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 .
Election/Restrictions
Claims 103, 107 and 147 were cancelled in the amendment filed on 7/20/26 and remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention. Election was made without traverse in the reply filed on 12/30/25.
Upon further consideration, Formulas II-IV in amended claims 1, 10 and 11 are rejoined with the elected species and examined.
Specification
The substitute specification filed 7/20/26 has not been entered because it does not conform to 37 CFR 1.125(b) and (c) because: the amendment does not include the amendment to the specification filed on 5/18/23. The amendment did address the objection to the specification regarding any trademark issue(s).
Please reply to the non-complaint amendment with the response to the instant office action at the same time to avoid processing issues at the Office.
Response to Arguments
Any rejection or objection not reiterated herein has been overcome by amendment. Applicant’s amendments and arguments have been thoroughly reviewed but are not persuasive to place the claims in condition for allowance for the reasons that follow.
Claim Rejections - 35 USC § 103
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, 10, 11, 28, 129, 138 and 145 are rejected under 35 U.S.C. 103 as being obvious over of taken with Korro (WO 2020154342, EFD 1/2/19, cited on an IDS) taken with Houpaniemi (Europ. J. Hum. Genet. 7: 368-376, 1999, of record).
The applied references have a common assignee and inventor(s) with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2).
This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
‘342 teaches a method of treating a disorder in a subject in need thereof, comprising administering to the subject an effective amount of the oligonucleotide in claim 1. See pages 85-92.
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See also pages 1-18 and 85-92. ‘342 teaches treating genetic diseases, including diseases associated with an eye of a subject (page 36).
‘342 does not specifically teach using the chemically modified RNA-editing oligonucleotide in a RNA editing method for an adenosine to inosine alteration of a RS1 nucleotide sequence encoding a protein, wherein the sequence has a SNP-associated with XLRS.
However, Huopaniemi et al. teach that mutations in the RS gene are responsible for XLRS in humans (pages 369-375 and Table 4). The disease is very common in Finland. The human RS1 polynucleotide encoding an RS1 protein comprising an amino acid comprising a lysine at position 72 resulting in the SNP was well known in the prior art as taught by Huopaniemi et al. Huopaniemi et al. found that glu72 to lys and gly74 to val in the XLRS1 gene account for RS in western Finland (page 374).
It would have been prima facie obvious to a person of ordinary skill in the art before the time of the effective filing date to combine the teaching of ‘342 to edit the RS1 nucleotide sequence associated with XLRS as taught by Huopaniemi et al., namely to arrive at the claimed invention. As made obvious by ‘342 (page 27), one of ordinary skill in the art would have been motivated to combine the teaching to use an ex vivo or an in vivo method to edit the RS1 polynucleotide in a cell, wherein the RS1 polynucleotide comprising a SNP associated with XLRS (RS1 amino acid sequence having a lysine at position 72) and/or treat XLRS in a subject in need thereof. Since the disorder is an eye disorder, it would have been obvious to use ocular administration to deliver the oligonucleotide to the subject in need thereof.
Furthermore, ‘342 teaches making and using single stranded RNA-editing oligonucleotides, wherein the oligonucleotide is 18 to 50 nucleotides or no longer than 10-17 nucleotides. The oligonucleotide comprising a nucleotide sequence that is complementary to a target RNA in a cell, wherein the nucleotide corresponding to the target adenosine is a mismatch (cytidine, a deoxycytidine, a uridine, or a deoxyuridine), wherein the nucleotides directly 5' and/or 3' from the nucleotide opposite the target adenosine comprise a ribose with a 2'-OH group or a deoxyribose with a 2'-H group (pages 88-89 of ‘342). The oligonucleotide has a central triplet region, wherein the middle nucleotide opposite is the mismatch to the adenosine. The oligonucleotide can be used to edit a target RNA applying adenosine deaminase. The oligonucleotide has 2-6 terminal nucleotides linked by phosphorothioate at the 5' and 3' terminus of the oligonucleotides (page 43). The oligonucleotide has at least 20% of the nucleotides on the 5' or 3' end of the central triplet are 2'-O-methyl groups to reduce degradation (page 89).
‘342 specifically teaches the structure: [Am]-X1-X2-X3-[Bn], wherein A and B are nucleotides; m and n are each independently 5 to 40 nucleotides in length; X1, X2, and X3 are each, independently, a nucleotide, wherein at least one of the X1, X2, or X3 has the structure of formula I: Formula I:
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, wherein N1 is hydrogen or a nucleobase; and R1 is hydroxy, halogen, or C1-C6 alkyl.
In addition, a person of ordinary skill in the art would possess the knowledge that ADARs are endogenously expressed in human cells (page 1 of ‘342). See MPEP 2141 II.C. Rationales to support rejections under 35 U.S.C. 103 recites, "Prior art is not limited to the references being applied, but includes the understanding of one of ordinary skill in the art." See MPEP 2141. FACTORS TO CONSIDER IN DETERMINING LEVEL OF ORDINARY SKILL.
It would have been obvious to one of the ordinary skill in the art before the effective filing date of the claimed invention to modify at least one nucleotide (nucleoside) of the central triplet region of the oligonucleotides taught by ‘342 taken with Huopaniemi et al. ‘342 teaches at least four terminal phosphorothioate linkages; at least five terminal 2'-O-methyl nucleotides; and/or at least 20% of the nucleotides of A or B are 2'-O-methyl nucleotides (page 91).
Therefore the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains.
Claims 1, 10-11, 28, 129, 138, and 145 are rejected under 35 U.S.C. 103 as being unpatentable as Bryson (WO2019217943, published 11/14/19 and EFD 5/11/18) taken with Huopaniemi et al. (Europ. J. Hum. Genet. 7: 368-376, 1999) and Turunen et al. (WO2018041973) in further view of Li et al. (Biochemistry 45, pages 4141- 4152, 2006), all of record.
Bryson teaches composition comprising a polynucleotide encoding a based editor, where the base editor contains a polynucleotide programmable DNA binding domain and an adenosine deaminase domain; and one or more guide polynucleotide that target the based editor to effect A.T of the SNP in the gene and methods for using the programmable nucleobase editor (e.g., pages 1 and 7-18, 21-40, 183-208, and 257-277). The guide polynucleotide can be chemical modification, including sugar modified analogs, 2'-O-methyl ribonucleosides and phosphorothioate (pages 110-111). Phosphorothioate bonds can be introduced between the last 3-5 nucleotides at the 5' or 3' end of the gRNA which can inhibit exonuclease degradation. The adenosine deaminase can be used to correct any single point A to G mutation. The deamination of the mutant A to I corrects the mutation. The method can be used in a cell of a subject, wherein the cell is in the subject or delivered to the subject. The method can be used to edit a disease associated RS1, wherein the R102W or R141C are changed and use an A to G based editor (ABE) (Table 3B).
Bryson teaches using genomic (DNA) editing for a RS1 polynucleotide, but does not specifically teach using the RNA editing method for an adenosine to inosine alteration of a RS1 nucleotide sequence encoding a protein, wherein the sequence has a SNP-associated with XLRS.
However, Huopaniemi et al. teach that mutations in the RS gene are responsible for XLRS in humans (pages 369-375 and Table 4). The disease is very common in Finland. The human RS1 polynucleotide encoding an RS1 protein comprising an amino acid comprising a lysine at position 72 resulting in the SNP was well known in the prior art as taught by Huopaniemi et al. Huopaniemi et al. found that glu72 to lys and gly74 to val in the XLRS1 gene account for RS in western Finland (page 374).
Futhermore, ‘973 teaches that RNA editing is a natural process in eukaryotic cells to alter a RNA sequence in a site-specific and precise way (page 1). The CRISPR/Cas system has drawbacks as it requires co-delivery to the target cell of the CRISPR/Cas9 enzyme, or an expression system construct encoding the same, together with the guide oligonucleotide (pages 2-3). '973 teaches making and using single stranded RNA-editing oligonucleotides, wherein the oligonucleotide is 18 to 50 nucleotides or no longer than 10-17 nucleotides (i.e., pages 32-48). The oligonucleotide has a central triplet region, wherein the middle nucleotide opposite is the mismatch to the adenosine. The oligonucleotide can be used to edit a target RNA applying adenosine deaminase. The oligonucleotide comprising a nucleotide sequence that is complementary to a target RNA in a cell, wherein the nucleotide corresponding to the target adenosine is a mismatch (cytidine, a deoxycytidine, a uridine, or a deoxyuridine), wherein one or more nucleotides in the oligonucleotide outside the central triplet comprises a modification selected from DNA, a 2’-O-alkyl, a 2’-F group or combinations thereof (pages 32-48). ‘973 provides working examples studying different chemical modifications in the oligonucleotide targeting human RNA sequences to increase stability, including 2’-fluoro. The working examples show that a person of ordinary would have engaged in routine experimentation to optimize the stability of the oligonucleotide, including studying 2’-flouro. The specification of the instant disclosure does not appear to disclose that the instant chemical modifications are critical to carrying out the claimed method. See MPEP 2144.05(II) A and B. ’973 also teach that the oligonucleotide can have 2-6 terminal nucleotides linked by phosphorothioate at the 5' and 3' terminus of the oligonucleotides (pages 45-48). The oligonucleotide has at least 20% of the nucleotides on the 5' or 3' end of the central triplet are 2'-O-methyl groups to reduce degradation (pages 32-48). Genetic diseases caused by G to A mutations are preferred diseases because adenosine deamination at the mutated target adenosine will reverse the mutation to a wild-type (pages 21-24).
It would have been prima facie obvious to a person of ordinary skill in the art before the time of the effective filing date to combine the teaching as a simple substitution to use the RNA editing method taught by ‘973 in place of the DNA editing method taught by Bryson to edit the RS1 nucleotide sequence associated with XLRS as taught by Huopaniemi et al., namely to arrive at the claimed invention. See MPEP 2143(I)B or (E). As made obvious by ‘973 (e.g., pages 17-18), one of ordinary skill in the art would have been motivated to combine the teaching to use an ex vivo or an in vivo method to edit the RS1 polynucleotide in a cell, wherein the RS1 polynucleotide comprising a SNP associated with XLRS (RS1 amino acid sequence having a lysine at position 72) and/or treat XLRS in a subject in need thereof. It would have been prima facie obvious to a person of ordinary skill in the art before the time of the effective filing date to combine the teaching of Bryson taken with Huopaniemi et al. to use the antisense oligonucleotides of '973 because they are shorter, which makes them cheaper to produce and easier to use and manufacture (page 9 of ‘973). See MPEP 2143(I)F. '973 teach at least four terminal phosphorothioate linkages and/or at least 20% of the nucleotides of A or B are 2'-O- methyl nucleotides.
Bryson, Huopaniemi et al. and ‘973 do not specifically teach the structure: [Am]-X1-X2-X3-[Bn], wherein A and B are nucleotides; m and n are each independently 5 to 40 nucleotides in length; X1, X2, and X3 are each, independently, a nucleotide, wherein at least one of X1-X2-X3 has the structure of formula I:
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, wherein N1 is hydrogen or a nucleobase; and R1 is hydroxy, halogen, or C1-C6 alkyl.
However, Li teaches that 2'-fluoro-arabinonucleid acid (ANA) analogue displays increased RNA affinity compared to both PS-DNA or DNA (page 4141). "… observed trend for the stability of heteroduplexes between RNA and antisense oligonucleotides (AONs) is as follows: FANA > RNA > DNA > PS-DNA » ANA" (page 4141). ANA have nuclease resistance to serum and cellular nuclease that exceed those by DNA (page 4141). Also Figure 1 below:
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It would have been obvious to one of the ordinary skill in the art before the effective filing date of the claimed invention to modify at least one nucleotide (nucleoside) of the central triplet region of the oligonucleotides taught by Bryson Huopaniemi et al. taken with '973 in further view of the arabino nucleotides (ANA or FANA) taught by Li et al.. One of the ordinary skill in the art would be motivated to combine the teaching because FANA analogue displays increased RNA affinity compared to both DNA and PS-DNA and have nuclease resistance to serum and cellular nucleases that exceed those by DNA as taught by Li et al.
A person of ordinary skill in the art would have possessed the knowledge that ADARs are endogenously expressed in human cells (see pages 1-4 of '973). See also MPEP 2141 II.C. Rationales to support rejections under 35 U.S.C. 103 recites, "Prior art is not limited to the references being applied, but includes the understanding of one of ordinary skill in the art." See MPEP 2141. FACTORS TO CONSIDER IN DETERMINING LEVEL OF ORDINARY SKILL.
'973 teaches at least four terminal phosphorothioate linkages; at least five terminal 2'-O-methyl nucleotides; and/or at least 20% of the nucleotides of A or B are 2'-O-methyl nucleotides (page 45).
Therefore, the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains.
Response to Arguments
Applicant's arguments filed 7/20/26 have been fully considered but they are not persuasive.
To expedite prosecution of the instant application, the Office will address the arguments against the new 103 rejection because the only difference between the 103 rejection in the previous office action and the new 103 rejection is the replacement of Turunen (WO ‘751) with Turunen (WO ‘973). NOTE: it appears that a section of the applicant’s argument are referring to the teaching in WO 2018041973 and not WO2017220751. For example, ‘751 does not recite the statement regarding steric hindrance and 2’F at paragraph 110, but ‘973 does provide that teaching.
In response to applicant’s argument that the rejection is flawed because the teaching of Bryson is directed to editing genomic DNA with an exogenous, engineered Cas9-deaminase fusion protein, not RNA via ADAR as recited in the instant claims and a person of ordinary skill in the art would not have look at a document focused on DNA editing using the CRISPR-Cas9 system for guidance on how to modify antisense oligonucleotides for ADAR RNA editing, the rejection is under 103 and not 102. In addition, pages 2-3 of ‘973 discuss the drawbacks to the CRISPR-Cas system and offer RNA editing using an oligonucleotide sequence as a better alternative to editing a sequence in an eukaryotic cell. The rejection of record provides a reason for why one of ordinary skill in the art would have been motivated as a simple substitution to use an antisense oligonucleotide for ADAR RNA editing taught by ‘973 in place of the DNA editing method taught by Bryson, wherein the method uses a nucleotide sequence encoding a base editor containing a programmable DNA binding domain and an adenosine deaminase domain and one or more guide RNAs that target the based editor to effect an A-T to G-C alteration of the SNP in a gene.
Applicant argues that the Office has not established that a person of ordinary skill in the art would have been motivated to modify at least one nucleotide in the central triplet region of an oligonucleotide in the cited with either ANA or FANA as described by Li et al. (see MPEP 2143.01(IV) and MPEP 2143(A) citing in re Omeprazole Patent Litigation, 536 F.3d, 1361 (Fed. Cir. 2008).
Applicant’s arguments are not found persuasive because the Office provided an objective reason(s) (2’ FANA analogue displays increased RNA affinity and oligonucleotides of '973 are shorter than the composition used in Bryson, which makes the oligonucleotide cheaper to produce and easier to use and manufacture (page 9 of '973). See also MPEP 2143(I)F) to combine the teaching of the references to arrive at the claimed method. This is nothing disclosed in the specification of the instant disclosure regarding a problem or new feature associated with using a 2’ FANA or 2’ ANA in the central triplet region of the oligonucleotide.
Applicant further argues that Li compares FANA’s improved stability to unmodified RNA and DNA and the Office has not established that a person of ordinary skill in the art would have been motivated to introduce FANA into an already modified RNA/DNA. For example, Turunen discloses that oligonucleotides comprising a 2’-F ribosyl moiety and reported that modification provides nuclease protection and is “small enough not to cause steric hindrance with ADAR2”. See paragraph 110. NOTE: it appears that the applicant is referring to the teaching in WO 2018041973 and not WO2017220751 because ‘751 does not recite this statement at paragraph 110.
Applicant’s arguments are not found persuasive because Li et al. teach that 2’ FANA has the highest binding RNA affinity compared to other well-known oligonucleotides used in the prior art. A person of ordinary skill in the art would have been motivated to increase the binding affinity of the central triplet to the targeted region of the human RS1 polynucleotide sequence to improve RNA editing.
In response to applicant’s argument that the Office has not established why Li’s general teaching about FANA’s RNA affinity compared to unmodified RNA/DNA would motivate one of ordinary skill in the art to replace a modification that Turunen already teaches provides a beneficial effect (i.e., nuclease protein), the argument is not found persuasive because Li teaches that FANA has high RNA affinity and nuclease resistance. Turunen teaches that it would have been routine optimization to study different known chemical modifications in the nucleotide(s) in the central region. A person of ordinary skill in the art would have been motivated to study using 2’ FANA in the central repeat to study a possible increase in binding affinity of the central triplet to the targeted region of the human RS1 polynucleotide sequence to improve RNA editing.
Applicant also argues that the Office has not established why one of ordinary skill in the art would select the specific arabinose configuration of formula I from among the various sugar modifications known in the prior art since many sugar modifications may provide stability or affinity benefits and the Office has not explained why one would choose FANA out of the many other possible modifications for the central triplet of the claimed oligonucleotide. This is especially important since one of ordinary skill in the art would have been leery of inserting FANA near or at the orphan position where ADAR editing is occurring. As the Office well knows, an arabinose sugar unity has 2’ substitution in the opposite direction to that of a ribose making the positioning of the 2’ moiety on the same plane as the sugar of the nucleobase. The steric implication would be unknown and certainly unpredictable. The person of ordinary skill in the art would have no reasonable expectation of success that such an orientation would be successful for an ADAR-editing oligonucleotide.
Applicant’s arguments are not found persuasive because in view of the teaching of Li et al. that inserting FANA chemical modification in an oligonucleotide can result in an increase RNA binding affinity to a targeting nucleotide sequence, it would have been obvious for one of ordinary skill in the art to try FANA in the central triplet region of the oligonucleotide taught by ‘973. See MPEP 2143(I)E. Furthermore, Li et al. teach a 2’ fluorine substituent, either the ribo (2’ F RNA) or arabino configuration (FANA) promoters conformational properties that result in significantly higher affinity of 2’-fluoro analogues compared to the corresponding oligonucleotides with a 2’-OH substituent (RNA and ANA, respectively (page 4149). In view of Li et al., it appears that a person of ordinary skill in the art would have had a reasonable expectation of success for using either 2’F or FANA in the oligonucleotide for observing higher RNA affinity. See MPEP 2144.05(II) A and B.
The arguments (one of ordinary skill in the art would have been leery of inserting FANA near or at the orphan position were ADAAR editing is occurring and steric implication would be unknown and certainly unpredictable and a person of ordinary skill in the art would have no reasonable expectation of success that such an orientation would be successful for an ADAR-editing oligonucleotide) are not found persuasive because other than applicant's assertion(s), there is no evidence of record to support applicant's assertion(s). “The arguments of counsel cannot take the place of evidence in the record.” See In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997) (“An assertion of what seems to follow from common experience is just attorney argument and not the kind of factual evidence that is required to rebut a prima facie case of obviousness.”).
Conclusion
See attached PTO-326 for disposition of claims.
The art made of record and not relied upon is considered pertinent to applicant's disclosure. Campbell et al. (ACS Chem. Biol. 2025, 20, 2637-2648) studied using gRNA having 2’FANA modifications in the central triplet region in RNA editing methods.
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/BRIAN WHITEMAN/ Primary Examiner, Art Unit 1636
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