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.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 30 December 2025 has been entered.
Status of the Application
Applicant’s response and amendment filed 30 December 2025 are acknowledged and entered.
Applicant has not amended, canceled, or added any claims.
Response to Amendment
Applicant has submitted a substitute Spec; the objections to the Spec. are withdrawn.
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Rejections not reiterated here are withdrawn.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.
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 updated.
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 +34 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.
Furthermore, an artisan would have been motivated to apply the different modifications with the aim of optimizing editing efficacy. As noted in In re Aller, 105 USPQ 233 at 235, more particularly, where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. MPEP 2144.05 provides: It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions (In re Williams, 36 F.2d 436, 438 (CCPA 1929).
Here, the focus is that general conditions of an ASO editor for SERPINA E342K, the ASO comprising modified linkages and nt, was known in the prior art and changes in its form or substitution of similar components known in the prior art is not patentable. Substitution of similar components in terms of identifying optimal locations and proportions of modifications, including PS, PO, and mesyl linkages and 2F, 2’MOE, and 2OMe nt modifications, would have been obvious because WO908 shows that varying the positions of these modifications within an ASO editor to improve results was well-known in the prior art.
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 claim 1-51 of copending Application No. 19401664 (“App664”) in view of WO908, of record. This rejection is new because App664 was filed on 26 November 2025 which is after the mail date of the previous Office action.
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 recite (at least Claims 2-3) 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 recite a chemically modified oligo comprising SEQ ID NO 1 wherein X is T. That sequence wherein X = T is 100% identical to claimed SEQ ID NO 192, as shown by this alignment:
RESULT 1
NASEQ2_01132026_125212
Query Match 97.0%; Score 32; DB 1; Length 34;
Best Local Similarity 97.1%;
Matches 33; Conservative 0; Mismatches 1; Indels 0; Gaps 0;
Qy 1 GCCCCAGCAGCTTCAGTCCCTTTCTCNTCGATGG 34
|||||||||||||||| |||||||||||||||||
Db 1 GCCCCAGCAGCTTCAGNCCCTTTCTCNTCGATGG 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 App664 claims do not recite 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 App664 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 30 December 2025 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. 8-11. Examiner references to Arguments/Remarks ¶ # count the first full ¶ on a page as ¶1. Applicant argues that the claimed mesyl linkages at positions +24, +13, -2, and -8 are not made obvious in view of the cited prior art. Notably, Applicant has not found fault with or argued against any other aspects of the rejection.
Applicant first argues that the obvious to try rationale does not support a conclusion of obviousness because that rational requires an artisan to (1) choose from a finite number of identifiable, predictable solutions and (2) have a reasonable expectation of success in doing so. Applicant cites (p. 9 ¶1) case law to argue that “finite” means small or easily traversed, and argues that the total number of possible combinations of mesyl linkages in a 34-mer oligo is 233 which is a very large number.
That argument is not found persuasive for several reasons. First, MPEP §2143(I)(E) discusses that: Courts appear to be applying the KSR requirement for "a finite number of identified predictable solutions" in a manner that places particular emphasis on predictability and the reasonable expectations of those of ordinary skill in the art. [emphasis added.] That passage indicates that what is considered a "a finite number of identified predictable solutions" is a calculation that takes into account predictability and the reasonable expectations of those of ordinary skill in the art. Secondly, the arguments are not persuasive because the prior art shows that modifying inter-nt linkages was known to affect ASO stability and, therefore, efficacy.
Note that the art of WO278 has been added to 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. That means it was routine and conventional for an artisan to place a mesyl linkage between each pair of nt. As discussed, WO278 teaches (pp. 5-6 L27-7) an AON that mediates adenosine deamination wherein the AON comprises one or more linkage modifications comprising an internucleoside linkage structure according to formula (I). Formula (I) is a mesyl linkage. WO278 further teaches (p. 7 L1-7) a linkage numbering scheme that is the same as the claimed invention 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. Clearly WO278 teaches mesyl linkages between nt at the 5’ and 3’ ends and at position -2 which is the same location relative to the target nt as claimed position -2. Since WO278 teaches a 34-mer AON and mesyl linkages between nt at the 5’ and 3’ ends, they also teach mesyls at positions that are equivalent to claimed positions +24 and -8. Furthermore, WO278 teaches an AON comprising one or more mesyls and WO278 Fig. 4 shows changing the position of the mesyl linkage to each position within an AON and AONs comprising more than one mesyl linkage. WO278 Figs. 1 and 3 show the position of the mesyl linkage affects editing efficacy.
Those data and teachings indicate it was routine and conventional to “walk” the position of a mesyl linkage to each position within an AON to determine which position(s) produce the best pharmacokinetic properties. Therefore, in contrast to Applicant’s arguments, it was entirely reasonable for an artisan to test a variety of AONs wherein a mesyl linkage was placed at each position. Moreover, WO278 teaches three out of the four positions instantly claimed: between the two nt at the 5’end (i.e., “+24”), the two nt at the 3’end (i.e., “-8”), and at position -2 relative to the target. WO278 teaches incorporating more than one mesyl linkage and both WO908 and WO278 teach altering modifications within an AON to optimize pharmacokinetic properties.
Therefore Applicant’s arguments regarding the 103 rejection cannot be considered to overcome the rejection.
Next, Applicant argues (pp. 9-11) that their claimed ASO comprising mesyl inter-nt linkages at positions +24, +13, -2, and -8 produces enhanced editing efficiency but ASOs comprising mesyl inter-nt linkages at other positions were not particularly beneficial in enhancing editing efficiency.
Applicant first points to Example 4/Fig. 4. Those data are deemed irrelevant to the claimed invention because they do not show an ASO comprising four mesyl linkages at the claimed positions. Purported unexpected results must compare the claimed invention and the closest art.
See In re Baxter Tavenol Labs., 952 F.2d 388, 392 (Fed. Cir. 1991): “When unexpected results are used as evidence of nonobviousness, the results must be shown to be unexpected compared with the closest prior art.”
Regarding Applicant’s statement that the data in FIG. 4 demonstrates that mesyl internucleoside linkages at some positions are particularly beneficial in enhancing editing, that was already known in the art because WO278 shows that (see Figs. 1 and 3-4) mesyl internucleoside linkages at some positions are particularly beneficial in enhancing editing while such linkages at other positions have the opposite effect. Therefore those arguments and data cannot be deemed to overcome the obviousness rejection.
Applicant then (p. 10) points to Example 11/Fig. 11. Again, none of those compounds comprise mesyl linkage at only the four claimed positions. Therefore they cannot be used to demonstrate the claimed invention produces unexpected results.
Applicant then discusses (pp. 10-11) Example 8/Fig. 8 and Example 13/Fig. 13. Example 8 shows in vitro data comparing an ASO mesyl walk. Compound AI-2491 comprises mesyl linkages at the four claimed positions. While Applicant argues that the compound unexpectedly showed more than two times the editing efficacy of the parental ASO [i.e., AI-1987] at 4 nM, those data do not substantiate that a mesyl linkage at specifically position +13 produces better results. Most of the 20 nM dose—including the parent—result in ≈60-70% editing. The 4 nM dose has more variation but still shows compounds that nearly double the editing efficacy. Several of the compounds shown in Fig. 8 exhibit editing similar to that of AI-2491 (which comprises mesyls at the 4 claimed positions): AI-2486, -2487, -2488. Further to the point that mesyl linkages were known to affect editing efficacy, data in WO278 show results from a mesyl walk. Those data indicate that doubling of editing efficacy is expected depending on which position(s) within an AON comprise a mesyl linkage. Furthermore, results in WO908 (see discussion below) demonstrate that altering an ASO/AON’s modification pattern was known to affect editing efficacy and none of the results shown in Fig. 8 demonstrate an improvement in editing efficacy beyond what an artisan would expect.
The data shown in Fig. 8 don’t show unexpected results because (1) many of the ASOs in the walk—not just AI-2491—have much better editing than the parent and those comprise mesyls at different locations, and (2) WO278 demonstrates that mesyl-walking was known to produce AONs that exhibit a range of editing efficacy when administered at a dose of 100 nM (see WO278 pp. 41-42 L14-18), depending on the position of the mesyl. Therefore the arguments and data about Example 8/Fig. 8 cannot be deemed to overcome the obviousness rejection.
Regarding Example 13/Fig. 13, Applicant points to Figs. 13C and 13D which show in vivo data. But those data do not show anything unexpected because (1) the editing shown in Fig. 13C is very similar and practically overlaps. Secondly, although Fig. 13D shows the ASO comprising mesyls at the four claimed positions produces higher editing, that is nothing more than what would be expected in view of the prior art because WO278 shows that including more mesyls and including mesyls as linkages between the two nt at the 5’end, the two nt at the 3’end, and position -2 improves editing efficacy. WO278 Fig. 3 shows that the compounds RM107378 and RM107380 have the most effective editing efficiencies of any of the tested compounds. Those compounds comprise mesyls as linkages between the two nt at the 5’end, the two nt at the 3’end, and position -2. WO278 Figs. 3/4 don’t show including more than 3 mesyls but 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. For example, compare RM107385 and (2 mesyl linkages) with RM107378 and RM107380 (3 mesyl linkages). Then it would have been obvious to mesyl walk an additional mesyl at each position. WO278 Fig. 3 shows in vitro data but there is no evidence an artisan shouldn’t or wouldn’t expect improved in vivo editing when applying more mesyl linkages to an AON.
Altogether, Applicant’s arguments that what is shown in the Spec. is unexpected cannot be considered persuasive.
In addition, WO908—which is silent with respect to mesyl linkages—shows (Example 9/Fig. 10/Table 9; Example 10/Fig. 11/Table 10; Example 17/Fig. 20/Table 19) SERPINA E342K targeting editors that comprise various lengths and different modifications. Figs. 10-11 and 20 show that variable editing efficiencies are expected from changing modification patterns of AONs (administered at 300 ng plasmid in 50 µL Opti-MEM, see WO908 ¶182). The variation in editing efficiency shown in those figures is on the same order as what is shown in the figures discussed in Applicant’s arguments.
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.
To overcome this rejection, Applicant should present data showing that ASOs comprising mesyl linkages at the claimed positions are less toxic than ASOs comprising mesyl linkages at other positions. Alternatively Applicant can present data showing the claimed compositions (comprising mesyl at positions +24, +13, -2, and -8) perform better than what would have been expected based on the prior art.
Until those data are presented, it is not possible to determine that the data show the claimed compositions perform better (in terms of improved editing or reduced toxicity) compared with what would have been obvious and expected based on the prior art.
Altogether, the claimed invention falls under an Obvious to Try rationale; see MPEP 2143(I)(E):
To reject a claim based on this rationale, Office personnel must resolve the Graham factual inquiries. Then, Office personnel must articulate the following:
(1) a finding that at the relevant time, there had been a recognized problem or need in the art, which may include a design need or market pressure to solve a problem;
(2) a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem;
(3) a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success; and
(4) whatever additional findings based on the Graham factual inquiries may be necessary, in view of the facts of the case under consideration, to explain a conclusion of obviousness.
The rationale to support a conclusion that the claim would have been obvious is that "a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely that product [was] not of innovation but of ordinary skill and common sense.
In the case of the claimed invention, WO908 teaches (¶89-92, ¶94-100, ¶109-110) about costs and benefits of various modifications including specifically that (¶91) maximum stability is their aim and teaches (¶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. Those teachings indicate that KSR’s requirement of a finding of (1) is satisfied.
Regarding (2), a person of ordinary skill would recognize that any oligont comprises a finite length and therefore comprises only a finite number of linkages that may be modified. An artisan would also recognize that an oligont comprises an inter-nt linkage between any two nucleosides. As discussed, the art provides motivation to make any linkage a mesyl: exceptional resistance to nucleases and an absence of toxic effects. The art provides motivation for changing any PO linkage to a mesyl: Patutina teaches mesyl inter-nt linkages exhibit exceptional stability. Swapping a mesyl linkage for a PO linkage would have made an oligont more stable. The art also provides motivation for changing a PS linkage to a mesyl: WO908 teaches the number of PS linkages in an oligont must be limited because they are toxic and Patutina teaches that mesyl inter-nt linkages—unlike PS linkages—exhibit no toxic effects. Swapping a mesyl linkage for a PS linkage would have made an oligont less toxic. Furthermore, WO278 teaches (Figs. 3-4) walking the position of the mesyl(s) within an AON. Therefore, the art indicates that swapping a mesyl for any PO or PS linkage within an oligont would have predictably improved the oligont by increasing its stability and lessening its toxicity and that it would have been obvious to place a mesyl at any position(s) within an AON. Altering any of a finite number of inter-nt linkages by swapping a mesyl inter-nt linkage for any other linkage creates only a finite number of solutions which, as discussed, would have provided foreseeable benefits discussed by WO908 and Patutina. Therefore, an artisan would reasonably recognize that KSR’s requirement of a finding of (2) is satisfied.
Regarding (3), WO908 teaches about costs and benefits of various modifications and balancing the amount of PS linkages to minimize toxicity. WO361 demonstrates it was customary in the art to use mesyl inter-nt linkages in oligont for editing RNA including SERPINA1. WO278 teaches (Figs. 3-4) walking the position of the mesyl(s) within an AON to find which positions result in the best editing. As discussed in the rejection, the art teaches SERPINA1-targeting sequences of varying lengths, including 34-mers. Altogether, an artisan would have known 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 a reasonable expectation of making the oligont more stable and less toxic. Therefore an artisan would reasonably recognize that KSR’s requirement of a finding of (3) is satisfied.
Any other findings relevant to KSR’s requirement of (4) are thoroughly and convincingly explained in the rejection because Applicant did not argue any other point aside from the obviousness of placing mesyl linkages at positions +24, +13, -2, and -8.
Altogether, the facts dictate that it would have been obvious to try producing the claimed oligont, including the mesyl linkages at positions +24, +13, -2, and -8, in view of the combination of prior art.
NSDP
Applicant argues against the NSDP rejections (pp. 10-13) 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 because those claims indeed recited mesyl linkages at positions +24, +13, -2, and -8.
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, an artisan would have known (1) to replace linkages between nt at the 5’ and 3’ends and position -2 with mesyl linkages and that (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 a reasonable expectation of making the oligont more stable and less toxic. 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.
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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