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 .
Application Status/Election
Claims 1-40 are pending. Applicant’s election with traverse 4/6/26 is acknowledged. Applicants argue that the claimed dsRNA agents form a single general inventive concept because of shared technical features of the species, however, a shared technical feature is not relevant to this application under US restriction practice. Applicants further argue against search burden established, however, sufficient search burden is established in the restriction of record filed 1/9/26.
The species election are as follows:
1. Applicant elects a dsRNA molecule wherein the thermally destabilizing
modification is GNA.
2. Applicant a dsRNA molecule wherein the racemic state is (S).
3. Applicant elects a dsRNA molecule wherein the thermally destabilizing modification of the duplex is an unlocked nucleic acid (UNA).
4. Applicant elects a dsRNA molecule wherein the thermally destabilizing modification of the duplex is located at position 6 of the antisense strand counting from the 5'-end.
5. Applicant elects a dsRNA molecule wherein the antisense strand comprises 2'- fluoro modifications at positions 2, 14, and 16, counting from the 5'-end of the antisense strand.
6. Applicant elects a dsRNA molecule wherein the at least one ligand comprises a trisaccharide.
7. Applicant elects a dsRNA molecule wherein a ligand is attached at the 3'-end of the sense strand.
8. Applicant elects a dsRNA molecule wherein a ligand comprises one or more GalNAc molecules attached through a trivalent branched linker.
9. Applicant elects a dsRNA molecule wherein each of the sense and antisense strands comprise at least two 2'-fluoro modifications.
10. Applicant elects a dsRNA molecule wherein the sense strand has 2'-fluoro modifications at positions complimentary to positions 11, 12, 13, and 15 of the antisense strand, counting from 5'end of the antisense strand.
11. Applicant elects a dsRNA molecule wherein at least the terminal two nucleotides at both ends of the antisense strand are linked through phosphorothioate internucleotide linkages.
12. Applicant elects a dsRNA molecule wherein the terminal three nucleotides at one
end of the antisense strand are linked through phosphorothioate internucleotide linkages.
13. Applicant elects a dsRNA molecule wherein the antisense strand comprises a phosphoryl analog.
14. Applicant elects a dsRNA molecule wherein the antisense strand comprises 2'- fluoro modifications at positions 2, 6, 8, 9, 14, and 16, counting from the 5'-end of the antisense strand.
Examiner removes the species requirement for species 2, 3, 6, 7, 9, 11, 12, and 13.
Examination on the merits commences on claims 1-40.
Claim Rejections - 35 USC § 112(a) – Written Description
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.
Claim(s) 1-40 is/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.A3.(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.”
For claims drawn to a genus, MPEP 2163.II.A3.(a).(ii) states, “written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species” where “representative number of species’ means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.”
The claims encompass a genus of modified dsRNA agents that inhibit the expression of any target wherein the dsRNA agents comprise a sense and antisense strand forming a double stranded duplex of 12-40 nucleotides wherein the antisense strand comprises a region of complementarity of any target and wherein the strands are each independently in the range of 14-40 nucleotides in length and wherein the antisense strand comprises any thermally destabilizing modification of the formula, at position 5, 6, 7, or 8, counting from the 5'-end of the antisense strand and the antisense strand comprises 2, 3, 4, 5 or 6 2'-fluoro modifications. Accordingly, the claims encompass an enormous number of different dsRNA agents which meet the structural limitations of the claims (i.e., in the range of 14-40 nucleotides in length, having any region of complementarity, any sequence, and including dsRNAs which would not likely having the function of inhibiting expression of every target gene. The application only appears to disclose a limited number of dsRNA nucleotide sequences with specific modifications and for specific targets (as seen in Table 11, pg 177, Genes C5, HBV, TTR, GO1, TMP, and AAT). While the claims include structural language that apparently limits the siRNAs in length, the specification does not teach one of skill in the art how to distinguish molecules that inhibit expression and those that do not. That is, the specification does not teach any structure/function relationship one of skill in the art at the time the application was filed to envision the structure of all such agents, with any thermally destabilizing modification at the claimed positions, capable of targeting any gene. The fact that it may be possible to screen, assay, or evaluate all such molecules to determine whether they associated with dsRNA inhibit expression is not the standard; what is needed is a description of the identifying features of the molecules themselves.
Thus, adequate written description does not exist in the instant application for the entire genus of dsRNA agents encompassed by the claims. That is, the specification does not adequately allow persons of ordinary skill in the art to recognize that applicant was in possession of the entire genus of modified dsRNA agents that inhibit any target gene. There is no art-recognized correlation between the structure and function, and the specification does not provide the support needed to allow one skilled in the art to predict with a reasonable degree of confidence the structure of the claimed inventions from a recitation of function.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states that applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the written description inquiry, whatever is now claimed. Because the level of skill and knowledge in the art increases over time, it is essential to determine possession as of the effective filing date.
In the instant case, the specification does not clearly allow persons of ordinary skill in the art to recognize that Applicant had possession of the entire scope of what is now claimed. The application does not enable the skilled artisan to clearly envision the detailed chemical structure of the encompassed genus of dsRNAs encompassed by the claims.
MPEP §2163 states, in part: “[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated. A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when … the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed. In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004).”
The description of the individual agents themselves is critical, since the prior art clearly indicates that, in general, significant variability exists with regard to the functionality of individual siRNAs targeting the same gene. For example, Harborth et al. (2001) J. Cell Science 114:4557-4565, in a study of siRNA mediated knockdown of different genes in cultured mammalian cells, state (page 4563) that, “For vimentin and T antigen we found that the first RNA duplex tested was ineffective, yet already the second duplex directed against a different region of the target resulted in gene silencing.” “Inspection of the sequences of the ineffective siRNA duplexes did not reveal any unusual feature.” “Currently we do not know whether the occasional ineffectiveness of an RNAi duplex arises from a local secondary structure of the mRNA, protection of the mRNA by a binding protein, or an as yet unidentified feature in the sequence of the duplex.”
Similarly, Holen et al. (2002) Nucleic Acids Res. 30:1757–1766 tested several siRNAs corresponding to different target sequences in human coagulation trigger tissue factor (hTF) for their ability to induce silencing of the hTF gene (Figures 2-4). Of the several siRNAs synthesized and tested only a few produced significant reduction in expression of hTF, suggesting that accessible siRNA target sites may be rare in some human mRNAs. Moreover, siRNAs targeting different sites in hTF demonstrated dramatic differences in silencing potency. Although strong positional effects were observed and regions of high GC content seem to be targeted less efficiently than those of low GC content, Holen et al. concluded that the factors determining the differences in siRNA efficiency remain unclear and that susceptible RNAi target sites in some genes may be rare.
The results of Holen et al. suggest that it is difficult to predict a priori what sequences to target in a gene with dsRNAs to induce efficient inhibition of gene expression. It was also known in the art that dsRNA efficacy is highly dependent upon target position. For example, two dsRNAs that target the same RNA, but that are shifted even one nucleotide in either direction can have a dramatic effect on the silencing effect of the iRNA agent.
Accordingly, the art at the time of filing indicates that researchers must empirically determine which dsRNA agents encompassed by the claims actually function as required by the claims. Thus, in view of these teachings, it can be concluded that variability in Applicants’ instantly claimed genus clearly exists. However, the instant application does not sufficiently describe the genus of dsRNA molecules encompassed by the claims such that one of skill in the art would recognize that Applicants were in possession of the genus of claimed dsRNAs.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116). It is noted that conception is not achieved until reduction to practice has occurred regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
Thus, the instant claims are rejected for lack of written description, because adequate 35 USC §112, first paragraph, written description support for the complete genus of dsRNA agents, as currently claimed, does not exist in the instant application.
Claim Rejections - 35 USC § 102
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.
Claim(s) 1-14, 19-34, and 36-40 is/are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Manoharan (US 2013/0130378), claims 1 and 5 as evidenced by Greenberg (Greenberg, Marc M. "Abasic and oxidized abasic site reactivity in DNA: enzyme inhibition, cross-linking, and nucleosome catalyzed reactions." Accounts of chemical research 47.2 (2014): 646-655.).
Regarding claim 1, Manoharan teaches oligonucleotides comprising modified acyclic and abasic monomers and methods for their use (abstract). Manoharan teaches exemplary modified monomers are illustrated (Figure 3) and include Tgn and Tgns (Table 1, [0570]). Manoharan teaches the oligonucleotide as a double stranded siRNA [0035]. Manoharan teaches oligonucleotides and double stranded oligonucleotides of various lengths and range from 10 to 50 nucleotides in length and where the double-stranded oligonucleotides are sufficiently complementary to hybridize to form a duplex structure for RNAi activity [0069-0077]. Manoharan teaches the oligonucleotide comprises at least one modification of acyclic and/or abasic monomer at the 5'-end, within the first 5, 6, 7, 8, 9 or 10 positions from said end [038].
Regarding thermally destabilizing modifications in claim 1, Manoharan teaches the modified abasic nucleoside monomers for enhanced stability having the structure of formula (I), formula (II), formula (III), where the monomers are placed at any position in a double stranded siRNA oligonucleotide on the sense or antisense strand and can contain 20 or more of such monomers [0021], therefore can be in every position of the antisense strand. Abasic modifications are thermally destabilizing as evidenced by Greenberg who teaches abasic sites are electrophilic and inherently chemically unstable, prone to strand scission at higher temperatures (abstract).
Regarding 2′-F modifications , Manoharan teaches the modified oligonucleotide according to the formulas described above can include modification of all or some of the sugar groups of the nucleic acid including 2′-Fluoro modifications [0143]. These modified oligonucleotides can be placed at any position in a double stranded siRNA oligonucleotide on the sense or antisense strand and can contain 20 or more of such monomers [0021], i.e. comprises 2-6 2′-F modifications.
Regarding claim 2-4, Manoharan teaches ligands can be coupled to the oligonucleotides described in the invention which can include naturally occurring molecules, or recombinant or synthetic molecules such as glycols [0304] which include
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(GNA) also known as Glycol Nucleic Acid, as the structure in instant claims 2-4 (Figures 1 and 2, [0008] and Example 1 [0550]). Manoharan further teaches monomers and oligonucleotides of the invention contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-, α or β, or as (D)- or (L)- including all such possible isomers, as well as their racemic and optically pure forms [0044], i.e. an (S)-GNA modification.
Regarding claim 5, Manoharan teaches oligonucleotides comprising modified acyclic and abasic monomers and methods for their use (abstract). Manoharan teaches exemplary modified monomers are illustrated (Figure 3) and include Tgn and Tgns (Table 1, [0570]), i.e. abasic modifications. Abasic modifications are thermally destabilizing as evidenced by Greenberg who teaches abasic sites are electrophilic and inherently chemically unstable, prone to strand scission at higher temperatures (abstract).
Regarding claims 6-9, Manoharan teaches the modified oligonucleotide according to the formulas described above applied in claim 1 which can include modification of all or some of the sugar groups of the nucleic acid including 2′-Fluoro modifications [0143]. These modified oligonucleotides can be placed at any position in a double stranded siRNA oligonucleotide on the sense or antisense strand and can contain 20 or more of such monomers [0021], therefore can be in every position including the positions of claims 6-9.
Regarding claim 10-12, Manoharan teaches targeting ligands of the sense and antisense strands which are multivalent and contain monosaccharide units, including GalNAc ligands [0313-0314 and 0321]. Manoharan teaches ligands conjugated to either the 3′ or 5′ end of oligonucleotide [0131].
Regarding claim 13, Manoharan teaches ligands can be coupled to the oligonucleotides at various places, for example, 3′-end, 5′-end, and/or at an internal position.
Regarding claim 14, Manoharan teaches targeting ligands of the sense and antisense strands which are multivalent and contain monosaccharide units, including GalNAc ligands [0313-0314 and 0321]. Manoharan teaches ligands of the invention attached to the oligonucleotide through trivalent branched linkers [0342].
Regarding 2′-Fluoro modifications positions of claims 19-22, Manoharan teaches the modified oligonucleotide according to the formulas described above applied in claim 1 which can include modification of all or some of the sugar groups of the nucleic acid including 2′-Fluoro modifications [0143]. These modified oligonucleotides can be placed at any position in a double stranded siRNA oligonucleotide on the sense or antisense strand and can contain 20 or more of such monomers [0021], therefore can be in every position including the positions of claims 19-22.
Regarding phosphorothioate positions of claims 23-27, Manoharan teaches the modified oligonucleotide according to the formulas described above applied in claim 1 which can include phosphorothioate linkage modifications [0021]. These modified oligonucleotides phosphorothioate linkages can be placed at any position in a double stranded siRNA oligonucleotide on the sense or antisense strand and can contain 20 or more of such monomers [0021], therefore can be in every position including the terminal and interior positions of claims 22-27.
Regarding claims 28 and 29, Manoharan teaches dsRNA with a blunt end at the 3'-end or 5'-end of the antisense strand [0192].
Regarding claim 30, Manoharan teaches two nucleotide overhangs at 3'end of the antisense strand [0192].
Regarding claim 31, Manoharan teaches oligonucleotides and double stranded oligonucleotides of various lengths and range from 10 to 50 nucleotides in length [0069].
Regarding claim 32, Manoharan teaches the sense strand with 21 nucleotides and the antisense strand with 23 nucleotides [0079-0081].
Regarding claim 33, Manoharan teaches an AU base pair at the 5 prime end of the antisense strand [0195].
Regarding claim 34, Manoharan teaches an antisense 5'-phosphate group [0021]
Regarding 2′-Fluoro modifications positions of claims 36-40, Manoharan teaches the modified oligonucleotide according to the formulas described above applied in claim 1 which can include modification of all or some of the sugar groups of the nucleic acid including 2′-Fluoro modifications [0143]. These modified oligonucleotides can be placed at any position in a double stranded siRNA oligonucleotide on the sense or antisense strand and can contain 20 or more of such monomers [0021], therefore can be in every position including the positions of claims 36-40.
Claim Rejections - 35 USC § 103
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.
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 15-18 and 35 are rejected under 35 U.S.C. 103 as being unpatentable over Manoharan (US 2013/0130378) applied to claim 1, evidenced by Greenberg (Greenberg, Marc M. "Abasic and oxidized abasic site reactivity in DNA: enzyme inhibition, cross-linking, and nucleosome catalyzed reactions." Accounts of chemical research 47.2 (2014): 646-655.) applied to claim 1, in view of Prakash (US 2015/0315594).
The teachings of Manoharan as applied above to claim 1 are incorporated here. Manoharan teaches multivalent GalNAc as a targeting ligand and teaches the saccharide units may be attached to a scaffold molecule, but do not teach the structure shown in instant claim 15.
Regarding claim 15, Prakash teaches modified double stranded oligonucleotides for target gene inhibition [0231]. Prakash teaches multivalent and trivalent ASGPR GalNAc ligands suitable for conjugation to oligonucleotides [0017, 1443] and teaches such as targeting moiety with a structure identical to that of instant claim 15 [042].
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to produce the oligonucleotides of Manoharan et al. with a multivalent GalNAc ligand having the structure of instant claim 15. The person of ordinary skill in the art would have reason to do so because Manoharan et al. explicitly teach oligonucleotides may be conjugated to multivalent GalNAc ligands and Prakash et al. teach specific GalNAc ligands and how to synthesize them and further teach such ligands improve the cellular delivery of oligonucleotides.
Regarding claims 16-18, Manoharan teaches chemical modifications to oligonucleotides to increase their usefulness in diagnostics, as research reagents and as therapeutic entities and to stabilize against nucleases [0004]. Manoharan teaches a variety of ligands specifically employed to stabilize the oligonucleotide against nucleases including conjugation of a ligand moiety ([0220-0221] and [0131]). Although, Manoharan teaches a variety of ligand and lipid conjugates as oligonucleotide modifications [0062], Manoharan does not specifically disclose a lipid comprised within a ligand or a ligand comprising a cell targeting peptide. However, in the targeting method described above, Prakesh teaches the GalNAc ligands of the invention, such as applied above for claim 15, comprise a targeting moiety and conjugate linker [0107]. Prakesh teaches the conjugate linker comprises a peptide binding moiety which comprises a lipid [0396].
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to produce the oligonucleotides of Manoharan et al. with a multivalent GalNAc ligands conjugated to a moiety such as Prakesh’s lipid or peptide targeting moiety in order to enhance oligonucleotide targeting and stabilize against nucleases. The person of ordinary skill in the art would have reason to do so because Manoharan et al. explicitly teach oligonucleotides may be conjugated to multivalent GalNAc ligands with various modifications to stabilize against nucleases and Prakash et al. teach specific GalNAc ligands such as conjugated to lipids and peptide targeting moieties and how to synthesize them and further teaches such ligands improve the cellular delivery of oligonucleotides.
Regarding claim 35, Manoharan teaches a variety of ligands combinations as modifications to the oligonucleotides of the invention including coupling to phosphonate groups ([0304] and claim 26). Manoharan does not specifically disclose 5'-vinyl phopshonates, however, Prakesh teaches examples of nucleosides with modified moieties include 5′-vinyl groups [0744]. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to produce the oligonucleotides of Manoharan et al. with an antisense 5'-vinyl phosphonate group. The person of ordinary skill in the art would have reason to do so because Manoharan et al. explicitly teach oligonucleotides may be coupled to phosphonate groups and Prakash et al. teach specific ligands such as 5′-vinyl groups and how to synthesize them and further teaches such ligands for improving the cellular delivery of oligonucleotides.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-40 are rejected on the grounds of nonstatutory double patenting as being unpatentable over Claims 1-20 of patent No. US12173287B2 (reference application) in view of Manoharan (US 2013/0130378) applied to claims 1-14, 19-34, and 36-40, evidenced by Greenberg (Greenberg, Marc M. "Abasic and oxidized abasic site reactivity in DNA: enzyme inhibition, cross-linking, and nucleosome catalyzed reactions." Accounts of chemical research 47.2 (2014): 646-655.) applied to claims 1 and 5, in view of Prakash (US 2015/0315594), applied to claims 15-18 and 35.
Regarding instant claims 1-40, the teachings of Manoharan, Greenberg, and Prakash are incorporated here. Although the claims at issue are not identical, they are not patentably distinct from the reference claims because the reference claims teach:
1. A double-stranded RNA (dsRNA) molecule capable of inhibiting the expression of a target gene, comprising: a sense strand and an antisense strand, each stranding having 14 to 40 nucleotides, wherein the antisense strand has sufficient complementarity to the target sequence to mediate RNA interference, wherein said sense strand, at position 1 of the 5′ end, comprises a 5′-deoxynucleoside with a morpholino at the 5′-carbon.
2. The dsRNA molecule of claim 1, wherein said antisense strand comprises at least one thermally destabilizing modification of the duplex within the first 9 nucleotide positions of the 5′ region, wherein said sense strand comprises an asialoglycoprotein receptor (ASGPR) ligand.
3. The dsRNA molecule according to claim 2, wherein the dsRNA comprises at least four 2′-fluoro.
4. The dsRNA molecule according to claim 3, wherein there are no 2′-fluoro modifications at nucleotide positions 3-9 of the antisense strand.
5. The dsRNA molecule according to claim 1, further having the following characteristics:
a) the thermally destabilizing modification of the duplex is located in position 4-8 of the 5′ region of the antisense strand;
b) and each of the sense and antisense strands comprise at least two 2′-fluoro modifications; and
c) an ASGPR ligand attached to either end of the sense strand.
6. The dsRNA molecule according to claim 5, wherein there are no 2′-fluoro modifications at nucleotide positions 3-9 of the antisense strand.
7. The dsRNA molecule according to claim 1, wherein the antisense strand has at least two of the following characteristics:
a) the thermally destabilizing modification of the duplex modification is located in position 4 to 8 of the antisense strand;
b) at least two 2′-fluoro modifications;
c) phosphorothioate internucleotide linkages between nucleotide positions 1 and 2 (counting from the 5′ end);
d) it has a length of 18 to 35 nucleotides.
8. The dsRNA molecule according to claim 7, wherein there are no 2′-fluoro modifications at nucleotide positions 3-9 of the antisense strand.
9. The dsRNA molecule according to claim 1, wherein the sense strand has at least one of the following characteristics:
a) the ASGPR ligand attached to either end of the sense strand;
b) at least two 2′-fluoro modifications;
c) the sense strand and the antisense strand show sufficient complementarity to form a double stranded region spanning at least 19 nucleotide positions and wherein the thermally destabilizing modification of the duplex is located within said double-stranded region.
10. The dsRNA molecule according to claim 9, wherein there are no 2′-fluoro modifications at nucleotide positions 3-9 of the antisense strand.
11. The dsRNA molecule according to claim 2, wherein the thermally destabilizing modification of the duplex is selected from the group consisting of
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wherein B is nucleobase.
12. The dsRNA molecule according to claim 2, wherein the thermally destabilizing modification is located in position 7 of the antisense strand.
13. The dsRNA molecule according to claim 2, wherein the ASGPR ligand is one or more N-acetylgalactosamine (GalNAc) derivatives attached through a bivalent or trivalent branched linker.
14. The dsRNA molecule of claim 9, wherein the ASGPR ligand is:
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15. The dsRNA molecule according to claim 1, wherein the antisense strand comprises at least one thermally destabilizing modification of the duplex within the first 9 nucleotide positions of the 5′ region, and the dsRNA has a melting temperature of from about 40° C. to about 80° C.
16. The dsRNA of claim 1, wherein the dsRNA further has at least one of the following characteristics: (i) the antisense comprises 2, 3, 4, 5 or 6 2′-fluoro modifications; (ii) the antisense comprises 1, 2, 3 or 4 phosphorothioate internucleotide linkages; (iii) the sense strand is conjugated with a ligand; (iv) the sense strand comprises 2, 3, 4 or 5 2′-fluoro modifications; (v) the sense strand comprises 1, 2, 3 or 4 phosphorothioate internucleotide linkages; (vi) the dsRNA comprises at least four 2′-fluoro modifications; (vii) the dsRNA comprises a duplex region of 12-40 nucleotide pairs in length; (viii) a blunt end at 5′ end of the antisense strand; and (ix) the sense strand comprises one or more LNA modifications.
17. The dsRNA of claim 16, wherein there are no 2′-fluoro modifications at positions 3-9 of the antisense strand.
18. The dsRNA molecule according to claim 1, wherein the sense strand has 21 nucleotides, and the antisense strand has 23 nucleotides.
19. A method for silencing a target gene in a cell, the method comprising a step of introducing the dsRNA molecule of claim 1 into the cell.
20. A method for suppressing off-target effects caused by the sense strand of dsRNA molecules, the method comprising a step of introducing the dsRNA molecule of claim 1 into a cell.
It would have been obvious to combine the patented claims into a single embodiment of the instant claims, given the teachings of Manoharan (US 2013/0130378) applied to claims 1-14, 19-34, and 36-40, evidenced by Greenberg (Greenberg, Marc M. "Abasic and oxidized abasic site reactivity in DNA: enzyme inhibition, cross-linking, and nucleosome catalyzed reactions." Accounts of chemical research 47.2 (2014): 646-655.) applied to claims 1 and 5, in view of Prakash (US 2015/0315594), applied to claims 15-18 and 35, given the anticipation rejection above applied to claims 1-14, 19-34, and 36-40 and obviousness rational provided above applied to claims 15-18 and 35.
Claims 1-40 are rejected on the grounds of nonstatutory double patenting as being unpatentable over Claims 1-20 of patent No. US 12247203 B2 (reference application) in view of Manoharan (US 2013/0130378) applied to claims 1-14, 19-34, and 36-40, evidenced by Greenberg (Greenberg, Marc M. "Abasic and oxidized abasic site reactivity in DNA: enzyme inhibition, cross-linking, and nucleosome catalyzed reactions." Accounts of chemical research 47.2 (2014): 646-655.) applied to claims 1 and 5, in view of Prakash (US 2015/0315594), applied to claims 15-18 and 35.
Regarding instant claims 1-40, the teachings of Manoharan, Greenberg, and Prakash are incorporated here. Although the claims at issue are not identical, they are not patentably distinct from the reference claims because the reference claims teach, claim 1: A double-stranded RNA (dsRNA) molecule capable of inhibiting the expression of a target gene, comprising a sense strand and an antisense strand, each strand having 14 to 40 nucleotides, wherein the antisense strand has sufficient complementarity to the target sequence to mediate RNA interference, wherein said antisense strand comprises one thermally destabilizing modification of the duplex within the first 9 nucleotide positions of the 5′ region, counting from the 5′-end of the antisense strand, wherein the destabilizing modification is a Modified Unlocked Nucleic Acid (mUNA), and wherein (i) said sense strand comprises an ASGPR ligand; or (ii) the dsRNA has a melting temperature of from about 40° C. to about 80° C. The reference claims further teach various 2′-fluoro modifications at multiple positions.
It would have been obvious to combine the patented claims into a single embodiment of the instant claims, given the teachings of Manoharan (US 2013/0130378) applied to claims 1-14, 19-34, and 36-40, evidenced by Greenberg (Greenberg, Marc M. "Abasic and oxidized abasic site reactivity in DNA: enzyme inhibition, cross-linking, and nucleosome catalyzed reactions." Accounts of chemical research 47.2 (2014): 646-655.) applied to claims 1 and 5, in view of Prakash (US 2015/0315594), applied to claims 15-18 and 35, given the anticipation rejection above applied to claims 1-14, 19-34, and 36-40 and obviousness rational provided above applied to claims 15-18 and 35.
Claim 1-40 are rejected on the grounds of nonstatutory double patenting as being unpatentable over Claims 1-42 of patent No. US11504391B1 (reference application) in view of Manoharan (US 2013/0130378) applied to claims 1-14, 19-34, and 36-40, evidenced by Greenberg (Greenberg, Marc M. "Abasic and oxidized abasic site reactivity in DNA: enzyme inhibition, cross-linking, and nucleosome catalyzed reactions." Accounts of chemical research 47.2 (2014): 646-655.) applied to claims 1 and 5, in view of Prakash (US 2015/0315594), applied to claims 15-18 and 35.
Regarding instant claims 1-40, the teachings of Manoharan, Greenberg, and Prakash are incorporated here. Although the claims at issue are not identical, they are not patentably distinct from the reference claims because independent reference claim 1 teaches a method for silencing a target gene in a cell, the method comprising a step of introducing a dsRNA molecule into the cell, wherein the dsRNA molecule comprises a sense strand and an antisense strand, each strand having 14 to 40 nucleotides, wherein the antisense strand has sufficient complementarity to the target sequence to mediate RNA interference, wherein said antisense strand comprises at least one thermally destabilizing modification of the duplex within the first 9 nucleotide positions of the 5′ region of the antisense strand or a precursor thereof, wherein the antisense strand further comprises one or both of the following characteristics:
(i) 2, 3, 4, 5 or 6 2′-fluoro modifications; and
(ii) 1, 2, 3, 4 or 5 phosphorothioate internucleotide linkages; and said sense strand comprises one, two or three of the following characteristics:
(i) an asialoglycoprotein receptor (ASGPR) ligand;
(ii) 2, 3, 4, or 5 2′-fluoro modifications; and
(iii) 1, 2, 3, 4 or 5 phosphorothioate internucleotide linkages.
It would have been obvious to combine the patented claims into a single embodiment of the instant claims, given the teachings of Manoharan (US 2013/0130378) applied to claims 1-14, 19-34, and 36-40, evidenced by Greenberg (Greenberg, Marc M. "Abasic and oxidized abasic site reactivity in DNA: enzyme inhibition, cross-linking, and nucleosome catalyzed reactions." Accounts of chemical research 47.2 (2014): 646-655.) applied to claims 1 and 5, in view of Prakash (US 2015/0315594), applied to claims 15-18 and 35, given the anticipation rejection above applied to claims 1-14, 19-34, and 36-40 and obviousness rational provided above applied to claims 15-18 and 35.
Claim 1-40 are rejected on the grounds of nonstatutory double patenting as being unpatentable over Claims 1-41 of patent No. 10995336 (reference application) in view of Manoharan (US 2013/0130378) applied to claims 1-14, 19-34, and 36-40, evidenced by Greenberg (Greenberg, Marc M. "Abasic and oxidized abasic site reactivity in DNA: enzyme inhibition, cross-linking, and nucleosome catalyzed reactions." Accounts of chemical research 47.2 (2014): 646-655.) applied to claims 1 and 5, in view of Prakash (US 2015/0315594), applied to claims 15-18 and 35.
Regarding instant claims 1-40, the teachings of Manoharan, Greenberg, and Prakash are incorporated here. Although the claims at issue are not identical, they are not patentably distinct from the reference claims because the independent reference claim 1 teaches a dsRNA agent that inhibits expression of Serpina1, comprising a sense strand and an antisense strand of specific sequence, wherein the antisense strand is 23 nucleotides long and comprises at least one thermally destabilizing modification at one of positions 4-8 from the 5'-end. The antisense strand may further comprise 2'-F modified nucleotides at positions 2, 14, and 16. The sense strand is 21 nucleotides long and comprises an ASGPR ligand and may further comprise three or four 2'-F modified nucleotides at specific position. The reference claims further teach 2'-F modified nucleotides at various other positions.
It would have been obvious to combine the patented claims into a single embodiment of the instant claims, given the teachings of Manoharan (US 2013/0130378) applied to claims 1-14, 19-34, and 36-40, evidenced by Greenberg (Greenberg, Marc M. "Abasic and oxidized abasic site reactivity in DNA: enzyme inhibition, cross-linking, and nucleosome catalyzed reactions." Accounts of chemical research 47.2 (2014): 646-655.) applied to claims 1 and 5, in view of Prakash (US 2015/0315594), applied to claims 15-18 and 35, given the anticipation rejection above applied to claims 1-14, 19-34, and 36-40 and obviousness rational provided above applied to claims 15-18 and 35.
Claim 1-40 are provisionally rejected on the grounds of nonstatutory double patenting as being unpatentable over Claims 28-49 of application #19/025,271 (reference application) in view of Manoharan (US 2013/0130378) applied to claims 1-14, 19-34, and 36-40, evidenced by Greenberg (Greenberg, Marc M. "Abasic and oxidized abasic site reactivity in DNA: enzyme inhibition, cross-linking, and nucleosome catalyzed reactions." Accounts of chemical research 47.2 (2014): 646-655.) applied to claims 1 and 5, in view of Prakash (US 2015/0315594), applied to claims 15-18 and 35.
Regarding instant claims 1-40, the teachings of Manoharan, Greenberg, and Prakash are incorporated here. Although the claims at issue are not identical, they are not patentably distinct from the reference claims because the independent reference claims teach:
28. A double-stranded RNA (dsRNA) capable of inhibiting the expression of a target gene, comprising a sense strand and an antisense strand, each strand having 14 to 40 nucleotides, wherein the dsRNA comprises a duplex region of 12-40 nucleotide pairs in length, and wherein the antisense strand has sufficient complementarity to the target sequence to mediate RNA interference; and the antisense strand comprises one modification of the formula, at position 5, 6, 7, or 8, counting from the 5'-end of the antisense strand, wherein B is nucleobase.
29. The dsRNA of claim 28, wherein the dsRNA contains one or more characteristic selected from the group consisting of, (i) the antisense strand comprises only 2, 3, 4, 5, or 6 2'- fluoro modifications; (ii) the antisense strand comprises only 1, 2, 3, or 4 phosphorothioate internucleotide linkages; (iii) the sense strand comprises only 2, 3, 4, or 5 2'-fluoro modifications; (iv) the sense strand comprises only 1, 2, 3, or 4 phosphorothioate internucleotide linkages; and (v) comprising a blunt end at 5'-end of the antisense strand.
30. The dsRNA of claim 28, wherein there are no 2'-fluoro modifications at nucleotide positions 3-9 of the antisense strand.
31. The dsRNA of claim 28, wherein, the sense strand is conjugated with a ligand.
32. The dsRNA of claim 31, wherein the ligand is a cell or tissue targeting agent.
33. The dsRNA of claim 31, wherein the ligand is an antibody.
34. The dsRNA of claim 31, wherein the ligand is an alkyl or substituted alkyl group.
35. The dsRNA of claim 31, wherein the ligand is an ASGPR ligand comprising one or more GalNAc derivatives attached through a bivalent or trivalent branched linker.
36. The dsRNA of claim 35, wherein the ASGPR ligand is:
37. The dsRNA of claim 28, wherein the thermally-destabilizing modification is located in position 6 of the antisense strand, counting from the 5'-end of the antisense strand.
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38. The dsRNA of claim 28, wherein the thermally-destabilizing modification is located in position 7 of the antisense strand, counting from the 5'-end of the antisense strand.
39. The dsRNA of claim 28, wherein the sense strand has 21 nucleotides, and the antisense strand has 23 nucleotides.
40. The dsRNA of claim 28, wherein the dsRNA has a melting temperature of from about 55oC to about 67oC.
41. The dsRNA of claim 28, wherein the antisense strand comprises 2'-fluoro modifications at positions 2, 14 and 16, counting from the 5'-end of the antisense strand. Acid Sequence Disclosures filed March 19, 2025
42. The dsRNA of claim 41, wherein the antisense strand comprises 2'-fluoro modifications at only positions 2, 6, 8, 9, 14 and 16, counting from the 5'-end of the antisense strand.
43. The dsRNA of claim 41, wherein the antisense strand comprises 2'-fluoro modifications at only positions 2, 6, 14, and 16, counting from the 5'-end of the antisense strand.
44. The dsRNA of claim 41, wherein the sense strand comprises 2'-F modifications at positions opposite or complimentary to (i) positions 11, 12 and 15 or (ii) positions 11, 12, 13 and 15, of the antisense strand counting from the 5'-end of the antisense strand.
45. The dsRNA of claim 41, wherein the sense strand comprises a block of two, three, or four 2'-fluoro nucleotides.
46. The dsRNA of claim 28, wherein the first base pair within the duplex region from the 5'- end of the antisense strand is an AU base pair
47. A method for silencing a target gene in a cell, the method comprising a step of introducing the dsRNA of claim 28 into the cell.
48. The method of claim 47, wherein the dsRNA is administered through subcutaneous or intravenous administration.
49. A method for suppressing off-target effects caused by the antisense strand of a dsRNA, the method comprising a step of introducing the dsRNA of claim 28 into a cell.
It would have been obvious to combine the patented claims into a single embodiment of the instant claims, given the teachings of Manoharan (US 2013/0130378) applied to claims 1-14, 19-34, and 36-40, evidenced by Greenberg (Greenberg, Marc M. "Abasic and oxidized abasic site reactivity in DNA: enzyme inhibition, cross-linking, and nucleosome catalyzed reactions." Accounts of chemical research 47.2 (2014): 646-655.) applied to claims 1 and 5, in view of Prakash (US 2015/0315594), applied to claims 15-18 and 35, given the anticipation rejection above applied to claims 1-14, 19-34, and 36-40 and obviousness rational provided above applied to claims 15-18 and 35.
This is a provisional rejection because the copending claims have not yet been patented.
Conclusion
All claims are rejected.
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/JOHN CHARLES MCKILLOP/Examiner, Art Unit 1637
/EKATERINA POLIAKOVA-GEORGANTAS/Primary Examiner, Art Unit 1637
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