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
Applicant’s remarks and amendments to the claims, drawings, and specification filed January 28, 2026 are acknowledged. Claim 48 was amended. Claims 45-64 are pending.
Restriction/Election
Claims 61-64 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention. Claims 45-60 are under consideration hereinafter.
Priority
Applicant’s claim for priority based on Application No. PCT/EP2022/083943, filed November 30, 2022, and PCT/EP2023/083741, filed November 30, 2023 is acknowledged. It is noted that a copy of PCT/EP2022/083943 has not been retrieved by the Office, although Applicant has provided access to the application via the Priority Document Exchange (see filing receipt dated September 16, 2025). Nevertheless, Examiner has reviewed the contents of the as-filed applications in WIPO PatentScope. The claims under examination find support in PCT/EP2022/083943, and therefore, the effective filing date of the claims is November 30, 2022.
Withdrawn Rejections
Applicant’s response overcomes the objections to the claims, specification, and drawings.
Applicant’s remarks and amendments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow. Any rejection or objection not reiterated herein has been overcome by amendment.
Notice to Joint Inventors
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 Rejections - 35 USC § 103 - Moelhart Hoeg in view of Merkle
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.
Claims 45-54, and 56-60 are rejected under 35 U.S.C. 103 as being unpatentable over Moelhart Hoeg (Moelhart Hoeg and Merkle, WO 2024/017817 A9, published 25 January 2024, effectively filed 18 July 2022 with respect to the subject matter relied upon to reject the following claims; of record) in view of Merkle (Merkle, Tobias., “Engineering Antisense Oligonucleotides for Site-directed RNA Editing with Endogenous ADAR,” Eberhard Karls Universitat Tubingen, “Dissertation_Tobias_Merkle.pdf” of 22.6 MB available 21 June 2021 as evidenced by the WayBack Machine; of record). The rejections that follow are maintained from the prior action.
Regarding claim 45, Moelhart Hoeg teaches a chemically modified oligonucleotide 23-38 nucleosides in length comprising a nucleic acid sequence complementary to a target sequence in SERPINA1 messenger RNA (mRNA) (SEQ ID NO: 26, CMP 26_8; Tables 3-4 and Fig. A below). Moelhart Hoeg teaches the oligonucleotide comprises a central base triplet (CBT) of 3 nucleosides, wherein the central nucleoside is directly opposite a target adenosine to be edited to an inosine (pg. 13, lines 19-27; pg. 50, lines 13-29). Moelhart Hoeg teaches the target adenosine is the result of a G to A mutation in SERPINA1 gene that results in a E342K substitution in the alpha-1 antitrypsin (A1AT) protein (pg. 11, lines 4-21). As shown in Fig. A below, Moelhart Hoeg’s oligonucleotide comprises at least 4 nucleosides 3’ of the CBT (underlined) and at least 16 nucleosides 5’ of the CBT. Each nucleoside of Moelhart Hoeg’s oligonucleotide is selected from a 2’-O-Me (mN), 2’-F (fN), or 2’-MOE modified nucleoside, and a 2’-deoxyribonucleoside (dN), at least 50% of the linkages between the nucleosides are PS linkages (*), and the oligonucleotide does not comprise a stereopure PS linkage (“[sP] is a phosphorothioate internucleoside linkage,” pg. 72, line 21).
Figure A. SEQ ID NO: 26, CMP 26_8 from Tables 3-4, adapted to use the notation of the instant application using Moelhart Hoeg’s description at pg. 70-74.
SEQ ID NO: 26, CMP 26_8
mG*mC*mC*mC*fC*mA*fG*mC*fA*mG*fC*mU*fU*mC*fA*mG*fU*mC*fC*mC*fU*mU*fU*mC*dT*dC*dI*mU*fC*mG*mA*mU
Moelhart Hoeg uses the opposite numbering relative to the instant application; nucleosides 5’ of nucleoside N0 are designated with positive values, and nucleosides 3’ of nucleoside N0 are designated with negative values (pg. 6, lines 19-34). See Fig. B below. For the remainder of this action, positions will be converted from Moelhart Hoeg’s numbering to the instant application’s numbering. As shown in Fig. B, applying the core sequence numbering used in instant claim 45 to the oligonucleotide in Fig. A above, N0 is a deoxycytidine, and at least two of the three nucleotides of the CBT are deoxyribonucleosides, a, d, e, and f are phosphorothioate (PS) linkages, N+2 is a 2’-O-Me modified nucleoside, and N+3 is a 2’-F modified nucleoside.
Figure B. SEQ ID NO: 26, CMP 26_8 “core sequence” with numbering of instant claim 45.
5’ - fU*mU*fU*mC*dT*dC*dI*mU*fC*mG - 3’ SEQ ID NO: 26, CMP 26_8
5’ - N-5aN-4bN-3cN-2dN-1eN0fN+1gN+2h N+3iN+4j - 3’ instant numbering
5’ – N+5+4N+4+3N+3+2N+2+1N+10N0-1N-1-2N-2-3N-3-4N-4-5 – 3’ prior art numbering
As shown above, each linkage of the oligonucleotide is a PS linkage. Therefore, Moelhart Hoeg does not teach that “up to 3 of internucleoside linkages selected from b, c, f, g, and j are PS linkages,” or that “internucleoside linkage h is a phosphate (PO) linkage,” wherein the term “phosphate (PO) linkage” is interpreted as referring to a phosphodiester linkage (“phosphate linkages in natural DNA and RNA,” [0064]).
However, Moelhart Hoeg teaches that the content and position of phosphodiester linkages in an oligonucleotide alters the editing efficiency (pg. 44, line 15 to pg. 46, line 12; Fig. 19-23). Moelhart Hoeg teaches oligonucleotides wherein internucleoside linkages b, c, f, g, h, and/or j are phosphodiester linkages (“the internucleoside linkage between nucleosides at positions +1 and 0 is a phosphodiester internucleoside linkage; and/or the internucleoside linkage between nucleosides at positions 0 and -1 is a phosphodiester internucleoside linkage; and/or the internucleoside linkage between nucleosides at positions -2 and -3 is a phosphodiester internucleoside linkage,” pg. 46, lines 5-12; Fig. 19-23, wherein “3” corresponds to b, “2” corresponds to c, “-1” corresponds to f, “-2” corresponds to g, “-3” corresponds to h, and “-5” corresponds to j). Moelhart Hoeg demonstrates that an oligonucleotide with phosphodiester linkages at one or more of the aforementioned positions has comparable or increased editing efficiency relative to a fully phosphorothioated oligonucleotide (Fig. 19-23).
The teachings of Moelhart Hoeg are further supported by Merkle. Merkle teaches oligonucleotides for the purpose of guiding ADAR to a target region comprising a target adenosine, in which “PS linkages [] stabilize the [oligonucleotide] against nucleases,” but “replacing all phosphate with phosphorothioate linkages decreased editing yields…” (pg. 49-50). Specifically, Merkle teaches that “PS linkages in the middle of the ASO seemed to reduce the editing yields,” which Merkle teaches is due to the “many contacts of the ADAR deaminase domain with phosphates on the strand opposite of the target site… Exchanging these phosphates by PS-linkages probably results in unfavorable binding of the ADAR deaminase domain” (pg. 50).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the oligonucleotide of Moelhart Hoeg, i.e., . SEQ ID NO: 26, CMP 26_8, such that “up to 3 of internucleoside linkages selected from b, c, f, g, and j are PS linkages,” and “internucleoside linkage h is a phosphate (PO) linkage” as required of instant claim 45. It would have amounted to applying a known oligonucleotide design strategy to a known oligonucleotide, by known means to yield predictable results. Taken together, Moelhart Hoeg and Merkle would have illustrated to the skilled artisan that PS linkages are important to stabilize oligonucleotides and promote effective editing, but that one or more phosphodiester linkages would be desirable in the target site region, due to the “many contacts of the ADAR deaminase domain” which would otherwise be impeded by PS linkages. The skilled artisan would have had a reasonable expectation of success in modifying the oligonucleotide to arrive at the invention of instant claim 45 because Moelhart Hoeg and Merkle teach oligonucleotides in which one or more of the recited internucleoside linkages are phosphodiester linkages. The skilled artisan would have had a reasonable expectation that such modification would improve the editing efficiency based on the teachings of Merkle (“PS linkages in the middle of the ASO seemed to reduce the editing yields…”). The skilled artisan would have been motivated to modify the oligonucleotide of Moelhart Hoeg in an effort to improve editing yield for applications of the technology, e.g., methods of treatment.
Regarding claim 46, as shown in Fig. C below, Moelhart Hoeg’s oligonucleotide comprises one or more mismatches, wobble bases, and/or bulges with respect to the target sequence, i.e., “… 5’- GACAAGAAA -3’ …” (“The codon for K342 is AAG (shown underlined in the sequence below) and the first adenosine in the AAG codon is A1024 (shown in bold below). SERPINA1 mRNA E342K mutant coding sequence – SEQ ID NO: 186:..,” pg. 11, line 27 to pg. 12, line 24).
Figure C. Alignment between portion of SEQ ID NO: 26, CMP 26_8 including the editing triplet (bolded, underlined) and portion of the SERPINA1 mRNA E342K mutant coding sequence including the target adenosine (bolded) in the target codon (underlined).
5’- …GACAAGAAA… - 3’
3’ - …CUICTCUUU… - 5’
Regarding claim 47, as shown in Fig. A above, at least 10% of nucleosides are 2’-F modified 11/32 nucleosides total = 34%), and at least 10% of nucleosides are 2’-O-alkyl modified (18/32 nucleosides total = 56%).
Regarding claim 48, as shown in Fig. A above, 20-70% of nucleosides are 2’-F modified (11/32 =, and 56% of nucleosides are 2’-O-Me modified (18/32 nucleosides total = 56%). Thus, Moelhart Hoeg’s oligonucleotide does not comprise 22-55% 2’-O-Me modified nucleosides.
Merkle teaches oligonucleotides for the purpose of guiding ADAR to a target region comprising a target adenosine, in which 2’-F modifications were incorporated over the entire sequence with the exception of the pyrimidine nucleotides around the editing site (pg. 120). Merkle teaches that such a pattern was “well accepted” (pg. 120). Merkle also teaches that “The 2’-Fluoro modification at the pyrimidines could also be substituted by 2’-OMe with only slight loss in editing yield” (pg. 121). Elsewhere, in an approach similar to that of the instant invention, Merkle teaches that “Using 2’-OMe instead of 2’F modifications… decreased editing yield” (pg. 57).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the oligonucleotide rendered obvious above, such that between 22-55% of the nucleosides are 2’-O-Me modified nucleosides as required of instant claim 48. It would have amounted to applying a known oligonucleotide design strategy to a known oligonucleotide, by known means to yield predictable results. Taken together, the teachings of Merkle would illustrate to the skilled artisan that 2’-F modified nucleosides are well tolerated in oligonucleotides at pyrimidines, and that substitution of a 2’-O-Me modification with a 2’-F modification at one or more pyrimidines in an oligonucleotide would result in a similarly functioning, or improved oligonucleotide. The substitution of one 2’-O-Me nucleoside would result in an oligonucleotide within the percentages claimed (i.e., 17 2’-O-Me/32 nucleosides in total = 53% and 12 2’-F/32 nucleosides in total = 38%). The skilled artisan would have had a reasonable expectation of success in modifying the oligonucleotide to arrive at the invention of instant claim 48 because Moelhart Hoeg and Merkle teach oligonucleotides comprising alternating patterns of 2’-O-Me and 2’-F modified nucleosides, and both utilize iterative design processes to optimize editing yield. The skilled artisan would have had a reasonable expectation that an oligonucleotide comprising such a substitution would function comparably, or exhibit improved editing efficiency, based on the teachings of Merkle. The skilled artisan would have been motivated to modify the oligonucleotide in an effort to improve editing yield for applications of the technology, e.g., methods of treatment.
Regarding claim 49, as shown in Fig. A above, SEQ ID NO: 26, CMP 26_8 does not comprise more than 4 consecutive nucleosides with the same modification.
Regarding claim 50, as shown in Fig. A above, SEQ ID NO: 26, CMP 26_8 does not comprise more than 4 continuous 2’-O-Me modified nucleosides.
Regarding claims 51 and 53, as shown in Fig. A above, SEQ ID NO: 26, CMP 26_8 comprises no more than 7 2’-MOE modified nucleosides.
Regarding claims 52 and 54, as shown in Fig. A above, SEQ ID NO: 26, CMP 26_8 comprises no 2’-deoxyribonucleosides outside of the CBT.
Regarding claim 56, Moelhart Hoeg teaches the oligonucleotides form a double-stranded molecule (i.e., ADAR target) by hybridizing with the target nucleic acid in the region of the target adenosine (pg. 10, lines 1-11). Thus, Moelhart Hoeg’s oligonucleotides, including SEQ ID NO: 26, CMP 26_8, do not comprise a loop-hairpin structured ADAR recruitment motif (see also Tables 3-4 and Fig. A above for evidence of lack of nucleosides to form such a secondary structure).
Regarding claims 57-59, Moelhart Hoeg teaches a triantennary N-acetyl galactosamine (GalNAc3) conjugated to the 3’ or 5’ terminus of the oligonucleotide (“the at least one conjugate moiety is covalently attached to the 5’ end of the oligonucleotide… the at least one conjugate moiety is covalently attached to the 3’ end of the oligonucleotide,” pg. 60, line 18-20; “the conjugate moiety is a trivalent GalNAc,” pg. 60, line 21 to pg. 62, line 3).
Regarding claim 60, Moelhart Hoeg teaches a composition comprising the oligonucleotide (“The invention provides a pharmaceutical composition comprising the oligonucleotide…,” pg. 65, line 22 to pg. 66, line 6).
Claim Rejections - 35 USC § 103 - Moelhart Hoeg and Merkle in view of Fraley and Clavé
Claim 55 is rejected under 35 U.S.C. 103 as being unpatentable over Moelhart Hoeg (Moelhart Hoeg and Merkle, WO 2024/017817 A9, published 25 January 2024, effectively filed 18 July 2022 with respect to the subject matter relied upon to reject the following claims; of record) in view of Merkle (Merkle, Tobias., “Engineering Antisense Oligonucleotides for Site-directed RNA Editing with Endogenous ADAR,” Eberhard Karls Universitat Tubingen, “Dissertation_Tobias_Merkle.pdf” of 22.6 MB available 21 June 2021 as evidenced by the WayBack Machine; of record) as applied to claims 45-54, and 56-60, and in further view of Fraley (Fraley et al., US 2020/0399303 A1, published 24 December 2020; of record) and Clavé (Clavé et al., 8 December 2020, RSC Chem. Biol. 2021, 2, pg. 94-150; of record). The rejection that follows is maintained from the prior action.
The teachings of Moelhart Hoeg and Merkle are described above and applied as to claims 45-54, and 56-60 therein.
Regarding claim 55, neither Moelhart Hoeg nor Merkle teach that the oligonucleotide comprises one or more 3’-phosphoramidate linkages.
Fraley also teaches chemically modified oligonucleotides for the purpose of recruiting an ADAR to a target mRNA region comprising a target adenosine ([0005]-[0006]; [0104]). Fraley teaches that the oligonucleotides may have phosphodiester, phosphorothioate, or 3’-phosphoramidate linkages ([0106]; [0126]). Clavé teaches that phosphoramidate linkages, like phosphorothioate linkages, enhance stability of oligonucleotides (section 3.1.1, at least pg. 98, right col.; section 3.1.3, at least pg. 105, right col.).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the oligonucleotide rendered obvious above, such that it comprises one or more 3’-phosphoramidate linkages as required of instant claim 55. It would have amounted to a simple substitution of one known internucleoside linkage modification, for another known internucleoside linkage modification, by known means to yield predictable results. The skilled artisan would have had a reasonable expectation of success in preparing the oligonucleotide with one or more 3’-phosphoramidate linkages because Fraley and Clavé teach oligonucleotides comprising such linkages, and accordingly, means were known in the prior art to prepare such oligonucleotides. The skilled artisan would have been motivated to modify the oligonucleotide to comprise one or more 3’-phosphoamidate linkages because Clavé teaches that phosphoramidate linkages, like phosphorothioate linkages, enhance stability of oligonucleotides.
Response to Remarks – 35 USC § 103
Applicant’s remarks regarding the § 103 rejections raised in the prior action have been reviewed. Applicant submits that “based on the teachings of the cited references, there is no reason for one skilled in the art to select CMP 26_8 for modification nor is there a motivation to modify CMP 26_8 in such a way to arrive at the claimed chemically modified oligonucleotides” and that “one skilled in the art would have no expectation of success in doing so.” Examiner respectfully disagrees with Applicant’s assertions; the rejection above describes reasons to modify CMP 26_8 in such a way as to arrive at the claimed oligonucleotide, and reasons why the skilled artisan would have had a reasonable expectation of success in preparing the claimed oligonucleotide. In support of their arguments that there is no motivation or reasonable expectation of success, Applicant submits the following:
I. “CMP 26_8 is one of hundreds of oligonucleotide disclosed in Moelhart Hoeg,” and due to the “superior editing efficiency” of other oligonucleotides disclosed by Moelhart Hoeg, the skilled artisan would not have selected CMP 26_8 for further modification.
Examiner has reviewed the disclosure of Moelhart Hoeg for teachings regarding CMP 26_8, specifically, and teachings regarding further modification of oligonucleotides, in general. Moelhart Hoeg does not appear to teach that the skilled artisan should not select CMP 26_8 for further modification, or that the skilled artisan should only select oligonucleotides of a certain level of efficiency for further modification. “[T]he prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed….” In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004). Moelhart Hoeg does not appear to explicitly or implicitly teach away from further modifying CMP 26_8. These remarks are not found convincing.
II. “Moelhart Hoeg does not teach or suggest an oligonucleotide wherein up to 3 of internucleoside linkages selected from b, c, f, g, and j are PS linkages (i.e., 3 or more internucleoside linkages of b, c, f, g, h, and j are not PS linkages).”
First, Examiner disagrees with Applicant’s interpretation of the claim limitations. Claim 45 recites “up to 3 of internucleoside linkages selected from b, c, f, g, and j are PS linkages, internucleoside linkage h is a phosphate (PO) linkage….” These limitations are not equivalent to “3 or more internucleoside linkages of b, c, f, g, h, and j are not PS linkages” as asserted by Applicant’s remarks. The limitations are interpreted as requiring that internucleoside h is a phosphodiester linkage, and allowing 1, 2, or 3 phosphorothioate linkages at positions b, c, f, g, or j (e.g., PS linkages at b, f, and g; PS linkages at f and j; a PS linkage at f, etc.). The rejection states that “Moelhart Hoeg does not teach that “up to 3 of internucleoside linkages selected from b, c, f, g, and j are PS linkages,” or that “internucleoside linkage h is a phosphate (PO) linkage,” wherein the term “phosphate (PO) linkage” is interpreted as referring to a phosphodiester linkage (“phosphate linkages in natural DNA and RNA,” [0064]).” However, Examiner disagrees that Moelhart Hoeg does not “suggest” the aforementioned claim limitations. The rejection cites that “Moelhart Hoeg teaches oligonucleotides wherein internucleoside linkages b, c, f, g, h, and/or j are phosphodiester linkages (“the internucleoside linkage between nucleosides at positions +1 and 0 is a phosphodiester internucleoside linkage; and/or the internucleoside linkage between nucleosides at positions 0 and -1 is a phosphodiester internucleoside linkage; and/or the internucleoside linkage between nucleosides at positions -2 and -3 is a phosphodiester internucleoside linkage,” pg. 46, lines 5-12; Fig. 19-23, wherein “3” corresponds to b, “2” corresponds to c, “-1” corresponds to f, “-2” corresponds to g, “-3” corresponds to h, and “-5” corresponds to j).” As Applicant indicates, Moelhart Hoeg’s teachings correspond to an oligonucleotide wherein positions e, f, and/or h may be phosphodiester linkages. The teachings of Merkle are cited to provide further guidance and motivation to modify the linkages of Moelhart Hoeg’s oligonucleotide to arrive at an oligonucleotide comprising a phosphodiester linkage at position h, and up to 3 phosphorothioate linkages at positions b, c, f, g, or j. The rejection above identifies the limitations which are not taught by Moelhart Hoeg, and states teachings in Moelhart Hoeg and Merkle which would lead the skilled artisan to arrive at the instantly claimed invention with a reasonable expectation of success. These remarks are not found convincing.
III. “the data shown in FIGS. 19-23 do not motivate one skilled in the art to modify CMP 26_8 to arrive at the oligonucleotide of the instant claims nor do they provide any expectation that doing so would be successful,” because the oligonucleotides tested therein are designed to a different target, and allegedly exhibit “modest,” “marginal,” and in some instances “poor,” editing efficiency relative to parent oligonucleotides, highlighting “variability” when modifying phosphorothioate linkage positioning.
Examiner has evaluated Figs. 19-23, and the disclosures of Moelhart Hoeg and Merkle related to phosphorothioate linkage positioning within an oligonucleotide. Moelhart Hoeg teaches that the content of linkages in an oligonucleotide alters the editing efficiency (pg. 44, line 15 to pg. 46, line 12; Figs. 19-23). Merkle teaches that “PS linkages in the middle of the ASO seemed to reduce the editing yields,” likely due to the “many contacts of the ADAR deaminase domain with phosphates on the strand opposite of the target site… Exchanging these phosphates by PS-linkages probably results in unfavorable binding of the ADAR deaminase domain” (pg. 50). Thus, the skilled artisan, familiar with the teachings of Moelhart Hoeg and Merkle, would have been motivated to modify the oligonucleotide of Moelhart Hoeg, which is fully phosphorothioated, to comprise phosphodiester linkages to improve the binding of the ADAR deaminase domain. The skilled artisan would have had a reasonable expectation of success in preparing the oligonucleotide based on the many functional examples described by Moelhart Hoeg, at least in Figs. 19-23.
Examiner agrees with Applicant that the data in Figs. 19-23 is derived from oligonucleotides directed to a different target, and consequently, with different structures that that of the claimed oligonucleotide. However, the skilled artisan would not have interpreted the teachings of Moelhart Hoeg and Merkle regarding internucleoside linkage content to apply exclusively to the exemplary oligonucleotides in the references, e.g., GAPDH. The skilled artisan would have interpreted Moelhart Hoeg’s and Merkle’s teachings as applying to ADAR-recruiting oligonucleotides in general given their shared mechanism of action.
Examiner respectfully disagrees that the teachings of Fig. 19 related to the overall phosphorothioate content of an oligonucleotide would have led the skilled artisan away from the claimed invention. The skilled artisan would have known based on Moelhart Hoeg and Merkle that phosphorothioate linkages are critical to stabilize an oligonucleotide, and therefore, that high phosphorothioate content is “tolerated, and even preferred” as described by Moelhart Hoeg (pg. 153, line 15). However, the skilled artisan would have understood based on the teachings of Merkle that phosphorothioate linkages, particularly in the ADAR binding region (i.e., the region of the instantly claimed positions), are not desirable. The instant claims do not limit the overall phosphorothioate content of the oligonucleotide, and at present, only 3 total linkages in the oligonucleotide’s “core sequence,” must be phosphodiester linkages (i.e., linkage h, and at least two additional linkages, selected from b, c, g, and j). The teachings of Fig. 19 do not appear contradictory to the teachings of the prior art in general, or the structural limitations of the claimed invention.
The editing efficiencies disclosed by Moelhart Hoeg for linkage modified oligonucleotides also do not appear to “show significant variability” as asserted by Applicant. For example, the editing efficiencies of linkage modified oligonucleotides in Figs. 21 and 22 are comparable to the parent compounds. Applicant specifically cites that oligonucleotide “92_46,” which is an “oligonucleotide[] with internucleoside linkages as recited in the instant claims,” exhibits “poor editing efficiency compared to the parent compound.” The values of the parent compound (“92_1”) and “92_46” are comparable as shown in Fig. 21. Based on further consideration of Figs. 19-23 and Applicant’s remarks, Examiner maintains that the skilled artisan would have recognized that oligonucleotides with phosphodiester linkages at one or more of the claimed positions would have comparable or increased editing efficiency relative to a fully phosphorothioated oligonucleotide (Fig. 19-23). The skilled artisan would have been motivated to modify the oligonucleotide of Moelhart Hoeg based on the teachings of Merkle, e.g., regarding the decreased efficiency of fully phosphorothioated oligonucleotides and oligonucleotides with PS linkages in the ADAR binding region (“PS linkages in the middle of the ASO seemed to reduce the editing yields…”).
IV. “Merkle only very generally teaches that PS linkages in the middle of the ASO seem to reduce editing yields” (emphasis preserved from remarks). Applicant submits that this teaching is “derived from an uninformative sample size, does not teach the internucleoside linkages of the instant claims, and does not motivate one skilled in the art to arrive at “the specific internucleoside linkages” of the instant claims.
These remarks do not provide convincing evidence that the skilled artisan would have been taught away from the claimed invention, or would have had no reasonable expectation of success in arriving at the claimed invention. It is clear from the prior art that oligonucleotides with mixtures of phosphodiester and phosphorothioate linkages could be prepared, and could reasonably be expected to function. The skilled artisan would not have interpreted Merkle’s use of the word “seemed,” or the allegedly “uninformative sample size” as teaching away from the claimed invention, at least because Merkle’s statement is accompanied by a mechanistic explanation of their observations (“many contacts of the ADAR deaminase domain with phosphates on the strand opposite of the target site… Exchanging these phosphates by PS-linkages probably results in unfavorable binding of the ADAR deaminase domain…”), and supported by other cited prior art, i.e., Moelhart Hoeg, which shows that oligonucleotides comprising phosphodiester linkages at selected positions within a “core sequence” are functional. Furthermore, Applicant’s claims are not directed to oligonucleotides with “specific internucleoside linkages” as asserted, but rather, to a large genus of oligonucleotides wherein up to three linkages selected from b, c, f, g, and j are phosphorothioate linkages, and h is a phosphodiester linkage. The rejection above describes how the skilled artisan would have arrived at these limitations based on the teachings of Moelhart Hoeg and Merkle. The rejection above does not need to arrive at “specific internucleoside linkages” because the claim, at present, encompasses many different oligonucleotides with unspecified combinations of phosphorothioate and phosphodiester linkages.
Applicant also submits that oligonucleotides “within the scope of claim 45… unexpectedly demonstrate high editing efficiency.” Applicant refers specifically to the editing efficiency of oligonucleotides “v117.85, v117.141, v117.142, v117.168, v117.177, v117.178, and v117.170” disclosed in Figs. 10-11 of the application.
Applicant’s assertions regarding the “unexpectedly… high editing efficiency” have been reviewed. The oligonucleotides referred to by Applicant are specific species encompassed by the claimed genus. The oligonucleotides have between 31.4-65.3% editing efficiency based on Figs. 10-11 (i.e., 117.85 (36.5%), v117.141 (43.2%), v117.142 (31.4%), v117.168 (65.3%), v117.177 (47.5%), v117.178 (40.5%), and v117.170 (51.9%)). However, oligonucleotides encompassed by the claims do not have similarly “high editing efficiencies” as the oligonucleotides referred to by Applicant (e.g., v117.87 (25.9%), v117.86 (24.2%), v117.88 (11.9%), v117.91 (20.5%), v117.83 (7.4%) v117.167 (21.9%), v117.169 (10.8%)). There is insufficient evidence that the genus of oligonucleotides encompassed by the claims at present exhibit a trend of “high editing efficiency.” The evidence proffered by Applicant is, therefore, not commensurate with the scope of the claims. The editing efficiencies obtained from oligonucleotides encompassed by the claims were also compared to the closet prior art, i.e., Moelhart Hoeg. SERPINA1 E342K targeting oligonucleotides disclosed by Moelhart Hoeg exhibit similar editing efficiencies to the oligonucleotides encompassed by the instant claims (e.g., 26_2, 26_3, or 26_8 shown in Fig. 3 of Moelhart Hoeg, 19_1, 23_1, 27_1 shown in Fig. 6B of Moelhart Hoeg). At present, there is insufficient evidence that the editing efficiencies of oligonucleotides encompassed by the claims would have been “unexpected” based on the prior art.
Taken together, Applicant’s arguments are not sufficient to overcome the § 103 rejections over Moelhart Hoeg and Merkle, which are maintained, accordingly.
Finally, Applicant submits that Fraley and Clavé fail to remedy the alleged deficiencies of Moelhart Hoeg and Merkle. Applicant’s remarks regarding the alleged deficiencies of Moelhart Hoeg and Merkle are addressed above. The remarks are not found convincing to overcome the § 103 rejections. The rejection of claim 55 is maintained, accordingly.
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.
Application No. 18/565,415
Claims 45-60 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-41 of co-pending Application No. 18/565,415 in view of Moelhart Hoeg (Moelhart Hoeg and Merkle, WO 2024/017817 A9, published 25 January 2024, effectively filed 18 July 2022 with respect to the subject matter relied upon to reject the following claims; of record) and Merkle (Merkle, Tobias., “Engineering Antisense Oligonucleotides for Site-directed RNA Editing with Endogenous ADAR,” Eberhard Karls Universitat Tubingen, “Dissertation_Tobias_Merkle.pdf” of 22.6 MB available 21 June 2021 as evidenced by the WayBack Machine; of record). Although the claims at issue are not identical, they are not patentably distinct from each other for the reasons that follow. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented. The rejections that follow are maintained from the prior action.
Claim 41 recites a “chemically modified oligonucleotide or a pharmaceutical composition for use of claim 40, wherein the mutation is selected from the list comprising: SERPINA1 E342K,” wherein the chemically modified oligonucleotide is according to “any one of claims 1 to 36” (see claims 37-38). Claims 1, 8, and 11 recite a chemically modified oligonucleotide with the core sequence motif of instant claim 45, and a central base triplet (CBT) wherein N0 is directly opposite the target adenosine to be edited. Claims 1, 8, and 11 recite ranges that encompass the length required of instant claim 45. Claim 31 encompasses oligonucleotides in which N0 is deoxycytidine. Claims 1, 8, and 11 recite that at least 2 of 3 nucleosides of the CBT are chemically modified at the 2’-position of the sugar moiety, deoxyribonucleosides, or a combination thereof. Claim 16 recites that linkages h and i are phosphate (PO) linkages. Claim 28 recites an oligonucleotide wherein N+2 is a 2’-O-Me modified nucleoside, and N+3 is a 2’-fluoro modified nucleoside. Claim 22 encompasses oligonucleotides comprising no stereopure PS linkage.
Regarding instant claim 45, the co-pending claims do not recite that a, d, e, and f are phosphorothioate (PS) linkages, up to 3 of internucleoside linkages selected from b, c, f, g, and j are PS linkages, that each nucleoside is selected from a 2’-O-Me, 2’-F, or 2’-MOE modified nucleoside, or a 2’-deoxyribonucleoside, or that at least 50% of the linkages between the nucleosides are PS linkages.
The teachings of Moelhart Hoeg and Merkle are described above. The obviousness of modifying the SERPINA1 E342K targeting chemically modified oligonucleotide of the co-pending claims, with the teachings of Moelhart Hoeg and Merkle with respect to PO and PS internucleoside linkages, and 2’ modifications, to arrive at the aforementioned limitations of instant claim 45 is described in paragraphs 11 and 14 above and applied hereinafter.
Co-pending claim 36 meets the limitations of instant claim 46. At least co-pending claims 1, 8, and 11 meet the limitations of instant claim 47. Co-pending claim 3 meets the limitations of instant claim 48. Co-pending claim 28 (which encompasses co-pending claim 17) meets the limitations of instant claims 49-50. Co-pending claim 24 meets the limitations of instant claims 51 and 53. Co-pending claim 9 meets the limitations of instant claims 52 and 54. Co-pending claim 13 meets the limitations of instant claim 55. Co-pending claim 35 meets the limitations of instant claim 56. The aforementioned instant claims are also obvious over Moelhart Hoeg and Merkle.
Regarding instant claims 57-60, the co-pending claims do not recite a chemically modified oligonucleotide or pharmaceutical composition comprising the oligonucleotide in which the oligonucleotide comprises a 3’ or 5’-terminal GalNAc3.
The teachings of Moelhart Hoeg and Merkle are described above. As stated therein, Moelhart Hoeg teaches a triantennary N-acetyl galactosamine (GalNAc3) conjugated to the 3’ or 5’ terminus of the oligonucleotide (pg. 60, line 18-20; pg. 60, line 21 to pg. 62, line 3). Moelhart Hoeg teaches that SERPINA1 is synthesized in the liver, and that GalNAc3 enhances uptake of oligonucleotides to the liver (pg. 1, lines 30-32; pg. 61, lines 5-10). Merkle also teaches such conjugates, and teaches that triantennary GalNAc is a valuable option for tissue specific delivery in vivo (pg. 60; pg. 70).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the oligonucleotide rendered obvious above to comprise a 3’ or 5’-terminal GalNAc3 in view of Moelhart Hoeg and Merkle. It would have amounted to a simple combination of an obvious oligonucleotide with a known conjugate, by known means to yield predictable results. The skilled artisan would have had a reasonable expectation of success in modifying the oligonucleotide as such because Moelhart Hoeg and Merkle teach oligonucleotides with a 3’ or 5’-terminal GalNAc3, and thus, the conjugate and means to prepare such oligonucleotides were known in the prior art. The skilled artisan would have been motivated to modify the oligonucleotide in an effort to prepare an oligonucleotide for tissue (i.e., liver) specific delivery in vivo.
Application No. 18/565,733
Claims 45-54, and 56-60 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 24 of co-pending Application No. 18/565,733, in view of Moelhart Hoeg (Moelhart Hoeg and Merkle, WO 2024/017817 A9, published 25 January 2024, effectively filed 18 July 2022 with respect to the subject matter relied upon to reject the following claims; of record) and Merkle (Merkle, Tobias., “Engineering Antisense Oligonucleotides for Site-directed RNA Editing with Endogenous ADAR,” Eberhard Karls Universitat Tubingen, “Dissertation_Tobias_Merkle.pdf” of 22.6 MB available 21 June 2021 as evidenced by the WayBack Machine; of record). Although the claims at issue are not identical, they are not patentably distinct from each other for the reasons that follow. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented. The rejections that follow are maintained from the prior action.
Claim 24 recites a chemically modified oligoribonucleotide according to claim 1 for use in the treatment or prevention of “alpha1-antitrypsin deficiency by targeting the common E342K mutation in human SERPINA1.” The chemically modified oligoribonucleotide of claim 1 comprises a sequence 25 to 80 nucleotides in length, comprises a central base triplet, wherein the central nucleotide is opposite the target adenosine to be edited to an inosine, wherein at least 90% of the pyrimidine nucleosides outside the CBT are chemically modified, either at the 2’ position of the sugar moiety, are deoxyribonucleosides, or a combination thereof, wherein no more than 6 consecutive nucleosides are chemically modified with 2’-O-Me, wherein at least two of the three nucleosides of the CBT are chemically modified at the 2’ position of the sugar moiety, or are deoxyribonucleosides, or a combination thereof, and wherein at least 30% of the linkages between the nucleosides are phosphorothioate (PS) linkages.
Regarding instant claim 45, the co-pending claim does not recite that N0 is a deoxycytidine, that a, d, e, and f are phosphorothioate (PS) linkages, up to 3 of internucleoside linkages selected from b, c, f, g, and j are PS linkages, that N+2 is a 2’-O-Me modified nucleoside and N+3 is a 2’-fluoro modified nucleoside, that each nucleoside is selected from a 2’-O-Me, 2’-F, or 2’-MOE modified nucleoside, or a 2’-deoxyribonucleoside, or that at least 50% of the linkages between the nucleosides are PS linkages.
The teachings of Moelhart Hoeg and Merkle are described above. Moelhart Hoeg teaches a successful SERPINA1 E342K targeting chemically modified oligonucleotide encompassed by the genus recited in co-pending claim 24 (see Tables 3-4, and Fig. 3A).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have selected Moelhart Hoeg’s successful SERPINA1 E342K targeting oligonucleotide for the use recited in co-pending claim 24 (i.e., treatment or prevention of alpha1-antitrypsin deficiency by targeting the common E342K mutation in human SERPINA1). It would have amounted to selecting a known oligonucleotide encompassed by the genus recited in the co-pending claim, and successfully used for the same purpose recited in the co-pending claim. The skilled artisan would have been motivated to select Moelhart Hoeg’s oligonucleotide, and had a reasonable expectation of success in using the oligonucleotide, based on the guidance in Tables 3-4, and results described in at least Fig. 3A of Moelhart Hoeg.
The obviousness of modifying the selected species of SERPINA1 E342K targeting oligonucleotide rendered obvious above, with the teachings of Moelhart Hoeg and Merkle with respect to PO and PS internucleoside linkages, and 2’ modifications, to arrive at the aforementioned limitations of instant claim 45 is described in paragraphs 11 and 14 above and applied hereinafter.
In rendering obvious the use of Moelhart Hoeg’s SERPINA1 E342K targeting oligonucleotide and its modification in view of Moelhart Hoeg and Merkle with respect to PO and PS internucleoside linkages, and 2’ modifications, instant claims 46-54, and 56 are also obvious as these are each features of the obvious oligonucleotide.
Regarding claims 57-59, the co-pending claim does not recite a chemically modified oligonucleotide or pharmaceutical composition comprising the oligonucleotide in which the oligonucleotide comprises a 3’ or 5’-terminal GalNAc3.
The teachings of Moelhart Hoeg and Merkle are described above. As stated therein, Moelhart Hoeg teaches a triantennary N-acetyl galactosamine (GalNAc3) conjugated to the 3’ or 5’ terminus of the oligonucleotide (pg. 60, line 18-20; pg. 60, line 21 to pg. 62, line 3). Moelhart Hoeg teaches that SERPINA1 is synthesized in the liver, and that GalNAc3 enhances uptake of oligonucleotides to the liver (pg. 1, lines 30-32; pg. 61, lines 5-10). Merkle also teaches such conjugates, and teaches that triantennary GalNAc is a valuable option for tissue specific delivery in vivo (pg. 60; pg. 70).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the oligonucleotide rendered obvious above to comprise a 3’ or 5’-terminal GalNAc3 in view of Moelhart Hoeg and Merkle. It would have amounted to a simple combination of an obvious oligonucleotide with a known conjugate, by known means to yield predictable results. The skilled artisan would have had a reasonable expectation of success in modifying the oligonucleotide as such because Moelhart Hoeg and Merkle teach oligonucleotides with a 3’ or 5’-terminal GalNAc3, and thus, the conjugate and means to prepare such oligonucleotides were known in the prior art. The skilled artisan would have been motivated to modify the oligonucleotide in an effort to prepare an oligonucleotide for tissue (i.e., liver) specific delivery in vivo.
The co-pending claim does not recite a composition comprising the oligonucleotide. The teachings of Moelhart Hoeg and Merkle are described above. As stated therein, Moelhart Hoeg teaches such compositions (pg. 65, line 22 to pg. 66, line 6).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have combined the oligonucleotide rendered obvious above with another element, e.g., a buffer, to arrive at the composition of instant claim 60. It would have amounted to a simple combination of an obvious oligonucleotide with one or more known elements of a composition, by known means to yield predictable results. The skilled artisan would have had a reasonable expectation of success in preparing such a composition because based on at least Moelhart Hoeg, such compositions were known in the prior art. The skilled artisan would have been motivated to prepare a composition comprising the oligonucleotide for the purposes of delivery, e.g., to cells in vitro or in vivo.
Claim 55 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 24 of co-pending Application No. 18/565,733, in view of Moelhart Hoeg (Moelhart Hoeg and Merkle, WO 2024/017817 A9, published 25 January 2024, effectively filed 18 July 2022 with respect to the subject matter relied upon to reject the following claims; of record) in view of Merkle (Merkle, Tobias., “Engineering Antisense Oligonucleotides for Site-directed RNA Editing with Endogenous ADAR,” Eberhard Karls Universitat Tubingen, “Dissertation_Tobias_Merkle.pdf” of 22.6 MB available 21 June 2021 as evidenced by the WayBack Machine; of record), and in further view of Fraley (Fraley et al., US 2020/0399303 A1, published 24 December 2020; of record) and Clavé (Clavé et al., 8 December 2020, RSC Chem. Biol. 2021, 2, pg. 94-150; of record). The rejection that follows is maintained from the prior action.
The co-pending claim does not recite that the oligonucleotide comprises one or more 3’-phosphoramidate linkages. The teachings of Fraley and Clavé are described above. The obviousness of modifying the obvious oligonucleotide above, such that it comprises one or more 3’-phosphoramidate linkages as required of instant claim 55 is described in paragraph 26 above and applied hereinafter.
Response to Remarks – Nonstatutory Double Patenting
Applicant’s remarks regarding the nonstatutory double patenting rejections raised in the prior action have been reviewed. Applicant submits that the deficiencies of the claims in the reference applications are not remedied by the disclosures of the prior art for the reasons described in the remarks related to the § 103 rejections. Applicant’s remarks regarding the § 103 rejections are addressed above. The remarks are not found convincing to overcome the § 103 rejections. The co-pending claims remain patentably indistinct from the instant claims in view of the prior art for the reasons described above. The nonstatutory double patenting rejections are maintained, accordingly.
Conclusion
No claims are allowed.
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.
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/JENNA L PERSONS/Examiner, Art Unit 1637
/Soren Harward/Primary Examiner, TC 1600