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 .
This is a Track One application.
Claims 67-86 are pending.
Status of the Application
Applicant’s response and amendment filed 16 April 2026 are acknowledged and entered.
Applicant has not amended, canceled, or added any claims.
Response to Amendment
Applicant has argued the 103 rejection; the 103 rejection is maintained.
Applicant has argued the NSDP rejections; the NSDP rejections are maintained.
Claims 67-86 are examined.
Arguments applicable to newly applied rejections to amended or newly presented claims are addressed below. Arguments that are no longer relevant are not addressed.
Rejections not reiterated here are withdrawn.
Priority
Acknowledgment is made of applicant's claim for foreign priority based on an application filed in EU on 15 August 2023. It is noted, however, that applicant has not filed a certified copy of the EP2023/072474 application as required by 37 CFR 1.55.
Note that on 24 October 2025, an attempt by the Office to electronically retrieve, under the priority document exchange program, the foreign priority application was made but failed.
Information Disclosure Statement
The IDS has been considered.
Claim Interpretation
Claim 67 recites a methanesulfonyl (mesyl) internucleoside linkage. The Spec. clarifies (¶30) that mesyl linkages are also called mesyl phosphoramidate linkages. Therefore those three terms (i.e., “mesyl phosphoramidate”, “mesyl”, and “methanesulfonyl”) are interpreted as all referring to the same chemical structure.
Claim 68 recites that the chemically modified oligo comprises at least one wobble base with respect to the target sequence. That is interpreted as meaning that the chemically modified oligo comprises a mismatch (vs. perfect complementarity) to the target sequence.
Claim 77 recites that the modified oligo compris[es] the nucleobase sequence of SEQ ID NO 192. In that context, the term nucleobase sequence is interpreted to refer strictly to the nitrogenous base sequence, not the whole nucleotide. Therefore the full modification and inter-nt linkage pattern shown in the Spec. for SEQ ID NO 192 is not required by the claim.
REJECTIONS REITERATED FROM OFFICE ACTION DATED 16 JANUARY 2026
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.
Claim(s) 67-86 are rejected under 35 U.S.C. 103 as being unpatentable over International Application Publication Number WO 2024/114908 (published on 06 June 2024 but effectively filed on 30 November 2022, “WO908”, of record) in view of Patutina (et al. 2020. Mesyl phosphoramidate backbone modified antisense oligonucleotides targeting miR-21 with enhanced in vivo therapeutic potency. PNAS 117[51]:32370–32379, “Patutina”, of record), International Application Publication Number WO 2024/013361 (published on 18 January 2024 but effectively filed on at least 14 July 2023, “WO361”, of record), and International Application Publication Number WO 2024/200278 (published on 03 October 2024 but effectively filed on 24 March 2023, “WO278”, of record on IDS). This rejection is maintained and edited to correct a typographical error in one sentence.
Although WO908 was published 06 June 2024, the content relied upon for this rejection was effectively filed on 30 November 2022, which is approximately 8.5 months before the earliest document of the instant application. The WO908 content discussed in this rejection are entitled to the priority date of 30 November 2022 and are considered prior art under 35 U.S.C. 102(a)(2).
Although WO361 was published 18 January 2024, the content relied upon for this rejection was effectively filed on at least 14 July 2023, which is approx. 1 month before the earliest provisional document of the instant application. The WO361 content discussed in this rejection are entitled to the priority date of at least 14 July 2023and are considered prior art under 35 U.S.C. 102(a)(2).
Although WO278 was published 03 October 2024, the content relied upon for this rejection was effectively filed on at least 24 March 2023, which is approx. 4.5 months before the earliest provisional document of the instant application. The WO278 content discussed in this rejection are entitled to the priority date of at least 24 March 2023and are considered prior art under 35 U.S.C. 102(a)(2).
If the issue date of the U.S. patent or publication date of the U.S. patent application publication or WIPO published application is not before the effective filing date of the claimed invention, it may be applicable as prior art under AIA 35 U.S.C. 102(a)(2) if it was "effectively filed" before the effective filing date of the claimed invention in question with respect to the subject matter relied upon to reject the claim. MPEP § 2152.01 discusses the "effective filing date" of a claimed invention. AIA 35 U.S.C. 102(d) sets forth the criteria to determine when subject matter described in a U.S. patent document was "effectively filed" for purposes of AIA 35 U.S.C. 102(a)(2).
2154.01(a) WIPO Published Applications [R-11.2013]
[Editor Note: This MPEP section is only applicable to applications subject to examination under the first inventor to file (FITF) provisions of the AIA as set forth in 35 U.S.C. 100 (note). See MPEP § 2159 et seq. to determine whether an application is subject to examination under the FITF provisions, and MPEP § 2131-MPEP § 2138 for examination of applications subject to pre-AIA 35 U.S.C. 102.]
The WIPO publication of a PCT international application that designates the United States is an application for patent deemed published under 35 U.S.C. 122(b) for purposes of AIA 35 U.S.C. 102(a)(2) under 35 U.S.C. 374. Thus, under the AIA , WIPO publications of PCT applications that designate the United States are treated as U.S. patent application publications for prior art purposes, regardless of the international filing date, whether they are published in English, or whether the PCT international application enters the national stage in the United States. Accordingly, a U.S. patent, a U.S. patent application publication, or a WIPO published application that names another inventor and was effectively filed before the effective filing date of the claimed invention, is prior art under AIA 35 U.S.C. 102(a)(2). This differs from the treatment of a WIPO published application under pre-AIA 35 U.S.C. 102(e), where a WIPO published application is treated as a U.S. patent application publication only if the PCT application was filed on or after November 29, 2000, designated the United States, and is published under PCT Article 21(2) in the English language. See MPEP § 2136.03, subsection II.
§MPEP 2154.01
See also §MPEP 2152.01.
Notes: the p. # in references to WO documents refers to the PDF p. #. The terms ASO and AON are used interchangeably.
WO908 teaches a chemically modified oligont for editing A[Wingdings font/0xE0]I in RNA. WO908 explicitly teaches or makes obvious all the limitations of the claimed invention, aside from the mesyl internucleoside (inter-nt) linkage.
Regarding Claim 1: WO908 teaches (¶15) a chemically modified ASO that comprises specific nucleoside modifications, specifically sugar and inter-nt linkages modifications. WO908 teaches (¶18) their ASO comprises a central base triplet [CBT] of 3 nt (5’-N-1eN0fN+1g-3’) wherein the central nucleotide N0 is directly opposite the target adenosine in the target RNA. WO908 teaches (¶166) the invention can be used to treat a disease that can benefit from an A[Wingdings font/0xE0]I conversion and explicitly teaches treating (¶148) A1AT deficiency and the SERPINA E342K mutation. WO908 teaches (¶95) the ASO can be 23-40 or exactly 34 nt long.
WO908 teaches (¶18) a position numbering scheme wherein nt 5’ of the CBT are numbered N-5, N-4…N-1, wherein the central nt (N0) is directly opposite to the target adenosine in the target RNA, and nt 3’ of the CBT are numbered N+2, N+3. That numbering scheme is the opposite of what is instantly claimed (wherein nt 5’ of the CBT are numbered “+” and nt 3’ of the CBT are numbered “-“), but a different numbering scheme does not alter the actual physical structure of the claimed ASO.
Regarding modified nt, WO908 teaches (¶87) nts can be modified with a mixture of modified inter-nt linkages, 2’-O-alkyl modifications (which [¶67] include 2’-OMe and 2’-MOE mods) and 2’F modifications. WO908 teaches (¶86) a mixture of 2’-F and 2’-O-alkyl modifications is beneficial and that a minimum of 10% of each is desirable. WO908 teaches (¶109) 2’-MOE mods reduce toxicity without affecting overall editing yield and the best number of MOEs to include is 6, 7, or 8. WO908 teaches (¶86) at least two of the three nt in the CBT should comprise a 2’-modified sugar or be DNA, or a comprise a combination thereof and that (¶87) the N+2 nt should have a 2’-O-alkyl mod, and the N+3 nt should have a 2’-F mod. As described, the WO908 numbering scheme is different from the instantly claimed numbering scheme: WO908’s N+2 corresponds to what is claimed as the -2 position, and N+3 corresponds to the -3 position. WO908 teaches (¶182, Table 1, e.g., V117.42) embodiments wherein each nt is a DNA, a 2’-O-alkyl, or a 2’-F-modified nt.
WO908 teaches (¶86) having at least 15% modified linkages on an ASO is beneficial to achieve good RNA editing and (¶94) the number of linkage modifications can comprise 15-90%. WO908 teaches PS linkages have a positive effect on pharmacokinetics and stability, protein binding, and intracellular localization of ASO, but that it is desirable to reduce overall PS content to reduce toxicity and nonspecific protein binding. Those teachings would have indicated to an artisan that it is necessary to balance the proportion of PS/nonPS linkages to optimize stability and pharmacokinetics while minimizing toxicity and nonspecific effects.
WO908 teaches (¶64) inter-nt linkages such as PS can be stereorandom or chirally controlled (“stereopure”) and that (¶8) the different stereoisomers are hypothesized to influence ASO properties, but that notion is controversial. WO908 teaches (¶105) their invention relates to stereorandom PS-modified ASOs, which are generally easier and cheap in their production and they have found stereopure linkages are not necessary for efficient RNA editing.
WO908 teaches (¶127, Table A) a few different preferred asymmetries; those include 25-3-5 and 28-3-9 (5’terminus–CBT–3’terminus) asymmetrical patterns for targeting SERPINA, which are very close to the claimed 25-1-8 asymmetry.
Regarding asymmetry, WO908 teaches (¶217-219) different asymmetries and different length ASO can affect editing efficacy, but ultimately (¶219) a 24- or 25-mer 5’terminus + a 5-mer 3’terminus is particularly effective. Note that a 5-mer 3’terminus is, in terms of the claimed invention, actually a 7-mer 3’terminus because WO908 does not include 2 nt within the 3-mer CBT as part of the 3’terminus.
WO908 teaches (¶12) it is common to optimize an ASO by modifying the nt that comprise the CBT and the nt around the CBT.
Regarding Claim 68: WO908 teaches (¶69)perfect complementarity between the ASO and its target is not required and one or more wobbles or mismatches may be within or outside the CBT. Therefore WO908 teaches limitations of Claim 68.
Regarding Claims 69-70: WO908 teaches (¶92) embodiments wherein 20-70% of nt are 2’-F modified. 20-70% 2’-F encompasses at least 20% and 20-30% 2’-F modifications. WO908 teaches (¶92) embodiments wherein 20-60% or 25-55% of nt are 2’-OMe modified. Therefore WO908 teaches limitations of Claims 69-70.
Regarding Claims 71-72, WO908 teaches (¶225) using a combination of chemical modifications to optimize editing efficacy and stability.
Regarding Claim 73: WO908 teaches (¶124) in some embodiments there are no more than 3-8 consecutive inter-nt linkage modifications. WO908 teaches (¶102) oligos comprising no more than 4 consecutive nt that are 2’-F modified and no more than 4-6 consecutive nt that are 2’-O-alkyl modified. WO908 teaches (¶220) their data show that blocks of continuous sugar modifications should be avoided and to obtain efficient editing yields: uniform 2’-modification blocks [should] not exceed 6 nt or even 3 nt. No more than 3-6 continuous 2’-F or 2’-OMe modifications encompasses no more than 4 continuous 2’-F or 2’-OMe modifications. Therefore WO908 teaches some limitations of Claim 73.
Regarding Claim 74, WO908 teaches (¶98) limiting the number of DNA nt outside of the CBT, and teaches the regions outside of the CBT have no more than 1-4 DNA bases or those regions comprise a total DNA content of 5-50%. Those teachings encompass no more than 6% of nt outside the CBT being DNA.
Regarding Claim 75, WO908 teaches (¶259, Table 19, e.g., V117.109) a SERPINA-targeting 40-mer ASO that comprises PS linkages at positions -1, 0, and +4. Those correspond to claimed positions +1, 0, and -4. That ASO is shown in a modified excerpt of the table here:
PNG
media_image1.png
252
787
media_image1.png
Greyscale
WO908 teaches (¶215, Table 9 and ¶221, Table 10) SERPINA-targeting 34- and 33-mers comprising PS linkages at those same positions, as shown in the following modified excerpts of those tables:
PNG
media_image2.png
196
837
media_image2.png
Greyscale
PNG
media_image3.png
205
795
media_image3.png
Greyscale
The 3-mer CBT is shown underlined in each of those sequences.
Regarding Claim 76, WO908 teaches (¶63) natural PO linkages can be replaced by modified linkages. That indicates that natural linkages are the default, in which case all of the positions specified in Claim 76 would be natural (PO) linkages.
Regarding Claim 77, WO908 teaches SEQ ID NOs 128 and 147 which comprise identical nucleobase sequences and which comprise 100% identity to claimed SEQ ID NO 192. An alignment of WO908 SEQ ID NO 147 to claimed SEQ ID NO 192 is shown here, and an alignment showing WO908 SEQ ID NOs 128 and 147 are identical is shown below that:
BPL44237
ID BPL44237 standard; RNA; 40 BP.
XX
AC BPL44237;
XX
DT 01-AUG-2024 (first entry)
XX
DE SERPINA1 E342K targeting ASO V117.54, SEQ ID 147.
XX
KW Alpha 1 antitrypsin; DNA-RNA hybrid; SERPINA1 gene; achondroplasia;
KW age related macular degeneration; alpha-1 antitrypsin deficiency;
KW alzheimers disease; antiallergic; antiasthmatic; antiinflammatory;
KW antiparkinsonian; antisense oligonucleotide; asthma; beta thalassemia;
KW charcot marie tooth disease; chronic obstructive pulmonary disease;
KW cystic fibrosis; cytostatic; dermatological; dermatological disease;
KW gastrointestinal disease; gastrointestinal-gen.; genetic disorder;
KW genetic-disease-gen.; growth disorder; growth-disorder-gen.;
KW hematological-gen.; hepatotropic; hurler syndrome; motor neurone disease;
KW musculoskeletal disease; musculoskeletal-gen.; neoplasm;
KW neurological disease; neuroprotective; nootropic; ocular disease;
KW ophthalmological; parkinsons disease; pharmaceutical; phosphorothioate;
KW prophylactic to disease; respiratory-gen.; ss; stargardt disease;
KW therapeutic.
XX
OS Homo sapiens.
OS Synthetic.
XX
FH Key Location/Qualifiers
FT modified_base 1..40
FT /*tag= a
FT /mod_base= OTHER
FT /note= "OTHER = phosphorothioate linkage"
FT modified_base 1..3
FT /*tag= b
FT /mod_base= OTHER
FT /note= "OTHER = 2'-O-methyl"
FT modified_base 6
FT /*tag= c
FT /mod_base= OTHER
FT /note= "OTHER = 2'-fluoro"
FT modified_base 7
FT /*tag= d
FT /mod_base= OTHER
FT /note= "OTHER = 2'-O-methyl"
FT modified_base 8
FT /*tag= e
FT /mod_base= OTHER
FT /note= "OTHER = 2'-fluoro"
FT modified_base 9
FT /*tag= f
FT /mod_base= OTHER
FT /note= "OTHER = 2'-O-methyl"
FT modified_base 12
FT /*tag= g
FT /mod_base= OTHER
FT /note= "OTHER = 2'-fluoro"
FT modified_base 15
FT /*tag= h
FT /mod_base= OTHER
FT /note= "OTHER = 2'-O-methyl"
FT modified_base 16
FT /*tag= i
FT /mod_base= OTHER
FT /note= "OTHER = 2'-fluoro"
FT modified_base 17
FT /*tag= j
FT /mod_base= OTHER
FT /note= "OTHER = 2'-O-methyl"
FT modified_base 18
FT /*tag= k
FT /mod_base= OTHER
FT /note= "OTHER = 2'-fluoro"
FT modified_base 21
FT /*tag= l
FT /mod_base= OTHER
FT /note= "OTHER = 2'-O-methyl"
FT modified_base 22
FT /*tag= m
FT /mod_base= OTHER
FT /note= "OTHER = 2'-fluoro"
FT modified_base 23
FT /*tag= n
FT /mod_base= OTHER
FT /note= "OTHER = 2'-O-methyl"
FT modified_base 24
FT /*tag= o
FT /mod_base= OTHER
FT /note= "OTHER = 2'-fluoro"
FT modified_base 25
FT /*tag= p
FT /mod_base= OTHER
FT /note= "OTHER = 2'-O-methyl"
FT modified_base 26
FT /*tag= q
FT /mod_base= OTHER
FT /note= "OTHER = 2'-fluoro"
FT modified_base 27
FT /*tag= r
FT /mod_base= OTHER
FT /note= "OTHER = 2'-O-methyl"
FT modified_base 28
FT /*tag= s
FT /mod_base= OTHER
FT /note= "OTHER = 2'-fluoro"
FT misc_feature 29..31
FT /*tag= t
FT /label= misc_DNA
FT /note= "deoxyribo nucleotide"
FT modified_base 31
FT /*tag= u
FT /mod_base= i
FT modified_base 32
FT /*tag= v
FT /mod_base= OTHER
FT /note= "OTHER = 2'-O-methyl"
FT modified_base 33
FT /*tag= w
FT /mod_base= OTHER
FT /note= "OTHER = 2'-fluoro"
FT modified_base 36
FT /*tag= x
FT /mod_base= OTHER
FT /note= "OTHER = 2'-O-methyl"
FT modified_base 39
FT /*tag= y
FT /mod_base= OTHER
FT /note= "OTHER = 2'-fluoro"
FT modified_base 40
FT /*tag= z
FT /mod_base= OTHER
FT /note= "OTHER = 2'-O-methyl"
XX
CC PN WO2024114908-A1.
XX
CC PD 06-JUN-2024.
XX
CC PF 30-NOV-2022; 2022WO-EP083943.
XX
PR 30-NOV-2022; 2022WO-EP083943.
XX
CC PA (UTEK ) UNIV TUEBINGEN EBERHARD-KARLS.
XX
CC PI Stafforst T, Pfeiffer LS, Latifi N;
XX
DR WPI; 2024-59485B/054.
XX
CC PT New chemically modified oligonucleotide capable of binding to target
CC PT sequence in target RNA useful in pharmaceutical composition for e.g.
CC PT treating or preventing genetic disorder, condition, or disease e.g.
CC PT retinitis pigmentosa.
XX
CC PS Example 19; SEQ ID NO 147; 139pp; English.
XX
CC The invention relates to a novel a chemically modified oligonucleotide,
CC useful in pharmaceutical composition for treating or preventing genetic
CC disorder. The invention further claims: 1) an in vitro method for editing
CC a target adenosine in a target nucleic acid involves contacting the
CC target nucleic acid with the oligonucleotide; and 2) an in vitro method
CC for deaminating at least one specific adenosine present in a target RNA
CC sequence in a cell. The chemically modified oligonucleotide is useful in
CC a pharmaceutical composition for treating or preventing a genetic
CC disorder, condition or disease such as Retinitis pigmentosa (RP),
CC Stargardt macular degeneration, age-related macular degeneration (AMD),
CC Cystic fibrosis (CF), Hurler Syndrome, alpha-1 -antitrypsin (A1AT)
CC deficiency, Parkinson's disease, Alzheimer's disease, albinism,
CC Amyotrophic lateral sclerosis, Asthma, p-thalassemia, Cadasil syndrome,
CC Charcot-Marie Tooth disease, Chronic Obstructive Pulmonary Disease
CC (COPD), Distal Spinal Muscular Atrophy (DSMA), Duchenne/Becker muscular
CC dystrophy, Dystrophic Epidermolysis bullosa, Epidermolysis bullosa, Fabry
CC disease, Factor V Leiden associated disorders, Familial Adenomatous,
CC Polyposis, Galactosemia, Gaucher's Disease, Glucose-6-phosphate
CC dehydrogenase, Haemophilia, Hereditary Hematochromatosis, Hunter
CC Syndrome, Huntington's disease, Inflammatory Bowel Disease (IBD),
CC Inherited polyagglutination syndrome, Leber congenital amaurosis (LCA),
CC Lesch-Nyhan syndrome, Lynch syndrome, Marfan syndrome,
CC Mucopolysaccharidosis, Muscular Dystrophy, Myotonic dystrophy types I and
CC II, neurofibromatosis, Niemann-Pick disease type A, B and C, NY-eso1
CC related cancer, Peutz-Jeghers Syndrome, Phenylketonuria, Pompe's disease,
CC Primary Ciliary Disease, Prothrombin mutation related disorders. The
CC chemically modified oligonucleotide has an increased lysosomal half-life
CC such as improved lysosomal stability, and facilitates ease of production.
XX
SQ Sequence 40 BP; 5 A; 15 C; 8 G; 4 T; 7 U; 1 Other;
Query Match 100.0%; Score 34; Length 40;
Best Local Similarity 82.4%;
Matches 28; Conservative 6; Mismatches 0; Indels 0; Gaps 0;
Qy 1 GCCCCAGCAGCTTCAGTCCCTTTCTCNTCGATGG 34 SEQ ID NO 192
|||||||||||::|||:|||:::|||||||||||
Db 5 GCCCCAGCAGCUUCAGUCCCUUUCTCNTCGATGG 38 WO908 SEQ ID NO 147
US-18-565-415-128
Query Match 100.0%; Score 39; DB 1; Length 40;
Best Local Similarity 100.0%;
Matches 40; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 CATGGCCCCAGCAGCTTCAGTCCCTTTCTCNTCGATGGTC 40 WO908 SEQ ID NO 128
||||||||||||||||||||||||||||||||||||||||
Db 1 CATGGCCCCAGCAGCTTCAGTCCCTTTCTCNTCGATGGTC 40 WO908 SEQ ID NO 147
Since WO908 teaches ASOs of various lengths and shows changing the exact nucleobase sequence and modification pattern to optimize editing efficacy and ASO stability, it would have been obvious to use modified versions of SEQ ID NO 128 that comprise shorter sequences and different modification patterns.
Regarding Claim 78, WO908 teaches (¶10) ASOs that specifically edit adenosines in target RNA and which do not form a hairpin or stem loop. WO908 teaches (¶131) embodiments of their invention wherein the ASO does not comprise a loop-hairpin structured ADAR recruitment motif. Therefore WO908 teaches limitations of Claim 78.
Regarding Claims 79-81, WO908 teaches (¶136) a GalNAc that is preferably conjugated to the 3’terminus of the ASO to enhance cellular uptake.
Regarding Claim 82, WO908 teaches (¶21) a pharmaceutical composition comprising the ASO or a pharmaceutically acceptable salt thereof.
Regarding Claims 83-86, WO908 teaches (¶161) subcutaneous administration of an ASO of the invention for (¶162-166) beneficial editing of an RNA when a subject or patient can benefit from an A[Wingdings font/0xE0]I conversion, such as (¶148) A1AT deficiency. WO908 teaches (¶82) the patient can be a human patient.
Altogether, WO908 teaches: using all of the modifications claimed, a sequence that comprises the exact same nucleobase sequence as claimed SEQ ID NO 192, and reasons for modifying sequence length and modifying the nt and inter-nt linkage modification patterns.
WO908 does not teach any mesyl linkages.
However, Patutina, drawn to therapeutic antisense oligonucleotides comprising a modified mesyl phosphoramidate backbone, teaches about (§Abstract) a new kind of backbone linkage, namely mesyl phosphoramidate (or “µ”) that demonstrates high affinity to RNA and exceptional nuclease resistance. Patutina teaches (§Main text ¶3) it is common to produce mixmers that combine in one structure several modifications to improve clinical performance of oligos. Patutina teaches (§Main text ¶4) DNA oligos comprising a few mesyl groups in the backbone showed improved RNA binding and mesyl oligos demonstrate high affinity to RNA and exceptional resistance to nucleases.
Patutina does not teach using mesyl inter-nt linkages in editing ASOs.
However, WO361, drawn to oligont (“AON”) for ADAR-mediated RNA editing and uses thereof, teaches using mesyl linkages in their editing oligos. WO361 teaches (p. 16 L15-21) their AON can comprise modified internucleoside (inter-nt) linkages including mesyl phosphoramidate and that (p. 19 L30-35) in some embodiments the AON comprises at least one mesyl linkage.
WO361 teaches (p. 25 L12-15) their editing AONs can be used to treat A1AT deficiency which (p. 15 L5) can be caused by mutations in the SERPINA1 gene.
WO278 is drawn to chemically modified antisense oligonucleotides comprising a mesyl phosphoramidate (called in WO278 “PNms”) for use in ADAR-mediated RNA editing. WO278 is broadly directed to AONs for use in ADAR editing (see §Abstract), so an artisan would have recognized that their teachings are widely applicable to AONs/ASOs for use in ADAR editing of any target. WO278 teaches (pp. 5-6 L27-7) an AON that mediates adenosine deamination… wherein the AON comprises one or more linkage modifications with a structure according to formula (I), shown in this modified excerpt:
PNG
media_image4.png
389
760
media_image4.png
Greyscale
WO278 teaches (p. 7 L1-7) a linkage numbering scheme that is the same as the claimed invention and wherein the AON comprises mesyl linkages at the linkage connecting the 5’ and 3’ terminal nucleosides and at linkage position -2:
…an AON, wherein the nucleotide that is directly opposite the target adenosine is the orphan nucleotide, wherein the internucleoside linkage numbering is such that linkage number 0 is the linkage 5’ from the orphan nucleotide, the linkage positions in the oligonucleotide are positively (+) incremented towards the 5’ end and negatively (-) incremented towards the 3’ end, and wherein the linkage modification according to formula (I) is present at: linkage position -2; at the linkage position connecting the 5’ terminal two nucleosides in the AON; and/or at the linkage position connecting the 3’ terminal nucleosides in the AON. [emphasis added.]
That passage indicates that WO278 recommended placing a mesyl at inter-nt linkage position -2 and between nts at the 5’ and 3’ terminal ends. WO278 also teaches (p. 19 L21-22) an AON that is 34 nt long. Together, those passages indicate that it was known in the art to place mesyl linkages between nts at what is claimed as linkage positions +24 and -8 (i.e., between nts at the 5’ and 3’ terminal ends) as well as position -2.
WO278 shows (Fig. 2) AONs comprising mesyl linkage(s) exhibit much higher stability than AONs lacking a mesyl linkage. WO278 discusses (pp. 8-9 L16-5) modifying AONs (including inter-nt linkages) to improve their pharmacokinetic properties. To that end, data in WO278 demonstrate that performing a “mesyl walk” on an ASO used for RNA editing—wherein each linkage within the ASO is systematically replaced with a mesyl linkage—is routine and conventional. WO278 Fig. 4 shows walking the position of the mesyl linkage to each position within the AON and (Figs. 1 and 3) some of the resulting AONs edit the target more effectively than others. WO278 also shows (Fig. 4) AONs comprising multiple mesyl linkages.
As discussed above, WO908 teaches (¶8) modifying inter-nt linkages within their ASOs to improve their properties by protecting them against nucleases and increasing their effectiveness and (¶95) modifying ASO length because of benefits and/or tradeoffs that occur with both shorter and longer ASOs.
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the chemically modified oligo of WO908 with the mesyl inter-nt linkage of Patutina and WO361 and the mesyl linkages at different positions and mesyl walk of WO278 for the benefit of improving nuclease resistance of an editing ASO. One would have been motivated to do so with a reasonable expectation of success because Patutina teaches the mesyl inter-nt linkages exhibits exceptional nuclease resistance and because WO361 teaches the mesyl inter-nt linkage can be incorporated into an ASO editor for remediating a mutation in the SERPINA1 gene. One would have been motivated to do so with a reasonable expectation of success because WO278 specifically teaches placing mesyls at the linkages between the nts at the 5’ and 3’ ends and at position -2 from the target to be edited and allows for including more mesyl linkages. One would have been motivated to do so with a reasonable expectation of success because WO908 teaches (¶8) modifying inter-nt linkages within their ASOs to improve their properties by protecting them against nucleases and increasing their effectiveness and because WO278 discusses (pp. 8-9 L16-5) modifying inter-nt linkages within AONs to improve their pharmacokinetic properties. One would have been motivated to modify the length of the WO908 ASO because WO908 teaches (¶95) benefits and costs of both shorter and longer ASOs and teaches their ASOs may be of varying lengths.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the chemically modified oligo of WO908 with the mesyl inter-nt linkage (including mesyl linkages between nts at the 5’ and 3’ terminal ends and at position -2) of Patutina, WO361, and WO278 with the mesyl walk of WO278 for the benefit of and finding the specific positions where a mesyl has the greatest effect. One would have been motivated to try mesyl linkages at different positions because WO278 demonstrates (Figs 1 and 3-4) placing a mesyl between any two nt within an AON, and shows “walking” the location of the mesyl linkage through the entire AON modifies its pharmacokinetic properties. Therefore, modifying the ASOs of WO908 with the teachings of Patutina, WO361, and WO278 would have produced the limitations of the claimed invention.
Regarding the claimed DNAs at N0 and N-1 (Claim 67) and 2’-F at -3 (Claim 71), it was discussed above that WO908 teaches (¶86) at least two of the three nt in the CBT should comprise a 2’-modified sugar or be DNA and that (¶87) the N+3 nt should have a 2’-F mod. Additionally, WO908 teaches (¶87) applying 2-O-alkyl modifications, including (¶67) 2’-MOE.
Regarding the other specific modified inter-nt linkages at claim-specified positions (Claims 67 and 75), the 2’-F modifications at claim-specified positions (Claim 71), the 2’-MOE modifications at claim-specified positions (Claim 72), the PO linkages at claim-specified positions (Claim 76), those are merely variations of known patterns. Furthermore, WO908 teaches (¶225) optimizing ASO editing efficacy and stability by using a combination of chemical modifications and inter-nt linkages, and optimizing length and asymmetry. As discussed, WO908 teaches (¶12) specific modifications were known to improve editing. WO908 broadly teaches (¶89-92, ¶94-100, ¶109-110) about costs and benefits of various modifications including specifically that (¶91) maximum stability is their aim and suggests replacing each RNA with either a 2’-modified RNA or a DNA. WO908 teaches (¶94) balancing the amount of PS linkages to minimize toxicity.
Since maximum stability of an ASO editor is the aim and Patutina teaches the mesyl inter-nt linkage’s exceptional nuclease resistance, an artisan would have been motivated to apply the mesyl inter-nt linkage of Patutina, WO361, and WO278.
Regarding the exact nucleobase sequence of claimed SEQ ID NO 192 (Claim 77), that sequence is encompassed by WO908’s SEQ ID NO 147/128 (which as explained/shown above, comprise the exact same nucleobase sequences); at least one of those (i.e., SEQ ID NO 128) was known to target SERPINA (and text in the alignment above teaches SEQ ID NO 147 targets the SERPINA E342K mutation). WO908 Table 19 shows that the 40-mer ASOs for editing SERPINA E342K-targeting, V117.82 and V117.109, comprise the exact same nucleobase sequence, and Fig. 20 shows that the two 40-mer ASOs are the most effective editors. WO908 teaches (¶95) ASOs comprising exactly 34 nt and teaches shorter ASO have better endosomal escape and higher specificity. WO908 teaches there are trade-offs between shorter and longer ASOs.
All of those teachings would have motivated an artisan to modify the length and modification pattern of the sequences for targeting the SERPINA E342K mutation. It would have been obvious to try producing various ASOs comprising shortened SEQ ID NO 128 and different modifications because the art demonstrates that all modifications were previously known to impart some benefits but that costs could be associated with the modifications, or too many of the same consecutive modification. Those teachings demonstrate that there was a finite number of identified, predictable potential solutions to the recognized need or problem of producing a modified ASO for editing the SERPINA E342K mutation. In this case, as discussed above, WO908 teaches an ASO comprising a mixture of 2’-F and 2’-O-alkyl nt modifications (it teaches 2’-O-alkyl mods can comprise 2’-OMe and 2’MOE) and a limited number of the same consecutive modification. WO908 teaches (¶86) ASOs should comprise a mix of 2’-F and 2’-O-alkyl mods because that imparts lysosomal stability and RNA editing efficacy. WO908 teaches modified inter-nt linkages including PS and others, Patutina teaches the mesyl inter-nt linkage provides high affinity to RNA and exceptional nuclease resistance, WO361 teaches using mesyl inter-nt linkages in ASO editors, and WO278 teaches placing one or more mesyls between nt at 5’ and 3’ ends and at position -2. In addition, WO278 demonstrates (Figs 1 and 3-4) it was routine and conventional to walk the position of the mesyl linkage to determine what position or combinations of positions produces the AON with the most desirable pharmacokinetic properties for any given application. The teachings indicate that applying different modification patterns to maximize benefits and minimize costs was known and those teachings indicate that applying different modifications had predictable results. Since the ASO comprising WO908 SEQ ID NO 128 was known to edit the SERPINA E342K mutation and (WO908 ¶219) shorter sequences were also known to successfully edit, successfully producing editors by shortening SEQ ID NO 128 and applying various modifications would have been a reasonable expectation.
Therefore the limitations of Claims 67-86 would have been obvious in view of WO908, Patutina, WO361, and WO278.
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.
Claims 67-86 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4-8, 12-15, 17, 19, 37, 54-56, 62, 67, 69, 72, and 74-76 of copending Application No. 17256092 (“App092”, of record) in view of International Application Publication Number WO 2024/114908 (published on 06 June 2024 but effectively filed on 30 November 2022, “WO908”, of record) in view of Patutina (et al. 2020. Mesyl phosphoramidate backbone modified antisense oligonucleotides targeting miR-21 with enhanced in vivo therapeutic potency. PNAS 117[51]:32370–32379, “Patutina”, of record), International Application Publication Number WO 2024/013361 (published on 18 January 2024 but effectively filed on at least 14 July 2023, “WO361” of record) and International Application Publication Number WO 2024/200278 (published on 03 October 2024 but effectively filed on 24 March 2023, “WO278”, of record on IDS). This rejection is maintained.
Although the claims at issue are not identical, they are directed to overlapping subject matter because the instant claims are directed to modified ASO editors for targeting the SERPINA E342K mutation and for treating A1AT deficiency. The claimed ASOs comprise various nt modifications and inter-nt linkage modifications at various positions, other features, and can comprise SEQ ID NO 192.
The App092 claims are directed to an artificial nucleic acid for site-directed editing in a target RNA, wherein the ASO comprises modified nt (including wherein the modified nt can be selected from the group consisting of 2’-H, 2’-OMe, 2’-MOE, and 2’-F), modified inter-nt linkages, a GalNAc, and wherein the artificial nucleic acid is used in a method of treating a patient with A1AD and wherein the target RNA is a SERPINA1 transcript. Both claim sets are directed to chemically modified ASO editors for editing a SERPINA RNA and for treating A1AD deficiency.
The App092 claims do not recite the exact modifications in the instant claims, SEQ ID NO 192, and they do not recite any mesyl linkage that is required by the instant claims.
However, WO908 teaches most of the claimed features (¶10, 12, 18-20, 64, 69, 92, 104, 131, 146, 148, 161) and nt modifications (DNA, 2’-MOE, 2’-F, and 2’OMe) and inter-nt linkage PS and motivations for applying them, including (¶91) maximizing stability. WO908 also teaches altering the length of the ASO, including (¶95) making it a 34-mer. WO908 also teaches SEQ ID NO 128 which comprises the nucleobase sequence of SEQ ID NO 192, as shown by the following alignment:
RESULT 35
BPL44237
ID BPL44237 standard; RNA; 40 BP.
XX
AC BPL44237;
XX
DT 01-AUG-2024 (first entry)
XX
DE SERPINA1 E342K targeting ASO V117.54, SEQ ID 147.
XX
KW Alpha 1 antitrypsin; DNA-RNA hybrid; SERPINA1 gene; achondroplasia;
KW age related macular degeneration; alpha-1 antitrypsin deficiency;
KW alzheimers disease; antiallergic; antiasthmatic; antiinflammatory;
KW antiparkinsonian; antisense oligonucleotide; asthma; beta thalassemia;
KW charcot marie tooth disease; chronic obstructive pulmonary disease;
KW cystic fibrosis; cytostatic; dermatological; dermatological disease;
KW gastrointestinal disease; gastrointestinal-gen.; genetic disorder;
KW genetic-disease-gen.; growth disorder; growth-disorder-gen.;
KW hematological-gen.; hepatotropic; hurler syndrome; motor neurone disease;
KW musculoskeletal disease; musculoskeletal-gen.; neoplasm;
KW neurological disease; neuroprotective; nootropic; ocular disease;
KW ophthalmological; parkinsons disease; pharmaceutical; phosphorothioate;
KW prophylactic to disease; respiratory-gen.; ss; stargardt disease;
KW therapeutic.
XX
OS Homo sapiens.
OS Synthetic.
XX
[truncated to save space]
XX
SQ Sequence 40 BP; 5 A; 15 C; 8 G; 4 T; 7 U; 1 Other;
Query Match 100.0%; Score 34; Length 40;
Best Local Similarity 82.4%;
Matches 28; Conservative 6; Mismatches 0; Indels 0; Gaps 0;
Qy 1 GCCCCAGCAGCTTCAGTCCCTTTCTCNTCGATGG 34
|||||||||||::|||:|||:::|||||||||||
Db 5 GCCCCAGCAGCUUCAGUCCCUUUCTCNTCGATGG 38
Additionally, Patutina teaches (§Abstract) that the mesyl linkage provides RNA specificity and exceptional nuclease resistance and WO361 teaches (p. 18 L30-35) it was common to use the mesyl linkage in ASO editors. WO278 teaches (§Abstract, pp. 5-6 L27-7) chemically modified antisense oligonucleotides comprising a mesyl phosphoramidate (called in WO278 “PNms”) for use in ADAR-mediated RNA editing; (p. 7 L1-7) a linkage numbering scheme that is the same as the claimed invention and wherein the AON comprises mesyl linkages at the linkage connecting the 5’ and 3’ terminal nucleosides and at linkage position -2; and (Figs. 1-4) systematically walking the position of the mesyl linkage to each position within the AON to identify AONs that most effectively edit a target. WO278 also shows (Fig. 4) AONs comprising multiple mesyl linkages.
It would have been obvious before the effective filing to modify the App092 claims with the teachings of WO908, Patutina, WO361, and WO278, for the benefit of maximizing stability and editing efficacy of the ASOs and effectively editing the SERPINA E342K mutation. Doing so would have produced the instant claims.
This is a provisional nonstatutory double patenting rejection.
Claims 67-86 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-24 of copending Application No. 18565733 (“App733”) in view of WO908, Patutina, WO361, and WO278. This rejection is maintained. All references of record or of record on IDS.
Although the claims at issue are not identical, they are directed to overlapping subject matter because the instant claims are directed to modified ASO editors for targeting the SERPINA E342K mutation and for treating A1AT deficiency. The claimed ASOs comprise various nt modifications and inter-nt linkage modifications at various positions, other features, and can comprise SEQ ID NO 192.
The App733 claims are directed to chemically modified ASO for site-directed A[Wingdings font/0xE0]I editing of a target RNA, the ASOs comprising a CBT, modified nt, modified inter-nt linkages, no more than 4-5 consecutive nt comprising the same modification; wherein the ASOs can comprise other features and can be used for treating A1AT deficiency by targeting E342K mutation in SERPINA. Both claim sets are directed to chemically modified ASO editors for editing a E342K mutation in SERPINA.
The App733 claims do not recite the exact modifications in the instant claims, SEQ ID NO 192, and they do not recite any mesyl linkage that is required by the instant claims.
However, WO908 teaches most of the claimed features (¶10, 12, 18-20, 64, 69, 92, 104, 131, 146, 148, 161) and nt modifications (DNA, 2’-MOE, 2’-F, and 2’OMe) and inter-nt linkage PS and motivations for applying them, including (¶91) maximizing stability. WO908 also teaches altering the length of the ASO, including (¶95) making it a 34-mer and (¶136) adding a GalNAc to increase cell uptake. WO908 also teaches SEQ ID NO 128 which comprises the nucleobase sequence of SEQ ID NO 192, as shown by the following alignment:
RESULT 35
BPL44237
ID BPL44237 standard; RNA; 40 BP.
XX
AC BPL44237;
XX
DT 01-AUG-2024 (first entry)
XX
DE SERPINA1 E342K targeting ASO V117.54, SEQ ID 147.
XX
KW Alpha 1 antitrypsin; DNA-RNA hybrid; SERPINA1 gene; achondroplasia;
KW age related macular degeneration; alpha-1 antitrypsin deficiency;
KW alzheimers disease; antiallergic; antiasthmatic; antiinflammatory;
KW antiparkinsonian; antisense oligonucleotide; asthma; beta thalassemia;
KW charcot marie tooth disease; chronic obstructive pulmonary disease;
KW cystic fibrosis; cytostatic; dermatological; dermatological disease;
KW gastrointestinal disease; gastrointestinal-gen.; genetic disorder;
KW genetic-disease-gen.; growth disorder; growth-disorder-gen.;
KW hematological-gen.; hepatotropic; hurler syndrome; motor neurone disease;
KW musculoskeletal disease; musculoskeletal-gen.; neoplasm;
KW neurological disease; neuroprotective; nootropic; ocular disease;
KW ophthalmological; parkinsons disease; pharmaceutical; phosphorothioate;
KW prophylactic to disease; respiratory-gen.; ss; stargardt disease;
KW therapeutic.
XX
OS Homo sapiens.
OS Synthetic.
XX
[truncated to save space]
XX
SQ Sequence 40 BP; 5 A; 15 C; 8 G; 4 T; 7 U; 1 Other;
Query Match 100.0%; Score 34; Length 40;
Best Local Similarity 82.4%;
Matches 28; Conservative 6; Mismatches 0; Indels 0; Gaps 0;
Qy 1 GCCCCAGCAGCTTCAGTCCCTTTCTCNTCGATGG 34
|||||||||||::|||:|||:::|||||||||||
Db 5 GCCCCAGCAGCUUCAGUCCCUUUCTCNTCGATGG 38
Additionally, Patutina teaches (§Abstract) that the mesyl linkage provides RNA specificity and exceptional nuclease resistance and WO361 teaches (p. 18 L30-35) it was common to use the mesyl linkage in ASO editors. WO278 teaches (§Abstract, pp. 5-6 L27-7) chemically modified antisense oligonucleotides comprising a mesyl phosphoramidate (called in WO278 “PNms”) for use in ADAR-mediated RNA editing; (p. 7 L1-7) a linkage numbering scheme that is the same as the claimed invention and wherein the AON comprises mesyl linkages at the linkage connecting the 5’ and 3’ terminal nucleosides and at linkage position -2; and (Figs. 1-4) systematically walking the position of the mesyl linkage to each position within the AON to identify AONs that most effectively edit a target. WO278 also shows (Fig. 4) AONs comprising multiple mesyl linkages.
It would have been obvious before the effective filing to modify the App733 claims with the teachings of WO908, Patutina, WO361, and WO278, for the benefit of maximizing stability and editing efficacy of the ASOs and effectively editing the SERPINA E342K mutation. Doing so would have produced the instant claims.
This is a provisional nonstatutory double patenting rejection.
Claims 67-86 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11, 15, 22, 24-26 of copending Application No. 19024757 (“App757”) in view of WO908, Patutina, WO361, and WO278. This rejection is maintained. All references of record or of record on IDS.
Although the claims at issue are not identical, they are directed to overlapping subject matter because the instant claims are directed to modified ASO editors for targeting the SERPINA E342K mutation and for treating A1AT deficiency. The claimed ASOs can comprise various nt modifications and inter-nt linkage modifications at various positions and SEQ ID NO 192. The App757 claims are directed to mixmer ASOs comprising various nt modifications at various positions and can comprise 95% identity to 30-60 nt of SEQ ID NO 87. App757 SEQ ID NO 87 comprises a 34-mer that is identical to the claimed SEQ ID NO 192:
US-19-024-757-87
Query Match 100.0%; Score 33; DB 1; Length 77;
Best Local Similarity 100.0%;
Matches 34; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 GCCCCAGCAGCTTCAGTCCCTTTCTCNTCGATGG 34
||||||||||||||||||||||||||||||||||
Db 14 GCCCCAGCAGCTTCAGTCCCTTTCTCNTCGATGG 47
Both claim sets are directed to ASO editors for editing a E342K mutation in SERPINA.
The App757 claims do not recite the exact modifications in the instant claims and they do not recite any mesyl linkage that is required by the instant claims.
However, WO908 teaches most of the claimed features (¶10, 12, 18-20, 64, 69, 92, 104, 131, 146, 148, 161) and nt modifications (DNA, 2’-MOE, 2’-F, and 2’OMe) and inter-nt linkage PS and motivations for applying them, including (¶91) maximizing stability. WO908 also teaches altering the length of the ASO, including (¶95) making it a 34-mer and (¶136) adding a GalNAc to increase cell uptake. Patutina teaches (§Abstract) that the mesyl linkage provides RNA specificity and exceptional nuclease resistance and WO361 teaches (p. 18 L30-35) it was common to use the mesyl linkage in ASO editors. WO278 teaches (§Abstract, pp. 5-6 L27-7) chemically modified antisense oligonucleotides comprising a mesyl phosphoramidate (called in WO278 “PNms”) for use in ADAR-mediated RNA editing; (p. 7 L1-7) a linkage numbering scheme that is the same as the claimed invention and wherein the AON comprises mesyl linkages at the linkage connecting the 5’ and 3’ terminal nucleosides and at linkage position -2; and (Figs. 1-4) systematically walking the position of the mesyl linkage to each position within the AON to identify AONs that most effectively edit a target. WO278 also shows (Fig. 4) AONs comprising multiple mesyl linkages.
It would have been obvious before the effective filing to modify the App757 claims with the teachings of WO908, Patutina, WO361, and WO278, for the benefit of maximizing stability and editing efficacy of the ASOs. Doing so would have produced the instant claims.
This is a provisional nonstatutory double patenting rejection.
Claims 67-86 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 52-72 of copending Application No. 19401664 (“App664”). This rejection is maintained and updated in view of the copending claim amendments/numbering.
Although the claims at issue are not identical, they are directed to overlapping subject matter because the instant claims are directed to modified ASO editors for targeting the SERPINA E342K mutation and for treating A1AT deficiency. The claimed ASOs comprise various nt modifications and inter-nt linkage modifications at various positions, other features, and can comprise SEQ ID NO 192.
The App664 claims are directed to chemically modified ASO for site-directed A[Wingdings font/0xE0]I editing of a target RNA, the ASOs comprising a CBT, modified nt, modified inter-nt linkages; wherein the ASOs can comprise other features and can be used for treating A1AT deficiency by targeting E342K mutation in SERPINA. The App664 claims show (at least Claims 52-53) that the ASO comprises a sulfonylphosphoramidate linkage (which can be a mesyl linkage) at positions +24, +13, -2, and -8. Those are the exact mesyl linkages recited in the instant claims. The App664 claims show (Claims 52-53) a chemically modified oligo comprising a sequence of nucleobases that is 100% identical to claimed SEQ ID NO 192, as shown by this alignment:
RESULT 1
NASEQ2_05042026_191806
Query Match 100.0%; Score 33; DB 1; Length 34;
Best Local Similarity 100.0%;
Matches 34; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 GCCCCAGCAGCTTCAGTCCCTTTCTCNTCGATGG 34
||||||||||||||||||||||||||||||||||
Db 1 GCCCCAGCAGCTTCAGTCCCTTTCTCNTCGATGG 34
The App664 claims show (Claims 52-53) ASOs with the exact same mods as the claimed invention: N+1 is 2’-MOE, N0 is DNA, and N-1 is DNA; 2’-F mods and 2’-MOE mods at the same positions as instant Claims 71-72; PO mods at the same positions as instant Claim 76; and the GalNAc of instant Claim 81. Both claim sets are directed to chemically modified ASO editors for editing a E342K mutation in SERPINA, wherein the ASO comprises mesyl linkages at positions +24, +13, -2, and -8. Both claim sets are directed to ASOs comprising the same SEQ with the same modification pattern, and to methods of using them to induce site directed A-to-I editing.
Therefore the instant claims and App664 claims are directed to the same subject matter.
This is a provisional nonstatutory double patenting rejection.
Claims 67-86 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-66 of copending Application No. 19510750 (“App750”) in view of WO908, of record. This rejection is necessitated by IDS with fee.
Although the claims at issue are not identical, they are directed to overlapping subject matter because the instant claims are directed to modified ASO editors for targeting the SERPINA E342K mutation and for treating A1AT deficiency. The claimed ASOs comprise various nt modifications and inter-nt linkage modifications at various positions, other features, and can comprise SEQ ID NO 192.
The App750 claims are directed to chemically modified ASO for site-directed A[Wingdings font/0xE0]I editing of a target RNA, the ASOs comprising a CBT, modified nt, modified inter-nt linkages; wherein the ASOs can comprise other features and can be used for treating A1AT deficiency by targeting E342K mutation in SERPINA. The App750 claims recite (at least Claim 1) that the ASO comprises a methanesulfonyl (mesyl) linkage at positions +24, +13, -2, and -8 (see Claims 14-22). Those are the exact mesyl linkages recited in the instant claims. The App750 claims (see Claim 29) recite 2’-F mod at the same positions as the claimed invention. The App750 claims (see Claim 37) recite N+1 is 2’-MOE, N0 is DNA, and N-1 is DNA. The App750 claims recite a chemically modified oligo comprising SEQ ID NO 217. That sequence wherein is 100% identical to claimed SEQ ID NO 192, as shown by this alignment:
RESULT 9
BQW47543
ID BQW47543 standard; RNA; 34 BP.
XX
AC BQW47543;
XX
DT 17-APR-2025 (first entry)
XX
DE Human SERPINA1 gene targeted modified antisense oligo, SEQ ID 217 #2.
XX
KW Alpha 1 antitrypsin; DNA-RNA hybrid; Gene silencing; Genome editing;
KW Phosphorothioate; SERPINA1 gene; antisense oligonucleotide;
KW antisense therapy; cardiovascular disease; cardiovascular-gen.;
KW hepatotropic; liver disease; metabolic disorder; metabolic-gen.;
KW neurodegenerative disease; neuroprotective; ss; therapeutic.
XX
OS Homo sapiens.
OS Synthetic.
XX
FH Key Location/Qualifiers
FT modified_base 1..34
FT /*tag= a
FT /mod_base= OTHER
FT /note= "OTHER = Optionally modified with methyl group,
FT fluoro group, inosine and Phosphorothioate backbone"
XX
CC PN WO2025036984-A1.
XX
CC PD 20-FEB-2025.
XX
CC PF 15-AUG-2024; 2024WO-EP073031.
XX
PR 15-AUG-2023; 2023WO-EP072474.
XX
CC PA (AIRN-) AIRNA CORP.
CC PA (AIRN-) AIRNA BIO GERMANY GMBH.
XX
CC PI Merkle T;
XX
DR WPI; 2025-16796W/020.
XX
CC PT New chemically modified oligonucleotide used for e.g. treating disease or
CC PT disorder, e.g. liver, metabolic, and neurodegenerative comprising
CC PT sequence capable of binding to target sequence in target RNA and central
CC PT base triplet of nucleotide.
XX
CC PS Claim 57; SEQ ID NO 217; 125pp; English.
XX
CC The present invention relates to a novel chemically modified
CC oligonucleotide designed for the treatment of diseases or disorders, such
CC as those affecting the liver, metabolism, and neurodegeneration. This
CC oligonucleotide includes a sequence capable of binding to a target
CC sequence in RNA, specifically targeting the central base triplet of a
CC nucleotide. The invention further encompasses: (1) a composition
CC comprising the chemically modified oligonucleotide; and (2) a method for
CC site-directed A-to-I editing of a target RNA in vitro, which involves
CC contacting the target RNA with the chemically modified oligonucleotide or
CC the composition. The chemically modified oligonucleotide is useful for
CC site-directed A-to-I editing of target RNA within cells, utilizing
CC endogenous adenosine deaminase acting on RNA (ADAR). It has therapeutic
CC applications for treating diseases or disorders, particularly those
CC linked to genetic conditions. These conditions include liver, metabolic,
CC neurodegenerative, or cardiovascular diseases, especially those
CC associated with gain-of-function (GOF) or loss-of-function (LOF)
CC mutations. Notably, the invention can be used to treat diseases related
CC to the SERPINA1 gene or alpha-1-antitrypsin deficiency (A1AD or AATD).
CC Note: The present sequence is described as SEQ ID NO:217 in Table 12, but
CC it differs from the SEQ ID NO:217 in the sequence listing (see BQW47419).
XX
SQ Sequence 34 BP; 4 A; 13 C; 7 G; 5 T; 4 U; 1 Other;
Query Match 100.0%; Score 33; Length 34;
Best Local Similarity 88.2%;
Matches 30; Conservative 4; Mismatches 0; Indels 0; Gaps 0;
Qy 1 GCCCCAGCAGCTTCAGTCCCTTTCTCNTCGATGG 34
||||||||||||:|||||||::|||||:||||||
Db 1 GCCCCAGCAGCTUCAGTCCCUUTCTCNUCGATGG 34
Both claim sets are directed to chemically modified ASO editors for editing a E342K mutation in SERPINA, wherein the ASO comprises mesyl linkages at positions +24, +13, -2, and -8. Both claim sets are directed to ASOs comprising the same SEQ.
The App750 claims do not recite all the exact modifications in the instant claims.
However, WO908 teaches most of the claimed features (¶10, 12, 18-20, 64, 69, 92, 104, 131, 146, 148, 161) and nt modifications (DNA, 2’-MOE, 2’-F, and 2’OMe) and inter-nt linkage PS and motivations for applying them, including (¶91) maximizing stability. WO908 also teaches altering the length of the ASO, including (¶95) making it a 34-mer and (¶136) adding a GalNAc to increase cell uptake. WO908 also teaches SEQ ID NO 128 which comprises the nucleobase sequence of SEQ ID NO 192, as shown by the following alignment:
It would have been obvious before the effective filing to modify the App750 claims with the teachings of WO908 for the benefit of maximizing stability and editing efficacy of the ASOs and effectively editing the SERPINA E342K mutation. Doing so would have produced the instant claims.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant's arguments filed 16 April 2026 have been fully considered but they are not persuasive. Arguments that are no longer relevant are not addressed.
103
Applicant argues against the 103 rejection on pp. 6-16. Examiner references to Arguments/Remarks §¶ # count the first full ¶ within a § (i.e., I or I.A, etc.) as ¶1.
Applicant argues that (1) the obviousness to try rationale is not satisfied, (2) the cited references don’t teach or suggest each element of the claims, and (3) their data support surprising results.
Applicant first argues that (§I.A ¶1-6) the obvious to try rationale does not support a conclusion of obviousness because (§I.A ¶2,4-5) of the large number of options available which needs to be taken into consideration when determining predictability and reasonable expectation of success. Applicant argues that a mesyl walk accounts for only the position of a single mesyl and not all the other claimed variables. Applicant argues that the length, the particular asymmetry, and the specific locations of the mesyl linkages are all factors in nonobviousness. Applicant argues further (pp. 13-14 §II ¶1-3) about the claimed 25-1-8 asymmetry and that it isn’t disclosed in WO908.
Those arguments aren’t persuasive because the cited art teaches that all of the variables Applicant asserts are nonobvious were known in the art and varying them was known in the art to produce variable results. Most of those variables aren’t individually explained in the rejection because the primary reference, WO908, teaches all of those variables and teaches modifying those all variables with an aim of improving ASO properties was routine and conventional. Those WO908 passages are cited in the rejection (e.g., ¶8, ¶86-87, ¶102, ¶225, among others).
For example and regarding the claimed 25-1-8 asymmetry that Applicant asserts (§II ¶1-3) isn’t obvious, WO908 teaches (¶125-127) the ASO can be asymmetric and lays out guidelines for various asymmetries:
(¶126) …in certain embodiment the ASO may be asymmetric…there might be 20-40 nt at the 5’ terminus and 5-15 nt at the 3’ terminus. In one embodiment, there are
a) at least 4 nucleotides 3’ of the CBT; or
b) at least 16 nucleotides 5’ of the CBT.
In some embodiments, there are 4-30 nt 3’ of the CBT. In some embodiments, there are no more than 10 nt 3’ of the CBT. In some embodiments, the 3’ terminus is shortened to a length of 5 nt 3’ of the CBT. In some embodiments, the 3’ terminus is shortened to a length of 4 nt 3’ of the CBT. In one embodiment, the region 3’ to the CBT contains 4, 5, or 6 nt. In some embodiments, there are 4-30 nt 5’ of the CBT. In one embodiment, there are no more than 35 nt 5’ of the CBT. In one embodiment, the 5’ terminus is shortened to a length of 25 nt or 26 nt 5’ of the CBT. In one embodiment, the region 5’ to the CBT contains 24, 25, or 26 nt. [emphasis added.]
That passage and the following ¶ (¶127) discloses that making an asymmetric ASO was known in the art. As discussed in the 103 rejection, WO908’s CBT comprises 3 nt including N-1, N0, and N+1, wherein WO908’s N-1 is the same as claimed position N+1, WO908’s N0 is the same as claimed N0, and WO908’s N+1 is the same as claimed N-1. That means that WO908’s teachings in the quoted ¶126-127 encompass 25-1-8 asymmetries: whereas WO908 counts the 5’-most nt of the CBT to be part of the CBT, the claimed invention counts it as the 3’-most nt of the 5’ segment. Therefore WO908’s 24-mer segment 5’ of the CBT would be a 25-mer segment in terms of the instant claims (24-mer + 1 nt of the CBT = 25-mer). WO908’s N0 is the same as claimed N0; as discussed, that is part of WO908’s CBT. Then WO908’s 3’-most nt of the CBT is the same as what is claimed as N-1. The passage quoted above teaches that the segment 3’ of the CBT can be no more than 10 nt long. Such segments encompass those that are 7-mer; adding the 3’-most nt of the CBT would mean the 3’ segment is a total of 8 nt. That is exactly how an artisan would have produced the 25-1-8 symmetry of the instant claims.
While WO908 discloses (Table A) some embodiments, they also teach further embodiments and strategies/guidelines for producing asymmetric ASOs (as cited). Therefore WO908 teaches elements of various asymmetries and indicates that those elements are simply obvious variants of one another. WO908 teaches (same § and ¶220) different asymmetries and proportions of 2’-F and 2’-OMe modifications produce different effects. That indicates that the claimed invention merely modifies variables that were known in the art to produce variable results. Applicant hasn’t provided data demonstrating that 25-1-8 produces results that are better than what would have been expected using other asymmetries, or that 25-1-8, when applied to a variety of sequences/targets, produces better effects than any other asymmetry. The finding in the rejection is that any of these asymmetries or modifications in any combination would have been obvious in view of the prior art because they were all known to affect efficacy and it was routine and conventional to alter any or all of the known variables.
Applicant also argues that (§I.A ¶3-4, ¶6) WO278 discloses mesyl walk of but a single mesyl linkage and gives limited consideration of the effect of combinations of multiple mesyl linkages at different positions within an ASO. Applicant argues that WO278’s limited testing indicates it isn’t routine for an artisan to brute force every combination of mesyl linkages. Applicant argues that the references don’t teach the mesyl linkages at exactly positions +24, +13, -2, and -8 within a 34-mer ASO, and that WO278 doesn’t teach an ASO with a 4 mesyl pattern. Applicant concedes that WO278 teaches mesyl walking was a known technique (i.e., this reasoning only demonstrates that mesyl walking as an experimental technique was known, not that the outcome at position +13…) but argues that the mesyl at position +13 in a 34-mer ASO was not predictable.
That is not found persuasive because WO278 discloses 34-mer ASOs (see p. 19 L21-23) and discloses (p. 7 L1-10) mesyl linkages at the precise locations that encompass, in a 34-mer ASO, mesyl linkages at (in terms of the instant claims) positions +24, -2, and -8. WO278 teaches (pp. 23-24 L34-34 but especially L34-5) a 34-mer ASO can comprise 4 (or more) mesyl linkages. Regarding the mesyl at specifically position +13, WO278 teaches not only the mesyl walk but also (pp. 24-26 L3-14) mesyl at multiple positions increases editing efficacy. An artisan studying WO278’s mesyl-walk results (Figs. 3-4) would have noticed that ASOs comprising more mesyls (2-3 mesyls vs. 1 mesyl) and both terminal and internal mesyls were clearly the best editors (see RM107378 and RM107380 which comprise both terminal mesyl linkages and an internal mesyl linkage vs. the others). The full teachings of WO278 would have motivated an artisan to apply WO278’s known preferred mesyl positions (i.e., +24, -2, and -8) and then mesyl walk additional positions. Taking into account WO278’s full teachings, they would have systematically added a further mesyl linkage or linkages via a mesyl walk. That’s why the claimed ASOs would have been obvious in view of the teachings of the prior art.
Regarding Applicant’s specific statement that mesyl walking was a known technique but that the mesyl at position +13 in a 34-mer ASO was not predictable, that is not found persuasive because the art explicitly teaches 3 out of 4 specific positions and teaches a technique to find others. Furthermore, an artisan would have expected that there would be variation in the editing efficacy of the compounds produced via a mesyl walk. The finding that some perform better than others—even over twice as well—is not unexpected. For example, WO278’s Fig. 3 shows that RM107378 and RM107380 perform more than twice as well as other compounds tested. The point is that WO278 teaches a variable, namely the presence and position(s) of mesyl linkages, was known to affect editing efficacy and produce ASOs with different levels of editing efficacy. Modifying a variable(s) known to affect editing efficacy and finding altered editing efficacy cannot be considered unexpected.
Then Applicant continues to argue that (§I.B ¶1) mesyl positioning couldn’t have been pursued with a reasonable expectation of success: there was a high degree of unpredictability of the effect of mesyl linkages at certain positions on ADAR editing activity, and some child ASOs (comprising a mesyl linkage) have lower editing activity than parent. Applicant states this directly refutes the Examiner’s allegation that “an artisan could readily extrapolate from what is shown that including more mesyls at additional positions to the 5’ and 3’ends and -2 would produce better editing[”]. Applicant states that WO278 doesn’t provide direction how to extrapolate mesyl positioning to 34-mers with any predictability.
Those arguments aren’t found persuasive because the ASOs that have lower editing activity compared with the parent comprise only a single mesyl linkage whereas WO278 teaches (p. 26 L10-11) replacing multiple linkages with mesyl linkages almost doubled the editing percentage; that would have motivated an artisan to apply multiple mesyls. And, based on the results in Fig. 1, an artisan would not have placed a mesyl linkage at a single position demonstrated to have worse editing, none of which happens to be any of the claimed positions. Furthermore, WO278 teaches using more than one mesyl and shows doing so produces better results: Fig. 4 shows that any of the ASOs comprising more than one mesyl linkage provided higher editing.
Regarding what Applicant asserts is WO278’s failure to provide any direction for extrapolation to longer ASOs, such as 34-mers, WO278 teaches (p. 19 L21-22; p. 24 L3-5) their invention encompasses 34-mers with multiple mesyls. Even more relevant, WO278 describes (p. 7 L1-7) the placement of mesyl linkages strictly in relation to terminal ends and the N0 position—not in terms of a numbering scheme based on ASO length. A person of ordinary skill would therefore understand not only how to apply WO278’s mesyl placements to an ASO of any disclosed length but also that WO278 described their preferred positions in terms of static entities—terminal ends and the N0 position—because they intended their teachings to apply to ASOs of any disclosed lengths.
Applicant argues (I.B ¶2-7) that Patutina teaches full modified oligont that are for a completely different purpose than ADAR-based editing, does not test or contemplate position-specific variability, and that if swapping any linkage to mesyl were so predictably beneficial the mesyl walk data in WO278 would have shown uniform improvement. Applicant argues that position-dependent nature of the effect are insufficient to direct an artisan to the specific positions claimed. Applicant argues that unless an artisan knows exactly which positions will enhance or diminish editing, they don’t have a reasonable expectation of success in selecting any particular position. Applicant presents their data to demonstrate unpredictability.
Arguments directed to Patutina are not persuasive because that reference is relied up for teaching that mesyl linkages have a known benefit and a person of ordinary skill would have understood that the structure of the linkage, not any intended use of the oligonucleotides, imparts the benefit. The finding of obviousness considers what a person of ordinary skill would have understood in view of the synthesis of the references.
Applicant’s arguments that if position didn’t matter WO278’s mesyl walk would show uniform improvement, that position-dependent nature of the effect are insufficient to direct an artisan to the specific positions claimed, and the assertion that unless an artisan knowns exactly which positions will enhance or diminish editing, they don’t have a reasonable expectation of success in selecting any particular position are also not found persuasive.
The rejection never asserts that position doesn’t matter (and, notably, Applicant hasn’t cited where it supposedly states that) and wouldn’t have asserted that because WO278’s mesyl walk data show the opposite—position does matter. The rejection asserts that certain positions were known to impart beneficial qualities—as explained, WO278 teaches specific positions which when applied to a 34-mer ASO (also taught by WO278) would be at the same positions that are claimed: positions +24, -2, and -8. The rejection then discusses that WO278 allows for—and passages cited in the rejection and arguments discuss that WO278 encourages—incorporation of more mesyls and teaches a mesyl walk to identify the best positions to place them. Those findings are what leads to the conclusion of obviousness.
Applicant’s assertion that an artisan has to know the exact positions to place a mesyl linkage to have a reasonable expectation of success are not persuasive because WO278 employed the mesyl walk strategy specifically to find which positions are most advantageous for their target sequences. WO278 demonstrates that variation in ASO editing capability was a known outcome of changing mesyl position, and an artisan would understand that WO278 tested each position because they were well aware that while position-dependent variation would occur, mesyl linkages at some positions would inevitably provide a better result than a parent lacking mesyl linkages. The position-dependent nature of the effect of mesyl linkages would have motivated a person to apply WO278’s mesyl walk. WO278’s mesyl walk was employed precisely because it was known that the position of a mesyl linkage affects editing efficiency, with some positions increasing efficacy to a larger extent than others. Artisans know position-dependent changes in efficacy are possible because WO278 suggested (p. 7 L1-7) placing the mesyl linkage at specific positions and tested (Figs. 1 and 3-4) position-dependent effects. Therefore a person of ordinary skill would have employed a known technique to find which mesyl position(s) within any ADAR editor produce the best editors. Regarding Applicant’s arguments that WO278’s Fig. 1 shows there is no clear pattern as to which mesyls would improve editing, that is inaccurate because WO278 suggested (p. 7 L1-7) placing mesyl linkage(s) at specific positions: the terminal ends and at linkage position -2; a desire to identify other positions is why WO278 employed a mesyl walk.
A person of ordinary skill is a person of ordinary creativity and they would have been able to synthesize what is known in the art to optimize known ASOs.
"A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton." KSR, 550 U.S. at 421, 82 USPQ2d at 1397. "[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle." Id. at 420, 82 USPQ2d at 1397. Office personnel may also take into account "the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at 418, 82 USPQ2d at 1396.
In addition to the factors above, Office personnel may rely on their own technical expertise to describe the knowledge and skills of a person of ordinary skill in the art. The Federal Circuit has stated that examiners and administrative patent judges on the Board are "persons of scientific competence in the fields in which they work" and that their findings are "informed by their scientific knowledge, as to the meaning of prior art references to persons of ordinary skill in the art." In re Berg, 320 F.3d 1310, 1315, 65 USPQ2d 2003, 2007 (Fed. Cir. 2003). In addition, examiners "are assumed to have some expertise in interpreting the references and to be familiar from their work with the level of skill in the art ." PowerOasis, Inc. v. T-Mobile USA, Inc., 522 F.3d 1299, 86 USPQ2d 1385 (Fed. Cir. 2008) (quoting Am. Hoist & Derrick Co. v. Sowa & Sons, 725 F.2d 1350, 1360, 220 USPQ 763, 770 (Fed. Cir. 1984). See MPEP § 2141.03 for a discussion of the level of ordinary skill.
MPEP §2141(II)(c)
Regarding Applicant’s arguments that their application underscores the unpredictability of different lengths and ASO asymmetries, those arguments and data aren’t persuasive because they don’t show any results that go beyond what would have been expected based on WO278. All of the variables at play were well known to affect ASO efficacy (that is why WO908 and WO278 teach altering those variables) and the presented results reiterate that previously established fact.
Regarding Applicant’s arguments that their data demonstrate surprising results (§II.B ¶6-7; §III), it is noted that the instant claims are directed to a broad genus of compounds, not a single species. The claims broadly encompass a genus of oligonucleotide compounds that target a SERPINA E342K substitution, comprise 25-1-8 asymmetry, and wherein mesyl is at specific locations. The claims do not recite any particular nucleobase sequence. The claims require only that the ASO target a SERPINA E342K substitution and N0 is directly opposite the target adenosine to be edited. Claims 67-76 do not recite any specific SEQ ID NO or require that the oligonucleotide comprise any specific nucleobase sequence. Therefore, they encompass multiple compounds that target the SERPINA E342K substitution.
The results Applicant asserts are unexpectedly good show only variations of one particular nucleobase sequence, SEQ ID NO 152, wherein the position of one mesyl linkage is altered. However, since the claims don’t recite any SEQ ID NO or nucleobase, they encompass a large number of nucleobase sequences. The “surprising results” presented don’t establish that 25-1-8 symmetry or mesyls at positions +24, +13, -2 and -8, when applied to any different nucleobase sequences that target SERPINA E342K for editing, produce unexpectedly good results. The claims encompass more than just a single compound/nucleobase sequence; yet Applicant presents “surprising results” obtained from only a single compound.
Applicant’s arguments asserting the low 4 nM dose shows more granular differences than a higher dose are compelling as they pertain to the particular nucleobase sequence shown in Fig. 8. However, ultimately, the arguments and results shown in Fig. 8 are not persuasive of superior performance because the claims broadly encompass numerous compounds (i.e., a genus of ASOs comprising a variety of nucleobase sequences) but the “surprising results” show results from only a single compound, namely AI-2491. The discussion in Remarks (§III) and results in Fig. 8 show AI-2491 performs well, but the claims encompass many more compounds than just AI-2491; Applicant hasn’t shown that more than one single compound performs unexpectedly well. Therefore the 103 rejection must be maintained.
Altogether, based on the results shown in WO908 and WO278, a person of ordinary skill would determine that altering the modification patterns or number and placement of mesyl linkages within a editing AON would be expected to alter editing efficiency, and that the data Applicant has pointed out do not demonstrate a level of change that would have been unexpected across the full breadth of the claimed compounds.
NSDP
Applicant argues against the NSDP rejections (pp. 16-19) on the same basis as they argued against the 103 rejection, namely that the mesyl linkages at positions +24, +13, -2, and -8 would not have been obvious in view of the prior art because the cited references don’t mention mesyl linkages at those positions.
That argument is not found persuasive for copending App664 and App750 because those claims indeed recite or show mesyl linkages at positions +24, +13, -2, and -8. Regarding Applicant’s argument that App664 is a later-filed application, NSDP rejections over later-filed applications aren’t dropped until allowable subject matter has been indicated and the NSDP rejection is the only rejection left. Those conditions haven’t been met at this point.
Regarding I, II, and III (App092, App733, and App757) that argument is not found persuasive for the same reason the argument against the 103 rejection was not found persuasive: WO908 teaches (¶89-92, ¶94-100, ¶109-110) about costs and benefits of various modifications including (¶94) balancing the amount of PS linkages to minimize toxicity. Patutina reiterates that point (§Main text ¶2): despite the number of benefits, one of the significant drawbacks of PS ASOs that limit its clinical utility is substantial toxicity. Patutina teaches (§Abstract, §Toxicity of Oligonucleotides ¶1) mesyl linkages do not present that drawback (i.e., toxicity) and their biochemical blood tests showed that μ [i.e., mesyl] ASOs exhibited no toxic effect on the liver and kidneys of mice. Patutina teaches mesyl linkages impart exceptional nuclease resistance. WO361 demonstrates it was customary in the art to use mesyl inter-nt linkages in oligont for editing RNA including SERPINA1. Furthermore, WO278 teaches (p. 7 L1-7) placing mesyl linkages between nt at specifically the 5’end, the 3’end, and the -2 position relative to the nt targeted for editing. In addition, WO278 demonstrates (Figs. 1 and 3-4) it was routine and conventional in the art to perform a mesyl walk wherein the mesyl inter-nt linkage(s) within an AON is systematically moved to each position to determine which position(s) produce the most effective editing.
Altogether, it would have been obvious to artisan (1) that they could replace linkages between nt at the 5’ and 3’ends and position -2 with mesyl linkages and (2) they could replace any of the linkages between two bases with a mesyl linkage for the benefits discussed in the preceding ¶s, and would have known (from Patutina’s teachings) doing so would have had a reasonable expectation of making the oligont more stable and less toxic. A more stable ASO would persist longer in a body and be more likely to have longer-term effects. Furthermore, WO278’s mesyl walk demonstrates (Figs. 3-4) that the number and placement of mesyl linkage(s) with an ASO was known to affect the ASO’s editing efficiency. The mesyl walk was employed precisely because it was known that the position of a mesyl linkage affects editing efficiency, with some positions increasing efficacy to a larger extent than others. The combination of copending claims and prior art would have motivated an artisan to place a mesyl linkage between nt at any positions, including +24, +13, -2, and -8, and in so doing they would have produced the claimed invention.
Conclusion
No claim is allowed.
Applicant's submission of an information disclosure statement under 37 CFR 1.97(c) with the timing fee set forth in 37 CFR 1.17(p) on 16 April 2026 prompted the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 609.04(b). 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 RUTHIE S ARIETI whose telephone number is (571)272-1293. The examiner can normally be reached M-Th 8:30AM-4PM, alternate Fridays 8:30AM-4PM (ET).
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, Ram R Shukla can be reached at (571)272-0735. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
RUTHIE S ARIETI
Examiner (Ruth.Arieti@uspto.gov)
Art Unit 1635
/RUTH SOPHIA ARIETI/Examiner, Art Unit 1635
/NANCY J LEITH/Primary Examiner, Art Unit 1636
Prosecution Insights