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 .
Response to Amendment/Status of Claims
Receipt of Arguments/Remarks filed on 06/12/2025 is acknowledged. Claim 2 was cancelled. Claims 1,3,5 and 21 were amended. Claims 1-14,18 and 20-24 are pending. Claims 14,18 and 20 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 02/11/2025. Claims 1,3-13 and 21-24 are directed to the elected invention and are under examination.
Response to Arguments
Applicant’s arguments, see pages 8-10, filed 06/12/2025, with respect to the objection to the specification, objection to the drawings, and amendment to the sequence listing have been fully considered and are persuasive. The objection to the specification and drawings has been withdrawn, due to applicant submitting a substitute specification including SEQ ID NOs for the antisense oligonucleotides on pages 24-25, replacement drawings in black and white and labeled “FIG.”, and amendments to the sequence listing including antisense oligonucleotides shown on pages 24-25 of the specification, which are now SEQ ID NOs: 30-39.
Applicant’s arguments, see page 10, filed 06/12/2025, with respect to the objection to claim 1 have been fully considered and are persuasive. The objection to claim 1 has been withdrawn, due to the amendment to claim 1 reciting the fully name of ADAR, “Adenosine Deaminase Acting on RNA”.
Applicant’s arguments, see page 11, filed 06/12/2025, with respect to claims 1,7-8,10-13 and 23 rejected under 35 U.S.C. 101 have been fully considered and are persuasive. The rejection of claims 1,7-8,10-13 and 23 under 35 U.S.C. 101 has been withdrawn due to the amendment to claim 1 incorporating the limitations of claim 2 which was not included in the rejection, regarding the chemical modifications to the AON, and therefore the amended claims are not directed to a product of nature.
Applicant’s arguments, see pages 14-15, filed 06/12/2025, with respect to the NSDP rejections have been fully considered and are persuasive. Therefore the rejections have been withdrawn, due to the amendment to claim 1 to include the limitations of claim 2 that was not rejected in the NSDP rejections.
The following rejections are reiterated but have been amended to reflect the amendments to the claims. They constitute the complete set presently being applied to the instant application.
Claim Rejections - 35 USC § 102
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim Interpretation: Regarding claim 1, the function that the antisense oligonucleotide is capable of inhibiting ADAR-mediated deamination of a target adenosine present in an editing-site sequence (ESS) of an endogenous target molecule, wherein under physiological conditions the ESS would hybridize with an editing-site complementary sequence (ESCS) of an endogenous RNA molecule to form a double stranded RNA complex, is a property of the antisense oligonucleotide. The only structural limitation of the AON is that it comprises a sequence configured to compete with the ESCS for hybridization with the ESS, and wherein the nucleotide in the AON opposite the target adenosine and/or the nucleotides in the AON opposite the nucleotides surrounding the target adenosine is/are chemically modified and therefore an AON comprising such a sequence and chemical modification would have the above function. The claimed antisense oligonucleotide would have the same sequence to “an editing-site complementary sequence”.
The functional limitation of claim 4, “to compete with the ESCS and inhibit the ADAR-mediated deamination of each corresponding adenosine in the target RNA molecule” would be a function that would result from the structure of the nucleotide in the AON opposite all adenosines in the target RNA molecule being chemically modified.
The functional limitation in claim 10, “wherein under physiological conditions the ESS would hybridize with the ESCS to form a double stranded RNA complex in a cell”, would result from the structure of the antisense oligonucleotide in claim 1 (comprises a sequence configured to compete with ESCS for hybridization with the ESS and wherein the nucleotide in the AON opposite the target adenosine and/or the nucleotides in the AON opposite the nucleotides surrounding the target adenosine is/are chemically modified).
The functional limitation in claim 24, “wherein the ESS and ESCS would hybridize under physiological conditions to form a stem-loop structure” would result from the structure of the AON when the ESS and ESCS are located on the same RNA molecule.
Claims 1,3-13 and 21-24 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by WO 2017220751 (‘751), Published 28 December 2017, cited on an IDS.
See claim interpretation above.
Regarding claims 1 and 10, ‘751 teaches antisense oligonucleotides capable of forming a double stranded complex with a target RNA in a cell, for the deamination of a target adenosine present in the target RNA by an ADAR enzyme present in the cell, wherein the AON is complementary to a target RNA region comprising the target adenosine (Page 3, lines 31-35, and claims 1-7). ‘751 teaches to prevent undesired editing of adenosines in the target RNA sequence in the region of overlap with the oligonucleotide construct, the oligonucleotide can be chemically modified with 2’-O-methylation of the ribosyl-moiety opposite an adenosine in the target RNA sequence which reduces deamination of that adenosine by ADAR, and improves specificity of editing, and that 2’-MOE and 2’-O-dimethylallyl groups may also reduce unwanted editing of the opposite adenosine in the target RNA sequence, and that all of these modifications may be applied to the oligonucleotides of the present invention (page 19, lines 16-24).
Regarding claims 3-6,21 and 22, ‘751 teaches an antisense oligonucleotide, ADAR65-2, in which the nucleotide opposite the target adenosine is a 2’-O methyl modified RNA nucleotide, as well as the two adjacent bases in the 3’ direction and the two adjacent bases in the 5’ direction being 2’-O-methyl modified nucleotides (page 34, lines 15, 21-25). See below.
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Regarding claim 7, ‘751 teaches the nucleotide opposite the target adenosine is uridine (Page 4, lines 4-5 and claim 5).
Regarding claims 8 and 23, ‘751 teaches the ADAR used is ADAR1 or ADAR2, and human ADAR1 and ADAR2 (page 18, lines 32-34).
Regarding claims 9 and 24, ‘751 teaches that adenosine deaminases have recognition domains that recognize a specific double stranded RNA (dsRNA) sequence and/or conformation (page 1, lines 19-21). Therefore, as ‘751 teaches that the target RNA molecule is double stranded, the ESS and ESCS would be located on the same RNA molecule, and would result in hybridization of the ESS and ESCS to form a stem-loop structure.
Regarding claim 11, ‘751 teaches the ESS is of a pre-messenger RNA (antisense oligonucleotides directed towards the pre-mRNA of an Idua sequence used in RNA editing (Example 2, lines 25-26).
Regarding claim 12, ‘751 teaches the target adenosine is within a coding sequence of an RNA molecule as ‘751 shows upper strand sequences of the antisense oligonucleotide and lower strand sequences which are the 5’-3’ target RNA and is part
of the Idua coding sequence which comprises a target adenosine (Example 2, page 33, lines 20-41).
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Regarding claim 13, ‘751 teaches a pharmaceutical composition comprising the AON according to the invention and a pharmaceutically acceptable carrier (Page 4, lines 38-39).
Response to Arguments
Applicant's arguments filed 06/12/2025 have been fully considered but they are not persuasive.
Applicant argues, see page 12, that Turunen relates to use of artificial AONs that hybridize to a target RNA to cause deamination of a target adenosine, and in the absence of the artificial AONs of Turunen, the target RNA is not deaminated. Applicant argues that Turunen relates to a target RNA which comprises a nucleotide somewhere in its sequence that needs correction, and the artificial AONs of Turunen force a correction of the erroneous nucleotide in the target RNA. Applicant cites Example 2 pertaining to Hurler Syndrome caused by a 1205G>A mutation that exists in the IDUA gene and discloses sequence that bind to the IDUA gene, recruit endogenous ADAR, force ADAR to deaminate the adenosine at position 1205 to give inosine which undergoes processing to yield guanosine and reverting the RNA to encoding a healthy protein. Applicant argues the present invention relates to a target RNA wherein the absence of artificial AONs the target RNA does undergoes spontaneous deamination, and the target of the AONs are endogenous RNA under attack by ADAR causing undesired deamination, and that the spontaneous deamination occurs because an endogenous ESCS binds to an endogenous ESS in the target RNA which recruits ADAR to effect the undesired deamination reaction and the present invention is protected the target RNA from this attack by endogenous ADAR and concludes the sequences of the AONs of claim 1 must be different from those disclosed in Turunen.
Applicant argues on page 13, that the AONs of claim 1 are not designed to cause deamination but to inhibiting the endogenous binding and simultaneously are not capable of driving ADAR-mediated deamination in their own right.
This is not found persuasive, because the instant specification discloses that “the AON of the invention comprises a sequence configured to compete with the ESCS for hybridization with the ESS. This means that the AON of the present invention has a sequence that is substantially complementary to the ESS. In an embodiment, the AON is fully complementary to the ESS, but this is not a requirement for inhibition. Indeed the AON can comprise one or more mismatches, bulges or loops and still hybridize with the ESS. The design of AONs that hybridize with sense sequence while bearing one or more mismatches, bulges or loops is known and it can be readily determined if there is sufficient complementarity for an AON to hybridize with the ESS under physiological conditions” (page 5, lines 4-12). Based on the claim interpretation provided in the non-final office action and amended above to incorporate the amendments to claim 1, the examiner interpreted the only structural limitation of the AON in claim 1 is that it comprises a sequence configured to compete with the ESCS for hybridization with the ESS, and wherein the nucleotide in the AON opposite the target adenosine and/or the nucleotides in the AON opposite the nucleotides surrounding the target adenosine is/are chemically modified. Therefore, as the instant specification defines “the AON of the invention comprises a sequence configured to compete with the ESCS for hybridization with the ESS” to mean that “the AON has a sequence that is substantially complementary to the ESS”, an AON with a sequence substantially complementary (and which may include one or more mismatches, bulges or loops) to the ESS and which has the nucleotide in the AON opposite the target adenosine and/or nucleotides in the AON opposite the nucleotide surrounding the target adenosine chemically modified with any chemical modification, meets the structural limitations of instant claim 1. AONs with the same structure would necessarily have the function of inhibiting ADAR mediated deamination of a target adenosine present in an editing site sequence of an endogenous target RNA molecule, wherein under physiological conditions, the ESS would hybridize with an editing-site complementary sequence (ESCS) of an endogenous RNA molecule to form a double stranded RNA complex. See MPEP 2112.01: "Products of identical chemical composition cannot have mutually exclusive properties." A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. In re Spada, 911 F.2d 705,709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990).
Additionally, it is noted that a claim that uses “capable of” type language covers products (in this case oligonucleotides) that have the recited components and which are capable of performing the recited functions, and therefore a claim element that uses capable of type language does not impose any requirements that the device or composition actually perform the function.
Additionally, applicant points to Example 2 of Turunen regarding the IDUA gene and which discloses sequences that bind to the IDUA gene. The examiner pointed to one of these AON sequences in the rejection. It is noted that instant Example 1 also discloses IDUA mRNA, and a guide strand (ESCS) IDUA7 and antisense oligonucleotides that are chemically modified (ADAR102-20 and ADAR102-32) and that the RNA guide strand (IDUA7), ADAR102-20 and ADAR102-32 were annealed to mIDUA target RNA, and also refers to Figures 1 and 2 which shows the sequences of the IDUA RNA target strand, the IDUA7 RNA guide strand, and AON ADAR102-20 and ADAR102-32 and the duplexes with the RNA guide strand and AONs. Therefore, the mRNA target and AONs exemplified in Turunen are highly similar to the structures of the mRNA target and AONs in instant Example 1, regarding the instant claimed limitations.
Nevertheless, even though applicant argues that Turunen relates to AONs that hybridize to a target RNA to cause deamination of a target adenosine, the examiner maintains that as cited in the rejection, Turunen does teach preventing undesired editing of adenosines in the target RNA sequence in the region of overlap with the oligonucleotide construct by chemical modification of the oligonucleotide with 2’-O-methylation of the ribosyl-moiety opposite an adenosine in the target RNA sequence which reduces deamination of that adenosine by ADAR, and improves specificity of editing, and that 2’-MOE and 2’-O-dimethylallyl groups may also reduce unwanted editing of the opposite adenosine in the target RNA sequence, and that all of these modifications may be applied to the oligonucleotides of the present invention (page 19, lines 16-24). Turunen teaches AONs where the AON comprises a sequence configured to compete with the ESCS for hybridization with the ESS, because as explained above based on the instant specification, the AON comprises a sequence substantially complementary to the editing site sequence (ESS) (page 33), as shown below.
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Turunen shows the same AON on page 34 with the chemical modifications wherein lowercase letters are 2’-O-methyl modified RNA nucleotides, and therefore ADAR65-2 has 2’-O-methyl modifications on all it nucleotides.
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Therefore, Turunen teaches antisense oligonucleotides with the same structural limitations of the instant claims, including the same chemical modifications (2’-O-Me) for preventing undesired editing of adenosines.
Applicant appears to be arguing preferred embodiments regarding the teachings of Turunen despite Turunen also teaching preventing undesired editing of adenosines in the target RNA sequence in the region of overlap with the oligonucleotide construct by chemical modification of the oligonucleotide with 2’-O-methylation of the ribosyl-moiety opposite an adenosine in the target RNA sequence which reduces deamination of that adenosine by ADAR, and which was cited in the rejection. In response, "The use of patents as references is not limited to what the patentees describe as their own inventions or to the problems with which they are concerned. They are part of the literature of the art, relevant for all they contain." In re Heck, 699 F.2d 1331, 1332-33, 216 USPQ 1038, 1039 (Fed. Cir. 1983) (quoting In re Lemelson, 397 F.2d 1006, 1009, 158 USPQ 275, 277 (CCPA 1968)). A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments. Merck & Co. v. Biocraft Labs., Inc. 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989). See also Upsher-Smith Labs. v. Pamlab, LLC, 412 F.3d 1319, 1323, 75 USPQ2d 1213, 1215 (Fed. Cir. 2005) (reference disclosing optional inclusion of a particular component teaches compositions that both do and do not contain that component); Celeritas Technologies Ltd. v. Rockwell International Corp., 150 F.3d 1354, 1361, 47 USPQ2d 1516, 1522-23 (Fed. Cir. 1998) (The court held that the prior art anticipated the claims even though it taught away from the claimed invention. "The fact that a modem with a single carrier data signal is shown to be less than optimal does not vitiate the fact that it is disclosed.").
Even if Turunen did not teach inhibiting ADAR-mediated deamination of the target adenosine by chemical modification of the AON of the nucleotide opposite the target adenosine and/or nucleotides opposite the nucleotides surrounding the target adenosine, it is well settled that "any need or problem known in the field of endeavor at the time of invention and addressed by the patent can provide a reason for combining the elements in the manner claimed." KSR Int 'l Co. v. Teleflex Inc., 550 U.S. 398, 420 (2007). As long as some suggestion to combine the elements is provided by the prior art as a whole, the law does not require that they be combined for the reason or advantage contemplated by the inventor. In re Beattie, 974 F.2d 1309, 1312 (Fed. Cir. 1992); In re Kronig, 539 F.2d 1300, 1304 (CCPA 1976). MPEP 2143.01 and 2144 (IV).The reason or motivation to modify the reference may often suggest what the inventor has done, but for a different purpose or to solve a different problem. It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant. See, e.g., In re Kahn, 441 F.3d 977, 987, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006) (motivation question arises in the context of the general problem confronting the inventor rather than the specific problem solved by the invention); Cross Med. Prods., Inc. v. Medtronic Sofamor Danek, Inc., 424 F.3d 1293, 1323, 76 USPQ2d 1662, 1685 (Fed. Cir. 2005) ("One of ordinary skill in the art need not see the identical problem addressed in a prior art reference to be motivated to apply its teachings.").
Applicant has provided no further structural limitations to the antisense oligonucleotide to distinguish it from the prior art, or claimed any sequences of the antisense oligonucleotide.
Therefore, the rejection of claims 1,3-13 and 21-24 under 35 U.S.C. 102(a)(1) as being anticipated by WO 2017220751 (Turunen) is maintained.
Claims 1,4-6,8,10-12 and 21-23 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Vogel et al. (Angewandte Chem Int. Ed. 2014, 53, 6267-6271), cited on an IDS.
See claim interpretation above.
Regarding claims 1,8,10-12 and 23, Vogel et al. teach antisense oligonucleotides (guide RNAs) for RNA editing using human ADAR1 to direct RNA editing (page 6267), and teach a chemically modified guide RNA for editing an eCFP mRNA having a target adenosine (Figure 1B, page 6268).
Regarding claims 4-6 and 21-22 Vogel et al. teach the guide RNA in which the nucleotide opposite the target adenosine and an adjacent base on both the 3’ and 5’ side of the nucleotide opposite the target adenosine are 2’-OMe modified bases (Figure 1B, page 6268).
Response to Arguments
Applicant argues, see page 13, that amended claim 1 is not anticipated by Vogel for analogous reasons to those presented above with respect to Turunen. Applicant states that Vogel discloses artificial target RNA and not an endogenous ESS, and the target RNA in Vogel is representative of a target RNA that comprises somewhere in its sequence a nucleotide that requires correction. Applicant states that the target RNA is a reporter construct having a sequence that does not lead to fluorescence and the AON forces ADAR to perform A-to-I deamination that leads to desired fluorescence readout, and Vogel’s disclosures are directed to inducing a functional change by causing deamination. Applicant argues that therefore amended claim 1 is novel with respect to Vogel for the reasons above and the target RNA is different from the target RNA in Vogel and therefore the sequence of the AON is different, and the AONs of claim 1 inhibit ADAR-mediated deamination not cause deamination.
This is not found persuasive, because the instant claims are directed to an AON product, rather than a method, and the functional limitations recited in the claims would be carried out by an AON with the structural limitations of the instant claims. The ESCS and ESS are not part of the structure of the AON. It is noted that a claim that uses “capable of” type language covers products (in this case oligonucleotides) that have the recited components and which are capable of performing the recited functions, and therefore a claim element that uses capable of type language does not impose any requirements that the device or composition actually perform the function.
See also the response to arguments above to Turunen that are applicable to this rejection and response as well.
Vogel et al. teach an antisense oligonucleotide that meets the structural requirements of instant claims 1,4-6,8,10-12 and 21-23 as it teaches a chemically modified guide RNA (antisense oligonucleotide) complementary to a target mRNA, and which comprises 2’-OMe modifications in the nucleotide opposite the target adenosine as well as in the adjacent base in both directions (Figure 1B, page 6268), and therefore anticipates claims 1,4-6,8,10-12 and 21-23 and the rejection of these claims is maintained.
Conclusion
Claims 1,3-13 and 21-24 remain rejected.
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 STEPHANIE L SULLIVAN whose telephone number is (703)756-4671. The examiner can normally be reached Monday-Friday, 7:30-3:30 EST.
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/STEPHANIE L SULLIVAN/Examiner, Art Unit 1635
/ABIGAIL VANHORN/Primary Examiner, Art Unit 1636