DETAILED ACTION
This Action is in response to the communication filed on 11/12/2025.
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 .
Status of the Claims
Claims 1, 3-8, 12-15, 17, 19, 37, 54-56, 62, 67, 69, 72, 74-76 are pending.
Claims 62, 67 and 75 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 09/23/2024 and 04/15/2025.
Claims 1, 3-8, 12-15, 17, 19, 37, 54-56, 69, 72, 74, 76 are under consideration.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1, 4-6, are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Vogel et al (Agnew. Chem. Int. Ed. (2014) 53:6267-6271 and supplemental supporting information; of record 12/24/2020 IDS; hereafter “Vogel (Agnew. Chem. Int. Ed.)”) .
Claim 1 is drawn to an artificial nucleic acid for site-directed editing of a target RNA in a human cell. It is noted that “for site-directed editing of a target RNA in a human cell” is an intended use for the artificial nucleic acid and does not impart any structural limitations to the claimed nucleic acid.
Regarding claims 1 and 4, Vogel (Agnew. Chem. Int. Ed.) teaches an artificial nucleic acid that is capable of recruiting ADAR and comprises a sequence complementary to a target RNA sequence (e.g., see Scheme 1). Vogel (Agnew. Chem. Int. Ed.) also teaches that the artificial nucleic acid comprises at least one nucleotide with a chemical modification at the 2’ position and phosphothioate modifications (e.g., see p. 6268 first column which teaches incorporation of 2’-O-methyl which is an alkoxy, and Figure 1F where small red letters are 2’-OMe-modified bases and phosphothioate linkages are indicated as small green “s”). Vogel (Agnew. Chem. Int. Ed.) also teaches that at least one of the two nucleotides positioned 5’ or 3’ of the position corresponding to a nucleotide to be edited comprising an alkoxy group substituted at the 2’ carbon atom (e.g., see p. 6286, Figures 1B, 1D and 1E - it is noted the 2’-OMe (-OCH3) is an alkoxy; also see Table S1 in supporting information).
Regarding claims 5-6, Vogel teaches that at least 40% of the nucleotides of the targeting sequence comprise a chemical modification at the 2' position and that the position corresponding to the nucleotide to be edited in the target sequence, is a cytidine nucleotide, a deoxycytidine nucleotide or a variant thereof (e.g., see Figure 1F, etc.).
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.
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.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1, 3-6, 8, 12-15, 17, 37, 54-56, 69, 72 and 76 are rejected under 35 U.S.C. 103 as being unpatentable over WO2016097212 (of record 12/24/2020 IDS; hereafter “Klein”) in view of Vogel et al (Agnew. Chem. Int. Ed. (2014) 53:6267-6271 and supplemental supporting information; of record 12/24/2020 IDS; hereafter “Vogel (Agnew. Chem. Int. Ed.)”; all of record).
Regarding claims 1, 69 Klein teaches an artificial nucleic acid that is capable of recruiting ADAR and comprises a sequence complementary to a target RNA sequence and teaches that the artificial nucleic acid comprises at least one nucleotide with a chemical modification at the 2’ position (including a 2’O-Me modification) as well a modified phosphate group (phosphothioate modifications) (e.g., see abstract; claims 1, 18-19; page 17 lines 9-17).
Klein does not teach that at least one of the two nucleotides positioned 5’ or 3’ of the position corresponding to a nucleotide to be edited comprising an alkoxy group substituted at the 2’ carbon atom.
However, as indicated above, Vogel (Agnew. Chem. Int. Ed.) also teaches an artificial nucleic acid for site-directed editing of a target RNA wherein the artificial nucleic acid is capable of recruiting ADAR and comprises a targeting sequence wherein at least one of the two nucleotides positioned 5’ or 3’ of the position corresponding to a nucleotide to be edited comprising an alkoxy group substituted at the 2’ carbon atom (e.g., see p. 6286, Figures 1B, 1D and 1E - it is noted the 2’-OMe (-OCH3) is an alkoxy; also see Table S1 in supporting information).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art prior to the day the claimed invention was filed to modify the artificial nucleic acid taught by Klein to have at least one of the two nucleotides positioned 5’ or 3’ of the position corresponding to a nucleotide to be edited comprising an alkoxy group substituted at the 2’ carbon atom, as taught by Vogel, with a reasonable expectation of success. It would have been a matter of simple substitution of one known modification for another and there would have been a reasonable expectation of success based on the positive results reported by Vogel.
Regarding claim 3, Klein teaches that the artificial nucleic acid wherein the chemical modification at the 2’ position can be a LNA nucleotide (e.g., see p. 14 lines 12-28).
Regarding claims 4 and 72, Klein teaches that the modified phosphate group can be a phosphorothioate modification (e.g., see pages 14 and 17).
Regarding claim 5-6, Klein teaches that at least 40% of the nucleotides of the targeting sequence comprise a chemical modification at the 2’ position and the nucleotide at the position corresponding to the nucleotide to be edited is a cytidine nucleotide (see p. 32 which indicates all of the nucleotides of the targeting sequence are 2’-modified (2’-OMe) except for nucleotide corresponding to the mutant A position – double underlined c-, thus more than 40% chemically modified).
Regarding claim 8, Klein teaches that the nucleotide at the position corresponding to the nucleotide to be edited is a cytidine nucleotide (see p. 32) but does not teach that the nucleotide 5’ to the position corresponding to the nucleotide to be edited is a pyrimidine that is chemically modified at the 2’ position.
However, Vogel (Agnew. Chem. Int. Ed.) teaches a similar artificial nucleic acid for RNA editing using ADAR wherein the nucleotide 5’ to the position corresponding to the nucleotide to be edited is a pyrimidine that is chemically modified at the 2’ position. For example see Figures 1B, 1D, 3C, Table S1, etc.).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art prior to the day the claimed invention was filed to modify the artificial nucleic acid taught by Klein to have the nucleotide 5’ to the position corresponding to the nucleotide to be edited be a pyrimidine that is chemically modified at the 2’ position, as taught by Vogel, with a reasonable expectation of success. It would have been a matter of simple substitution of a known modification and there would have been a reasonable expectation of success based on the positive results reported by Vogel.
Regarding claim 12, Klein teaches that indicates all of the nucleotides of the targeting sequence can be modified including having a modified phosphate group (e.g., see p. 32; p. 35 Example 4).
Regarding claims 13, Klein does not appear to reduce to practice the artificial nucleic acid molecule wherein at least two of the five nucleotides at the 3' terminus of the targeting sequence are LNA nucleotides. However, Klein does teach, “Both the targeting portion and the recruiting portion may comprise or consist of nucleotides having chemical modifications that alter nuclease resistance, alter affinity of binding (expressed as melting temperature) or other properties. Examples of chemical modifications are modifications of the sugar moiety, including by cross-linking substituents within the sugar (ribose) moiety (e.g. as in LNA or locked nucleic acids),” (See p. 17 lines 9-20).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art prior to the day the claimed invention was filed to modify an artificial nucleic acid reduced to practice by Klein to have LNA nucleotides at least two of the five nucleotides at the 3' terminus of the targeting sequence. Kline’s indication that the targeting portion may consist of chemically modified nucleotides, including LNA nucleotides, provides motivation to include LNA nucleotides throughout the targeting portion except for the triplet nucleotides corresponding to the target nucleotide.
Regarding claim 14, Klein teaches the targeting sequence can comprise at least one nucleotide comprising a modified phosphate group; at least one nucleotide comprising a chemical modification at the 2' position including an LNA nucleotide, and at least one nucleotide comprising a substituent at the 2' carbon atom, wherein the substituent can be an alkoxy group such a 2’-O-methyl (see pages 14, 17, and 32, as indicated above).
Regarding claim 15, Klein teaches that the targeting sequence can be characterized by a modification pattern according to formulae (Ia): 3' Na C Nb 5' wherein N is a nucleotide; C is the nucleotide at the position corresponding to the nucleotide to be edited in the target sequence and wherein C is a cytidine nucleotide, a deoxycytidine nucleotide or a variant thereof; a is an integer in a range from 1 to 40; b is an integer in a range from 4 to 40; and wherein a+b is in a range from 15 to 80 (e.g., see page 4 lines 33 through page 5 line 8, page 28 lines 21-34, etc.).
Regarding claim 17, although Klein does not reduce the nucleic acid of claim 17 to practice, Klein teaches the targeting sequence can comprise a nucleic acid sequence wherein, with the exception of the cytidine nucleotide or the variant thereof, the deoxycytidine nucleotide or the variant thereof at the position corresponding to the nucleotide to be edited in the target sequence, with the exception of LNA nucleotides, all nucleotides comprises a substituent are chemically modified at the 2' carbon atom, wherein the substituent can be an alkoxy group (2’-O-Me). Kline’s indication that the targeting portion may consist of chemically modified nucleotides, including LNA nucleotides and 2’-O-Me nucleotides, provides motivation to include LNA and 2’-O-Me nucleotides throughout the targeting portion except for the triplet nucleotides corresponding to the target nucleotide (see pages 17 and 32, as indicated above).
Regarding claims 37, Klein does not appear to reduce to practice the artificial nucleic acid molecule wherein at least two of the five nucleotides at the 5' terminus of the targeting sequence comprise a phosphorothioate group. However, Klein does teach, “Both the targeting portion and the recruiting portion may comprise or consist of nucleotides having chemical modifications that alter nuclease resistance, alter affinity of binding (expressed as melting temperature) or other properties… In addition, the phosphodiester group of the backbone may be modified by thioation, dithioation, amidation and the like to yield phosphorothioate, phosphorodithioate, phosphoramidate, etc., internucleosidic linkages.” (See p. 17 lines 9-20).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art prior to the day the claimed invention was filed to modify an artificial nucleic acid reduced to practice by Klein to have phosphorothioate linkages at least two of the five nucleotides at the 5' terminus of the targeting sequence. Kline’s indication that the targeting portion may consist of chemically modified nucleotides, including phosphorothioate linkages, provides motivation to include phosphorothioate linkages throughout the targeting portion except for the triplet nucleotides corresponding to the target nucleotide.
Regarding claims 54-56, Klein teaches that construct can modify target RNA sequences in eukaryotic cells, including a human HELA cells (see page 19 lines 9-11; page 31 lines 3-6, Figure 4); that the construct can be administered in an aqueous solution that has excipients (e.g., see p. 26 lines 15-20); and that nucleic acid can be complexed by a cationic compound, specifically lipofectamine (e.g., see p. 26 lines 15-20).
Regarding claim 76, Klein teaches that the artificial nucleic acid molecule can target a SERPINA1 transcript in liver cells (e.g., see p. 35 lines 33-37, etc.).
Claims 7 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over WO2016097212 (of record 12/24/2020 IDS; hereafter “Klein”) in view of Vogel et al (Agnew. Chem. Int. Ed. (2014) 53:6267-6271 and supplemental supporting information; of record 12/24/2020 IDS; hereafter “Vogel (Agnew. Chem. Int. Ed.)”), as applied to claims 1, 3-6, 8, 12-15, 17, 37, 54-56, 69, 72 and 76 in the rejection above, further in view of WO2018/041973 (of record IDS reference; hereafter “Turunen”); all of record.
Klein and Vogel, as applied to the instant claims, are described in the rejection above.
Neither Klein nor Vogel teach the artificial nucleic acid according to claim 1 wherein least one of the two nucleotides or variants thereof, which are positioned 5' or 3' of the position corresponding to the nucleotide to be edited in the target sequence, comprises a modified phosphate group, as required by claims 7 and 19. It is noted that the combination of Klein and Vogel teach all of the other limitations of claim 19, as indicate in the rejection above.
However, Turunen teaches an artificial nucleic acid molecule for site-directed editing of a target RNA using ADAR wherein the targeting sequence of the artificial nucleic acid molecule comprises a modified phosphate group, specifically a phosphorothioate, positioned 5’ to a C nucleotide that corresponds to the nucleotide to be edited in the target sequence (e.g., see Fig. 2 AONs named: ADAR60-5, ADAR65-20, ADAR65-21, ADAR65-22, ADAR65-30, ADAR93-9
Therefore, it would have been prima facie obvious to one of ordinary skill in the art prior to the day the claimed invention was filed to modify an artificial nucleic acid made obvious by the combination of Klein and Vogel, as indicated above, to have a modified phosphate group, specifically a phosphorothioate, as taught by Turunen.
Turunen’s indication that a phosphorothioate modification can be placed at position 5’ of the nucleotide corresponding to the target nucleotide, and the positive results provide motivation to make the change and also provides a reasonable expectation of success.
Claim 74 is rejected under 35 U.S.C. 103 as being unpatentable over WO2016097212 (of record 12/24/2020 IDS; hereafter “Klein”) in view of Vogel et al (Agnew. Chem. Int. Ed. (2014) 53:6267-6271 and supplemental supporting information; of record 12/24/2020 IDS; hereafter “Vogel (Agnew. Chem. Int. Ed.)”), as applied to claims 1, 3-6, 8, 12-15, 17, 37, 54-56, 69, 72 and 76 in the rejection above, further in view of WO 2014/118272; all of record.
Klein and Vogel, as applied to the instant claims, are described in the rejection above.
Neither Klein nor Vogel teach the artificial nucleic acid of claim 1 further comprising a moiety enhancing cellular uptake comprising triantennary N-acetyl galactosamine (GalNac3), wherein the GalNac3 is conjugated to the 3' terminus of the artificial nucleic acid.
However attaching a tri-antennary N-acetyl-galactosamine (GalNAc3) to the end of an oligonucleotide molecule for targeted delivery of the oligonucleotide molecule to hepatocytes was well known in the prior art. For instance, WO 2014/118272 teaches that a galactose cluster can be used for targeting hepatocytes in liver, and specifically teaches that a galactose cluster comprising three terminal N-acetyl-galactosamines is a preferred galactose cluster, commonly known in the art as tri-antennary galactose, which bind to the ASGPr with greater affinity than bi- or mono-antennary galactose structures (e.g., see page 45, lines 18-30). WO 2014/118272 explicitly teaches that the galactose cluster may be attached to the 3’ or 5’ end of the oligomer using methods known in the art (see page 46, lines 14-15).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art prior to the day the claimed invention was filed to modify an artificial nucleic acid made obvious by the combination of Klein and Vogel, as indicated above, to further modify the artificial nucleic acid molecule by attaching a tri-antennary N-acetyl-galactosamine (GalNAc3) to the 3’ end. The motivation to do so would be to target the artificial nucleic acid to hepatocytes in the liver for inhibition of SERPINA1 in the liver cells. The positive results recognized in the prior art provides a reasonable expectation of success.
Response to Arguments
Applicant's arguments filed 11/12/2025 have been fully considered and are addressed below. Applicant acknowledges that Vogel teaches a gRNA comprising modified phosphate groups such as phosphorothioate linkages as well nucleotides with modifications at the 2’-position, but argues that the nucleotides are not the two nucleotides positioned 5’ or 3’ of the position corresponding to a nucleotide to be edited. Applicant also argues that, with respect to the 103 rejection, Vogel provides data showing that including nucleotides with a 2’-O-Me modification at positions 5’ or 3’ of the position corresponding to a nucleotide to be edited in the target sequence failed to improve the effect of the gRNAs but in certain instances fully inhibited editing of the target adenosine, thus one skilled in the art would not have been motivated to modify the oligonucleotide disclosed in Klein.
In response, it is noted that claim 1 recites, “wherein at least one of the two nucleotides positioned 5' or 3' of the position corresponding to a nucleotide to be edited in the target sequence comprises a substituent at the 2' carbon atom…” Given the broadest reasonable interpretation (BRI) the claims only require that one of the two nucleotides 5’ of the position corresponding to a nucleotide to be edited, or at least one of the two nucleotides 3' of the position corresponding to a nucleotide must to be edited. The broad claims do not require that one of the nucleotides positioned one nucleotide upstream or one nucleotide downstream from the position corresponding to a nucleotide to be edited in the target sequence must be modified, which appears to be Applicant’s argument. Regarding the 102 rejection, given the BRI as indicated above, Vogel clearly teaches that at least one of the two nucleotides positioned 5’ or 3’ of the position corresponding to a nucleotide to be edited comprises an alkoxy group substituted at the 2’ carbon atom (e.g., see Figure 1). It is noted that upon further consideration, Applicant’s arguments with respect to claim 8 are persuasive as claim 8 explicitly requires the nucleotide which is positioned 5' of the position corresponding to the nucleotide to be edited is a pyrimidine nucleotide that is chemically modified at the 2' position. It is noted that claim 8 is addressed in the 103 rejection.
Therefore, Applicant’s arguments traversing the pending rejection of claims 1, 4-6under 35 USC 102 are not persuasive.
Regarding the rejection of claims under 35 USC 103, Applicant’s arguments (indicated above) have been fully considered but are not persuasive. In response to Applicant’s argument that Vogel provides data showing that including nucleotides with a 2’-O-Me modification at positions 5’ or 3’ of the position corresponding to a nucleotide to be edited in the target sequence failed to improve the effect of the gRNAs but in certain instances fully inhibited editing of the target adenosine, it is noted that Vogel only provides evidence that when the nucleotide corresponding to the nucleotide to be edited in the target sequence and the two immediately adjacent nucleotides all have a 2’-O-Me modification, editing is fully inhibited, referring to Figure 1B. That is, Vogel provides evidence of fully inhibited editing only when all three nucleotides are modified (i.e., the three centered around the nucleotide corresponding to the nucleotide to be edited). However, Vogel provides evidence of modification of the nucleotide immediately adjacent to the nucleotide corresponding to the nucleotide to be edited does not inhibit editing, as indicated in Figure 1D and 1E. In fact Vogel explicitly states, “Notably, a single modification one nucleotide up- or downstream from the counter base had nearly no or only very little influence on the overall editing yield (Figure 1 D,E).” Indicating that modification of one nucleotide upstream or downstream from the counter base did not result in inhibition, which is evident in Figure 1D and 1E, which is very similar to 1A where neither adjacent nucleotide is modified. Therefore, rather than indicating that one skilled in the art would not have been motivated to modify the oligonucleotide in Klein, the evidence indicates that there would have been a reasonable expectation that modifying one of the nucleotides adjacent to the nucleotide corresponding to the nucleotide to be edited would result in a modified functional oligonucleotide.
Therefore, Applicant’s arguments are not persuasive and the rejection of claims under 35 USC 103 is maintained.
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to J. E. Angell whose telephone number is (571)272-0756. The examiner can normally be reached Monday-Friday (8:30-5:00).
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J. E. Angell
Primary Examiner
Art Unit 1637
/J. E. ANGELL/ Primary Examiner, Art Unit 1637