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 .
Drawings
In view of MPEP 1606, the objection to the drawings is withdrawn.
Response to Arguments
Applicant’s arguments, see pages 6-7, filed 11/21/25, with respect to the rejection(s) of claim 1 under 103 based on WO 2020196890 (US 20220010348) and US 20110137010 have been fully considered and are persuasive. Therefore, the rejection has been withdrawn because applicant filed a certified English translation of the foreign priority application (JP2020072234 filed on 4/14/20). The applicant perfected the priority to the foreign application filed on 4/14/20.
Applicant’s arguments, see pages 6-7, filed 11/21/25, with respect to the rejection(s) of claim 1 under 103 based on WO9829430 taken with WO2017083747 have been fully considered and are persuasive. Therefore, the rejection has been withdrawn because of the amendment to claim 1 to recite at least one phosphorothioate bond and at least one 2’OMe modification. ‘430 and ‘747 do not teach or suggest making an oligonucleotide having both modifications.
Upon further consideration, a new ground(s) of rejection is made in view of the amendment to claim 1 and the addition of new claims 2 and 3.
The argument “it is general knowledge in the field of the claimed invention that as the strand length becomes longer, it is more difficult to obtain a nucleic acid with high purity.” is not found persuasive because other than applicant's assertion, there is no evidence of record to support applicant's assertion. “The arguments of counsel cannot take the place of evidence in the record.” See In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997) (“An assertion of what seems to follow from common experience is just attorney argument and not the kind of factual evidence that is required to rebut a prima facie case of obviousness.”). One of skill in the art could order the oligonucleotide from a biotechnology company, e.g., Dharmacon (horizondiscovery.com). This company can make a chemically modified long oligonucleotide with a desired purity for use in a research or a clinical setting. See Chen et al. (horizondiscovery.com, 1 page, 2018, retrieved on the line 2/3/26).
Claim Interpretation
The specification does not appear to disclose a utility for the oligomer, but the prior art teaches that one of ordinary skilled in the art could use the oligomer as a probe for detecting a target sequence in a sample or as a guide RNA (gRNA). For example, see Kanavarioti (Nature Scientific Reports 9:1019, 2019).
The broadest reasonable interpretation (BRI) of the amended claims now read on an oligomer having at least 90 nucleotides in length, and at least one phosphorothioate bond and at least one 2’-OMe, wherein the oligomer is at least 70% purity. The specification does not define the term ‘purity’. Thus, the BRI of the term ‘oligomer’ embraces double stranded or single stranded oligomers, including DNA, RNA, DNA/RNA, siRNA, antisense, aptamers, probes, primers, guide RNA (gRNA) having at least one phosphorothioate bond and at least one 2’OMe. The term ‘purity’ reads on purity in terms of side products or purity in terms of chirality (i.e. stereochemistry).
Iwamoto et al. (Nature Biotechnology pages 1011 2017) teach phosphorothioate (PS) substitution converts the achiral phosphodiester (PO) linkage into a chiral PS center having two distinct stereochemical configurations, designated Sp and Rp (Fig 1a).
Furthermore, one of ordinary skill in the art can purify an oligomer to a desired level based on its intended use. For example, one of skill in the art could order the oligonucleotide from any known biotechnology company.
Dr. Richard Hogrefe discusses the state of the art for purity of oligomers. When is my oligonucleotide pure enough? Trilink BioTechnologies retrieved on the line 1/29/26, pages 1-8, 2026.
The specifications for these products should be set no higher than what is needed for the assay to work routinely. The reason is that you want the assay to be robust, but at the lowest price possible. In this case, 80-90% is also usually good enough with the same careful attention given to the removal of free dyes or other interfering contaminants. Some specific applications may require higher purity, 95% or greater. A good rule of thumb is to use 80-85% pure material for pre-clinical animal studies, 85-90% for Phase I toxicity studies and 90-95% for Phase II/III studies.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1-3 are rejected under 35 U.S.C. 103 as being unpatentable over Hendel et al. Nat Biotechnol 33(9):985-989 and Supplementary Material pages 1-27.
Hendel et al. teach sgRNA comprising 100 nucleotides (nt) in length using 2’-O-thionocarbamate-protected nucleoside phosphoramidites and making additional sgRNAs having three additional chemical modifications at both termini (Page 2, Fig 1a, b, and Supplementary Table 1). Chemical modifications comprising 2’-O-methyl (M), 2’-O-methyl- 3’ phosphorothioate (MS), or (MSP) were incorporated at the three terminal nucleotides at both 5’ and 3’ ends. The chemically modified sgRNA can be made with an estimated purity in the range of 90% to 95% (pages 7-8 and Supplementary Table 1).
However, Hendel et al. does not specifically teach a sgRNA having at least 90 nucleotides, at least 90% purity; and the sgRNA comprises at least one phosphorothioate linkage and at least one 2’OMe.
It would have been prima facie obvious to a person of ordinary skill in the art before the time of the effective filing date to to pick a MS sgRNA (the sgRNA comprises at least one phosphorothioate linkage and at least one 2’OMe) for use in studying gene editing and use the method taught by Hendel with a reasonable expectation of success to make the sgRNA having at least 90% purity.
Therefore the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains.
Claims 1-3 are rejected under 35 U.S.C. 103 as being unpatentable over Iwamoto et al. (Nature Biotechnology pages 1-11 2017) taken with Butler (US 20150211006).
Iwamoto teaches control of phosphorothioate stereochemistry substantially increase the efficacy of antisense oligonucleotides.
Iwamoto developed a method of a scalable process (stereocontrolled oligonucleotide synthesis with iterative capping and sulfurization, SOSICS) that yields therapeutic antisense oligonucleotides (ASO) having a high stereochemical and chemical purity (pages 1-11). Mipomersen was used in the process and is a chemically modified DNA oligomer 20-mer with at least one phosphorothioate bond and at least one 2’OMe. “We demonstrate that phosphorothioate (PS) stereochemistry substantially affects the pharmacologic properties of ASOs.” “We report that Sp-configured PS linkages are stabilized relative to Rp, providing stereochemical protection from pharmacologic inactivation of the drug.” “Further, we elucidated a triplet stereochemical code in the stereopure ASOs, 3′-SpSpRp, that promotes target RNA cleavage by RNase H1 in vitro and provides a more durable response in mice than stereorandom ASOs.” See Abstract.
Iwamoto does not specifically teaching the length of the oligomer is at least 90 nucleotides in length.
However, Butler teaches making chirally controlled oligonucleotides, wherein the oligonucleotide can range from about 2 to about 200 nucleotides in length (paragraphs 104, 585-6, 618-652 and claims 1-100 on pages 405-409). The purity of the stereospecific oligonucleotide can be at least 96% (paragraph 1275 and page 408). The oligonucleotide can be chemically modified including a phosphorothioate linkage and/or 2’OMe. Pages 76-78 disclose that the oligonucleotide can be a microRNA and it can be used in the method of making. Pages 333-405 disclose microRNAs having at least 90 nucleotides that be used. Oligonucleotides, including microRNAs, can be used in a therapeutic or as a probe (paragraph 207).
It would have been prima facie obvious to a person of ordinary skill in the art before the time of the effective filing date to combine the teaching of Iwamoto taken with Butler to make a miRNA having at least 90 nucleotides in length and at least one phosphorothioate bond and at least one 2’OMe, namely to arrive at the claimed invention. Note: that claims to a more pure form has been held patentable while the prior art form was not suited to utility of the claimed product. See Farbenfabriken of Elberfeld Co. v. Kuehmsted, 171 F. 887, aff’d. 179 F 701 (7th Cir. 1910); Binney & Smith v. United Carbon Co. 125 F. 2d 255, 52 USPQ 205 (4th Cir. 1947); Ex parte Parke, 64 USPQ 335 (POBA 1944). See also MPEP 2144.04VII: “ the mere purity of a product, by itself, does not render the product nonobvious.” The specification does not appear to teach a use for the oligomer. The prior teaches that the oligonucleotide is suited for a utility (therapeutic or diagnostic). In addition Butler teaches a method of making stereospecific oligonucleotides with at least 96% purity. One of ordinary skill in the art would have been motivated to combine the teaching to make the oligomer with a reasonable expectation of success to increase the efficacy of an oligomer as taught by Iwamoto.
Therefore the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains.
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 1-3 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. 12540156 (formerly copending Application No. 17/996,058). NOTE: the rejection over the patent is the same rejection as the provisional NSDP rejection and was entirely foreseeable to applicant, and thus, they had a fair opportunity to respond. In addition, the amendment to claim 1 and the addition of claims 2 and 3 resulted in a new rejection based necessitated by the amendment). Although the claims at issue are not identical, they are not patentably distinct from each other because both set of claims embrace a modified oligomer having at least one 2’OMe and at least one phosphorothioate bond.
The difference between the instant claim and the patented claims is the ‘156 claims are directed to a method of making the oligomer and the length and purity of the oligomer is not recited in the claims of '156.
However, when a person of ordinary skill in the art looks for a definition of the length of the oligomer, they would arrive at columns 15-16 of the '156 disclosure. See MPEP 802(II)B1. Columns 15-16 of the '156 disclosure describe that the oligomer can be up to 200 nucleotides in length. In addition, column 32 teaches nucleic acid oligomers of strand lengths of n ≥ 100, and also n ≤ 200. 94.2% purity level is also taught column 37, para 0082. When one of ordinary skill in the art carries out the method steps of ‘156 they would arrive at an oligomer greater than 100 nucleotides with at least 94% purity.
Thus, the claimed product would be an obvious variant of the product made in the claims of '156.
Response to Arguments
Applicant's arguments filed 11/21/25 have been fully considered but they are not persuasive.
In response to applicant’s argument that the limitation (oligomer having at least 70% purity, length of at least 90 nucleotides and at least one phosphorothioate bond and at least one 2’OMe) in the amended claim and new claims are not recited or suggested by the claims of ‘058, the argument is not found persuasive because while it is acknowledged that that claims of ‘058 do not recite the new limitation, the new limitations are made obvious when one of ordinary skill in the art looks for a definition of the oligomer in the disclosure of ‘156. For the reasons set forth above, the instant claims are an obvious variant of the claims from the ‘156 application.
Claims 1-3 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 17/996117 (reference application).
Although the claims at issue are not identical, they are not patentably distinct from each other because both set of claims embrace a modified oligomer having at least one phosphorothioate bond and at least one 2’OMe. The difference between the instant claim and the '117 claims is the claims of '117 are directed to a method of making the oligomer and the length of the oligomer is not recited in the claims of '117.
However, when a person of ordinary skill in the art looks for a definition of the length of the oligomer, they would arrive at pages 15-16 of the '117 disclosure. See MPEP 802(II)B1. Page 16 of '117 specification discloses that the oligomer can be up to 200 nucleotides in length. Thus, the claimed product would be an obvious variant of the product made in the claims of '117.
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 11/21/25 have been fully considered but they are not persuasive.
In response to applicant’s argument that the limitation (oligomer having at least 70% purity, length of at least 90 nucleotides and at least one phosphorothioate bond and at least one 2’OMe) in the amended claim and new claims are not recited or suggested by the claims of ‘117, the argument is not found persuasive because while it is acknowledged that that claims of ‘117 do not recite the new limitation, the new limitations are made obvious when one of ordinary skill in the art looks for a definition of the oligomer in the disclosure of ‘117. For the reasons set forth above, the instant claims are an obvious variant of the claims from the ‘117 application.
Claims 1-3 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 of copending Application No. 18574655(reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because both set of claims embrace a modified oligomer having at least one phosphorothioate bond and at least one 2’OMe.
The difference between the instant claim and the '655 claims is the '655 claims are directed to an oligomer and a method of making the oligomer and the length of the oligomer is not recited in the claims of '655. However, when a person of ordinary skill in the art looks for a definition of the length of the oligomer, they would arrive at pages 15-16 of the '655 disclosure. See MPEP 802(II)B1. Pages 11 and 27 of the '655 specification disclose that the oligomer can be up to 200 nucleotides in length. Thus, the claimed product would be an obvious variant of the product or product made in the claims of '655.
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 11/21/25 have been fully considered but they are not persuasive.
In response to applicant’s argument that the limitation (oligomer having at least 70% purity, length of at least 90 nucleotides and at least one phosphorothioate bond and at least one 2’OMe) in the amended claim and new claims are not recited or suggested by the claims of ‘655, the argument is not found persuasive because while it is acknowledged that that claims of ‘655 do not recite the new limitation(s), the new limitation(s) are made obvious when one of ordinary skill in the art looks for a definition of the oligomer in the disclosure of ‘655. For the reasons set forth above, the instant claims are an obvious variant of the claims from the ‘655 application.
Conclusion
See attached PTO-326 for disposition of claims.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Kanavarioti (Nature Scientific Reports 9:1019, pages 1-13 and supplemental information pages 1-9, January 2019). Kanavarioti studied ion-repair reversed phrase chromatography (IP-RP) and HPLC methods to obtain pure RNA oligos (pages 1-9). The study involved two 32nt RNA oligos differing by 4 nucleotides, a canonical 100nt RNA and the 94nt truncated RNA with the same sequence as the 100nt, but missing 6nt at the 3′end, and a heavily methylated 100nt RNA of the identical sequence as the canonical 100nt, but with 46 2′OMe groups. In addition we tested tRNA (E. Coli) and two mRNAs, EGFP with 996nt and Cas9 with 4500nt. IEX HPLC method can be used for purity evaluation of sgRNA and tRNA and mRNA. IP-RP is less suitable to conventional ion-exchange (IEX) for analysis of 100 nt RNAs. Singe guide RNA (sgRNA) is typically 100nt long and used with CRISPR in gene editing. There is motivation to obtain pure RNA for sgRNA targeting FDA approval. The process taught Kanavarioti taught a good purity (Fig S5 and S6, supplementary information). The process could be improved by automation and preparation of IEX HPLC at ph12 could be used for sgRNA purification.
Kanavarioti does not specifically that methylated oligonucleotide having at least one phosphorothioate linkage..
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). 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.
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/BRIAN WHITEMAN/ Primary Examiner, Art Unit 1636