGACUUU 19
Db 3 UUAUUAAUAUGGUGACUUU 21
Dudek et al. teach: [0009] In some embodiments, an oligonucleotide comprises a 3 '-overhang sequence of one or more nucleotides in length, in which the 3 '-overhang sequence is present on the antisense strand, the sense strand, or the antisense strand and sense strand (instant claims 10 and 33).
Dudek et al. teach: [00042] In some embodiments, an overhang comprises one or more unpaired nucleotides extending from a duplex region at the 5' terminus or 3' terminus of a double- stranded oligonucleotide. In certain embodiments, the overhang is a 3' or 5' overhang on the antisense strand or sense strand of a double-stranded oligonucleotide. The overhang is 1-5 nucleotides [00064] (instant claims 10 and 33).
Dudek et al. teach: [00067] In some embodiments, oligonucleotides may be in the range of 21 to 23 nucleotides in length. In some embodiments, oligonucleotides may have an overhang ( e.g. ., of 1, 2, or 3 nucleotides in length) in the 3’ end of the sense and/or antisense strands. In some embodiments, oligonucleotides (e.g., siRNAs) may comprise a 21 nucleotide guide strand that is antisense to a target RNA and a complementary passenger strand, in which both strands anneal to form a l9-bp duplex and 2 nucleotide overhangs at either or both 3’ ends. See, for example, US9012138, US9012621, and US9193753, the contents of each of which are incorporated herein for their relevant disclosures. US 9012138 discloses 2 nt tt 3’ overhangs (column 28).
Dudek et al. teach: [00011] In some embodiments, an oligonucleotide comprises at least one modified nucleotide. In some embodiments, the modified nucleotide comprises a 2'-modification. In some embodiments, the 2'-modification is a modification selected from: 2'-aminoethyl, 2'-fluoro, 2'-0-methyl, 2'-0-methoxyethyl, and 2'-deoxy-2'-fluoro-P-d-arabinonucleic acid. In some embodiments, all of the nucleotides of an oligonucleotide are modified (instant claims 6 and 31).
Dudek et al. teach: [00092] A modified internucleotide linkage may be a phosphorodithioate linkage, a phosphorothioate linkage, a phosphotriester linkage, a thionoalkylphosphonate linkage, a thionoalkylphosphotriester linkage, a phosphoramidite linkage, a phosphonate linkage or a boranophosphate linkage. In some embodiments, at least one modified internucleotide linkage of any one of the oligonucleotides as disclosed herein is a phosphorothioate linkage (instant claims 7 and 21).
Dudek et al. teach: [000104] GalNAc is a high affinity ligand for asialoglycoprotein receptor (ASGPR), which is primarily expressed on the sinusoidal surface of hepatocyte cells and has a major role in binding, internalization, and subsequent clearance of circulating glycoproteins that contain terminal galactose or N-acetylgalactosamine residues (asialoglycoproteins). Conjugation (either indirect or direct) of GalNAc moieties to oligonucleotides of the instant disclosure may be used to target these oligonucleotides to the ASGPR expressed on these hepatocyte cells (instant claims 9 and 32).
Dudek et al. teach: [000105] In some embodiments, an oligonucleotide of the instant disclosure is conjugated directly or indirectly to a monovalent GalNAc. In some embodiments, the oligonucleotide is conjugated directly or indirectly to more than one monovalent GalNAc ( i.e. ., is conjugated to 2, 3, or 4 monovalent GalNAc moieties, and is typically conjugated to 3 or 4 monovalent GalNAc moieties). In some embodiments, an oligonucleotide of the instant disclosure is conjugated to one or more bivalent GalNAc, trivalent GalNAc, or tetravalent GalNAc moieties (instant claims 9 and 32).
Dudek et al. teach: [000107] Appropriate methods or chemistry ( e.g. ., click chemistry) can be used to link a targeting ligand to a nucleotide. In some embodiments, a targeting ligand is conjugated to a nucleotide using a click linker. In some embodiments, an acetal-based linker is used to conjugate a targeting ligand to a nucleotide of any one of the oligonucleotides described herein.
Dudek et al. teach: [000110] Accordingly, in some embodiments, a formulation comprises a lipid nanoparticle. In some embodiments, an excipient comprises a liposome, a lipid, a lipid complex, a microsphere, a microparticle, a nanosphere, or a nanoparticle, or may be otherwise formulated for administration to the cells, tissues, organs, or body of a subject in need thereof (instant claim 34).
Dudek et al. teach: [000123] In certain aspects, the disclosure provides a method for preventing in a subject, a disease, disorder, symptom, or condition as described herein by administering to the subject a therapeutic agent (e.g., an oligonucleotide or vector or transgene encoding same). In some embodiments, the subject to be treated is a subject who will benefit therapeutically from a reduction in the amount of PCSK9 protein, e.g., in the liver (instant claim 25).
Dudek et al. teach cells comprising the dsRNA (instant claim 26).
Dudek et al. teach: [000112] In some embodiments, a pharmaceutical composition is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), transmucosal, and rectal administration. Typically, the route of administration is intravenous or subcutaneous.
Dudek et al. teach: [000113] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. For intravenous or subcutaneous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL.TM. (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, and sodium chloride in the composition. Sterile injectable solutions can be prepared by incorporating the oligonucleotides in a required amount in a selected solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization (instant claim 27).
Dudek et al. does not teach instant SEQ ID NO: 338, but does teach a siRNA comprising instant SEQ ID NO: 339 (elected sequences of instant claim 2). SEQ ID NO: 338 is the result of an addition of 7 nucleotides to the 5’ end of SEQ ID NO: 339, which is within the size range for siRNAs taught by Dudek et al. and therefore it would have been obvious to extend the sequence of Dudek et al. within the size range of Dudek et al. as a matter of design choice.
Dudek et al. teach: [0008] In some embodiments, the antisense strand is 19 to 27 nucleotides in length. In some embodiments, the antisense strand is 21 to 27 nucleotides in length. In some embodiments, the oligonucleotide further comprises a sense strand of 15 to 40 nucleotides in length, in which the sense strand forms a duplex region with the antisense strand. In some embodiments, the sense strand is 19 to 40 nucleotides in length. In some embodiments, the duplex region is at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, or at least 22 nucleotides in length. In some embodiments, the antisense strand is 27 nucleotides in length and the sense strand is 25 nucleotides in length. In some embodiments, the antisense strand and sense strand form a duplex region of 25 nucleotides in length.
Dudek et al. teach: [0009] In some embodiments, an oligonucleotide comprises an antisense strand and a sense strand that are each in a range of 21 to 23 nucleotides in length. In some embodiments, an oligonucleotide comprises a duplex structure in a range of 19 to 21 nucleotides in length. In some embodiments, an oligonucleotide comprises a 3 '-overhang sequence of one or more nucleotides in length, in which the 3 '-overhang sequence is present on the antisense strand, the sense strand, or the antisense strand and sense strand. In some embodiments, an oligonucleotide further comprises a 3 '-overhang sequence on the antisense strand of two nucleotides in length. In some embodiments, an oligonucleotide comprises a 3 '-overhang sequence of two nucleotides in length, in which the 3 '-overhang sequence is present on the antisense strand, and in which the sense strand is 21 nucleotides in length and the antisense strand is 23 nucleotides in length, such that the sense strand and antisense strand form a duplex of 21 nucleotides in length.
McSwiggen et al. teach siRNAs targeted to PCSK9 and pharmaceutical compositions comprising the siRNAs and carriers (abstract). McSwiggen et al. teach that the sense and antisense strand are each about 15 to about 30 nucleotides in length [0067].
It would have been obvious to extend or shorten the siRNA of Dudek et al. in normal siRNA size range, which would result in SEQ ID NO: 338 and the complement thereof. Additionally, instant SEQ ID NOs: 620 and 631 are identical to the duplex of instant SEQ ID NOs: 310 and the complement thereof except for the addition of a TT overhang. Shortening the siRNA of Dudek et al. within the size range of Dudek et al. and McSwiggen et al. would arrive at instant SEQ ID NOs: 310 and the complement thereof. It would have been obvious to incorporate a TT overhang, which is taught by Dudek et al. and McSwiggen et al.
Both Dudek et al. and McSwiggen et al. teach incorporation of GalNac. McSwiggen et al. teaches a structure with substantially the same structural features of IgT3 (see Figure 29). The claims are not limited to any one static structure and the species of McSwiggen et al. render the instant genus obvious (instant claims 11, 13-15, and 17-20).
Additionally, it would have been obvious to incorporate the modifications known in the siRNA art at varying positions and quantities as a matter of routine optimization. McSwiggen et al. teaches combining phosphorothioate, ligands, 2’-O-methyl and 2’-F modifications at various positions and quantities and teaches placement on pyrimidines or purines differentially (instant claims 23 and 24).
Response to Arguments
Applicant argues that the nucleotide sequences of SEQ ID NOs: 323, 329, 331, 339, 341, 343, or 345 each comprises a 3' overhang, which comprises two consecutive dTs, as shown, for example, in Table 3 at page 52 of the specification as filed. In contrast, SEQ ID NO: 882 of Dudek, which is the complement of SEQ ID NO: 429, as cited by the Office, does not have a 3' dTdT overhang.
However, Dudek et al. teaches incorporation of 2 nt tt 3’ overhangs, as set forth above and therefore anticipate the dsRNA comprising instant SEQ ID NOs: 310 and 339.
Applicant argues that the claimed dsRNAs are based, at least in part, on the Applicant's discovery that certain siRNAs targeting specific regions of PCSK9 effectively knocked down human PCSK9 expression. Particularly, as shown in Example 4, the Applicant identified a group of siRNAs comprising the sequences recited in amended claim 1 and those exemplary siRNAs were both active and non-toxic when tested in vitro.
The instant claims are compound claims, not method claims, and the compound of claim 1 is anticipated by Dudek et al. because the siRNA anticipates each of the instantly required structural limitations.
Applicant argues that the claimed dsRNAs are not taught or suggested by the cited references, alone or in combination. Based on the teachings of the cited references, a skilled person would not have been motivated, or have had a reasonable expectation of success, to arrive at the claimed dsRNAs. Further, the present application provides surprising results that are not taught by, and cannot be predicted from, the disclosures of the cited references, alone or in combination. The basis of these assertions are unclear because the dsRNA of claim 1 is anticipated by Dudek et al. None of the instant claims are directed to a dsRNA consisting of any specific sequences.
Applicant argues that the siRNA cited by the Office is not among the list of particularly active siRNAs selected by Dudek. Simply because Dudek et al. focused on additional siRNAs does not negate that the compound of claim 1 is anticipated by Dudek et al. Applicant is arguing limitations that are not claimed. The claims are not limited to any specific dsRNA of any specific length consisting of any specific sequence; and do not require any specific level of activity. The claims are compound claims and the structure is anticipated and recited (claims 49 and 50) by Dudek et al.
II. A REFERENCE THAT CLEARLY NAMES THE CLAIMED SPECIES ANTICIPATES THE CLAIM NO MATTER HOW MANY OTHER SPECIES ARE NAMED
A genus does not always anticipate a claim to a species within the genus. However, when the species is clearly named, the species claim is anticipated no matter how many other species are additionally named. See Ex parteA, 17 USPQ2d 1716 (Bd. Pat. App. & Inter. 1990) (The claimed compound was named in a reference which also disclosed 45 other compounds. The Board held that the comprehensiveness of the listing did not negate the fact that the compound claimed was specifically taught. The Board compared the facts to the situation in which the compound was found in the Merck Index, saying that “the tenth edition of the Merck Index lists ten thousand compounds. In our view, each and every one of those compounds is ‘described’ as that term is used in [pre-AIA ] 35 U.S.C. 102(a), in that publication.”). Id. at 1718. See also In re Sivaramakrishnan, 673 F.2d 1383, 213 USPQ 441 (CCPA 1982) (The claims were directed to polycarbonate containing cadmium laurate as an additive. The court upheld the Board’s finding that a reference specifically naming cadmium laurate as an additive amongst a list of many suitable salts in polycarbonate resin anticipated the claims. The applicant had argued that cadmium laurate was only disclosed as representative of the salts and was expected to have the same properties as the other salts listed while, as shown in the application, cadmium laurate had unexpected properties. The court held that it did not matter that the salt was not disclosed as being preferred, the reference still anticipated the claims and because the claim was anticipated, the unexpected properties were immaterial.).
2131.04 Secondary Considerations [R-08.2012]
Evidence of secondary considerations, such as unexpected results or commercial success, is irrelevant to 35 U.S.C. 102 rejections and thus cannot overcome a rejection so based. In re Wiggins, 488 F.2d 538, 543, 179 USPQ 421, 425 (CCPA 1973).
It is noted that claim 1 is anticipated by Dudek et al., as set forth in the rejection under 35 USC 102. The rejection under 35 USC 103 is not required for claim 1. Additionally, applicant is arguing unexpected results of specific compounds wherein the claims are not limited to any specific compound.
Claims 1, 2, 5-7, 9-11, 13-21, 23-27, and 30-34 is/are rejected under 35 U.S.C. 103 as being obvious over Dudek et al. (WO 2019/204021 A1), in view of McSwiggen et al. (WO 2008/011431 A2), and Hofmeister et al. US 11,897,911 B2.
The applied reference has a common assignee with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2).
This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
Dudek et al. does not teach a structure identical to IgT3.
Hofmeister et al. teach an identical structure to IgT3 (see page 132, columns 222 and 223) for siRNA delivery and teaches structures identical to instant claims 11 and 13-20. It would have been obvious with a reasonable expectation of improve4d stability and potency, as taught by Hofmeister et al., to incorporate any of the structures and modifications taught by Hofmeister et al. into the siRNA of Dudek et al.
Applicant’s arguments
Applicant argues that Hofmeister does not explicitly teach the instant dsRNAs.
Hofmeister is not relied upon for the teachings asserted by applicant. The instant rejection is a rejection under 35 USC 103, not 102.
Conclusion
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/AMY ROSE HUDSON/Primary Examiner, Art Unit 1636
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