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
The following correspondence is in response to the papers filed on February 15, 2024. Pursuant to the Amendment to the claims filed on February 15, 2025 of which claims 1-3, 5-15, 18, 29, 63, 69 and 74 are currently pending, these claims are currently under examination to which the following grounds of rejection are applicable.
Priority
The present application is a 35 U.S.C. 371 national stage filing of the International Application Nos: PCT/CN2022/113304, filed August 18, 2022; PCT/CN2021/113290 filed August 18, 2021; and PCT/CN2022/085144 filed April 02, 2022.
Thus, the earliest possible priority for the instant application is August 18, 2021.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on February 21, 2024 was filed. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Specification
The listing of references in the specification is not a proper information disclosure statement. 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 or an official IDS, they have not been considered.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-3, 5-15, 18, 29, 63, and 74 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 is vague and indefinite in the recitation of “…capable of…” in both lines 4 and 7, since this phrase refers to a latent ability, and it is unknown whether the ability is expressed or observed in the invention. Note, it has been held that the recitation that an element is “capable of” performing a function is not a positive limitation, but only requires the ability to so perform. It does not constitute a limitation in any patentable sense. In re Hutchinson, 69 USPQ 138.
Furthermore, regarding steps (1) and (2) of claim 1, the claim is indefinite for the aforementioned reasons because it is not clear if the steps of (1) is “hybridizing to the target RNA” and/or for (2) “recruiting an adenosine deaminase acting on RNA (ADAR)” are active steps, or rather they are merely a property of the dRNA recited. If these steps are not active steps, then the claim only recites the active step of “introducing a deaminase-recruiting RNA ( dRNA) or a construct comprising a nucleic acid sequence encoding the dRNA into the host cell” recited in lines 2 - 3.
Additionally, the claim recites a “A method for editing a target adenosine in a target RNA in a host cell,” yet there is no such step recited in the claim as occurring, but rather the claim only recites the hybridization of the dRNA to the target RNA. For these reasons, the method of claim 1 is indefinite.
Claim 7 is indefinite for the language of “capable of” since this phrase refers to a latent ability, and it is unknown whether the ability is expressed or observed in the invention.
The term “substantially” in claims 9-11, and 69 is a relative term which renders the claim indefinite. The term “substantially” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. In particular, it is not clear the extent of secondary structures that are permitted with the linker and dRNA.
Claim 11 is vague and indefinite in the recitation of “…capable of…” in both lines 4, 8, and 9 since this phrase refers to a latent ability, and it is unknown whether the ability is expressed or observed in the invention. Consequently, the claim is indefinite for same reasons described above for claim 1.
Claim 13 is indefinite for the language of “capable of” since this phrase refers to a latent ability, and it is unknown whether the ability is expressed or observed in the invention.
Claim 18 is indefinite in the recitation of “at least about” for the following reason. “About” encompasses values above and below a reference point whereas “at least” encompasses only values above the reference point. Therefore, the combination of both terms (at least about) is confusing because one term is including values below the reference point whereas the other term is excluding values below the reference point.
Claims 2-3, 5-6, 8, 12, 14-15, 29, 63, and 74 are rejected by dependency to the rejected claims above, and due to not absolving the indefinite rejections set forth for these claims.
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 person shall be entitled to a patent unless –
(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 1-2, 5-9, 11-15, 29, 63, 69 and 74 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Wei et al. (US 2022/0243194 A1).
Regarding claim 1, Wei teaches a method for editing a target adenosine in a target RNA in a host cell, comprising introducing a deaminase-recruiting RNA ( dRNA) or a construct comprising a nucleic acid sequence encoding the dRNA into the host cell (“Provided are methods for editing RNA by introducing a deaminase-recruiting RNA in a host cell for deamination of an adenosine in a target RNA” (abstract)),
wherein: (1) the dRNA comprises a targeting RNA sequence that is capable of hybridizing to the target RNA to form a duplex RNA, wherein the duplex RNA comprises a bulge comprising a non-target adenosine in the target RNA (“The mismatch nucleotides in the dsRNA formed by hybridization between the dRNA and the target RNA can form bulges, which can promote the efficiency of editing of the target RNA. There may be one (which is only formed at the target adenosine) or more bulges formed by the mismatches.” (par 0150); “In some embodiments, the targeting RNA sequence comprises two or more consecutive mismatch nucleotides (e.g., 2, 3, 4, 5, or more mismatch nucleotides) opposite a non-target adenosine in the target RNa.” (par 0108));
and (2) the dRNA is capable of recruiting an adenosine deaminase acting on RNA (ADAR) (“The present disclosure relates generally to methods and compositions for editing RNAs using an engineered RNA capable of recruiting an adenosine deaminase to deaminate one or more adenosines in target RNAs.” (par 0003)).
Regarding claim 2, Wei teaches wherein the duplex RNA comprises a bulge at each non-target adenosine in the target RNA (“The mismatch nucleotides in the dsRNA formed by hybridization between the dRNA and the target RNA can form bulges, which can promote the efficiency of editing of the target RNA.” (par 0150)).
Regarding claim 5, Wei teaches wherein the method has reduced level of editing of the non-target adenosine in the target RNA compared to a method using a dRNA or a construct thereof comprising a targeting RNA sequence that has a nucleotide opposite the non-target adenosine in the target RNA based on employing guanosine that are opposite of non-target adenosines in order to reduce off-target effects by the ADAR (par 0108-0109). By doing so there is a low off-target editing rate, wherein some instances the method does not edit non-target As in the target RNA (par 0114; 0147).
Regarding claims 6-8, Wei teaches wherein the dRNA is a linear RNA that is also capable of forming a circular RNA (par 0011; Fig. 4A).
Regarding claim 9, Wei teaches the dRNA comprises a linker nucleic acid sequence flanking an end of the targeting RNA sequence, and furthermore in some instances the dRNA does not comprise a hairpin or loop (Fig. 4A; par 0104). Wei also teaches the dRNA may be entirely single-stranded, and therefore does not substantially form any secondary structure or have double-stranded and/or stem loop regions.
Regarding claims 11-13, the rejection to claims 1, 6-9 are applied herein since these limitations have been presented and rejected accordingly.
Regarding claims 14 & 15, Wei teaches circular dRNAs were flanked with 25-nt or 50-nt linker connecting to both ends ligation sequence (Fig. 4A, par 0307).
Regarding claim 29, Wei teaches wherein the dRNA is a circular RNA, and wherein the linker nucleic acid sequence connects the 5' end of the targeting RNA sequence and the 3' end of the targeting RNA sequence (Fig. 4A, par 0307).
Regarding claims 63 and 74, Wei teaches a method for treating or preventing a disease or condition in an individual, comprising editing a target RNA associated with the disease or condition in a cell of the individual according with the method taught by Wei of editing a target adenosine in a target RNA in a host cell (Sec. 2.4, par 0160-0169).
Regarding claim 69, Wei teaches the dRNA for editing a target RNA comprising a targeting RNA sequence that is capable of hybridizing to the target RNA, wherein the dRNA comprises a linker nucleic acid sequence flanking an end of the targeting RNA sequence, wherein the linker nucleic acid sequence does not substantially form any secondary structure with any part of the dRNA, and wherein the dRNA is a circular RNA or a linear RNA capable of forming a circular RNA (abstract, par 0011, Fig. 4A).
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.
Claims 1-3, 5-15, 29, 63, 69 and 74 are rejected under 35 U.S.C. 103 as being unpatentable over Wei et al. (US 2022/0243194 A1) as applied to claims 1-2, 5-9, 11-15, 29, 63, 69 and 74 above, and further in view of Chi et al. (US 2016/0304878 A1).
Regarding claim 1, the disclosure of Wei is applied as in the 102 rejections above, the content of which is incorporated above, in its entirety.
Wei teaches the method for editing a target adenosine in a target RNA in a host cell as recited in claim 1, wherein a dRNA is introduced into a host cell.
Regarding claim 3, Wei teaches the dRNA targeting sequence as forming a bulge with a target sequence due to nucleotide differences (par 0150); however Wei does not teach the lacking of one or more nucleotides opposite to non-target adenosines in the target RNA during hybridization of the targeting and target sequences.
Chi teaches (see description paragraph 53) the suppression off-target effects of RNA to target gene by mismatch base-pairing, or bulge formation by insertion of one or more nucleotides (par 0018, 0053).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have the targeting RNA sequence lacking one or more nucleotides opposite to non-target adenosines in the target RNA as a technique to reduce to off-target effects based on Chi teaching this technique with RNAi. Chi teaches that to achieve optimal suppression of off-target effects, it can include mismatch base-pairing to RNA of target gene by the substitution, or bulge formation by nucleotide(s) insertion (par 0053). Therefore, there is a reasonable expectation that inducing bulges for non-target adenosines would similarly reduce off-target effects by preventing deamination of these particular nucleotides.
Regarding claim 10, Wei teaches the dRNA as having linkers and ligation sequences on both the 5’ and 3’ ends wherein ligation forms a circular dRNA molecule (Fig. 4A). Furthermore, in some instances the dRNA does not comprise a hairpin or loop (i.e. secondary structure), and may be entirely single-stranded, and therefore does not substantially form any secondary structure or have double-stranded and/or stem loop regions (Fig. 4A; par 0104).
In respect to the limitation “replacing an end of the targeting RNA sequence,” this limitation would remain obvious based on no particular targeting sequence being disclosed, and therefore the number and particular nucleotides as being replaced are not clear. Since no limitations regarding the length of the targeting sequence with a corresponding SEQ ID No. are recited in the claims, it is not clear what nucleic acid sequence is considered replaced or rather not included in the targeting sequence.
Claims 1-2, 5-9, 11-15, 18, 29, 63, 69 and 74 are rejected under 35 U.S.C. 103 as being unpatentable over Wei et al. (US 2022/0243194 A1) as applied to claims 1-2, 5-9, 11-15, 29, 63, 69 and 74 above, and further in view of Mu at el. (Protein Cell. 2018 Jun 4;10(3):223–228).
Regarding claims 1 and 11, the disclosure of Wei is applied as in the 102 rejections above, the content of which is incorporated above, in its entirety.
Wei teaches the method for editing a target adenosine in a target RNA in a host cell as recited in claim 1, wherein a dRNA is introduced into a host cell.
Regarding claim 18, Wei teaches the dRNA as having linker sequences as depicted in Fig. 4A, yet the percentage of the linker sequence nucleotides as being adenosine or cytidine is not explicitly taught, specifically wherein at least 50% of the linker nucleic acid sequence comprises adenosine or cytidine; optionally wherein 100% of the linker nucleic acid sequence comprises adenosine or cytidine.
Mu teaches the addition of a 3’ polyA tract to a sgRNA enhanced stability as seen in an improved genome editing efficiency (abstract; Fig. 1).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have clarified the linkers as taught by Wei as comprising a polyA tract, based on it being known that polyA tails improve the stability of RNA as taught by Mu with sgRNAs wherein editing efficiencies improved after such modifications. Therefore, there is a reasonable expectation that modifying the dRNA linkers as largely comprising adenosines would similarly improve the stability of the total RNA molecule, and subsequently lead to enhanced outcomes with using the dRNA molecule.
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, 5-10, 63, and 69 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the following Applications with corresponding pending claims:
PNG
media_image1.png
200
400
media_image1.png
Greyscale
Claim 1 of the instant application is directed to: A method for editing a target adenosine in a target RNA in a host cell, comprising introducing a deaminase-recruiting RNA ( dRNA) or a construct comprising a nucleic acid sequence encoding the dRNA into the host cell, wherein: (1) the dRNA comprises a targeting RNA sequence that is capable of hybridizing to the target RNA to form a duplex RNA, wherein the duplex RNA comprises a bulge comprising a non-target adenosine in the target RNA; and (2) the dRNA is capable of recruiting an adenosine deaminase acting on RNA (ADAR).
Instant claim 1 limitations are the following:
Editing a target adenosine in a target RNA in a host cell
Introducing a deaminase-recruiting RNA ( dRNA) or a construct comprising a nucleic acid sequence encoding the dRNA into the host cell
The dRNA is capable of hybridizing to the target RNA to form a duplex RNA, wherein the duplex RNA comprises a bulge comprising a non-target adenosine in the target RNA
The dRNA is capable of recruiting an adenosine deaminase acting on RNA (ADAR)
Claims 6-8 are directed to the dRNA as a linear RNA, circular RNA, or dRNA capable of forming a circular RNA.
Although the claims at issue are not identical, they are not patentably distinct from each other because
the U.S. Pub. Applications listed with corresponding relevant claims encompass all the limitations recited above, despite reciting other limitations in some instances. The instant claims have not been amended accordingly to differentiate the claimed invention as being different than the listed applications as they include the limitations presented above.
It instances wherein the compared claims do not recite the limitation of a “bulge,” as recited in the instant claims, the compared claims do recite nucleotide mismatches and non-target adenosine in the target RNA; and therefore the bulge formation would be expected to be found as a consequence of these nucleotide differences between complementary sequences.
For these reasons, the instant claims are rejected for nonstatutory double patenting over the listed Applications recited above for the most recent pending claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
Claims 1-3, 5-15, 18, 29, 63, 69 and 74 are rejected. No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MICHAEL A RIGA whose telephone number is (571)270-0984. The examiner can normally be reached Monday-Friday (8AM-6PM).
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, Maria G Leavitt can be reached at (571) 272-1085. 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.
/MICHAEL ANGELO RIGA/Examiner, Art Unit 1634
/TERESA E KNIGHT/Primary Examiner, Art Unit 1634
Prosecution Insights