TNGDETAILED 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 1-3, 18, 24, 27, 33, 45, 49, and 57-58) in the reply filed on 27 January 2026 is acknowledged. Applicant’s election of one miRNA binding sequence as the species of criteria for RNA-modulating agent; only positions 2 to 8 of a target miRNA as the species of miRNA binding sequence complementary positions; docosanoic acid (DCA) linked to the 3' end of a RNA-modulating agent by a dTdT dinucleotide as the species of functional moiety and linkage of/to RNA-modulating agent; neuromuscular mRNA target Activin A as the species of target mRNA; and, miR-1, which is expressed in muscle tissue, as the species of target miRNA and its expression is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 1-3, 18, 24, 27, 33, 45, 49, 57, and 58 are amended. Claims 59, 65, 67, 73-75, and 80-82 are canceled. Claims 89-97 are newly added. Claim 49 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.
Claims 1-3, 18, 24, 27, 33, 45, 57, 58, and 89-97 are pending and being examined on the merits.
Priority
The application claims priority to application 63/336,585 filed 04/29/2022 and application 63/354,435 filed 06/22/2022.
Information Disclosure Statement
The information disclosure statements filed 1/07/2025 and 1/27/2026 have been acknowledged.
Drawings
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
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 1-3, 18, 24, 27, 33, 57-58, and 89-97 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.
For claims drawn to a genus, MPEP § 2163 states the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
Claim 1 is directed to an RNA-modulating agent comprising (i) an mRNA-binding sequence complementary to a portion of a target mRNA, linked to (ii) one or more miRNA-binding sequences complementary to at least positions 2-8 of a target miRNA, wherein the miRNA-binding sequence comprises at least one modified nucleotide at a position complementary to one or more of positions 2, 5, and 8 of the target miRNA. The claim encompasses RNA-modulating agents directed to essentially any target mRNA, any target miRNA, and numerous modification chemistries, including agents intended for use across a broad range of tissues and disease indications.
The specification does not reasonably convey to one of ordinary skill in the art that the inventors were in possession of the full scope of the claimed genus as of the filing date. The disclosure provides only a limited number of representative species, primarily involving activin A/miR-1, ApoC3/miR-122, Smad3/miR-192, and a small number of additional exemplified targets. The specification does not disclose representative species spanning the enormous number of potential target mRNA/target miRNA combinations encompassed by the claims, nor does it identify structural features common to the members of the claimed genus that would permit a skilled artisan to recognize which combinations will successfully produce the claimed RNA modulation.
The unpredictability of miRNA-mediated regulation further underscores the lack of possession of the full claimed genus. Grimson (Grimson et al., Molecular Cell 27:91-105 (2007)), demonstrated that seed complementarity alone is insufficient to predict functional repression and that multiple contextual determinants beyond sequence complementarity govern whether a miRNA-target interaction produces silencing [abstract]. Garcia (Garcia et al., Nature Structural & Molecular Biology 18:1139-1146 (2011)), likewise showed that complementary target sites frequently differ in silencing efficacy and that the presence of a target site does not reliably predict functional repression. Garcia teaches that targeting efficacy depends on factors such as seed-paring stability and target site context [abstract]. Broughton (Broughton et al., Molecular Cell 64:320-333 (2016)), further demonstrated that pairing outside the seed region contributes substantially to targeting specificity and activity.
In view of the art-recognized unpredictability of miRNA targeting, the limited number of examples disclosed in the specification do not reasonably demonstrate possession of the broad genus encompassing essentially all target mRNAs, all target miRNAs, and all claimed modification patterns.
Accordingly, the specification fails to provide adequate written description support commensurate in scope with claim 1.
Claims 1-3, 18, 24, 27, 33, 57, 58, and 89-97 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a RNA modulating agent comprising an mRNA-binding sequence directed to activin A/miR-1, ApoC3/miR-122, Smad3/miR-192, and other disclosed embodiments, does not reasonably provide enablement for any RNA modulating agent as broadly claimed. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Nature of the Invention and Breadth of the claims
Claim 1 encompasses RNA-modulating agents comprising an mRNA-binding sequence directed to any target mRNA and one or more miRNA-binding sequences directed to any target miRNA, wherein the miRNA-binding sequence contains one or more modified nucleotides at positions complementary to positions 2, 5, and/or 8 of the target miRNA. The claim therefore covers a vast genus of potential agents involving thousands of distinct mRNA targets, thousands of known miRNAs, numerous nucleotide modification chemistries, and innumerable combinations thereof.
State of the Art
The state of the art confirms that successful miRNA-mediated repression is highly unpredictable. Grimson (Grimson et al., Molecular Cell 27:91-105 (2007)), demonstrated that seed complementarity alone is insufficient to predict functional repression and that multiple contextual determinants beyond sequence complementarity govern whether a miRNA-target interaction produces silencing [abstract]. Garcia (Garcia et al., Nature Structural & Molecular Biology 18:1139-1146 (2011)), likewise showed that complementary target sites frequently differ in silencing efficacy and that the presence of a target site does not reliably predict functional repression. Garcia teaches that targeting efficacy depends on factors such as seed-paring stability and target site context [abstract]. Broughton (Broughton et al., Molecular Cell 64:320-333 (2016)), further demonstrated that pairing outside the seed region contributes substantially to targeting specificity and activity.
These references establish that not every theoretically complementary miRNA/mRNA pair functions equivalently and that target efficacy cannot be predicted reliably from sequence complementarity alone.
Guidance of the Specification
The specification provides only a limited number of working examples involving a small subset of targets and miRNAs, including activin A/miR-1 and ApoC3/miR-122. The specification does not provide guidance sufficient to predict which of the innumerable claimed mRNA/miRNA combinations will successfully recruit endogenous miRNA complexes and achieve the claimed modulation of target gene expression.
Experimentation Required
Accordingly, a person of ordinary skill in the art seeking to practice the full scope of the claimed invention would be required to engage in extensive empirical screening to identify operative combinations across the full scope of the claims. Because the specification provides only a small number of examples and does not teach how to determine, without substantial experimentation, which members of the claimed genus will successfully achieve the claimed RNA modulation, undue experimentation would be required to practice the full scope of claim 1. The breadth of the claim is therefore not commensurate with the scope of enablement provided in the specification. See In re Wands, 858 F.2d 731 (Fed. Cir. 1988); Amgen Inc. v. Sanofi, 598 U.S. 594 (2023).
Claim 58 is 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.
For claims drawn to a genus, MPEP § 2163 states the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
Claim 58 is directed to a method of treating a subject having a disease or disorder characterized by or caused by: (a) overexpression or overactivity of a normal cellular protein; (b) underexpression or underactivity of the normal cellular protein; (c) activity of a mutant protein; or (d) activity of a viral RNA or protein, comprising administering the RNA-modulating agent of claim 1, wherein the RNA-modulating agent binds to a target mRNA encoding the normal cellular protein, mutant protein, or viral RNA or protein and modulates expression thereof.
The specification does not reasonably convey to one of ordinary skill in the art that the inventors were in possession of the full scope of the claimed method as of the filing date. The claim encompasses treatment of an enormous number of unrelated diseases and disorders involving fundamentally different biological mechanisms, including diseases associated with overexpressed proteins, underexpressed proteins, mutant proteins, and viral gene products. Collectively, these categories encompass thousands of distinct therapeutic targets across essentially all fields of medicine.
In contrast, the specification provides only a limited number of examples involving a small number of target transcripts and miRNAs, including Activin A/miR-1, ApoC3/miR-122, Smad3/miR-192, and a limited number of additional exemplified targets. The specification does not provide representative examples demonstrating treatment of diseases caused by underexpression of proteins, diseases caused by mutant proteins generally, or diseases caused by viral RNAs or proteins across the breadth of the claim. Nor does the specification identify common structural or functional characteristics that would permit one of ordinary skill in the art to recognize which members of the vast number of disease targets encompassed by the claim are within the inventors’ possession.
The specification further identifies as a central aspect of the invention the use of modified nucleotides at positions complementary to miRNA seed positions 2, 5, and/or 8 to selectively recruit endogenous miRNAs and discriminate among closely related miRNAs. However, the specification provides only limited examples supporting such selective recruitment and does not demonstrate that the asserted mechanism operates broadly across the multitude of disease targets recited in claim 58.
The art recognized that successful miRNA-mediated regulation is highly context dependent. Grimson (Grimson et al., Molecular Cell 27:91-105 (2007)), demonstrated that seed complementarity alone is insufficient to predict functional repression and that multiple contextual determinants beyond sequence complementarity govern whether a miRNA-target interaction produces silencing [abstract]. Garcia (Garcia et al., Nature Structural & Molecular Biology 18:1139-1146 (2011)), likewise showed that complementary target sites frequently differ in silencing efficacy and that the presence of a target site does not reliably predict functional repression. Garcia teaches that targeting efficacy depends on factors such as seed-paring stability and target site context [abstract]. Broughton (Broughton et al., Molecular Cell 64:320-333 (2016)), further demonstrated that pairing outside the seed region contributes substantially to targeting specificity and activity.
In view of this unpredictability, the limited examples disclosed in the specification do not reasonably establish possession of methods for treating the vast universe of diseases encompassed by claim 58.
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.
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 1-3, 18, 24, 27, 45, 58, 89-97 are rejected under 35 U.S.C. 103 as being unpatentable over Zamore (WO 2005/078096) in view of Obad (US 2018/0201928 A1) and Broderick (WO 2016/049512 A1).
Regarding claim 1-3, Zamore teaches RNA-silencing agents that recruit endogenous miRNAs to a target mRNA to repress expression of the target transcript. Specifically, Zamore teaches RNA-silencing agents having the formula T-L-μ, wherein T is an mRNA-targeting moiety, L is a linking moiety, and μ is an miRNA-recruiting moiety. Zamore explains that “miRNAs can be recruited to block expression of a target mRNA through translational repression” and that the disclosed RNA-silencing agents “bring endogenous miRNAs within the vicinity of target mRNAs so as to promote RNA silencing of the target mRNA.” [Summary of the Invention, pg 2. Para 1-2]. Zamore further teaches an RNA-silencing agent comprising an mRNA-targeting portion complementary to a target mRNA and an endogenous miRNA-recruiting portion complementary to a selected miRNA [pg 2. Para 1-2]. Accordingly, Zamore teaches an RNA-modulating agent comprising: (1) an mRNA-binding sequence complementary to a target mRNA; (2) an miRNA-binding sequence complementary to a target miRNA; and (3) a linker joining the two domains. Zamore does not expressly disclose that the miRNA-binding sequence comprises a modified nucleotide positioned opposite miRNA positions 2, 5, and/or 8.
Obad teaches that miRNA recognition is governed principally by the miRNA seed region and that short oligonucleotides directed to the seed sequence are effective and highly specific miRNA-binding agents[0180]. Obad teaches very short oligonucleotides, including 7-10 nucleotide oligomers, complementary to miRNA sequences, wherein at least 50%, 70%, or 80% of the nucleotide units are modified nucleotides, including LNA nucleotides and 2’-substituted nucleotide analogues [0007]-[0011]. Obad further teaches that the preferred hybridization positions of the oligonucleotides are located within the miRNA seed sequence and specifically investigates optimization of oligonucleotide placement within the miRNA target-recognition region [Fig. 1, Fig. 11, 0021, 0032, 0381-0383]. Obad additionally teaches targeting conserved seed sequences to inhibit entire miRNA families and demonstrates that heavily modified oligonucleotides directed to seed-region nucleotides exhibit potent and selective miRNA recognition [0038-0040].
Regarding claim 18, Obad teaches a 7mer seedmer complementary to positions 2 to 8 of the target miRNA [Fig. 1; table 1].
Regarding claim 24, Obad teaches 8-10mer [Fig. 1, 0099].
Regarding claim 27, Obad teaches miR-1 and miR-122 [0100].
Regarding claims 92-93, Obad teaches discriminatory binding of the target miRNA relative to a non-target miRNA by teaching that that carefully designed short single stranded oligonucleotides comprising or consisting of nucleotide analogues, such as high affinity nucleotide analogues such as locked nucleic acid (LNA) units, show significant silencing of microRNAs; tight binding of said oligonucleotides to the so-called seed sequence, typically nucleotides 2 to 8 or 2 to 7, counting from the 5' end, of the target microRNAs was important; and micro RNA silencing is even more enhanced when LNA-modified single stranded oligonucleotides do not contain a nucleotide at the 3' end corresponding to this non-paired nucleotide 1 [0108-0119].
Regarding claim 95, Obad teaches where positions 10 and 11 are not complementary to the miRNA binding sequence [Fig. 1, 0098].
Regarding claims 1, and 89-90, Broderick teaches RNA-modulating agents of the same general tether architecture as Zamore and specifically teaches engineering miRNA-binding sequences complementary to miRNA seed nucleotides [pg. 11, lines 25-32]. Broderick teaches RNA-modulating agents that recruit endogenous miRNAs to target transcripts and teaches miRNA-binding sequences complementary to positions 2-8 of a target miRNA [pg. 43, fig. 11-14]. Broderick further teaches incorporation of modified nucleotides, including 2’-O-methyl nucleotides, LNA nucleotides, phosphorothioates, and bridged nucleotides into the miRNA-binding region [pg. 5, lines 12-22, regarding claim 89-90]. Broderick teaches modified nucleotides including 2’-O-methyl nucleotides and C2’-O,C4’-ethylene bridged nucleotides in the recruiting moiety [pg. 5, lines 12-22; pg. 17-18, bridging paragraph]. Broderick teaches that these oligonucleotides typically contain at least one region of modified nucleotides that confers one or more beneficial properties (such as, for example, increased nuclease resistance, increased uptake into cells, increased binding affinity for the target) [pg. 15, lines 8-10]. Moreover, Broderick specifically identifies miRNA seed nucleotides and evaluates discrimination between miR-1 and miR-122 through seed-region pairing arrangements [Fig. 6; 14; pg. 10, lines 1-9]. Figure 6B explicitly labels seed positions 2, 5, and 8 and compares miR-1 and miR-122 targeting constructs. Figure 7 further demonstrates selective targeting resulting from modifications and pairing strategies within the seed region.
Regarding claim 45, Broderick teach that the RNA-modulating agents also allow for cell type-specific or tissue-specific gene modulation (e.g., silencing) by recruitment of miRNA that are cell type-specific or tissue-specific (e.g., miR-1 20 which is muscle-specific) [pg. 2, lines 17-20].
Regrading claim 58, Broderick teaches a method of treating a subject having a disease or disorder characterized by or caused by: (a) the overexpression or overactivity of a normal cellular protein; (b) the underexpression or underactivity of a normal cellular protein; (c) the activity of a mutant protein; or (d) the activity of a viral RNA or protein, the method comprising administering to the subject an effective amount of an RNA-modulating agent, as disclosed herein, wherein the RNA-modulating agent binds to the mRNA encoding the protein and modulates expression of a protein [pg. 5-6, bridging para; .
Regarding claim 91, Broderick teaches that tethers designed to recruit miR-122 to the 3' UTR of an endogenous mRNA reduced mRNA abundance in cultured human hepatocytes by-50% [pg. 36, lines 10-11].
Regarding claim 94, Broderick teaches that RNA-modulating agents comprising two or more miRNA binding sequences are significantly more potent at inhibiting translation from target mRNA [pg. 2, lines 1-3].
It would have been obvious to one ordinary skilled in the art before the effective filing date of the claimed invention to modify the RNA-silencing agent of Zamore by incorporating modified nucleotides within the miRNA-binding sequence as taught by Obad and Broderick because both references teach that interactions within the miRNA seed region govern target recognition, specificity, and potency. Obad teaches that heavily modified oligonucleotides directed to seed-region nucleotides provide effective and selective miRNA recognition, while Broderick teaches modified nucleotides within miRNA-binding sequences and specifically evaluates interactions involving seed positions 2, 5, and 8. A person of ordinary skill in the art would therefore have recognized that positioning modified nucleotides opposite critical seed nucleotides, including positions 2, 5, and/or 8, would predictably improve binding affinity, mismatch discrimination, and selective recruitment of a desired miRNA while reducing recruitment of closely related non-target miRNAs.
Regarding claim 57, Zamore, Obad, and Broderick do not teach the specific chemical modification pattern of the RNA-modulating agent. Obad teaches the invention further provides for an oligomer wherein said oligomer (or contiguous nucleotide sequence) comprises either i) at least one phosphorothioate linkage and/or ii) at least one 3' terminal LNA unit, and/or iii) at least one 5' terminal LNA unit [0200-0203]. Obad teaches that the oligomer may therefore contain at least one phosphorothioate linkage, such as all linkages being phosphorthioates, and at least one 3' terminal LNA unit, and at least one 5' terminal LNA unit [0204]. Obad teaches that Table 1 below provides non-limiting examples of short microRNA sequences that could advantageously be targeted with an oligonucleotide of the present invention [184-0225]. Obad teaches possible chemical modification patterns for as designs for the oligomer [0226]. It would have been obvious to one ordinary skilled in the art before the effective filing date of the claimed invention to modify the molecule as taught and suggested by Zamore, Obad, and Broderick where specific chemical modification pattern of the RNA-modulating agent is 5'- (lN)#(mN)#(mN)#(lN)(mN)(mN)(lN)(mN)(mN)(mN)(lN)(mN)(mN)(lN)(mN)(mN)(lN)(mN)(mN)(lN)#(mN)#(mN)#(lN)-3' as claimed as this modification would be the result of routine sequence optimization of oligomers for the purpose of serving as an gene inhibitor.
Regarding claims 96 and 97, Zamore, Obad, and Broderick do not teach wherein the mRNA binding sequence comprises CUGUCUUCUCUGGAC or wherein the one or more miRNA binding sequences comprise ACAUUCCA. Zamore teaches that designing sequences in terms of size and complementarity to optimize binding to target sequences is well known in the art [pg. 18, para 1]. Broderick does teach RNA-modulating agents can be designed to recruit any small regulatory RNA molecule to any target mRNA where these tethers can be designed to recruit miRNAs to endogenous mRNAs targets [pg. 11, see II; pg. 36, lines 10-11; pg. 46, lines 16-18]. Therefore, it would have been obvious to one ordinary skilled in the art before the effective filing date of the claimed invention to modify the molecule as taught and suggested by Zamore, Obad, and Broderick where the mRNA binding sequence comprises CUGUCUUCUCUGGAC or the one or more miRNA binding sequences comprise ACAUUCCA as this modification would be the result of routine sequence optimization for the purpose of silencing genes.4
Claim 33 is rejected under 35 U.S.C. 103 as being unpatentable over Zamore (WO 2005/078096) in view of Obad (US 2018/0201928 A1) and Broderick (WO 2016/049512 A1) as applied to claim 1 and further in view of Narin (US 2021/0130419 A1) and Hong (Hong et al. Biochem. J. (2014) 461, 427–434).
The teachings of Zamore, Obad, and Broderick are discussed above as applied to claim 1 and similarly apply to claim 33.
Zamore, Obad, and Broderick do not teach where docosanoic acid (DCA) is linked to the 3' end of the RNA-modulating agent by a linker comprising a dTdT dinucleotide.
Narin teaches that DCA is a hydrophobic domain that can be appended via a linker to the side of a molecule to facilitate cellular uptake.
Hong teaches that for classical siRNA, a dTdT (deoxythymidine dinucleotide) overhang at the 3′-end of each strand is generally used because it provides several benefits, including reduced RNA synthesis cost and increased stability of siRNA oligomers to serum nucleases; and does not impair siRNA gene-silencing activity pg. 427, col. 2, para 2].
It would have been obvious to one ordinary skilled in the art before the effective filing date of the claimed invention to modify the RNA-silencing agent as taught and suggested by Zamore, Obad and Broderick where docosanoic acid (DCA) is linked to the 3' end of the RNA-modulating agent by a linker comprising a dTdT dinucleotide. One of ordinary skill would be motivated to make the modification for the advantage of increasing cellular uptake and increasing stability of the agent.
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 rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-3, 18, 24, 27, 33, 45, 57-58 and 89-97 of U.S. Patent No. US10556020B2 in view of Zamore (WO 2005/078096), Obad (US 2018/0201928 A1), Broderick (WO 2016/049512 A1), Narin (US 2021/0130419 A1) and Hong (Hong et al. Biochem. J. (2014) 461, 427–434).
Although the claims at issue are not identical, they are not patentably distinct from each other because claim 1 of the patented claims teach all the limitations of the current claims except where the one or more miRNA binding sequences are complementary to at least positions 2 to 8 of a target miRNA from a 5' end of the target miRNA and comprise at least one modified nucleotide at a nucleotide position that is complementary to any one or more of positions 2, 5, and 8 of the target miRNA from the 5' end of the target miRNA. The teachings of Zamore, Obad, and Broderick are discussed above. It would have been obvious before the effective date of the patented claims to modify the RNA-modulating agent of the patented claims such that the one or more miRNA binding sequences are complementary to at least positions 2 to 8 of a target miRNA from a 5' end of the target miRNA and comprise at least one modified nucleotide at a nucleotide position that is complementary to any one or more of positions 2, 5, and 8 of the target miRNA from the 5' end of the target miRNA. The combination of prior art elements according to known methods to yield predictable results supports can support a conclusion of obviousness. See MPEP 2143(I). One of ordinary skill in the art would have a reasonable expectation of success since the patented claims, Zamore, Obad, and Broderick all teach the use of RNA agents comprising a mRNA and miRNA binding sequence for gene silencing.
For additional limitations of the instant claims, see the additional teachings of the patented claims. To the extent that there are limitations that are not provided for by the patented claims, the teachings of Zamore, Obad, Broderick, Narin and Hong are discussed above. It would have been obvious to have modified the subject matter of the patented claims to arrive at the subject matter of the instant claims for substantially the same reasons as discussed above in view of the teachings of these references.
Conclusion
No claims allowed.
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/TIFFANY NICOLE GROOMS/Examiner, Art Unit 1637
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