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 .
Please note: The text of those sections of Title 35 U.S. Code not included in this action can be found in a prior Office action.
Election/Restrictions
Applicant's election with traverse of Group I (claims 1-11) in the reply filed on 6/10/2025 is acknowledged. The traversal is generally on the ground(s) that the shared technical features of Groups I and II are novel and not obvious over Kazakov et al. (WO2017112666; pg 2 of Remarks of 6/10/2025). Applicant’s arguments were carefully considered, but were not deemed persuasive for the reasons presented in the previous Office Action of 7/2/2025.
Claim Status
Claims 1-8, 10-14, and 16-20 are pending.
Claims 12-14 and 16-19 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 6/10/2025.
Claims 1-8, 10-11, and 20 are being examined on the merits.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement (for example, see pages 28-30). 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
No new information disclosure statements were filed with the most recent Request for Continued Examination of 3/12/2026, therefore the references in the specification not included on any prior IDSs, unless cited by the examiner on form PTO-892, remain unconsidered.
Abstract
The objection to the Abstract due to a typo is withdrawn in light of Applicant’s amendment to the specification to amend said typo.
Specification
The specification is objected to as failing to provide proper antecedent basis for the claimed subject matter. See 37 CFR 1.75(d)(1) and MPEP § 608.01(o). Correction of the following is required: The specification does not provide antecedent basis for the concept of “restricting extension” by a reverse transcription enzyme, as claimed in claim 1. There is no definition provided for what “restricting extension” entails, no mention of restricting extension, and no evidence provided as to what modifications may in fact lead to a restricting of extension by a reverse transcriptase.
Claim Objections
The objections to claims 5, 6, and 8 are withdrawn in light of Applicant’s amendments to the claims.
Withdrawn Claim Rejections - 35 USC § 112b - Indefiniteness
The rejection of claims 1-8 and 10-11 under 35 U.S.C. 112(b) in the Office Action of 10/17/2025 are withdrawn in light of Applicant’s amendments to the claims
Claim Rejections - 35 USC § 112a – New Matter
Claims 1-8, 10-11, and 20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1 has been amended to include the limitation that the random RNA linker “is free of any modification restricting extension by a reverse transcription enzyme in the reverse transcription rolling circular amplification of step (vi)”. There is no support for this limitation in the original disclosure. Applicant stated in Remarks of 9/8/2025 that “support for the amendments is found throughout the specification and claims as originally filed” but does not provide where in the disclosure this particular limitation can be found or is supported.
Using the clean copy of the substitute specification submitted on 9/8/2025 as reference, support for modified nucleotides of the random RNA linker can be found on pages 13-14. However, there is no mention as to whether any of these modifications would or would not restrict extension by a reverse transcription enzyme.
“…as with positive limitations, the disclosure must only 'reasonably convey[] to those skilled in the art that the inventor had possession of the claimed subject matter as of the filing date.' ... While silence will not generally suffice to support a negative claim limitation, there may be circumstances in which it can be established that a skilled artisan would understand a negative limitation to necessarily be present in a disclosure." Novartis Pharms. Corp. v. Accord Healthcare, Inc., 38 F.4th 1013, 2022 USPQ2d 569 (Fed. Cir. 2022) (quoting Ariad Pharm. Inc. v. Eli Lilly & Co., 589 F.3d 1336, 1351, 94 USPQ2d 1161, 1172). MPEP 2173.05(i)
Neither the disclosure nor the Remarks of 9/8/2025 provide evidence that those of ordinary skill in the art would understand the negative limitation to necessarily be present in the disclosure as filed. There is a lack of support for this new negative limitation in the disclosure as originally filed, therefore the amendment to claim 1 to include the above cited negative limitation constitutes new matter.
Claims 2-8, 10-11, and 20 depend from claim 1, inherit this deficiency, and are rejected on the same basis.
Response to Remarks
Applicant's arguments filed 3/12/2026 (pages 8-9 of Remarks) have been fully considered but they are not persuasive to withdrawn the rejection. The Declaration of Dr. Lion under 37 CFR 1.132 filed 3/12/2026 is insufficient to overcome the rejection of claims 1-8, 10-11, and 20 based upon the reasonings as set forth in the last Office action and maintained above for the following reasons.
Applicant has traversed the “written description” rejection and states that “a skilled person reading a specification would reasonably conclude that the inventors had possession of the element that the random RNA linker is free of any modification restricting extension by a revere transcription enzyme” (pg 8 of Remarks). However, this is not the issue at question. The amendment to the claim constitutes new matter that is not reasonably supported in the specification. MPEP 2163 (I)(B) states “While there is no in haec verba requirement, newly added claims or claim limitations must be supported in the specification through express, implicit, or inherent disclosure.” As noted in the objection to the specification above, the specification is silent with regard to restricting extension of a reverse transcriptase, and is also silent with regards to what type of modifications would do so. MPEP 2163 (I)(A) states “a description that merely renders a claimed invention obvious may not sufficiently describe the invention for the purposes of the written description requirement of 35 U.S.C. 112”. While it may be obvious to one skilled in the art that to perform the claimed methodology of RT-RCA one would not want modifications in the RNA linker that would inhibit doing so, the complete absence of modifications in the RNA linker that may restrict said methodology is not express, implicit or inherent. As noted above, the specification lists various modifications that can be present within the random RNA linker (pages 13-14), including things such as abasic sites and chain terminating nucleotide analogues. As taught by Küpfer et al. (2007), the reverse transcriptase MMLV (a reverse transcriptase recited in claim 7), terminates reverse transcription upon encountering an abasic site (Abstract). There is no indication in the specification that this modification should be excluded from the random RNA linker. Therefore, the rejection of claims 1-8, 10-11, and 20 under 112(a)-New Matter is maintained.
Claim Rejections - 35 USC § 102
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-3 and 5-7 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Kazakov et al. 2010 (hereinafter “Kazakov 2010”; WO2010120803A2, 2010; cited on PTO-892 of 7/2/2025).
Regarding claim 1: Kazakov 2010 teaches a method of preparing at least one RNA molecule contained in a biological sample for sequencing (pg 8, ln 19-32 and pg 9, ln 7). Kazakov 2010 teaching obtaining a sample comprising a plurality of linear RNA molecules wherein at least one linear RNA molecule bears a phosphate (3’-p) or a 2’,3’-cyclic phosphate group at the 3’ end (claim 1, step (i); pg 8-9, ln 33-37 and ln 1-8, pg 30, ln 6-8). Kazakov 2010 teaches obtaining the RNA from a biological sample (e.g., various mouse tissues; Figure 37). Kazakov 2010 teaches phosphorylating the linear RNA molecule to introduce a phosphate group at the 5’ end of the linear RNA molecule, thus obtaining a phosphorylated linear RNA molecule that bears a phosphate group at the 5’ end and a phosphate or a 2’,3’-cyclic phosphate (2’,3’>p) group at the 3’ end (claim 1, step (ii); pg 10, ln 7-8, pg 30, ln 5-6). Kazakov 2010 teaches converting the 3’-p or 2’,3’>p to a 3’-OH prior to ligation (pg 30, ln 7-8). Kazakov 2010 teaches ligating the 3’ end of the phosphorylated linear RNA to the 5’ end of a random RNA linker, wherein the random RNA linker bears a -OH group at both ends, thus obtaining a first ligation product (claim 1, step (iii); pg 8, ln 25-28, pg 10, ln 2-4). Kazakov 2010 teaches self-ligating the first ligation product to form a circular RNA molecule, thus obtaining a composition comprising the circular RNA molecule (claim 1, step (iv); pg 8, ln 28-29). Kazakov 2010 teaches treating the composition of circularized RNA-adapter molecules with an exoribonuclease suitable to enzymatically digest linear RNA molecules (claim 1, step (v); pg 9, ln 15-16, pg 50, ln 3-5). Kazakov 2010 teaches subjecting the circular RNA molecule to reverse transcription rolling circular amplification, thus obtaining a single-stranded cDNA molecule that comprises a nucleotide sequence comprising at least two copies (“multimer”) of the nucleotide sequence of the at least one linear RNA molecule (claim 1, step (vi); pg 10, ln 9-11, pg 43, ln 4-7). Kazakov 2010 teaches that random RNA linker has a length between 10 to 100 nucleotides and does not teach that any modifications are present within the sequence, thus reading on “free of any modification restricting extension by a reverse transcription enzyme in the reverse transcription rolling circular amplification” (claim 1, step (vi); pg 9, ln 31-36, pg 65, ln 13, Figure 13).
Regarding claim 2: Kazakov teaches a further step (vii) of generating a complementary cDNA strand of the single-stranded cDNA molecule, thus obtaining a double-stranded cDNA molecules that comprises a nucleotide sequence comprising at least 2 copies of the nucleotide sequence of that least one linear RNA molecule (pg 9, ln 3-6, pg 46, ln 7-11 and 28-31, pg 47, ln 1-2).
Regarding claim 3: Kazakov 2010 teaches that the phosphorylation of the 5’ end of the linear RNA molecule in step (ii) is accomplished using a T4 PNK (pg 48, ln 25).
Regarding claim 5: Kazakov 2010 teaches that the self-ligation in step (iv) is accomplished using T4 Rnl1 or T4 Rnl2 (pg 30, ln 15).
Regarding claim 6: Kazakov 2010 teaches that the digestion in step (v) is carried out using a 3’-5’ exoribonuclease (pg 50, ln 3-5).
Regarding claim 7: Kazakov 2010 teaches that the reverse transcription rolling circular amplification is carried out using SuperScriptII, which is an engineered MMLV-RT (pg 43, ln 15-16).
Claim Rejections - 35 USC § 103
Withdrawn 103 Rejections
The rejection of claims 1-7 under 35 U.S.C. 103 as being unpatentable over Kazakov et al. 2017 (hereinafter “Kazakov 2017”; WO2017112666A1, 2017; cited on PTO-892 of 7/2/2025) in view of Kazakov et al. 2010 (hereinafter “Kazakov 2010”; WO2010120803A2, 2010; cited on PTO-892 of 7/2/2025) is withdrawn in light of Applicant’s arguments and claim amendments.
The rejection of claim 8 under 35 U.S.C. 103 as being unpatentable over Kazakov et al. 2017 (hereinafter “Kazakov 2017”; WO2017112666A1, 2017; cited on PTO-892 of 7/2/2025) in view of Kazakov et al. 2010 (hereinafter “Kazakov 2010”; WO2010120803A2, 2010; cited on PTO-892 of 7/2/2025) as applied to claims 1-7 above, and further in view of Kamme et al. (US 20030175714 A1, 2003; cited on PTO-892 of 7/2/2025) is withdrawn in light of Applicant’s arguments and claim amendments.
The rejection of claim 10 under 35 U.S.C. 103 as being unpatentable over Kazakov et al. 2017 (hereinafter “Kazakov 2017”; WO2017112666A1, 2017; cited on PTO-892 of 7/2/2025) in view of Kazakov et al. 2010 (hereinafter “Kazakov 2010”; WO2010120803A2, 2010; cited on PTO-892 of 7/2/2025) as applied to claims 1-7 above, as evidenced by Trotta (PLoS One, 2014; cited on PTO-892 of 7/2/2025) is withdrawn in light of Applicant’s arguments and claim amendments.
The rejection of claim 11 under 35 U.S.C. 103 as being unpatentable over Kazakov et al. 2017 (hereinafter “Kazakov 2017”; WO2017112666A1, 2017; cited on PTO-892 of 7/2/2025) in view of Kazakov et al. 2010 (hereinafter “Kazakov 2010”; WO2010120803A2, 2010; cited on PTO-892 of 7/2/2025) as applied to claims 1-7 above, and further in view of Cooper et al. (Nucleic Acids Research, 2014; cited on PTO-892 of 7/2/2025) is withdrawn in light of Applicant’s arguments and claim amendments.
New 103 Rejections
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Kazakov et al. 2010 (hereinafter “Kazakov 2010”; WO2010120803A2, 2010; cited on PTO-892 of 7/2/2025) in view of Raines et al. (US 2013/0203635 A1).
The teachings of Kazakov 2010 as they apply to claim 1, from which claim 4 depends, are detailed in the 102 rejection above. Kazakov 2010 teaches obtaining a sample with linear RNA molecules that have a 3’-p or 2’,3’-cyclic phosphate group at the 3’ end. Kazakov 2010 teaches removing said end groups/converting them to 3’OH prior to ligation with a random RNA linker.
Kazakov 2010 does not teach directly ligating a random RNA linker with a 3’-p or 2’,3’-cyclic phosphate 3’ end. However, direct ligation of this 3’ end type of an RNA molecule with an oligonucleotide with a 5’-OH using RtcB is known in the art, as taught by Raines et al.
Raines et al. teaching a method for ligating an RNA fragment with a 3’p or a 2’,3’-cyclic phosphate with another oligonucleotide that comprises a 5’-OH using a RtcB RNA ligase (paragraph [0008-0011]).
It would have been prima facie obvious to one having ordinary skill in the art, before the effective filing date of the instant application, to have modified the method of Kazakov 2010 with that of Raines et al. to include direct ligation between the 5’-OH terminus of the random RNA linker and the 3’-p or 2’,3’-cyclic phosphate of the target linear RNA molecule. One would be motivated to do so given that direct ligation of the random RNA linker to the linear RNA molecule with 3’p or 2’,3’>p ends using an RtcB ligase would obviate the need for the extra step of removing said 3’ end modification, thus simplifying the methodology of Kazakov 2010 and removing a step of end modification of the 3’ RNA end. One would have a reasonable expectation of success given that Raines demonstrates successful ligation of RNA 3’-P ends with a 5’-OH terminus of RNA molecules (paragraph [0099-0100]) and discusses that the RtcB is known for ligation of 2’,3’>p ends with 5’-OH ends (paragraph [0005]).
Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Kazakov et al. 2010 (hereinafter “Kazakov 2010”; WO2010120803A2, 2010; cited on PTO-892 of 7/2/2025) in view of Kamme et al. (US 20030175714 A1, 2003; cited on PTO-892 of 7/2/2025).
The teachings of Kazakov 2010 as they apply to claims 1 and 2, from which claim 8 depends, are detailed in the 102 rejection above. Kazakov 2010 teaches a method of generating single-strand cDNA copies of a circularized RNA molecule-RNA linker product and generating a second strand of cDNA to create double-stranded cDNA, as described above.
Kazakov 2010 does not teach second strand cDNA synthesis using Taq DNA polymerase and the Gubler-Hoffman method. However, use of thermostable polymerases such as Taq DNA polymerase and the Gubler-Hoffman for generation of double-stranded cDNA was known in the art, as taught by Kamme et al.
Kamme et al. teach a method of amplifying RNA derived from biological samples that involves generation of cDNA via reverse transcription followed by second strand synthesis using a thermostable polymerase (paragraph [0015]). Kamme et al. indicate that the second strand cDNA synthesis is performed according to a well-known method in the art, the Gubler-Hoffman method (paragraph [0047]). Kamme et al. teach using Taq DNA polymerase as a thermostable polymerase to perform the Gubler-Hoffman method (paragraph [0049]). Taq DNA polymerase possesses a 5’-3’ exonuclease activity.
It would have been prima facie obvious to one having ordinary skill in the art, before the effective filing date of the instant application, to have modified the method of Kazakov 2010 to perform the second strand cDNA synthesis with a Taq DNA polymerase and according to the Gubler-Hoffman method, as taught by Kamme et al. One would be motivated to use Taq DNA polymerase, since this thermostable polymerase would allow for generation of large amounts of RNA from a small starting amount and in a smaller amount of time, as taught by Kamme et al. (paragraph [0015]). One would be motivated to employ the Gubler-Hoffman method for second strand DNA synthesis given that it is the most well-known and studied method of second strand cDNA synthesis in the art, as taught by Kamme et al. (paragraph [0047]). One would have a reasonable expectation of success given that Kamme et al. successfully perform second strand cDNA synthesis from RNA starting material according to the Gubler-Hoffman method with a Taq DNA polymerase.
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Kazakov et al. 2010 (hereinafter “Kazakov 2010”; WO2010120803A2, 2010; cited on PTO-892 of 7/2/2025), as evidenced by Trotta (PLoS One, 2014; cited on PTO-892 of 7/2/2025).
The teachings of Kazakov 2010 as they apply to claim 1, from which claim 10 depends, are detailed in the 102 rejection above. Relevant to the instantly rejected claim, Kazakov 2010 teaches a method of ligating a target RNA molecule with a linker RNA molecule that is between 10 to 100 nucleotides in length.
Kazakov 2010 does not explicitly teach that the linker RNA molecule has a minimum free energy between -3 and -150 kcal/mol. However, a length of 10 to 100 nucleotides of RNA nucleotides inherently has a minimum free energy between -3 and -150 kcal/mol, as taught by Trotta.
Trotta teaches that the minimum free energy of an RNA polynucleotide increases linearly with sequence length, and that the minimum free energy of a random sequence of RNA between 10 and 100 nucleotides long would be between -3 kcal/mol and -150 kcal/mol (Abstract and Figure 1).
It would have been prima facie obvious to one having ordinary skill in the art, before the effective filing date of the instant application, that the minimum free energy of the random RNA linker employed in the method of Kazakov 2010 would be between -3 and -150 kcal/mol, as taught by Trotta.
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Kazakov et al. 2010 (hereinafter “Kazakov 2010”; WO2010120803A2, 2010; cited on PTO-892 of 7/2/2025) in view of Cooper et al. (Nucleic Acids Research, 2014; cited on PTO-892 of 7/2/2025).
The teachings of Kazakov 2010 as they apply to claim 1, from which claim 11 depends, are detailed in the 102 rejection above. Relevant to the instantly rejected claim, Kazakov 2010 teaches a method of obtaining RNA molecules from a biological sample that bear a 3’ end of either a 3’ phosphate or 2’,3’-cyclic phosphate. These RNAs are then ligated to an RNA linker/adapter.
Kazakov 2010 does not teach generating these 3’ ends on the target RNA by treating the biological sample with an endoribonuclease, an exoribonuclease, a ribozyme, or a toxin. However, treatment of biological samples with endoribonucleases to generate RNA with 3’ ends consisting of 2’,3’-cyclic phosphate groups was known in the art, as taught by Cooper et al.
Cooper et al. teach a method in which viral RNA and host cell RNA is treated with RNAse L, an endoribonuclease that generates 2’,3’-cyclic phosphate ended RNA products (Abstract). Cooper et al. then teach specifically detecting these 2’,3’-cyclic phosphate ended RNA products via ligation to an RNA linker and subsequent sequencing (Materials and Methods). Cooper et al. treat viral RNA with RNAse L via incubation with purified RNAse L and treat HeLa cell cultures by transfecting them with pcDNA3 vectors expressing wild-type RNase L (Materials and Methods).
It would have been prima facie obvious to one having ordinary skill in the art, before the effective filing date of the instant application, to have modified the method of Kazakov 2010 to generate target RNAs using an endoribonuclease known to generate 2’,3’-cyclic phosphate 3’ ends on target RNAs, as taught by Cooper et al. One would be motivated to use a specific endoribonuclease with this method in order to study the target sites of said endoribonuclease, as taught by Cooper et al. who identified target sites of RNAse L using 2’3’-cyclic phosphate specific sequencing (Discussion, paragraph 1). One would have a reasonable expectation of success given that Cooper et al. successfully applied an endoribonuclease to viral RNA and cell culture to generate 2’,3’-cyclic phosphate containing RNA that could then be analyzed via sequencing.
Claim 20 is rejected under 35 U.S.C. 103 as being unpatentable over Kazakov et al. 2010 (hereinafter “Kazakov 2010”; WO2010120803A2, 2010; cited on PTO-892 of 7/2/2025) in view of Kono et al. (Dev Growth Differ., April 29, 2019).
The teachings of Kazakov 2010 as they apply to claim 1, from which claim 20 depends, are detailed in the 102 rejection above. Relevant to the instantly rejected claim, Kazakov 2010 teaches a method of sequencing multimer cDNA products of RT-RCA performed on circularized target RNAs (pg 9, ln 7). Kazakov 2010 teaches inclusion of sequences within the RNA adapter that aid in sequencing such as next generation high throughput sequencing (pg 10, ln 1-2, pg 17, ln 5).
Kazakov 2010 does not teach that the next generation sequencing method is nanopore sequencing. However, the use of nanopore sequencing in sequencing cDNA for information on RNA targets is known in the art, as taught by Kono et al.
Kono et al. teach that nanopore sequencing has been widely adopted and has benefited many scientific fields (Abstract). Kono et al. teach that nanopore sequencing can be used for transcriptome analysis (of cDNAs) and direct RNA sequencing (4 Transcriptome Analysis and Direct RNA Sequencing).
It would have been prima facie obvious to one having ordinary skill in the art, before the effective filing date of the instant application, to have modified the method of Kazakov 2010 to use nanopore sequencing as taught by Kono et al. One would be motivated to employ nanopore sequencing given the assertion by Kono et al. that nanopore sequencing provides benefits over other sequencing platforms such as the ability to detect nucleotides without imaging equipment, not requiring amplification and thus allowing even mega-base long reads, and the ability to detect base modifications (pg 316-317, col 2 and col 1, respectively). One would have a reasonable expectation of success given that Kono et al. notes that cDNA generated from RNA substrates was successfully sequenced using nanopore sequencing (4 Transcriptome Analysis and Direct RNA Sequencing).
Response to Remarks
Applicant's arguments filed 3/12/2026 (pages 9-13 of Remarks) have been fully considered and are persuasive to withdrawn the rejection. The Declarations of Drs. Lion and Del Piano under 37 CFR 1.132 filed 3/12/2026 are sufficient to overcome the rejection of claims 1-8 and 10-11 based upon the cited prior art as set forth in the last Office action.
However, upon further consideration, a new ground(s) of rejection is made in view of Kazakov 2010 (claims 1-3 and 5-7), and Kazakov 2010 in view of Raines et al. (claim 4), Kamme et al. (claim 8), Trotta et al. (claim 10), Cooper et al. (claim 11), and Kono et al. (claim 20).
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.
Withdrawn Double Patenting Rejections
The provisional double patenting rejection of claims 1-8 and 10-11 as being unpatentable over claims 1-9 of copending Application No. 18/794,611 in view of Kazakov et al. 2017 (hereinafter “Kazakov 2017”; WO2017112666A1, 2017), Kazakov et al. 2010 (hereinafter “Kazakov 2010”; WO2010120803A2, 2010), Kamme et al. (US 20030175714 A1, 2003), Trotta (PLoS One, 2014), and Cooper et al. (Nucleic Acids Research, 2014) based on the citations and rationales provided above is withdrawn in light of Applicant’s arguments against Kazakov 2017.
The provisional double patenting rejection of claims 1-8 and 10-11 as being unpatentable over claim 1-10 of copending Application No. 18/794,995 in view of Kazakov et al. 2017 (hereinafter “Kazakov 2017”; WO2017112666A1, 2017), Kazakov et al. 2010 (hereinafter “Kazakov 2010”; WO2010120803A2, 2010), Kamme et al. (US 20030175714 A1, 2003), Trotta (PLoS One, 2014), and Cooper et al. (Nucleic Acids Research, 2014) based on the citations and rationales provided above is withdrawn in light of Applicant’s arguments against Kazakov 2017.
New Double Patenting Rejections
Copending Application No. 18/794,611
Claims 1-3 and 5-7 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of copending Application No. 18/794,611 in view of Kazakov et al. 2010 (hereinafter “Kazakov 2010”; WO2010120803A2, 2010; cited on PTO-892 of 7/2/2025).
Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims are drawn to the same limitations. Any additional limitations of ‘611 claims are encompassed by the open claim language “comprising” found in the instant claims.
Regarding claim 1(v) and claim 6: The claims of ‘611 do not teach digesting the linear RNA molecules of the sample or using 3’-5’ exoribonuclease or 5’-3’ exoribonuclease to do so.
Kazakov 2010 teaches treating the composition of circularized RNA-adapter molecules with an exoribonuclease suitable to enzymatically digest linear RNA molecules (claim 1, step (v); pg 9, ln 15-16, pg 50, ln 3-5). Kazakov 2010 teaches that the digestion in step (v) is carried out using a 3’-5’ exoribonuclease (claim 6; pg 50, ln 3-5).
It would have been prima facie obvious to one having ordinary skill in the art, before the effective filing date of the instant application, to have modified the method of ‘611 with the method of Kazakov 2010. One would be motivated to degrade the non-circularized products given the assertion by Kazakov 2010 that it would “reduce a background signal that may evolve as a result of unintentional amplification of unrelated RNA molecules” (pg 31, ln 1-5). One would have a reasonable expectation of success given that Kazakov 2010 demonstrates successful usage of the Exonuclease 1 exoribonuclease to degrade linear RNA molecules and preserve circularized RNA molecules.
Regarding claim 1(vi) and claim 7: The claims of ‘611 do not teach performing reverse transcription rolling circular amplification of the circularized RNA-adapter molecule to generate a multimeric cDNA molecule, nor do they teach using an engineered MMLV to do so.
Kazakov 2010 teaches subjecting the circular RNA molecule to reverse transcription rolling circular amplification, thus obtaining a single-stranded cDNA molecule that comprises a nucleotide sequence comprising at least two copies (“multimer”) of the nucleotide sequence of the at least one linear RNA molecule (claim 1, step (vi); pg 10, ln 9-11, pg 43, ln 4-7). Kazakov 2010 teaches that the reverse transcription rolling circular amplification is carried out using SuperScriptII, which is an engineered MMLV-RT (claim 7; pg 43, ln 15-16).
It would have been prima facie obvious to one having ordinary skill in the art, before the effective filing date of the instant application, to have modified the method of ‘611 with the method of Kazakov 2010.One would be motivated to perform RT-RCA to obtain multiple copies for use in downstream applications, such as sequencing, without the need for additional amplification steps, as taught by Kazakov 2010 (pg 11, ln 35-36). Additionally, Kazakov 2010 teaches that when sequencing multimeric cDNA products, the presence of multiple copies allows for greater sensitivity when distinguishing between very closely related sequences (such as different isoforms within the same RNA family; pg 37, ln 30-34). One would have a reasonable expectation of success given that Kazakov 2010 successfully employs RT-RCA to obtain multimeric cDNA copies from a circularized RNA-RNA linker product. In regards to the use of MMLV-RT, one would be motivated to employ this specific reverse transcriptase given their successful application to circularized target RNA to generate multimer cDNA for sequencing.
Regarding claim 2: The claims of ‘611 teach performing amplification on the monomeric cDNA molecule generated from reverse transcription of the circularized RNA molecule. The claim of ‘611 do not teach generating a double-stranded cDNA molecule comprised of multiple copies of the target linear RNA molecule.
Kazakov teaches a further step (vii) of generating a complementary cDNA strand of the single-stranded cDNA molecule, thus obtaining a double-stranded cDNA molecules that comprises a nucleotide sequence comprising at least 2 copies of the nucleotide sequence of that least one linear RNA molecule (pg 9, ln 3-6, pg 46, ln 7-11 and 28-31, pg 47, ln 1-2).
It would have been prima facie obvious to one having ordinary skill in the art, before the effective filing date of the instant application, to have modified the method of ‘611 with the method of Kazakov 2010. One would be motivated to do so given the teaching by Kazakov that generation of a double-stranded cDNA by using limiting amounts of a forward primer “could significantly reduce background noise, thereby decreasing detection limits” (pg 37, ln 26-29). One would have a reasonable expectation of success given that Kazakov 2010 successfully performs various forms of PCR on the multimeric cDNA.
Regarding claim 3: The claims of ‘611 teach phosphorylating the 5’ end of at least on 3’P RNA in the biological sample. The claims of ‘611 do not specify what phosphorylating enzyme is used to perform this phosphorylation.
Kazakov 2010 teaches that the phosphorylation of the 5’ end of the linear RNA molecule in step (ii) is accomplished using a T4 PNK (pg 48, ln 25).
It would have been prima facie obvious to one having ordinary skill in the art, before the effective filing date of the instant application, to have modified the method of ‘611 with the method of Kazakov 2010. One would be motivated to do so given the teaching by Kazakov 2010 that this T4 PNK ligase can successfully phosphorylate 5’ ends of linear RNA molecules. One would have a reasonable expectation of success given that Kazakov 2010 demonstrates successful usage of T4 PNK for phosphorylation of RNA molecules to generate a 5’P end.
Regarding claim 5: Claim 1 of ‘611 teaches self-ligation of the first ligation product, but does not teach that this second ligation is performed with a specific second ligase enzyme.
Kazakov 2010 teaches that the self-ligation in step (iv) is accomplished using T4 Rnl1 or T4 Rnl2 (pg 30, ln 15).
It would have been prima facie obvious to one having ordinary skill in the art, before the effective filing date of the instant application, to have modified the method of ‘611 with the method of Kazakov 2010. One would be motivated to employ one of the ligases taught by Kazakov 2010 given the assertion by Kazakov 2010 that this type of ligation can be performed without usage of a splint oligonucleotide and is thus universal and not dependent on target sequences (pg 30, ln 17-19). One would have a reasonable expectation of success given that Kazakov 2010 demonstrates successful split-free self-ligation to form circular RNA molecules.
Claims 4, 8, 10-11, and 20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of copending Application No. 18/794,611 in view of Kazakov et al. 2010 (hereinafter “Kazakov 2010”; WO2010120803A2, 2010; cited on PTO-892 of 7/2/2025), as applied to claims 1-3 and 5-7, and further in view of Raines et al. (US 2013/0203635 A1), Kamme et al. (US 20030175714 A1, 2003; cited on PTO-892 of 7/2/2025), Trotta (PLoS One, 2014; cited on PTO-892 of 7/2/2025), Cooper et al. (Nucleic Acids Research, 2014; cited on PTO-892 of 7/2/2025), and Kono et al. (Dev Growth Differ., April 29, 2019) according to citations and rationales provided above.
This is a provisional nonstatutory double patenting rejection.
Copending Application No. 18/794,995
Claims 1-3 and 5-7 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of copending Application No. 18/794,995 in view of Kazakov et al. 2010 (hereinafter “Kazakov 2010”; WO2010120803A2, 2010; cited on PTO-892 of 7/2/2025) according to citations and rationales provided above.
Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims are drawn to the same limitations. Any additional limitations of ‘995 claims are encompassed by the open claim language “comprising” found in the instant claims.
Claims 4, 8, 10-11, and 20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of copending Application No. 18/794,995 in view of Kazakov et al. 2010 (hereinafter “Kazakov 2010”; WO2010120803A2, 2010; cited on PTO-892 of 7/2/2025), as applied to claims 1-3 and 5-7, and further in view of Raines et al. (US 2013/0203635 A1), Kamme et al. (US 20030175714 A1, 2003; cited on PTO-892 of 7/2/2025), Trotta (PLoS One, 2014; cited on PTO-892 of 7/2/2025), Cooper et al. (Nucleic Acids Research, 2014; cited on PTO-892 of 7/2/2025), and Kono et al. (Dev Growth Differ., April 29, 2019) according to citations and rationales provided above.
This is a provisional nonstatutory double patenting rejection.
Response to Remarks
Applicant traverses the double patenting rejections of the Office Action of 10/17/2025 on the grounds that the double patenting rejections are the only rejections remaining in the application (page 13 of Remarks). While the previous double patenting rejections were withdrawn in light of Applicant’s arguments regarding the Kazakov 2017 reference, new double patenting rejections have been made upon further consideration of the prior art.
Conclusion
No claims allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KAILEY E CASH whose telephone number is (571)272-0971. The examiner can normally be reached Monday-Friday 8:30am-6pm 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, Anne Gussow can be reached at (571)272-6047. 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.
/KAILEY ELIZABETH CASH/Examiner, Art Unit 1683
/STEPHEN T KAPUSHOC/Primary Examiner, Art Unit 1683
Prosecution Insights