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 .
Claims 1-15 are pending. Claims 11-12 and 15 are withdrawn from consideration as being drawn to nonelected invention. SEQ ID NO 6 is withdrawn as being drawn to a nonelected species.
Status of the Application
Applicant’s response and amendment filed 09 March 2026 are acknowledged and entered.
Applicant has amended Claims 4-8 and 14.
Response to Amendment
Applicant has amended the Spec. to overcome Objections; the objections are withdrawn.
Applicant has amended Claims 4-6 to overcome Objections; the objections are withdrawn.
Applicant has amended Claims4-5, 7-8, and 14 to overcome the 112(b) rejection; the 112(b) rejections are withdrawn.
The 103 rejection is maintained.
Claims 1-10 and 13-14 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Rejections not reiterated here are withdrawn.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 the European Patent Office (EPO) on 02 February 2021 and 08 November 2021. Certified copies of both priority applications (EP 21154701 and EP 21207002) as required by 37 CFR 1.55 are in the application file.
Information Disclosure Statement
The IDSs have been considered.
Claim Objections
Claims 4-5 and 8 are objected to because of the following informalities:
Claim 5 recites …or a combination thereof of trivalent GalNAc moieties but will be more straightforward if it recites …or a combination thereof or …or a combination of those trivalent GalNAc moieties.
Claims 4 and 8 should have a comma between each item in the list (i.e., after each conjugate listed before or).
Appropriate correction is required.
Claim Interpretation
Claims 13 and 14 recite: The antisense oligonucleotide of Claim 1, for use in…. Claims 13-14 are interpreted as claims to a compound that also recite an intended use. The intended use does not change the structure of the compound, so it provides no patentable weight. See MPEP §2173.05(q).
Although the Figs. themselves are not labeled with SEQ ID NOs, the Spec. describes that (p. 29; Table 1, p. 6) Fig. 1 shows a conjugate comprising SEQ ID NO 3, Fig. 2: SEQ ID NO 4, Fig. 4: SEQ ID NO 5, and Fig. 3: SEQ ID NO 6.
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 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
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) 1-10 and 13-14 are rejected under 35 U.S.C. 103 as being unpatentable over International Patent Application Publication No. WO 2020/011902, published 16 January 2020 (referred to as “WO902”). This rejection is maintained.
Note: All reference page #s refer to the PDF page #.
WO902 is drawn to antisense oligonucleotides for modulating RTEL1 expression. WO902 does not teach the exact same sequences as the instant application, but it teaches sequences comprising the claimed sequences, and the claimed sequences would have been obvious based on the teachings of WO902. WO902 teaches the limitations of all the other claims, as discussed below.
WO902 teaches (Table 3 and pp. 20-21, L25-5) the target nucleic acid is human RTEL1 pre-mRNA which is called SEQ ID NO 1. The following alignments show WO902 SEQ ID NO 1 is 100% complementary to claimed SEQ ID NOs 3-5:
BHE08030
ID BHE08030 standard; cDNA; 38444 BP.
XX
AC BHE08030;
XX
DT 05-MAR-2020 (first entry)
XX
DE Human RTEL1 premRNA, SEQ ID 1.
XX
KW RTEL1 gene; Regulator of telomere elongation helicase 1;
KW Telomere elongation helicase regulator; antiinflammatory;
KW antimicrobial-gen.; antisense oligonucleotide; antisense therapy;
KW chromosome-20; enzyme inhibition; gastrointestinal-gen.; gene silencing;
KW hepatitis b virus infection; hepatotropic; prophylactic to disease; ss;
KW therapeutic; virucide.
XX
OS Homo sapiens.
XX
CC PN WO2020011902-A1.
XX
CC PD 16-JAN-2020.
XX
CC PF 11-JUL-2019; 2019WO-EP068639.
XX
PR 13-JUL-2018; 2018EP-00183477.
XX
CC PA (HOFF ) HOFFMANN LA ROCHE & CO AG F.
CC PA (HOFF ) HOFFMANN LA ROCHE INC.
XX
CC PI Berrera M, Felber J, Hoflack J, Kammler S, Kam-Thong T;
CC PI Leonard B, Pedersen L, Tropberger P, Triyatni M, Turley DJ;
CC PI Wallier A, Zhang JD;
XX
DR WPI; 2020-065545/009.
XX
CC PT RTEL1 inhibitor is used for the treatment or prevention of Hepatitis B
CC PT virus (HBV) infection and is used for the preparation of a medicament for
CC PT the treatment or prevention of hepatitis B virus.
XX
CC PS Claim 11; SEQ ID NO 1; 90pp; English.
XX
CC The present invention relates to a novel regulator of telomere elongation
CC helicase 1 (RTEL1) inhibitor, useful for the treatment or prevention of
CC Hepatitis B virus (HBV) infection. The invention also provides: a single
CC stranded antisense oligonucleotide of 12-30 nucleotides in length, which
CC comprises a contiguous nucleotides sequence of 10 nucleotides which is
CC complementary to a mammalian RTEL1, in particular a human RTEL1, where
CC the oligonucleotide is capable of inhibiting the expression of RTEL1; a
CC method for modulating RTEL1 expression in a target cell which is
CC expressing RTEL1 in vivo or in vitro; and a method for treating or
CC preventing a disease. The disease is Hepatitis B virus (HBV). Note: This
CC sequence is described in the specification as a premRNA but is shown as a
CC DNA sequence.
XX
SQ Sequence 38444 BP; 6969 A; 11516 C; 11407 G; 8552 T; 0 U; 0 Other;
Query Match 100.0%; Score 18; Length 38444;
Best Local Similarity 100.0%;
Matches 18; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 AATTTTACATACTCTGGT 18 SEQ ID NO 3
||||||||||||||||||
Db 11774 AATTTTACATACTCTGGT 11757 WO902 SEQ ID NO 1
Query Match 100.0%; Score 19; Length 38444;
Best Local Similarity 100.0%;
Matches 19; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 AATTTTACATACTCTGGTC 19 SEQ ID NO 4
|||||||||||||||||||
Db 11774 AATTTTACATACTCTGGTC 11756 WO902 SEQ ID NO 1
Query Match 100.0%; Score 18; Length 38444;
Best Local Similarity 100.0%;
Matches 18; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 TTACATACTCTGGTCAAA 18 SEQ ID NO 5
||||||||||||||||||
Db 11770 TTACATACTCTGGTCAAA 11753 WO902 SEQ ID NO 1
WO902 teaches that (PDF p. 21 L5-15 and 25-29), the “target” sequence can be longer than the complementary oligonucleotide and that the oligonucleotide is a contiguous sequence of 10-35 nucleotides.
WO902 further teaches the oligo SEQ ID NO 36 which comprises the nucleotide sequences of claimed SEQ ID NO 3, as shown by the sequence alignment below:
Instant SEQ ID NO 3
Query Match 100.0%; Score 18; Length 19;
Best Local Similarity 100.0%;
Matches 18; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 AATTTTACATACTCTGGT 18 SEQ ID NO 3
||||||||||||||||||
Db 2 AATTTTACATACTCTGGT 19 WO902 SEQ ID NO 36
WO902 teaches SEQ ID NO 35 which comprises the nucleotide sequences of claimed SEQ ID NOs 3 and 4, as shown by the sequence alignments below:
Instant SEQ ID NO 3
Query Match 100.0%; Score 18; DB 85; Length 20; Best Local Similarity 100.0%;
Matches 18; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 AATTTTACATACTCTGGT 18
||||||||||||||||||
Db 2 AATTTTACATACTCTGGT 19 WO902 SEQ ID NO 35
Instant SEQ ID NO 4
Query Match 100.0%; Score 19; DB 85; Length 20; Best Local Similarity 100.0%;
Matches 19; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 AATTTTACATACTCTGGTC 19
|||||||||||||||||||
Db 2 AATTTTACATACTCTGGTC 20 WO902 SEQ ID NO 35
WO902 teaches the oligo SEQ ID NO 33 which comprises the nucleotide sequence of claimed SEQ ID NO 5, as shown by the sequence alignment below:
Query Match 100.0%; Score 18; DB 85; Length 20; Best Local Similarity 100.0%;
Matches 18; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 TTACATACTCTGGTCAAA 18
||||||||||||||||||
Db 3 TTACATACTCTGGTCAAA 20 WO902 SEQ ID NO 33
Regarding WO902 SEQ ID NO 33 specifically, the full oligo is TTttacatactctggtCAAA. WO902 teaches (PDF p. 69 L8-11) that the capital letters (shown here bolded) are beta-D-oxy LNA nucleosides, lowercase letters represent DNA nucleosides, all LNA C are 5-methyl cytosine… and all internucleoside linkages are phosphorothioate internucleoside linkages. Regarding all the reference oligonucleotides, WO902 teaches (p. 47 L 13-28) that the oligo comprises 1-8 LNA nucleosides which may be beta-D-oxy LNA nucleosides and which confer nuclease stability if placed at the 5’ and 3’ ends; that sometimes all LNA cytosine units are 5-methyl-cytosine; and that all internucleotide linkages may be phosphorothioate linkages. WO902 teaches (pp. 44-45 L10-10) that the oligonucleotides should be complementary to the target sequence and can be 16-22 contiguous nucleic acids in length or (p. 6 L24-36) 18 or 19 nt in length.
Therefore, it would have been obvious to an artisan before the effective filing date of the instant invention to shorten the WO902 sequences and to modify which bases are beta-D-oxy LNA nucleosides in order to arrive at claimed SEQ ID NOs 3-5. One would have been motivated to do so because WO902 teaches (p. 21 L12-15) that certain target regions may be preferred. Furthermore, WO902 teaches that (p. 7 L 14-21) the provided oligos comprise a library which exists with the purpose of identifying the most potent sequence within the library. Furthermore, WO902 teaches that (p. 22-23 L19-10) genes or gene transcripts are known to have some natural variation such as SNPs and that the invention includes oligos that target such natural variants, so long as there is sufficient complementarity between the target and the oligo. One would have been motivated to place LNA nucleosides at the 3’ and 5’ terminal ends because WO902 teaches (p. 47 L15-30) it is advantageous for the nuclease stability of the oligonucleotide or contiguous nucleotide sequence to have at least 1 LNA nucleoside at the 5' end and at least 2 LNA nucleosides at the 3’ end of the nucleotide sequence and because Table 6 (pp. 62-69) shows ASOs comprising 1-4 LNA nts at the 5’end and 2-4 LNA nts at the 3’end. Therefore, all the SEQ ID NOs of Claim 1 would have been obvious or would have been derived by an artisan through routine experimentation.
Regarding Claims 2-3: WO902 teaches (p. 33 L5-24) trivalent N-acetylgalactosamine conjugate moieties that can bind the asialoglycoprotein receptor and enhance uptake of the oligo by the liver. WO902 teaches that such moieties are covalently linked to an oligo.
Regarding Claims 4-5: Fig. 1D, shown below, teaches the structure of instant Fig. 5D:
PNG
media_image1.png
258
437
media_image1.png
Greyscale
Note that the bold lines show double bonds rendered in poor quality. That is made clear by the fact that WO902 teaches (Figs. 1AB) the same GalNAc structure where the double bonds are clear. WO902 teaches that (p. 49 L19-23) the conjugate moiety, such as that shown in Fig. 1D, is attached to the 3’ or 5’ end of the oligo.
Regarding Claims 6-7: Embodiments 75-78 (p. 61) teach a linker between the conjugate moiety and the antisense oligonucleotide. The linker is comprised of 2-5 consecutive phosphodiester linkages.
As described above, the sequences of Claim 1 would have been obvious to an artisan. Linking them to the conjugate moieties is explicitly taught by WO902. One would have been motivated to do so because the conjugates increase binding to the liver and HBV is a liver disease. Therefore, the limitations of Claims 2-7 would have been obvious to an artisan based on the teachings of WO902. Producing an antisense oligo covalently linked to the GalNAc moiety in WO902 Fig. 1D would have produced the limitations of Claim 8.
Regarding Claims 9-10: WO902 teaches (p. 49 L30-33) mixing the oligo or conjugated oligo with a pharmaceutically acceptable diluent, solvent, carrier, salt and/or adjuvant. P. 50 L23-25 teach pharmaceutical compositions comprising any of the aforementioned oligonucleotides and/or oligonucleotide conjugates or salts thereof and a pharmaceutically acceptable diluent, carrier, salt and/or adjuvant. Those passages describe a pharmaceutical composition comprising the antisense oligont; therefore, WO902 teaches the limitations of Claims 9-10.
Regarding Claims 13-14: WO902 teaches that (p. 3 L21-32) their invention is capable of inhibiting RTEL1 expression in vitro and in vivo and applies such inhibition to treating and/or preventing HBV infection. WO902 further teaches (p. 4 L5-15) that administering an effective amount of the invention modulates RTEL1 expression. WO902 specifies that (p. 2 L7) their invention also treats and/or prevents chronic HBV infection. WO902 specifies that (p. 4 L 14) the antisense oligos are for a subject suffering from or susceptible to the disease, disorder, or dysfunction. It is clear that these compounds are to be used in medicine or in the preparation of medicaments for treating and/or preventing HBV infection. Therefore, WO902 teaches the limitations of Claims 13-14. Claims 13-14 describe intended or potential uses (Claim 13 “in medicine”; Claim 14 “in treatment or prevention of HBV infection”). It is noted that a compound will have an effect no matter its intended use.
Regarding Claims 9-10 and 13-14, the sequences of Claim 1 would have been obvious to an artisan as described above. One would have been motivated to make these RTEL1-targeting sequences into a pharmaceutical composition for treating and/or preventing HBV or chronic HBV because WO902 teaches that its invention is (§Abstract) RTEL1-inhibiting antisense oligos that are useful for treating and/or preventing HBV including chronic HBV and because WO902 teaches (pp. 4-5 L30-2) HBV is responsible for approximately 686,000 deaths per year.
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 no7 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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1-10 and 13-14 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of US Pat. No. 12497621 (reference patent, “App797”), filed 13 January 2021 in view of International Patent Application Publication No. WO 2020/011902, published 16 January 2020 (referred to as “WO902”). Note: Application No. 17/147797 issued as US Pat. No. 12497621 on 16 December 2025 so this rejection has converted to a nonprovisional NSDP rejection; this rejection is not considered a new grounds of rejection. This rejection is maintained.
Although the claims at issue are not identical, they are not patentably distinct from each other because the claims are directed to overlapping subject matter. The instant claims are directed to antisense oligonucleotides for modulating RTEL1 expression and for treating HBV. The claimed ASOs comprise specific sequences and specific modifications. The claimed ASOs can comprise GalNAc.
The App797 allowed claims are directed to a method of treating or preventing HBV in a subject by administering an RTEL1 inhibitor that can be a 12- to 60-mer oligonucleotide that is at least 95% complementary to a mammalian RTEL1 target nucleic acid or to App797 SEQ ID NOs 1 or 2. An artisan would have readily recognized that the instantly claimed SEQ ID NOs are 18- to 19-mers that are 100% complementary to App797 SEQ ID NO 1 as shown by the following representative alignment of claimed SEQ ID NO 3:
US-17-147-797-1
Filing date in PALM: 2021-01-13
Sequence 1, US/17147797
Publication No. US20210147850A1
GENERAL INFORMATION
APPLICANT: Hoffmann-La Roche Inc.
TITLE OF INVENTION: OLIGONUCLEOTIDES FOR MODULATING RTEL1 EXPRESSION
FILE REFERENCE: 51551-005003
CURRENT APPLICATION NUMBER: US/17/147,797
CURRENT FILING DATE: 2021-01-13
PRIOR APPLICATION NUMBER: PCT/EP2019/068639
PRIOR FILING DATE: 2019-07-11
PRIOR APPLICATION NUMBER: EP 18183477.1
PRIOR FILING DATE: 2018-07-13
NUMBER OF SEQ ID NOS: 246
SEQ ID NO 1
LENGTH: 38444
TYPE: DNA
ORGANISM: hsapiens
Query Match 100.0%; Score 18; Length 38444;
Best Local Similarity 100.0%;
Matches 18; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 AATTTTACATACTCTGGT 18
||||||||||||||||||
Db 11774 AATTTTACATACTCTGGT 11757
Therefore, using the App797 method to inhibit RTEL1 to treat HBV would have been obvious to a person of ordinary skill in the art.
The App797 claims do not recite any modified LNA nt, 5-methyl Cs, PS linkages, or GalNAc, but the art of WO902 teaches the limitations that the App797 claims don’t teach.
WO902 teaches (PDF p. 69 L8-11) SEQ ID NOs comprising bolded capital letters that are beta-D-oxy LNA nucleosides, wherein lowercase letters represent DNA nucleosides, all LNA C are 5-methyl cytosine… and all internucleoside linkages are phosphorothioate internucleoside linkages. WO902 teaches (p. 47 L 13-28) that their oligos comprise 1-8 LNA nucleosides which may be beta-D-oxy LNA nucleosides and which confer nuclease stability if placed at the 5’ and 3’ ends; that sometimes all LNA cytosine units are 5-methyl-cytosine; and that all internucleotide linkages may be phosphorothioate linkages. WO902 teaches (p. 21 L12-15) that certain target regions may be preferred. Furthermore, WO902 teaches that (p. 7 L 14-21) the provided oligos comprise a library which exists with the purpose of identifying the most potent sequence within the library. Those teachings would have motivated an artisan to optimize RTEL1-targeting ASOs.
Furthermore, WO902 describes RTEL1-inhibiting ASOs that are covalently attached to GalNAc, including the instantly claimed GalNAc (see Fig. 1). WO902 Fig. 1D, shown below, teaches the structure of instant Fig. 5D:
PNG
media_image1.png
258
437
media_image1.png
Greyscale
Note that the bold lines show double bonds rendered in poor quality. That is made clear by the fact that WO902 teaches (Figs. 1AB) the same GalNAc structure where the double bonds are clear. WO902 teaches that (p. 49 L19-23) the conjugate moiety, such as that shown in Fig. 1D, is attached to the 3’ or 5’ end of the oligo. WO902 teaches (p. 33 L5-24) trivalent N-acetylgalactosamine conjugate moieties that can bind the asialoglycoprotein receptor and enhance uptake of the oligo by the liver. WO902 teaches that such moieties are covalently linked to an oligo.
It would have been obvious to a person of ordinary skill to attach the GalNAc of WO902 to the ASOs of the App797 clams for the benefit of enhancing uptake of the oligo by the liver when using the ASOs to treat HBV, a liver disease.
Therefore, the claimed antisense oligos for inhibiting RTEL1 to treat HBV would have been obvious to a person of ordinary skill in the art in view of the App797 claims and WO902.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-10 and 13-14 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over copending claims 4-7, 10-17, and 19-26 of copending Application No. 19/320635 (reference application, “App635”), filed 05 September 2025. This rejection is maintained.
Although the claims at issue are not identical, they are not patentably distinct from each other because the claims are directed to overlapping subject matter. The instant claims are directed to antisense oligonucleotides for modulating RTEL1 expression and for treating HBV. The claimed ASOs comprise specific sequences and specific modifications. The claimed ASOs can comprise GalNAc.
The copending App635 claims are directed to oligont RTEL1 inhibitors that can be a 12- to 60-mer oligonucleotide that is at least 95% complementary to a mammalian RTEL1 target nucleic acid or to App635 SEQ ID NOs 1 or 2; wherein the oligont can be a single-stranded ASO, can be 100% complementary to various SEQ ID NOs (SEQ ID NOs 3-237), wherein the oligont can comprise LNA nt; wherein the oligont can be incorporated into an ASO-moiety conjugate comprising a trivalent GalNAc attached to the ASO via a 5’ or 3’ linker or the specific GalNAcs in App635 Fig. 1; and a pharmaceutical composition comprising the ASO and a carrier or salt. An artisan would have readily recognized that the instantly claimed SEQ ID NOs are 18- to 19-mers that are 100% complementary to App635 SEQ ID NO 1 as shown by the following representative alignment of claimed SEQ ID NO 3:
US-19-320-635-1/c
Query Match 100.0%; Score 18; DB 1; Length 38444;
Best Local Similarity 100.0%;
Matches 18; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 AATTTTACATACTCTGGT 18
||||||||||||||||||
Db 11774 AATTTTACATACTCTGGT 11757
In addition, App635 claims recite SEQ ID NO 11 which comprises 100% complementarity to claimed SEQ ID NO 4, as shown by the following alignment:
US-19-320-635-11/c
Query Match 100.0%; Score 19; DB 1; Length 26;
Best Local Similarity 100.0%;
Matches 19; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 AATTTTACATACTCTGGTC 19
|||||||||||||||||||
Db 23 AATTTTACATACTCTGGTC 5
Although App635 claims do not explicitly recite 5-methyl modified cytosines, LNAs, or PS linkages, those claims recite SEQ ID NOs 22-237 so an artisan would have looked at the Spec. to understand what those are and they would have found (Table 6) those claimed SEQ ID NOs comprise beta-D-oxy LNAs, 5-methyl Cs, and PS linkages. An artisan wouldn’t know what are the GalNAcs shown in App635 Fig. 1 but they would have examined the Fig. and found that it shows the same GalNAcs as what are instantly claimed. Therefore, the claimed antisense oligos for inhibiting RTEL1 to treat HBV are merely variants of what is encompassed by the App635 claims and would have been obvious to a person of ordinary skill in the art, the product of routine optimization, and/or obvious to try.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-10 and 13-14 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over copending claims 1-23 of copending Application No. 18/742763 (reference application, “App763”, filed 13 June 2024) in view of WO902. This rejection is maintained.
Although the claims at issue are not identical, they are not patentably distinct from each other because the claims are directed to overlapping subject matter. The instant claims are directed to antisense oligonucleotides for modulating RTEL1 expression and for treating HBV. The claimed ASOs comprise specific sequences and specific modifications. The claimed ASOs can comprise GalNAc.
The copending App763 claims are directed to a composition comprising an inhibitor of RTEL1 and an inhibitor of PUBP1. The App763 claims recite that the RTEL1 inhibitor can be an oligont RTEL1 inhibitor that can be a 12- to 60-mer oligonucleotide that is at least 95% complementary to a mammalian RTEL1 target nucleic acid or to App763 SEQ ID NOs 1 or 2; that the inhibitor can be an RTEL1-inhibiting ASO comprising SEQ ID NOs 243-246 which comprise beta-D-oxy LNAs, 5-methyl Cs, and PS linkages. At least App763 SEQ ID NO 243 is 100% identical to claimed SEQ ID NO 3 as shown by the following alignment and snapshot of Claim 7:
US-18-742-763-243
Query Match 100.0%; Score 18; DB 1; Length 18;
Best Local Similarity 100.0%;
Matches 18; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 AATTTTACATACTCTGGT 18
||||||||||||||||||
Db 1 AATTTTACATACTCTGGT 18
PNG
media_image2.png
228
656
media_image2.png
Greyscale
The copending App763 claims do not recite any GalNAc but WO902 describes RTEL1-inhibiting ASOs that are covalently attached to GalNAc, including the instantly claimed GalNAc (see Fig. 1). WO902 Fig. 1D, shown below, teaches the structure of instant Fig. 5D:
PNG
media_image1.png
258
437
media_image1.png
Greyscale
Note that the bold lines show double bonds rendered in poor quality. That is made clear by the fact that WO902 teaches (Figs. 1AB) the same GalNAc structure where the double bonds are clear. WO902 teaches that (p. 49 L19-23) the conjugate moiety, such as that shown in Fig. 1D, is attached to the 3’ or 5’ end of the oligo. WO902 teaches (p. 33 L5-24) trivalent N-acetylgalactosamine conjugate moieties that can bind the asialoglycoprotein receptor and enhance uptake of the oligo by the liver. WO902 teaches that such moieties are covalently linked to an oligo.
It would have been obvious to a person of ordinary skill to attach the GalNAc of WO902 to the ASOs of the App763 clams for the benefit of enhancing uptake of the oligo by the liver when using the ASOs to treat HBV, a liver disease.
Therefore, the claimed antisense oligos for inhibiting RTEL1 to treat HBV would have been obvious to a person of ordinary skill in the art in view of the App763 claims and WO902.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicant's arguments filed 09 March 2026 have been fully considered but they are not persuasive. Arguments that are no longer relevant are not addressed.
103
Applicant argues that there must have been a motivation for an artisan to modify the teachings of the prior art.
That argument isn’t persuasive because the rejection discusses that WO902 teaches multiple sequences, (p. 21 L12-15) that there are certain preferred target regions and that (p. 7 L 14-21) the provided oligos comprise a library which exists with the purpose of identifying the most potent sequence within the library. That passage (p. 7) discusses design variants (child nucleic acid molecules) and other teachings in WO902 about length variation (e.g., p. 6 L24-36) would have indicated to an artisan that they could alter the parent ASO sequences within the parameters disclosed for the benefit of identifying the most potent sequence. Those WO902 passages indicate it was routine and conventional in the art of ASO design to shorten a parent ASO sequence within certain length parameters, including the specific lengths of 18- and 19-mer, which are the lengths of the claimed ASOs.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). Here, the rejection explains that each element of the claims was disclosed in the reference.
Then Applicant argues (p. 24, full ¶1-3) that the instantly claimed compounds have enhanced safety and efficacy compared with those in WO902. Applicant points to Example 5, Table 13, and Fig. 9. Applicant argues that claimed compound ID 5_1 demonstrates unexpected knockdown activity when compared to the compounds disclosed in [WO902], an effect maintained by the first and second metabolites, as demonstrated by their IC50 values, and that a person of skill would have no reason to expect the increased potency.
Those arguments aren’t found persuasive for several reasons. First, Applicant doesn’t specify which specific compounds in the Spec. should be compared with which specific compounds in WO902.
Assertions of unexpectedly good outcomes must be compared with the closest prior 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.”
Second, looking at the sequences, it is determined that the compound comprising claimed SEQ ID NO 3 (compound 3_1) has an IC50 of 0.7. The closest prior art is WO905 SEQ ID NOs 36 and 35 (Spec. SEQ ID NOs 21 and 22) which are, respectively, Spec. compounds 7_1 and 8_1 and which have, IC50s of, respectively, 0.6 and 0.3. Those are slightly lower than the IC5050 of the claimed compound comprising SEQ ID NO 3 (i.e., 0.7) which means the WO902 compounds are actually slightly more potent than the claimed compound.
Regarding claimed SEQ ID NO 4 (compound 4_1, IC50 = 0.2), the closest prior art is WO902 SEQ ID NO 35 which corresponds to Spec. compound 8_1, whose IC50 is 0.3. IC50 of 0.2 vs. 0.3 constitutes negligible differences well within the range of what might be expected when, e.g., using a shorter sequence comprising fewer toxic PS linkages. Those results are not anything unexpectedly good, or at least Applicant hasn’t explained why they are.
Finally, claimed SEQ ID NO 5 (compound 5_1) has an IC50 of 0.9 and the closest prior art is WO902’s SEQ ID NO 33 which corresponds to Spec. SEQ ID NO 26/compound 12_1), whose IC50 is 0.8 which is actually slightly less than that of the claimed compound comprising SEQ ID NO 5 (i.e., 0.9). All these comparisons are based on Spec. Table 11 and are compiled in the following Table.
Claimed
Closest prior art as tested in Spec.
Claimed SEQ ID NO
Compound ID in Spec.
IC50
SEQ ID NO in Spec.
(SEQ ID NO in WO902)
Compound ID in Spec.
(Compound ID in WO902)
IC50 in Spec.
Table 11
3
3_1
0.7
21 (36)
22 (35)
7_1 (36_1)
8_1 (35_1)
0.6
0.3
4
4_1
0.2
22 (35)
8_1 (35_1)
0.3
5
5_1
0.9
26 (33)
12_1 (33_1)
0.8
Spec. Table 13 doesn’t have a head-to-head basis for comparison of compound 5_1 vs 12_1, but the data in that table indicate that the IC50s of the WO902 SEQ ID NOs that correspond to Spec. compounds 7_1 and 8_1 are also lower than the IC50 of compound 5_1. Table 13 also shows that the compounds provide nearly identical knockdown efficiencies.
Applicant’s discussion of other metabolites aren’t relevant because those metabolites aren’t claimed.
Regarding Fig. 9, it doesn’t show any unexpectedly good results, either. Nothing shown in that figure shows that the claimed compounds have any sort of unexpected increased potency.
Applicant hasn’t discussed the details of the asserted enhanced safety, so that argument isn’t persuasive either.
Applicant also points to certain ¶# (¶488 and ¶447) but the Spec. doesn’t have any ¶#s, so those points are unclear and Applicant should clarify.
Altogether Applicant hasn’t discussed any results that can be deemed “unexpected”, so the 103 rejections are maintained.
NSDP
Applicant has stated that they will address the NSDP rejections once the claims are in condition for allowance. All the NSDP rejections are maintained.
Conclusion
Claims 1-10 and 13-14 are rejected.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to 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 on (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