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
Applicant’s election of group I (claims 3, 10, 11, 14-17, 19, 20, 103, 107, 129, 138 and 147) and species (Formula I) in the reply filed on 12/30/25 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)). NOTE: claim 1 is a linking claim.
Claims 103, 107 and 147 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 12/30/25.
Formula II-IV in claim 20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12/30/25.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892 or an IDS, they have not been considered.
Drawings
There are no drawings of record.
Specification
The use of the term “NCBI” and “GENBANK” on page 17, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term. Please review the specification for any other trade name or marks used in commerce.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 3, 10-11, 14-17, 19-20, 28, 129, 138, and 145 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The claimed invention embraces a method of editing a RS1 polynucleotide comprising a SNP associated with X-linked retinoschisis (XLRS) comprising contacting the RS1 polynucleotide in a cell with a guide oligonucleotide capable of altering an adenosine deaminase acting on RNA (ADAR)-mediated deaminase to inosine alteration of the SNP associated with XLRS. XLRS is usually found in juvenile males and rarely in females. See Vijayasarathy et al. (Progress in Retinal and Eye Research 87, pages 1-22, 2023).
The invention embraces a genus of RS1 polynucleotides comprising a SNP associated with XLRS and a genus of guide oligonucleotides capable of effecting an ADAR-mediated adenosine to inosine alteration of the SNP-associated with XLRS, thereby editing the RS1 polynucleotide.
With respect to a genus of RS1 polynucleotides, the genus broadly embraces human, primate, mouse, rat, pig, etc. In addition, the subject embraces males and females, an XLRS is mostly found in males. The specification contemplates the genus and describes human RS1 polynucleotides comprising a SNP associated with XLRS (NM_000330.3, SEQ ID NO: 57). The specification indicates that other RS1 mRNA are readily available using publicly available databases, GenBank, UniProt, and OMIM. Page 17 of the specification discusses the term “RS1” refers to the well-known gene and protein.
There are more than 196 different mutations of the RS1 gene that have been associated with XLRS (Kim et al. Science Opthalmol. 2013, 28, 392-6). Vijayasarathy et al. (supra) teach that there is a wide range genotypic and phenotypic variability with RS1 gene mutations. The missense mutations E72K is the most common mutations in RS1 in western populations. The phenotype varies depending on the mutation. Instant claim 16 and page 44 disclose human RS1 protein having a pathogenic amino acid comprising a lysine at position 72 and/or glutamine at position 102 resulting from the SNP. Page 44 discloses that there are many different SNPs that can influence one’s risk for XLRS. The specification contemplates a method of identifying a subject having an RS1 polynucleotide comprising a SNP associated with XLRS.
The specification only describes human RS1 polynucleotides having a SNP associated with XLRS. A description of human RS1 polynucleotide is not a description of the broad classes of vertebrate or mammalian RS1 polynucleotides. See MPEP 2163, “An invention involving chemical genus requires a written description with a precise definition, such as by structure, formula, or chemical name of the claimed subject matter sufficient to tell it apart from other materials. Regents of Univ. of Cal. v. Eli Lilly & Co., 119 F.3d 1559, 43 U.S.P.Q.2D (BNA) 1398 (Fed. Cir. July 22, 1997).” The prior art of record does not appear to disclose RS1 polynucleotides having a SNP associated with XLRS from other species (e.g., rat, mouse, primate, pig, etc.) were well known. See section 5.2 of Vijayasarathy et al. (supra). In general females who are heterozygous for an RS1 mutation remain asymptomatic and have no clinical features of the condition, although we have recently seen a young girl with the clinical features of XLRS1 and a reduced b‐wave on electroretinogram (Vijaysarathy et al., supra).
Other than human RS1 protein, neither the specification nor the prior art disclose an RS1 protein comprising a pathogenic amino acid comprising a lysine at position 72 and/or a glutamine at position 102 resulting from the SNP. A search of the prior art indicates that a human subject either has one or the other pathogenic amino acid, but not both SNPs. While one of skill in the art can use a method of identifying a subject having an RS1 polynucleotide comprising a SNP associated with XLRS, this does not provide written support for the genus of RS1 polynucleotides because one of skill in the art would have to further experiment with any RS1 polynucleotide to determine if it possesses the desired biological activity. This would indicate to the skilled artisan that the application does not have written support for the genus of RS1 polynucleotides based on an assay for identifying additional RS1 polynucleotides embraced by the claimed invention.
There is a substantial variation within the genus of RS1 polynucleotides and the specification does not describe a sufficient variety of species to reflect the variation within the genus.
In view of the description in the specification and prior art and currently, the claimed method appears to only have written support for human RS1 and rs1048949285 and rs61752068. Thus, it appears that the specification of the instant disclosure only provides written support for human RS1 polynucleotide having the desired function, wherein the polynucleotide encodes an RS1 protein comprising a pathogenic amino acid comprising a lysine at position 72 or a glutamine at position 102 resulting from the SNP.
With respect to a genus of guide oligonucleotides capable of effecting ADAR-mediated adenosine to inosine alteration of the SNP-associated with XLRS, the term ‘capable’ is not an active limitation and does not require that the oligonucleotide actually alter the SNP-associated with XLRS. The specification describes that the oligonucleotide is complementary to a target mRNA sequence, e.g., RS1 comprising the SNP associated with XLRS. The oligonucleotide can further comprise one or more ADAR-recruiting domains. A skilled artisan would possess the knowledge that ADAR is found in all mammalian cells Table 3 discloses oligonucleotides embraced by the claimed method. Table 5 in the specification provides chemically modified guide oligonucleotide targeting human RS1 (E72K).
The prior art of record (Chen et al. Biochemistry 2019, 1947-1957 and WO2018041973, both cited on an IDS) teaches ADAR editing works using a guide RNA to recruit endogenous ADAR to a specific site withing a target RNA, creating a double stranded RNA that is a substrate for ADAR. The efficiency of the guide RNA depends on the sequences surrounding the target adenosine, with ADARs preferring U and G directly flanking the A in the 5’ to 3’ direction.
In view of the prior art it appears that the guide oligonucleotide requires a mismatch at an adenosine of the RS1 mRNA. Pages 131 and 132 appears to disclose that the guide oligonucleotide comprising a central triplet, wherein the center nucleotide is a mismatch with the RS1 sequence. The specification also indicates that mismatches outside the central triplet were generally well tolerated and allowed to improve editing activity (page 132).
In view of the foregoing, it is clear that the specification of the instant disclosure fails to convey to the skilled artisan that the applicant had possession of the claimed genus of RS1 polynucleotides and genus of oligonucleotides that are capable of effecting ADAR-mediated adenosine to inosine alteration of the SNP associated with XLRS in claims 1, 3, 10-11, 14-17, 19-20, 28, 129, 138, 145, and 145 as of the effective filing date.
Claims 1, 3, 10-11, 14-17, 19-20, 28, 129, 138, and 145 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for editing a human RS1 polynucleotide comprising a SNP associated with XLRS comprising contacting the human RS1 polynucleotide in a cell in vitro (ex vivo) or an eye of a subject with a guide oligonucleotide using an ocular route, does not reasonably provide enablement for using any route of administration to contact a RS1 polynucleotides in a genus of cells. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The claimed invention embraces editing an RS1 polynucleotide comprising a SNP associated with XLRS comprising contacting the RS1 polynucleotide with a guide oligonucleotide capable of effecting an ADAR-mediated adenosine to inosine. The method is used to treat XLRS in a subject in need thereof using an ex vivo or in vivo method. The method also reads on contacting cells in vitro.
The prior art of record (WO2018041973; Chen et al. (supra); and Merkle et al. (Nat Biotechnol. 2019, 37:133-138), all cited on an IDS) teaches that RNA editing using ADAR can be used in vivo and in vitro for treating some genetic diseases in a subject in need thereof. Also see Zhang et al. Trends in Biotechnology 42, 2024, pages 1439-1452. ADAR editing works using a guide RNA to recruit endogenous ADAR to a specific site withing a target RNA, creating a double stranded RNA that is a substrate for ADAR. The efficiency of the guide RNA depends on the sequences surrounding the target adenosine, with ADARs preferring U and G directly flanking the A in the 5’ to 3’ direction. In view of the prior art it appears that the guide oligonucleotide requires a mismatch at an adenosine of the RS1 mRNA. Pages 131 and 132 of the as-field specification appear to teach that the guide oligonucleotide comprising a central triplet, wherein the center nucleotide is a mismatch with the RS1 sequence. The specification also indicates that mismatches outside the central triplet were generally well tolerated and allowed to improve editing activity (page 132).
The specification does not provide a working example of the method in a subject or treating RS1 in a subject. Table 5 of the specification teaches ADAR mediating guide oligonucleotide targeted RS1 (E72K). Page 44 of the specification show that SNP, rs104894928 and rs104894928 were converted by ADAR, thereby removing the pathogenic or disease causing mutation in RS1 protein.
The claimed invention embraces contacting a RS1 polynucleotide associated with XLRS in a genus of subjects. The specification contemplates the method, but does not teach contacting a subject having XLRS. The specification appears to provide enablement for editing two SNPs (rs104894928 and rs104894928) in cell lines.
The specification does not teach any other species having a RS1 polynucleotide associated with XLRS. In general females who are heterozygous for an RS1 mutation remain asymptomatic and have no clinical features of the condition, although we have recently seen a young girl with the clinical features of XLRS1 and a reduced b‐wave on electroretinogram (Vijayasarathy et al., supra). A search of the prior art does not result in other animals having either of these SNPs. The art of record does not appear to teach that other species having a RS1 polynucleotide having a SNP associated with XLRS was well-known to a skilled artisan. See Vijayasarathy et al. (supra). A search of the prior art indicates that a human subject either has one or the other pathogenic amino acid set forth in instant claim 16, but not both SNPs. Thus, it appears the specification is only enabled for editing two human SNPs (rs104894928 and rs104894928) in a cell using a guide oligonucleotide comprising a sequence that is complementary to human RS1 polynucleotide encoding a lysine at position 72 and/or a glutamine at position 102 resulting from the SNP. In view of the prior art, the method can be used to treat XLRS in a human subject.
With respect to the claimed invention embracing any route of administration to contact the RS1 polynucleotide, the specification contemplates any administration route for contacting the RS1. The RS1 gene transcript is highly abundant only in retina indicating cell-specific expression. Since the RS1 polynucleotide associated with XLRS is in the eye of a subject having XLRS, it would require a route for successfully delivery of the guide oligonucleotide to the eye. One of skill in the art could use ex vivo therapy to treat the subject since a skilled artisan can contact a cell ex vivo and deliver the cell to an eye of the subject in need thereof. See Vijayasarathy et al. (supra). However, neither the specification nor the prior art of record teach that a genus of administration routes for contacting a RS1 polynucleotide sequence was considered enabled. The art teaches that delivery to the eye is challenging due to its “immune privileged” status as part of the central nervous system and intricate ocular barriers that isolate it from the systemic circulation, posing significant challenges in treating ocular disease (Zhang et al. Trends in Biotechnology 42, 2024, pages 1439-1452).
Thus, it appears the specification is only enabled for ocular administration of the oligonucleotide to the subject.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 10, 11, and 14-17 are rejected under 35 U.S.C. 103 as being unpatentable over Bryson (WO2019217943, published 11/14/19 and EFD 5/11/18) taken with Huopaniemi et al. (Europ. J. Hum. Genet. 7: 368-376, 1999).
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 correction of pathogenic amino acids in a protein associated with a disease or disorder 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 the RNA editing for editing 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).
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 of the RNA 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. As made obvious by Bryson (e.g., page 212), 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.
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, and 14-17 are rejected under 35 U.S.C. 103 as being unpatentable over Bryson (WO2019217943, published 11/14/19 and EFD 5/11/18) taken with Saldana et al. (Am. J. Med. Genet. 143A: 608-609, 2007).
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 correction of pathogenic amino acids in a protein associated with a disease or disorder 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 disease associated RS1, wherein the R102W or R141C are changed and use an ABE (Table 3B).
Bryson 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, Saldana teaches mutations of the RS1 gene in humans causes XLRS. Saldana identified a heterozygous mutation in the RS1 gene, resulting in an arg102-to-gln (R102Q) substitution in the discoidin domain likely to interfere with retinoschisin secretion (page 608). “She had retinal pigmentary epithelial changes in both maculae and bilateral peripheral schisis associated with bridging vessels and vitreous veils (page 608).” “Her father, who also had the mutation, had a longstanding history of poor vision and ocular features consistent with retinoschisis (page 608).”
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 edit the RS1 nucleotide sequence associated with XLRS as taught by Saldana. As made obvious by Bryson (e.g., page 212), 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 a RS1 polynucleotide in a cell, wherein the RS1 polynucleotide comprising a SNP associated with XLRS (R102Q) and/or treat XLRS in a subject in need thereof.
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 3, 19, 129, and 138 are rejected under 35 U.S.C. 103 as being unpatentable over Bryson and either Huopaniemi et al. or Saldana et al. as applied to claims 1, 10, 11, and 14-17 above, and further in view of Turunen et al. (WO2017220751).
Bryson and either Huopaniemi et al. or Saldana et al. 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.
In addition, Bryson and Huopaniemi et al. or Saldana do not specifically teach a cell endogenously expresses ADAR.
However, a person of ordinary skill in the art would possess the knowledge that ADARs are endogenously expressed in human cells (see pages 18-22 of ‘751). 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. Furthermore, ‘751 teaches making and using single stranded RNA-editing oligonucleotides, wherein the oligonucleotide is 18 to 50 nucleotides or no longer than 10-17 nucleotides (pages 1-50). 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 10-11). 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 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 4, 31-42 and 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 (page 25).
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 either Huopaniemi et al. or Saldana et al. to use the antisense oligonucleotides of ‘751 because they are shorter, which makes them cheaper to produce and easier to use and manufacture (page 9 of ‘751). See MPEP 2143(I)F. ‘751 teach at least four terminal phosphorothioate linkages and/or at least 20% of the nucleotides of A or B are 2’-O-methyl nucleotides.
It would have been prima facie obvious to a person of ordinary skill in the art before the time of the effective filing date in view of ‘751, to possess the knowledge that human cells endogenously expressed ADAR and can be used to assist in the editing step.
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 20, 28, and 145 are rejected under 35 U.S.C. 103 as being unpatentable over Bryson and either Huopaniemi et al. or Saldana et al. and ‘751 as applied to claims 3, 19, 129, and 138 above, and further in view of Li et al. (Biochemistry 45, pages 4141-4152, 2006).
Bryson and Huopaniemi et al. or Saldana et al. and ‘751 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 the X1, X2, or X3 has the structure of formula I:
PNG
media_image1.png
151
145
media_image1.png
Greyscale
, wherein N1 is hydrogen or a nucleobase; and R1 is hydroxy, halogen, or C1-C6 alkyl.
However, Li teaches that 2'-fluoro-arabinonucleic 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:
PNG
media_image2.png
622
724
media_image2.png
Greyscale
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 either Huopaniemi et al. or Saldana et al. taken with ‘751 in further view of the arabino nucleotides (ANA or FANA) taught by Li et al., namely to arrive at instant invention. 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. ‘751 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.
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.
Conclusion
See attached PTO-326 for disposition of claims.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Brian Whiteman whose telephone number is (571)272-0764. The examiner can normally be reached on Monday thru Friday; 6:00 AM to 3:00PM.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Neil Hammell can be reached at (571)-270-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/BRIAN WHITEMAN/ Primary Examiner, Art Unit 1636