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 .
DETAILED ACTION
Status of Application/Amendment/Claims
Applicant's response filed 01/16/2026 has been considered. Rejections and/or objections not reiterated from the previous office action mailed 09/18/2025 are hereby withdrawn. The following rejections and/or objections are either newly applied or are reiterated and are the only rejections and/or objections presently applied to the instant application. The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
With entry of the amendment filed on 01/16/2025, claims 1-13, 15-17, 19, 20, 24, 28 and 34 are pending and are currently under examination.
The 102 and 103 rejections of record are withdrawn in response to claim amendments.
Claim Objections
Claim 9 is objected to because of the following informalities: The claim does not end in a period. Appropriate correction is required
New Rejections – necessitated by claim amendments
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1, 3, 4, 5, 8, 19, 20, 24 and 34 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Miraglia, et al. (US 2003/0203862).
Regarding claims 1, 3 and 8 Miraglia et al. teach an ASO comprising 20 nucleotides in length comprising 5’ and 3’ wings comprising 2'-methoxyethyl (2'-MOE) nucleotides and a central gap having 10 nucleotides wherein the ASO comprises a least 1 G-clamp modification as shown in Table 24.
Regarding claim 4, Miraglia et al. teach the G-clamp is in the wing (ISIS 139364 in Table 24).
Regarding claim 5, 19 and 20, Miraglia et al. teach the ASO comprising one or more phosphorothioate linkages (Table 24).
Regarding claims 24, Miraglia et al. teach pharmaceutical compositions (0054).
Regarding claims 34, Miraglia et al. teach methods of decreasing expression in a subject (0002, 0018).
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The oligonucleotides are shown in Table 24. ISIS 111175-111178, ISIS 139364 and ISIS 142960 are chimeric oligonucleotides ("gapmers") 20 nucleotides in length, composed of a central "gap" region consisting of 2'-deoxynucleotides, which is flanked on both sides (5' and 3' directions) by nucleotide "wings". The wings are composed of 2'-methoxyethyl (2'-MOE)nucleotides and are shown in bolded text. ISIS 111169-111174 and ISIS 138702 are phosporothioate oligonucleotides composed only of 2'-deoxynucleotides. The internucleoside (backbone) linkages are phosphorothioate (P.dbd.S) throughout all of the oligonucleotides. Select cytidine residues have been modified to 5-methylcytidine and these positions are noted in the table. In addition, certain cytosines have been replaced with the cytosine derivative, 1,3-diazaphenoxazine-2-one (G-clamp) and these are noted in the table. All sequences have SEQ ID NO: 15
Thus Miraglia et al. anticipates the instant claims.
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.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
Claims 7, 9-11, is/are rejected under 35 U.S.C. 103 as being unpatentable over Miraglia, et al. (US 2003/0203862) and Miroshnichenko et al. (PNAS | January 22, 2019 | vol. 116 | no. 4 | 1229–1234 cited on 892 mailed 09/18/2025).
Miraglia, et al. do not teach use of mesyl phosphoramidate linkages.
Miroshnichenko et al. teach the use of mesyl phosphoramidate linkages in antisense oligonucleotides as an alternative to phosphorothioate linkages (see page 1230 first col.). Miroshnichenko et al. teach an ASO fully modified with a mesyl phosphoramidate linkages which meets the limitations of claim 10. Miroshnichenko et al. concludes that μ-ODNs can be an attractive alternative to PS-ODNs as a potent tool in antisense applications and in other cases to prevent the synthesis, expression of RNAs and stability (see page 1233 last para col. 1 and abstract).
It would have been obvious to one of ordinary skill in the art to incorporate mesyl phosphoramidate linkages through the ASO taught by Miraglia, et al. to improve effects often seen with phosphorothioate linkages. One would have wanted to use said linkages because they are known to have advantages such as RNA affinity and nuclease stability as taught by Miroshnichenko et al.
Further, ASOs have the function by binding to RNA, triggering RNase H-mediated degradation of the target, and are used for silencing a target for inhibition of expression. Each inhibitory molecule is made up of nucleotides and phosphate linkages that would benefit from improvement in toxicity and functionality. Because Miroshnichenko et al. teach ASOs with mesyl linkages have lower toxicity compared to phosphorothioate and more efficient activation of RNase H, one of skill in the art would have wanted to try incorporating the mesyl linkages into the gapmers in different locations on the nucleotide strand to improve the toxicity and functiontionality. Moreover, given there was a need to improve ASOs and Miroshnichenko et al. teach a finite number of options, incorporation of mesyl linkages, one of skill in the art would have used this option.
Thus in the absence of evidence to the contrary, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed.
Claims 12 and 13 is/are rejected under 35 U.S.C. 103 as being unpatentable over Miraglia, et al. (US 2003/0203862) and Østergaard, Michael E., et al. ("Efficient synthesis and biological evaluation of 5′-GalNAc conjugated antisense oligonucleotides." Bioconjugate chemistry 26.8 (2015): 1451-1455 cited on 892 mailed 09/18/2025).
Miraglia, et al. is relied upon above but do not teach the ASO further comprises a galactosamine.
With respect to claims 12 and 13, Ostergaard et al. teach evaluation of antisense oligonucleotides comprising a GalNac conjugation and teach efficient delivery of the oligonucleotide using a conjugate with structures as claimed (see Table 1and Figure 1).
It would have therefore been obvious to conjugate a GalNac moiety as it was well known in the art as an efficient conjugate for delivery of antisense oligonucleotide to cells,
Thus in the absence of evidence to the contrary, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed.
Claims 1, 2, 12, 15, 17 and 28 is/are rejected under 35 U.S.C. 103 as being unpatentable over Javanbakh et al. (US 2016/0010093), Flanagan et al. (Proc. Natl. Acad. Sci. USA 96 (1999) cited on 892 mailed 09/18/2025) and Shrestha et al. ("Guanidine bridged nucleic acid (GuNA): an effect of a cationic bridged nucleic acid on DNA binding affinity." Chemical Communications 50.5 (2014): 575-577).
Javanbakh et al. teach Chronic hepatitis B infection (CHB) is an area of high unmet medical need. Javanbakh teach methods of treatment of HBV by liver-specific targeting using a LNA gapmer conjugated to a cluster of three N-acetylgalactosamine (GalNAc) moieties that direct specific binding to the asialoglycoprotein receptor (ASGPR) expressed specifically on the surface of hepatocytes (see Fig. 3). Javanbakh et al. teach the gapmer can have any one of motifs 3-10-3, 3-10-2, 3-9-3, 3-9-2, 3-8-3, 3-8-2 wherein the wings are LNA (870-876). Javanbakh et al. do not teach the antisense comprises a modified nucleotide such as a G-clamp or guanidine bridged nucleic acids (GuNA).
Flanagan et al. teach the G-clamp heterocycle modification, a cytosine analog that clamps on to guanine by forming an additional hydrogen bond, was rationally designed to enhance oligonucleotide-RNA hybrid affinity. Flanagan et al. teach incorporation of a single G-clamp modification into a previously optimized 20-mer phosphorothioate antisense S-ON targeting c-raf increased the potency of the S-ON 25-fold. The G-clamp heterocycle is a potent, mismatch-sensitive, automated synthesizer- compatible antisense S-ON modification that will have important applications in the elucidation of gene function, the validation of gene targets, and the development of more potent antisense-based pharmaceuticals (see abstract).S\
Shrestha et al. teach guanidine bridged nucleic acids (GuNA) modification of an antisense oligonucleotide, placed at the terminal ends, increased the binding affinity for the target and had increased stability (see Fig. 1 and page 576).
It would have been obvious to one of ordinary skill in the art to incorporate a G-clamp into the antisense oligonucleotide of Javanbakh et al. given Flanagan et al. teach the G-clamp increases potency. One would have been motivated to modify the antisense oligonucleotide of Javanbakh et al. in methods of treatment of HBV which is area of high unmet medical need. Further one of skill would have been motivated to incorporate guanidine bridged nucleic acids (GuNA) modification to increase the biding affinity to the target as shown by Shrestha et al.
Thus in the absence of evidence to the contrary, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed.
Response to Arguments
The rejections above were necessitated by amendments however some of the same references were used in the new rejections so arguments against those references will be addressed. Also Javanbakh et al. is the same author as in the previous 103 but this reference is a Patent Application.
Applicant argues Flanagan fails to teach or suggest the presently claimed ASO with one or more of the modified oligonucleotides such a G-clamp. In response, Flanagan was used in a 103 and the invention as a whole would have been obvious for the reasons disused above. Flanagan was not cited for teaching an ASO but was relied upon for making the use of a G-clamp in an ASO obvious.
Applicant then argues that the Examiner is required to consider all of the art of record and although Stanton was not part of the rejection, Stanton explicitly states longer ASOs were less active and because Stanton post-dates Flanagan by 13 years, it is closer to the understanding in the art as of the filing date.
With respect to Stanton stating the longer ASOs were less active, this argument is not persuasive because Stanton was referring to gapmers having a 5-10-5 configuration. The gapmers used in Stanton are 14 nt in length and the gapmers used in Javanbakh are 14-16 nucleotides in length and all show they are capable of knocking down expression (see Javanbakh et al. Table 5). Therefore the art does not dissuade one skilled in the art to modify the gapmer of Javanbakh with a G-clamp for use in targeting a gene.
Applicant’s argument regarding Stanton post-dating Flanagan by 13 and is closer to the understanding in the art as of the filling date is unsubstantiated and does not provide a convincing argument to negate what the reference teaches. Prior art references are used for what is taught, regardless of the date as compared to other reference dates in the rejections. A later filed reference does not mean that it is closer to the understanding in the art. Unless Applicant points to the Stanton reference where there is a conclusive statement that longer gapmers should not be used or gapmers with the configurations as taught in Javanbakh et al., the argument is not persuasive because there is no factual evidence provided. MPEP 2145 states an argument does not replace evidence wherein evidence is necessary, such as in this case. Moreover the arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965). (see MPEP 716.01(c)).
Applicant argues that Miroshnichenko et al. cannot be combined with a reference teaching gapmers because [t]hese references each address fundamentally different problems, and a person of ordinary skill would not combine them. Stanton relates to gapmer ASOs with phosphorothioate backbones and LNA wings for therapeutic gene knockdown (p. 345). Miroshnichenko, by contrast, targets microRNAs using fully mesyl phosphoramidate-modified oligonucleotides, demonstrating activity against miR-21 and others (pp. 1231-1232, Table 1). Applicant goes on to argue the tODNs disclosed in Miroshnichenko are NOT gapmers and function according to an altogether different mechanism of action. MPEP 2143.01(V) clearly instructs that "[i]f the proposed modification or combination of the prior art would change the principle of operation of the prior art invention being modified, then the teachings of the references are not sufficient to render the claims prima facie obvious," and here the principle of operation of Miroshnichenko'stODNs and Stanton's ASOs is objectively different.
Applicant’s arguments are not persuasive. Both the gapmer oligonucleotides cited above and the oligonucleotides of Miroshnichenko et al. function by binding to RNA, triggering RNase H-mediated degradation of the target, and are used for silencing a target for inhibition of expression. Each inhibitory molecule is made up of nucleotides and phosphate linkages that would benefit from improvement in toxicity and functionality. Because Miroshnichenko et al. teach ASOs with mesyl linkages has lower toxicity compared to phosphorothioate and more efficient activation of RNase H, one of skill in the art would have wanted to try incorporating the mesyl linkages into the gapmers cited above to improve the toxicity and functiontionality. Moreover, given there was a need to improve ASO’s and Miroshnichenko et al. teach a finite number of options, incorporation of mesyl linkages, one of skill in the art would have used this option.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a).
706.07(a) Final Rejection, When Proper on Second Action [R-07.2015]
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Second or any subsequent actions on the merits shall be final, except where the examiner introduces a new ground of rejection that is neither necessitated by applicant’s amendment of the claims, nor based on information submitted in an information disclosure statement filed during the period set forth in 37 CFR 1.97(c) with the fee set forth in 37 CFR 1.17(p). Where information is submitted in an information disclosure statement during the period set forth in 37 CFR 1.97(c) with a fee, the examiner may use the information submitted, e.g., a printed publication or evidence of public use, and make the next Office action final whether or not the claims have been amended, provided that no other new ground of rejection which was not necessitated by amendment to the claims is introduced by the examiner. See MPEP § 609.04(b).
Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee 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 date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KIMBERLY CHONG at 571-272-3111. The examiner can normally be reached Monday thru Friday 9-5 pm.
If attempts to reach the examiner by telephone are unsuccessful please contact the SPE for 1636 Neil Hammell at 571-272-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KIMBERLY CHONG/Primary Examiner, Art Unit 1636