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 .
Application Status
This action is written in response to applicant’s correspondence received 5 December 2025. Claims 1-20 are currently pending. Claims 1, 12, and 18 are presently amended. Accordingly, claims 1-20 are examined herein.
Any rejection or objection not reiterated herein has been overcome by amendment. Applicant' s amendments and arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow.
Because the newly recited 35 USC 101 rejection of record was not necessitated by the presently filed amendment, this action is NON-FINAL.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 12 and 16 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception without significantly more.
Step 1: Is the Claim to a Process, Machine, Manufacture, or Composition of Matter? YES.
Regarding claim 12, the claim recites a composition comprising a single-stranded target RNA comprising a guide-recognition sequence, an MpaAgo, and a guide having a sequence complementary to a single-stranded target RNA guide-recognition sequence, wherein the guide is operatively bound to the Argonaute forming an Argonaute:guide complex (see Claim 12).
Step 2A, Prong 1: Does the Claim Recite an Abstract Idea, Law of Nature, or Natural Phenomenon? YES.
Regarding claim 12, the appropriate counterparts to the currently claimed composition are as follows: a naturally occurring [emphasis added] single-stranded target RNA comprising a guide-recognition sequence, Mucilaginibacter paludism Argonaute, and a guide having a sequence complementary to a single-stranded target RNA guide-recognition sequence, wherein the guide is operatively bound to the Argonaute forming an Argonaute:guide complex.
The appropriate characteristics identified for analysis are the physical structures of the claimed target ssRNA, MpaAgo, and guide comprising a sequence that is complementary to the target ssRNA, wherein the guide is operatively bound to the Argonaute forming an Argonaute:guide complex.
Accordingly, the claim is directed towards a product of nature as evidenced by Li (Nucleic acids research 50.9 (2022): 5226-5238).
Li is directed towards a study concerned with the characterization of a programmable pAgo nuclease with RNA target preference from Mucilaginibacter paludis (Abstract). Li teaches the use of a novel Argonaute protein, termed “MbpAgo” that is derived from Mucilaginibacter paludis (i.e., Li teaches the use of an MpaAgo) (Abstract). Li teaches that the MbpAgo prefers to cleave target RNA sequences over target DNA sequences through the use of a DNA guide sequence that guides the MbpAgo to a target RNA of interest (i.e., a naturally occurring MpaAgo is directed to a target RNA through the use of a guide that comprises a sequence that is complementary to a sequence within a target RNA, wherein the guide can complex with the MbpAgo to form an Argonaute:guide complex) (Abstract). Li teaches that the MbpAgo’s ability to cleave RNA was tested via single-stranded nucleic acid cleavage assays and the Argonaute was able to cleave single-stranded RNA targets, but not double-stranded RNA targets (i.e., a naturally occurring MbpAgo is able to cleave ssRNA) (pg. 5236; see Supplementary Figure S8D).
Therefore, the claimed composition does not possess any markedly different characteristics when compared to a naturally occurring composition comprising a target ssRNA, an MpaAgo, and its guide molecule.
Step 2A, Prong 2: Does the Claim Recite Additional Elements that Integrate the Judicial Exception into a Practical Application? NO.
This judicial exception is not integrated into a practical application because there are no additional elements present in the composition.
Step 2B: Does the Claim Recite Additional Elements that Amount to Significantly More than the Judicial Exception? NO.
The claim does not include additional elements that are sufficient to amount to significantly more than the judicial exception because there are no additional elements present in the claim.
Therefore, claim 12 is rejected under 35 USC § 101 as being drawn to a product of nature that does not possess any markedly different characteristics when compared to a naturally occurring composition comprising a target ssRNA, an MpaAgo, and its guide molecule.
Regarding claim 16, the claim is directed towards a negative limitation requiring that the composition is free of any single-stranded binding protein. The teachings of Li, discussed above as applied to claim 12, do not teach or suggest that a naturally occurring composition comprising a target ssRNA, an MpaAgo, and its guide molecule further comprises a single-stranded binding protein. Thus, the claim is also rejected under 35 USC 101 as being directed towards a product of nature.
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 (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 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)(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) 1-2 and 9-17 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Li (Nucleic acids research 50.9 (2022): 5226-5238).
Regarding claims 1 and 12, Li is directed towards a study concerned with the characterization of a programmable pAgo nuclease with RNA target preference from Mucilaginibacter paludis (Abstract). Li teaches the use of a novel Argonaute protein, termed “MbpAgo” that is derived from Mucilaginibacter paludis (i.e., Li teaches the use of an MpaAgo) (Abstract). Li teaches that the MbpAgo prefers to cleave target RNA sequences over target DNA sequences through the use of a DNA guide sequence that guides the MbpAgo to a target RNA of interest (i.e., the MpaAgo of Li directed to a target RNA through the use of a guide that comprises a sequence that is complementary to a sequence within a target RNA, wherein the guide can complex with the MbpAgo to form an Argonaute:guide complex) (Abstract). Li teaches that the MbpAgo’s ability to cleave RNA was tested via single-stranded nucleic acid cleavage assays and the Argonaute was able to cleave single-stranded RNA targets, but not double-stranded RNA targets, to generate cleavage products (i.e., the MbpAgo is able to cleave target ssRNA) (pg. 5236; see Supplementary Figure S8D).
Regarding claims 2 and 9, Li teaches that the MbpAgo was able to generate ssRNA fragments that could be detected and analyzed (pg. 5236; see Supplementary Figure S8D).
Regarding claim 10, Li teaches that the analysis of the ssRNA cleavage products is accomplished via gel electrophoresis (i.e., analysis by electrophoretic analysis) (pg. 5236; see Supplementary Figure S8D).
Regarding claims 11 and 16, Li does not teach or suggest contacting the target RNA with, or utilizing, a single-stranded binding protein.
Regarding claims 13-14, Li teaches that the ssRNA cleavage reaction can be performed in a reaction buffer comprising HEPES (pg. 5227).
Regarding claim 15, Li teaches that the ssRNA cleavage reaction took place in a mixture comprising 800 nM MbpAgo was mixed with 400 nM gDNA or gRNA, and incubated for 10 min at 37°C for guide loading in buffer RB [10 mM HEPES–NaOH (pH 7.5), 100 mM NaCl, and 5% glycerol] with 5 mM MnCl2 (i.e., the ssRNA reaction mixture did not comprise a whole cell or a cell extract) (pg. 5227).
Regarding claim 17, Li teaches that the target ssRNA, MpaAgo, and guide can be in an aqueous buffer (i.e., in aqueous form) (pg. 5227).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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.
Claim(s) 3 and 6 is/are rejected under 35 U.S.C. 103 as being unpatentable over Li (Nucleic acids research 50.9 (2022): 5226-5238) as applied to claims 1-2 and 9-17 above, and further in view of Nakanishi (PG Pub No. WO 2018/112336 A1).
Regarding claim 3, Li anticipates claims 1-2 and 9-17 as described above.
Li further teaches that MbpAgo is a unique programmable nuclease with a strong preference for RNA targets and can potentially be used in RNA manipulations such as RNA targeting, antiviral and nucleic acid detection (pg. 5237). Li teaches that guides can be synthetically created and designed to target RNA of interest (pg. 5227).
Li does not teach or suggest that the single-stranded target RNA comprises at least 5000 nucleotides (Claim 3). Li does not teach or suggest that the target RNA is an lncRNA (Claim 6).
However, one of ordinary skill in the art would have considered the teachings of Nakanishi as both references are common fields of endeavor pertaining to the use of Argonaute proteins to cleave target RNA.
Nakanishi is drawn towards a study concerned with compositions, systems, and methods for cleaving RNA molecules (Abstract). Nakanishi teaches the use of a yeast Argonaute protein that can utilize a heterologous, single-stranded DNA oligonucleotide guide molecule that is complementary to a target RNA sequence and can induce cleavage of the target RNA sequence (pg. 2). Nakanishi teaches that the target molecule can be an lncRNA from a cancer cell or tumor (pg. 30). Nakanishi teaches that the target RNA can be 5,000 nucleotides in length (pg. 30). Nakanishi teaches that targeting RNA associated with cancer can provide a new therapeutic strategy for treating RNA-based diseases such as cancer (pg. 65).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the target RNA of Li for a target lncRNA that comprises at least 5,000 nucleotides in length and is derived from cancer, as described by Nakanishi. A person of ordinary skill in the art would have been motivated to do so in order to target lncRNA molecules from cancerous cells in order to provide a therapeutic measure against an RNA-based disease selected from cancer. A person of ordinary skill in the art would have had a reasonable expectation of success because both Li and Nakanishi teach the use of Argonaute proteins that can have designed guide molecules that can target RNAs of interest.
Claim(s) 4-5 and 18-20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Li (Nucleic acids research 50.9 (2022): 5226-5238) as applied to claims 1-2 and 9-17 above, and further in view of Fasching (PG Pub No. WO 2024/108016 A2, published 23 May 2024) and Sullivan (PG Pub No. US 2024/0115691 A1, published 11 April 2024).
Regarding claims 5 and 18-19, Li anticipates claims 1-2 and 9-17 as descried above.
Li further teaches that guides can be synthetically created and designed to target RNA of interest (pg. 5227). Li teaches that the guides can be designed and utilized in the clearance of RNA viruses (Abstract).
Li does not teach or suggest that the single-stranded RNA further comprises one or more modified nucleotides (Claim 4). Li does not teach or suggest that the guide has a sequence selected from SEQ ID NO: 10 (Claims 5 and 18).
However, one of ordinary skill in the art would have considered the teachings of Fasching and Sullivan as both references are common fields of endeavor pertaining to the use of proteins that can target RNA with guide sequences.
Fasching is drawn towards an invention concerned with the use of CRISPR-associated (Cas) proteins (Abstract). Fasching teaches the use of a guide nucleic acid that can direct a CRISPR complex to a target nucleic acid of interest via hybridization with the target nucleic acid ([0004]). Fasching teaches that the guide nucleic acid molecule may be 16 nucleotides in length ([00185]). Fasching teaches that the guide nucleic acid molecules can be designed and made to provide desired functions and target nucleic acids of interest ([00322]). Fasching teaches that the target nucleic acid can comprise a pathogenic mRNA sequence from a pathogenic virus responsible for the onset of a disease or infection ([00226]). Fasching teaches that the pathogenic virus may be selected from Sindbis virus ([00226]). Fasching teaches that the methods may be utilized to treat a disease or infection of interest ([00288]).
Sullivan is drawn towards a study concerned with nucleic acid molecules encoding viral replication proteins (Abstract). Sullivan teaches the use of a SINV mRNA molecule (i.e., a Sindbis virus mRNA molecule ([0217])) that comprises a region that is complementary to the claimed SEQ ID NO: 10 (pg. 149-152; see SEQ ID NO: 104 in previously attached sequence alignment). Sullivan teaches that the uracil nucleotides within the RNA molecules of the disclosure may be replaced with pseudouridine nucleotides (i.e., Sullivan teaches that the target RNA may comprise a modified nucleotide) ([0228], [0304]).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to try to modify the guide molecule of Li such that it comprised the claimed SEQ ID NO: 10 in order to deplete a pathogenic mRNA molecule comprising a modified nucleotide from a Sindbis virus, as described by Fasching and Sullivan. Fasching teaches that there had been a recognized need in the art to target pathogenic mRNA from a Sindbis virus in order to treat an infection. Fasching teaches that guide nucleic acids of a finite length could be designed to target a Sindbis virus mRNA molecule while Sullivan teaches that the complementary sequence of the claimed SEQ ID NO: 10 was a sequence known to be present within a Sindbis virus mRNA molecule. Both Li and Fasching also teaches that one of ordinary skill in the art could have pursued the potential solutions and designed guide molecules to target sequences present within a Sindbis virus mRNA molecule.
Claim(s) 7-8 is/are rejected under 35 U.S.C. 103 as being unpatentable over Li (Nucleic acids research 50.9 (2022): 5226-5238) as applied to claims 1-2 and 9-17 above, and further in view of Nakanishi (PG Pub No. WO 2018/112336 A1) and Desnoyers (The EMBO journal 28.11 (2009): 1551-1561).
Regarding claim 7, Li anticipates claims 1-2 and 9-17 as descried above.
Li does not teach or suggest that the single-stranded RNA is a polycistronic template comprising at least five guide recognition sequences (Claim 7). Li does not teach or suggest that at least one of the cleavage products comprises an IVT template (Claim 8).
However, one of ordinary skill in the art would have considered the teachings of Nakanishi and Desnoyers as both references are common fields of endeavor pertaining to the use of Argonaute proteins and the degradation of target RNA molecules.
Nakanishi is drawn towards a study concerned with compositions, systems, and methods for cleaving RNA molecules (Abstract). Nakanishi teaches the use of a yeast Argonaute protein that can utilize a heterologous, single-stranded DNA oligonucleotide guide molecule that is complementary to a target RNA sequence (i.e., the guide molecule is complementary to a guide-recognition sequence within the target RNA) and can induce cleavage of the target RNA sequence (pg. 2). Nakanishi teaches that a target RNA molecule may be contacted with at least 5 Argonaute:guide complexes and that the primary limiting feature of the number of Argonaute polypeptide:guide complexes which can be bound to the target RNA is the number of distinct ssDNA guide molecule which can bind to the target RNA (i.e., Nakanishi teaches that the target RNA molecule may comprise at least five guide recognition sequences) (pg. 35-36).
Desnoyers is drawn towards a study concerned with the degradation of iscRSUA polycistronic mRNA (Abstract). Desnoyers teaches that iscRSUA mRNA encodes multiple genes, including iscR, iscS, iscU, and iscA (i.e., iscRSUA is an IVT template) (Abstract, pg. 1557; see Figure 8). Desnoyers teaches that in low iron conditions, iscS, iscU, and iscA can be degraded and cleaved by RNA degradosomes following binding of a small regulatory RNA molecule, RyhB (Abstract, pg. 1557; see Figure 8). Desnoyers teaches that the degradation of the polycistronic mRNA is advantageous in low-iron conditions because the degradation allows for the expression of an iscR protein that allows for generation of Fe-S clusters in a low-iron environment (pg. 1557; see Figure 8). Desnoyers teaches that in cells that do not express RyhB, Fe-S clusters are not generated in low iron environments which results in an iron shortage within the cells (pg. 1558).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the target RNA of Li for a polycistronic template, as described by Desnoyers, and modify the polycistronic template to comprise at least five guide recognition sequences, as described by Nakanishi. A person of ordinary skill in the art would have been motivated to do so in order to allow for the generation of Fe-S clusters in cells that do not express RyhB in low iron environments. A person of ordinary skill in the art would have had a reasonable expectation of success because both Li and Nakanishi teach the use of Argonaute proteins that can have designed guide molecules that can target RNA molecules of interest via the use of multiple guide recognition sequences while Desnoyers teaches the use of a polycistronic template that can be degraded via cleavage of the polycistronic RNA molecule.
Response to Arguments
Applicant’s arguments with respect to claim(s) 1-4, 6, and 9-17 have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KYLE T REGA whose telephone number is (571)272-2073. The examiner can normally be reached M-R 8:30-4:30, every other F 8:30-4:30 (EDT/EST).
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, Neil Hammell can be reached at 571-270-5919. 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.
/KYLE T REGA/Examiner, Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636