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 .
Election/Restrictions
Applicant’s election without traverse of Group I (claims 3-4, 7-8, 13-14, 34-35, 47, 64, and 75-77) in the reply filed on May 27, 2026 is acknowledged.
Claim 83-84, 90-92, 103, and 107 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Group II, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on May 27, 2026.
Applicant’s election without traverse of the dsRNA of duplex AD-335905 as the single specific species of dsRNA agent in the replay filed on May 27, 2026 is acknowledged. The elected dsRNA comprises unmodified antisense sequence set forth as SEQ ID NO: 191, unmodified sense strand sequence set forth as SEQ ID NO: 97, the modified antisense sequence set forth as SEQ ID NO: 379, modified sense strand sequence set forth as SEQ ID NO: 285.
Claims 3-4, 7-8, 13-14, 34-35, 47, 64, and 75-77 are pending and under examination.
Priority
Acknowledgment is made of applicant's claim for priority based on a US Provisional Application
No. 63/166,406 filed on 03/26/2021.
Specification
The disclosure is objected to because it contains an embedded hyperlink (pg. 13, lines 10-13) and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Claim Objections
Claims 3, 14, and 64 are objected to because of the following informalities:
In claim 3, line 2, the acronym “ELOVL1” is recited, but not defined in the claim. An acronym should be defined the first time it appears in an independent claim or in the group of claims under an independent claim. For the purposes of examination, “ELOVL1” is interpreted to mean “elongation of very long chain fatty acids protein 1”, as defined in the specification (pg. 1, line 15).
In claim 14, line 16, there is a typographical error of two commas between the terms 5’ phosphate mimic and a glycol nucleic acid.
In claim 64, line 4, the acronym “GalNAc” is recited, but not defined in the claim. For the purposes of examination, “GalNAc” is interpreted to mean “N-acetylgalactosamine”, as defined in the specification (pg. 79, line 20).
Appropriate correction is required.
Claim Interpretation
Claim 3 recites a dsRNA agent that comprises a sense strand and an antisense strand forming a double stranded region. This is interpreted as meaning that double stranded region is formed by base pairing between the sense and antisense strands.
Claims 8, 34, and 35 recite “the one or more lipophilic moieties are conjugated to one or more internal positions”. In the interest of compact prosecution, “internal positions” is interpreted to mean any nucleotide of the dsRNA that is not a 5’- or 3’- terminal end.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Section 33(a) of the America Invents Act reads as follows:
Notwithstanding any other provision of law, no patent may issue on a claim directed to or encompassing a human organism.
Claim 75 is rejected under 35 U.S.C. 101 and section 33(a) of the America Invents Act as being directed to or encompassing a human organism. See also Animals - Patentability, 1077 Off. Gaz. Pat. Office 24 (April 21, 1987) (indicating that human organisms are excluded from the scope of patentable subject matter under 35 U.S.C. 101).
Claim 75 recites “a cell containing the dsRNA agent of claim 3”. The specification discloses that “RNAi compositions, which effect the RNA-induced silencing complex (RISC)-mediated cleavage of RNA transcripts of an ELOVL1 gene. The ELOVL1 gene may be within a cell, e.g., a cell within a subject, such as a human” (pg. 1, lines 32-34). Accordingly, the cell in claim 75 is present or intended to be present in a human being, said cell becoming integrated into the human being and therefore being an inseparable part of the human itself. The scope of the claim, therefore, encompasses a human being, which is non-statutory subject matter.
It would be remedial to amend claim 75 to recite “an isolated cell containing the dsRNA agent of claim 3”.
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 3-4, 7-8, 13-14, 34-35, 47, 64, and 75-77 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
MPEP 2163.II.A.3.(a).i) states, “Whether the specification shows that applicant was in possession of the claimed invention is not a single, simple determination, but rather is a factual determination reached by considering a number of factors. Factors to be considered in determining whether there is sufficient evidence of possession include the level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention”. MPEP § 2163 further states the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species.
Claim 3 is drawn to a genus of dsRNA agent comprising a sense strand and an antisense strand, wherein the antisense strand comprises a region of complementarity to an mRNA encoding ELOVL1, and this region comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from SEQ ID NO: 191. Further claim 3 recites the dsRNA is for inhibiting expression of ELOVL1. Thus, claim 3 encompasses a genus of dsRNA defined by structure and function.
SEQ ID NO: 191 consists of 23 nucleotides. The claimed minimum sequence identity threshold allows variation up to 3 nucleotides (3/23=13%), which could be nucleotide substitutions, insertions, and deletions. The claim encompasses a genus of dsRNA wherein the antisense strand comprises at least 87% sequence identity to SEQ ID NO: 191, while maintaining the claimed function. It is noted that there is no upper limit in the length of the antisense strand.
The specification discloses a total of 6 species of dsRNA within the claimed genus: (i) full-length SEQ ID NO: 191, (ii) SEQ ID NO: 190 and 189 differing from SEQ ID NO: 191 by one and two nucleotides, respectively, generated by shifting the antisense strand sequence toward the 5’- end of the target mRNA, and (iii) SEQ ID NO: 192, 193, and 194 differing from SEQ ID NO: 191 by one, two, and three nucleotides, respectively, generated by shifting the antisense strand sequence toward the 3’-end of the target mRNA. These disclosed species are not considered representative of the breadth of the claimed genus, as they correspond to neighboring antisense sequences that would be identified through conventional tilling or walking screens of dsRNA adjacent target sites.
The specification fails disclose additional antisense strands comprising substitutions, insertions, and/or deletions at different internal positions within the complementary region while preserving the claimed function, any common structural features or identifying sequence characteristics, or a recognized correlation between structure and function, such that one skilled in the art can recognize the members of the genus. Therefore, an ordinary skilled in the art would determine that Applicant has demonstrated possession of only SEQ ID NO: 191 itself.
The state of the art establishes that effective dsRNA requires sufficiently long strands, e.g., about 20 nucleotides, extensive complementarity between the antisense strand and the target mRNA, and specific functional regions in the antisense are tolerant of mismatches. Angart (Pharmaceuticals, 2013, 6:440-468) teaches the antisense strand’s seed region (bases 2-8) and splice site (bases 10-11) are the least tolerant of mismatches due to their active role in silencing, whereas the first nucleotide, and nucleotides of the 3’ overhang (bases 20-21) and bases 17-19 are the most tolerant of mismatches due to their ability to base pairs is partially blocked by enzyme Ago2 (pg. 447, caption of Fig. 2). Figure 2 is reproduced below for illustration. Further, position and base specific mismatches are tolerated at positions 8-16, but “target regions with as little as one nucleotide difference can change target knockdown efficiency significantly” (pg. 446, para. 4).
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As further demonstrated by Schwarz (PLoS Genetics, 2006, 2(9),e140:1307-1318), systematic evaluation of single mismatches throughout the antisense strand revealed that some positions tolerated single nucleotide mismatches whereas others substantially reduced or abolished RNAi activity, with mismatches in the seed region exhibiting different effects than those near the 3’-end (pg. 1308-1310, subsection “A Tiled Set of Functionally Asymmetric siRNAs Targeting Mutant SOD1”; Fig. 1A-1C). Thus, the prior art recognizes that mismatch tolerance is unpredictable. Further, the effect of nucleotide substitutions depends on multiple factors, including the position of the mismatch within the antisense strand, the identity of the substituted nucleotide, the type of mismatch, e.g., G:U wobble base paring versus purine:purine, and the adjacent sequence context.
Further, dependent claims 4, 7-8, 13-14, 34-35, 47, 64, and 75-77 recite limitations drawn to dsRNA’s length, modified nucleotides, lipophilic moieties conjugated at internal positions, and targeting ligand, which do not remedy the lack written description. Accordingly, the dependent claims are also rejected for depending from a rejected claim and failing to remedy the lack of written description therein.
Based on the preponderance of the evidence, including the relevant teachings of the specification, the absence of working examples, and the state of prior art including the knowledge of mutations tolerance on the antisense strand, one skilled in the art would conclude that Applicant was not in possession of the claimed genus of dsRNA wherein the region of complementarity in the antisense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from SEQ ID NO: 191.
Claim 7 is drawn to dsRNA agents that comprises one or more lipophilic moieties, which as defined by the specification a lipophilic moiety is “any compound or chemical moiety having an affinity for lipids” (pg. 22, lines 30-31). Thus, the claim encompasses a genus of lipophilic moieties not defined by any common structural characteristics, but rather by the broad function of binding to lipids.
The specification discloses various lipophilic moieties known in the art, including cholesterol, cholic acid, a thiocholesterol, an aliphatic chain, a phospholipid, a polyethylene glycol chain, and a palmityl moiety (pg. 74, lines 17-32). However, the specification does not disclose representative dsRNA conjugated to these listed lipophilic moieties. Rather, the only exemplified dsRNA conjugates comprise GalNAc ligand L96 (Table 3), which is disclosed as a targeting ligand rather than as a lipophilic moiety (pg. 79, lines 20-25). Thus, the specification fails to disclose representative number of species across the claimed genus.
Although the specification discloses lipophilic moieties known in the art, it fails to disclose structural characteristics common to the claimed genus of dsRNA comprising one or more lipophilic moieties beyond the broad functional property that the moieties have an affinity for lipids. The specification also fails to disclose a recognized correlation between structure and function that would enable one skill in the art to recognize which moiety is a member of the claimed genus. The disclosure of unrelated classes of lipophilic moieties are not representative members of the claimed genus.
The state of the art, particularly Juliano (NAR, 2016, 44(1):6518-6548) recognizes antisense oligonucleotides could employ numerous chemically distinct lipophilic moieties, including cholesterol, fatty acids, tocopherols, and phospholipids (pg. 6532, col. 1, para. 4; pg. 6538, col. 1, para. 2; pg. 6528, col. 1, para. 2). However, these moieties represent diverse chemical structures, rather than a single structurally-defined class.
Further, dependent claims 8, 34-35, and 64 recite limitations drawn to conjugation position of the lipophilic moiety and further comprising a targeting ligand, which do not remedy the lack written description. Accordingly, the dependent claims are also rejected for depending from a rejected claim and failing to remedy the lack of written description therein.
On the other hand, dependent claim 47 narrows the breadth of the claim to specific subgenus of lipophilic moieties defined by structure, specifically in claimed limitations (f)(g)(h)(i)(j)(k). Based on the teachings of the specification and the state of the prior art, one skilled in the art could recognize members the subgenus via the defined structural characteristics and function in the claim. Thus, one would conclude that claim 47 remedies the lack of written description therein.
In summary, based on the preponderance of the evidence, including the relevant teachings of the specification, the absence of working examples, and the state of prior art including the knowledge of mutations tolerance on the antisense strand, one skilled in the art would conclude that Applicant was not in possession of the full scope of claimed genus of dsRNA that comprises one or more lipophilic moieties.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 3-4, 7-8, 13-14, 34-35, 47, 64, and 75-77 are rejected under 35 U.S.C. 103 as being unpatentable over Swinnen (WO 2013/144325 A1; Published Date: Oct 03, 2013; cited in previous Office Action mailed on Mar 06, 2026) in view of NM_001256401.1 (Homo sapiens ELOVL fatty acid elongase 1 (ELOVL1), transcript variant 3, mRNA; NCBI Reference Sequence; Priority to Dec 28, 2019), Jadhav (US 2006/0148743 A1; Published Date: Jul 06, 2006), and Reynolds (Nat. Biol., 2004, 22(3):326-330).
Regarding claim 3, Swinnen teaches siRNA duplexes for inhibiting expression of ELOVL1 (pg. 13, lines 16-28), wherein the siRNA duplexes "may be assembled from two distinct nucleic acid strands or fragments wherein one fragment includes the sense region and the second fragment includes the antisense region of the RNA molecule" (pg. 22, lines 4-6), and contain two nucleotide overhangs at 3’-terminal (pg. 21, line 18). Accordingly, the siRNA duplexes of Swinnen match with instantly claimed double stranded ribonucleic acid agents comprising a sense strand and an antisense strand forming a double stranded region. Swinnen also teaches the "antisense oligonucleotide having a complementary or substantially complementary base sequence to ELOVL1" (pg. 19, lines 17-19), and comprises "about 21 to about 23nucleotides in length" (i.e., wherein the region of complementarity comprises at least 15 contiguous nucleotides) (pg. 20, lines 28-30).
However, Swinnen does not teach wherein the region of complementarity comprises at least 15 contiguous nucleotides differing by no more than 2 nucleotides from SEQ ID NO: 191.
NM_001256401.1 teaches the mRNA transcript of ELOVL1 is publicly available, and SEQ ID NO: 191 aligns to ELOVL1 mRNA at positions 1218 to 1235 (sequence alignment shown below).
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In addition, Jadhav teaches short interfering RNAs (i.e., dsRNA) for inhibiting expression of histone deacetylase gene (abstract). Jadhav further teaches a method for selection of dsRNA targeting a given gene or transcript([0489]), comprising steps of generating a list of subsequences of a particular length (e.g., 23 nucleotides), ranking the subsequences preferably containing 40-60% G/C content, ranking subsequences that contain dinucleotide UU on the 3’-end comprising a 3’-terminal deoxythymidine nucleotides or AA on the 5’-end, identifying resulting dsRNA to comprise a sense strand of 21 nucleotides and an antisense strand of 23 nucleotides, and screening the resulted dsRNA in an in vitro, cell culture or animal model system to obtain the most active dsRNA or most preferred target site within the target mRNA sequence ([0490]-[0498]). Further, Jadhav discloses additional design considerations are taught by Reynolds ([0499]).
Reynolds teaches a rational systematic analysis of a panel of siRNA duplexes (i.e., dsRNA) designed to target every other position of a mRNA sequence (pg. 326, col. 1, para. 1). Reynold teaches each dsRNA comprises of 21 nucleotides wherein the region of complementarity comprises 19 nucleotides (pg. 329, col. 2, para. 1), and the analysis incorporates a criteria of 30%-52% GC content in the dsRNA along with seven additional criteria for the sense strand that significantly improves potent dsRNA selection, including at least three ‘A/U’ bases at positions 15-19, absence of internal repeats, an ‘A’ base at position 19, an ‘A’ base at position 3, a ‘U’ base at position 10, a base other than ‘G’ or ‘C’ at position 19, and a base other than ‘G’ at position 13 (Table 1).
Thus, it would have been obvious to one of ordinary skill in the art before the effective filling
date of the invention to have modified Swinnen's dsRNA that comprises a region of complementarity to ELOVL1 to be SEQ ID NO: 191 because it would have merely amounted to choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success ("obvious to try"). One would have been motivated to have done so because the target sequence ELOVL1 and its CDS regions and transcripts were known, and designing siRNAs complementary to ELOVL1 would have been routine and predictable design. One would have had a reasonable expectation of success in doing so because siRNA design is constrained to a finite number of predictable target regions within a known transcript given that siRNA design is not open-ended due to the considerations taught by Swinnen (pg. 21, lines 15-27). Jadhav teaches a step-by-step method for selection of dsRNA targeting a given transcript, wherein the method details dsRNA length, G/C content, and strategy to rank the most active dsRNA. Reynolds also teaches a systematic analysis that allows one to rationally design a panel of dsRNAs by knowing the target mRNA sequence. For instance, Reynolds’ analysis would have yielded 692 dsRNA candidates tilling every other nucleotide in the mRNA of ELOVL1, which consists of 1385 nucleotides as taught by NCBI mRNA transcript. Further, the number of dsRNA candidates can be further narrowed by applying Jadhav’s selection criteria and Reynolds’ eight criteria. Therefore, only a finite number of dsRNA can be designed, and the instantly recited SEQ ID NO: 191 represent one of a limited number of predictable dsRNA candidates that would have been obtained through routine optimization.
Regarding claim 4, the obviousness to modify Swinnen’s dsRNA comprise SEQ ID NO: 191 as taught by NM_001256401.1, Jadhav and Reynolds are discussed above as applied to claim 3. The combination of prior art teaches the instantly recited limitations:
(b) NM_001256401.1 teaches the reverse complement, i.e., the sense strand, comprising instantly claimed SEQ ID NO: 191 (sequence alignment shown below).
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(c), (g), and (h), Swinnen teaches wherein the dsRNA is about 21 to 23 nucleotides in length (i.e., no more than 30 nucleotides) (pg. 20, line 29);
(d), (g), and (h), Jadhav teaches dsRNA comprise a sense strand of 21 nucleotides and an antisense strand of 23 nucleotides ([0497]); Thus, Jadhav teaches wherein at least one strand comprises a 3’ overhang of at least 1 nucleotide ([0092]);
(e) Swinnen and Jadhave teach wherein the double stranded region is about 19 base pairs (pg. 20, line 29; [0335] respectively);
(f) Jadhav teaches wherein the base pair at the 1 position of the 5’-end of the antisense strand is an AU base pair (Table 2);
(i) and (j), Jadhav teaches wherein the dsRNA further comprises 6-8 phosphorothioate internucleotide linkages ([0086]).
Regarding claim 7, the obviousness to have modified Swinnen’s dsRNA to comprise instantly claimed SEQ ID NO: 191 as taught by NM_001256401.1, Jadhav and Reynolds are discussed above as applied to claim 3.
However, Swinnen does not teach wherein the sense strand, the antisense strand, or both, is conjugated to one or more lipophilic moieties.
Jadhav teaches dsRNA molecules for inhibiting expression of histone deacetylase gene (abstract). Jadhav further teaches wherein the dsRNA comprises conjugate moieties (i.e., lipophilic moieties) include polymer cholesterol and co-factor N-acetyl-galactosamine (GalNAc) ([0077]), which are ligands that capable of interacting with cellular receptors ([0227]). Jadhav teaches GalNAc is a moiety having higher affinity for the asialoglycoprotein receptor than galactose, and the usage of galactosamine-based conjugate moieties to transport dsRNA across cell membranes can provide a targeted delivery approach for treatment. Further, the use conjugate moieties provide a reduction in the required dose of therapeutic dsRNA required for treatment, and allows modulation of pharmacodynamics and pharmacokinetic parameters ([0463]).
Thus, it would have been obvious to one of ordinary skill in the art before the effective filling date of the invention to have modified Swinnen’s dsRNA to comprise one or more lipophilic moieties as taught by Jadhav because it would have merely amounted to a simple combination of prior art elements according to known methods to yield predictable results. Each component in the combination performs the same function as they do separately: dsRNA retains its function of hybridizing to target mRNA sequence while the lipophilic moieties retain the function of intracellular delivery and interaction with cellular receptos. One would have been motivated to have done so for the advantage of transporting dsRNA across cell membranes for targeted delivery and reducing the required dose of dsRNA required for treatment as taught by Jadhav. One would have had a reasonable expectation of success in doing so because Jadhav teaches dsRNA of 23 nucleotides and comprises a region of complementarity ([0329]) as instantly claimed dsRNA, and Jadhav teaches dsRNA comprising one or more lipophilic moieties conjugated to the dsRNA.
Regarding claims 8 and 34, the obviousness to have modified Swinnen’s dsRNA to comprise one or more lipophilic moieties as taught by Jadhav is discussed above as applied to claim 7. Jadhav further teaches wherein the one or more lipophilic moieties is conjugated to one or more internal positions in the double stranded region of the dsRNA agent (FIG. 28, [0322]).
Regarding claims 13 and 14, the obviousness to have modified Swinnen’s dsRNA to comprise instantly claimed SEQ ID NO: 191 as taught by NM_001256401.1, Jadhav and Reynolds are discussed above as applied to claim 3. Swinnen further teaches wherein the dsRNA may be modified extensively to enhance stability by modification with nuclease resistant group, e.g., 2’-fluoro, 2’-O-methyl, and 2’-amino (pg. 22, lines 6-8).
In addition, Jadhav teaches wherein the dsRNA comprises phosphorothioate internucleotide linkages, and about 10 or more modified nucleotides including 2’-deoxy, 2’-O-methyl, and more ([0087]).
Regarding claim 35, the obviousness to have modified Swinnen’s dsRNA to comprise one or more lipophilic moieties as taught by Jadhav is discussed above as applied to claim 7. Further, Jadhav teaches wherein the one or more lipophilic moieties are “covalently attached to the chemically-modified siNA molecule via a biodegradable linker” (i.e., conjugated to one or more internal positions on at least one strand via a linker or carrier) ([0121]).
Regarding claim 47, the obviousness to have modified Swinnen’s dsRNA to comprise one or more lipophilic moieties as taught by Jadhav is discussed above as applied to claim 7. Jadhav teaches (g) wherein the one or more lipophilic moieties is cholesterol ([0077]). Fig. 39 shows cholesterol conjugated to the sense strand. Jadhav further teaches wherein the one or more lipophilic moieties are conjugated to one or more internal positions on at least one strand via a biodegradable linker ([0121]), which refers to a nucleic acid or non-nucleic acid linker ([0399]).
Regarding claim 64, the obviousness to have modified Swinnen’s dsRNA to comprise one or more lipophilic moieties as taught by Jadhav is discussed above as applied to claim 7. Jadhav further teaches (b) wherein the dsRNA comprises conjugate moieties (i.e., targeting ligand) including co-factor N-acetyl-galactosamine (GalNAc) ([0077]), which is a ligand that is capable of interacting with cellular receptors ([0227]). Additional teachings of Jadhav’s dsRNA comprising GalNAc are discussed above as applied to claim 7. Jadhav also teaches (h) wherein the dsRNA further comprises a 5’-methylphosphonate (i.e., a phosphate mimic) at the 5’-end of the antisense strand that improves stability ([0395]).
Regarding claim 75, the obviousness to have modified Swinnen’s dsRNA to comprise instantly claimed SEQ ID NO: 191 as taught by NM_001256401.1, Jadhav and Reynolds are discussed above as applied to claim 3. Swinnen further teaches isolated cells comprising the dsRNA (pg. 27, lines 32-33).
Regarding claim 76 and 77, the obviousness to have modified Swinnen’s dsRNA to comprise instantly claimed SEQ ID NO: 191 as taught by NM_001256401.1, Jadhav and Reynolds are discussed above as applied to claim 3. Jadhav further teaches wherein the dsRNA can comprise liposomes, carriers and diluents and their salts in pharmaceutically acceptable formulations for administration to a subject ([0420]).
Relevant Art Cited
The prior art made of record and not relied upon is considered pertinent to applicant’s disclosure. Foster (Molecular Therapy, 2018, 26(3):708-717) teaches a dsRNA agent comprising a sense strand and an antisense strand, each strand having a length of 21 and 23 nucleotides in length, respectively. Foster further teaches the sense strand, particularly DV18, comprises 2’-fluoro modifications at positions 7, 9, 10, and 11, and the corresponding antisense strand, comprises 2’-fluoro modifications at positions 2, 6, 8, 9, 14, and 16 (Fig. 2C). Thus, Foster teaches dsRNA comprising 2’-fluoro modifications at specific positions in the sense and antisense strand, matching with instantly claimed elected modified dsRNA comprising sense strand of SEQ ID NO: 285 and antisense strand of SEQ ID NO: 397.
Conclusion
No claims are allowable.
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/QIWEN SU-TOBON/
Examiner
Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636
Prosecution Insights